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Biomarcadores na Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia do HGF Secretário de Neurologia da ABNPG

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Page 1: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Biomarcadores na Doenccedila de Alzheimer

Norberto Anizio Ferreira Frota

Prof Curso de Medicina da UNIFOR

Coordenador da Residecircncia em Neurologia do HGF

Secretaacuterio de Neurologia da ABNPG

Roteiro

bull Conceito

bull Evoluccedilatildeo Histoacuterica

bull Criteacuterios Diagnoacutesticos

bull RM

bull PET

bull Liquor

bull Aplicabilidade cliacutenica

O QUE Eacute UM BIOMARCADOR

bull Os biomarcadores podem ser definidos como umamedida objetiva e especiacutefica de um processo bioloacutegicoou patogecircnico podendo ser usados para avaliar o riscoou o prognoacutesticos da doenccedila guiar o diagnoacutesticocliacutenico ou monitorar intervenccedilotildees terapecircuticas

bull O biomarcador ideal deve detectar precocemente ecom grande precisatildeo uma caracteriacutesitca patoloacutegica dadoenccedila

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

Biomarcadores na praacutetica cliacutenica

bull Glicemia

bull FAN

bull Reaccedilatildeo de Wasserman ndash Siacutefilis

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 2: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Roteiro

bull Conceito

bull Evoluccedilatildeo Histoacuterica

bull Criteacuterios Diagnoacutesticos

bull RM

bull PET

bull Liquor

bull Aplicabilidade cliacutenica

O QUE Eacute UM BIOMARCADOR

bull Os biomarcadores podem ser definidos como umamedida objetiva e especiacutefica de um processo bioloacutegicoou patogecircnico podendo ser usados para avaliar o riscoou o prognoacutesticos da doenccedila guiar o diagnoacutesticocliacutenico ou monitorar intervenccedilotildees terapecircuticas

bull O biomarcador ideal deve detectar precocemente ecom grande precisatildeo uma caracteriacutesitca patoloacutegica dadoenccedila

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

Biomarcadores na praacutetica cliacutenica

bull Glicemia

bull FAN

bull Reaccedilatildeo de Wasserman ndash Siacutefilis

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 3: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

O QUE Eacute UM BIOMARCADOR

bull Os biomarcadores podem ser definidos como umamedida objetiva e especiacutefica de um processo bioloacutegicoou patogecircnico podendo ser usados para avaliar o riscoou o prognoacutesticos da doenccedila guiar o diagnoacutesticocliacutenico ou monitorar intervenccedilotildees terapecircuticas

bull O biomarcador ideal deve detectar precocemente ecom grande precisatildeo uma caracteriacutesitca patoloacutegica dadoenccedila

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

Biomarcadores na praacutetica cliacutenica

bull Glicemia

bull FAN

bull Reaccedilatildeo de Wasserman ndash Siacutefilis

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 4: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

Biomarcadores na praacutetica cliacutenica

bull Glicemia

bull FAN

bull Reaccedilatildeo de Wasserman ndash Siacutefilis

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 5: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Biomarcadores na praacutetica cliacutenica

bull Glicemia

bull FAN

bull Reaccedilatildeo de Wasserman ndash Siacutefilis

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 6: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Detectar in vivo as alteraccedilotildees patoloacutegicas

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 7: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso Cliacutenico

bull Ident MLR 59 anos economista

bull QP rdquoMovimentos Repetitivosrdquo

bull HDA Haacute dois anos movimentos repetitivos em matildeos

bull Deixou de dirigir ndash natildeo sabia tempo para passar marcha

bull Dificuldade em usar smartphone

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 8: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso Cliacutenico

bull HPP cesariana depressatildeo

bull Med Desvenlafaxina 50mg Zolpiden 10mg

bull Haacutebitos etilismo leve

bull Alergia ndn

bull Hist Familiar Matildee com quadro demencial aos 62 anos

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 9: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Avaliaccedilatildeo Cognitivabull ACE76100

atenccedilatildeo OT5 OE5 MI3 AC93-x-x-72-x=1518Memoacuteria1+6+4+6+5=2226FP peru pato pinto passaro preacutedio parque pneu=7FA galinha peru pato baleia cachorro gato peixe camaratildeo rato tartaruga passaros cavalo leatildeo=13(3+4=714)LIng1+3+1+2+1+1+10+2+1=2226V-E0+0+4+3+3=1016

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 10: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Exame Neuroloacutegico

bull Equiliacutebrio movimentos em matildeo D e flexatildeoFM elevaccedilatildeo de MSD (levitaccedilatildeo e fica fazendo movimentos em MID)Reflexos Vivos

bull Apraxia evidente pior a DCoordenaccedilatildeo index nariz normal e leve disdiadococinesiaSensib Discreta anartestesia em MIDNC sem alteraccedilotildees

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 11: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Hipoacutetese Diagnoacutestica

bull Degeneraccedilatildeo Cortico-Basal

bull Doenccedila de Alzheimer atiacutepica

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 12: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

E agora

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 13: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Exames Complementares nas Demecircncias

bull Descartar causas secundaacuterias

bull Padrotildees especiacuteficos de atrofia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 14: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Nova Visatildeo

bull Diferenciaccedilatildeo dos tipos de demecircncia

bull Diagnoacutestico precoce

bull Marcador de evoluccedilatildeo

bull Resposta terapecircutica

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 15: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Ressonacircncia Magneacuteticabull Natildeo deve ser mais utilizado como somente para

excluir causas secundaacuterias

bull Eacute um biomarcador de dano neuronal

bull Avaliar com cuidado atrofias assimeacutetricas

The n ew en g l an d j o u r n a l of med i c i n e

n engl j med 36423 nejmor g june 9 20112230

A Swedish study showed that subjects with mild

cognitive impairment who had low levels of

β-amyloid peptide 42 (Aβ42) and elevated levels

of tau protein in cerebrospinal f luid were sig-

nif icantly more likely to undergo progression to

Alzheimerrsquos disease than subjects without this

prof ile (hazard ratio 177 95 conf idence inter-

val 53 to 589) a similar relative risk of progres-

sion was associated with a low ratio of Aβ42 to

tau in the cerebrospinal f luid28 An international

multicenter study of 750 subjects with mild cogni-

tive impairment corroborated these general f ind-

ings2930 but used different cutoff points for ab-

normal f indings The reliability of these markers

is highly variable across laboratories standard-

ization will be needed before they are considered

for incorporation into routine care

The use of molecular imaging particularly of

amyloid plaques in the brain (Fig 3) has also been

studied as a possible approach to risk stratif ica-

tion31-33 In several studies subjects with mild cog-

nitive impairment in whom amyloid was detected

on positron-emission tomography (PET) with the

use of the amyloid-binding carbon 11ndashlabeled Pitts-

burgh compound B had more rapid progression to

Alzheimerrsquos disease than did subjects in whom

amyloid was not detected34 The rationale for using

this technique to predict disease progression is that

the presence of amyloid in a patient with mild

cognitive impairment is likely to indicate that the

patient has early Alzheimerrsquos disease however

amyloid has been detected on autopsy in clinical-

ly normal persons indicating that the predictive

value of this measure requires further study35

Management

From a clinical perspective patients with mild cog-

nitive impairment should not be labeled as having

early Alzheimerrsquos disease prodromal Alzheimerrsquos

disease or mild cognitive impairment of the Alz-

heimerrsquos disease type since the patient and fam-

ily are likely to hear only ―Alzheimerrsquos disease and

not appreciate the uncertainty of the association

with Alzheimerrsquos disease36 Clinicians should make

it clear that mild cognitive impairment is an abnor-

mal condition but that the precise outcome is not

certain

At present no medication intended for the

treatment of mild cognitive impairment has been

approved by the Food and Drug Administration

(FDA) In several placebo-controlled clinical trials

there was no signif icant reduction in rates of

progression to dementia among patients with

mild cognitive impairment who were treated with

agents used to treat Alzheimerrsquos disease (donepe-

zil galantamine and rivastigmine administered

at standard doses for Alzheimerrsquos disease for 2 to

4 years)537-40 In one trial evaluating the effects of

high-dose vitamin E (2000 IU daily) or donepezil

in persons with mild cognitive impairment do-

nep ezil signif icantly reduced the risk of pro-

gression to Alzheimerrsquos disease for the f irst 12

months of the study (and for up to 24 months in

the subgroup of subjects who were carriers of

APOE ε4) but had no signif icant effect on the

risk of Alz heimerrsquos disease at 36 months which

was the primary study outcome vitamin E did

not signif icantly reduce the risk of progression

at any time point assessed5

A B C

Figure 2 Coronal MRI Scans from Patients with Normal Cognition Mild Cognitive Impairment and Alzheimerrsquos

Disease

The arrows depict the hippocampal formations and the progressive atrophy characterizing the progression from nor-

mal cognition (Panel A) to mild cognitive impairment (Panel B) to Alzheimerrsquos disease (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

cl i n i cal pr act i ce

n engl j med 36423 nejmor g june 9 2011 2231

One potential explanation for the apparent lack

of eff icacy in the clinical trials of interventions in

persons with mild cognitive impairment mdash other

than a true absence of drug eff icacy mdash concerns

the heterogeneity of the subjects As the diagnos-

tic threshold moves to an earlier point in the clini-

cal spectrum of cognitive impairment the subtle

changes in cognition could be due to a variety of

causes other than a degenerative brain disease

making it diff icult to determine whether an inter-

vention has had a signif icant effect

There is some evidence of a potential benefit

from cognitive rehabilitation including the use of

mnemonics association strategies and computer-

assisted training programs4142 A recent systematic

review of the literature on cognitive rehabilitation

programs for persons with mild cognitive impair-

ment including some data from randomized clin-

ical trials showed signif icant improvement in

cognitive function at the end of training42

Observational data have shown associations

between the presence of cardiovascular risk factors

in patients with mild cognitive impairment and an

increased risk of progression to dementia7 Such

risk factors should be addressed although there

is no definitive evidence that modif ication of risk

factors slows disease progression In a randomized

trial that used the Cognitive Subscale of the Alz-

heimerrsquos Disease Assessment Scale to compare the

effect of a physical exercise program (brisk walking

for 150 minutes per week) with that of usual care

and education in persons with subjective memory

loss the exercise group had better cognitive func-

tion at 6 months (the primary study outcome) with

some residual benefit noted at 18 months43

Ar eas o f Un cer t ai n t y

More data are needed regarding the usefulness of

various potential predictors of progression to de-

mentia and their role in clinical practice Further

data on these concerns are awaited from the Alz-

heimerrsquos Disease Neuroimaging Initiative under

way in the United States and Canada2744 and from

similar ongoing studies in Japan Europe and Aus-

tralia Some of the goals of these studies are to

better understand the role of MRI f indings (eg

hippocampal atrophy)2245 f indings on 18FDG-PET

(patterns of hypometabolism in the brain) cere-

brospinal f luid markers (levels of Aβ42 and tau)

and f indings on molecular imaging (amyloid

plaques in the brain) in identifying the subgroup

of persons with amnestic mild cognitive impair-

ment who are likely to undergo progression to

clinical Alz hei merrsquos disease274647 Major challeng-

es are to determine optimal cutoff points for these

tests and to compare their relative reliability (alone

and in combination) Randomized trials are need-

ed to assess the potential benefits of pharmaco-

logic and lifestyle interventions in persons with

mild cognitive impairment who are predicted to

be at high risk for rapid progression to Alzheimerrsquos

A B C

Figure 3 Axial Scans of the Brain Obtained with Positron-Emission Tomography and the Use of Amyloid-Binding

Carbon 11ndashLabeled Pittsburgh Compound B

The yellow and red areas indicate retention of the amyloid-binding tracer reflecting amyloid deposits The patient

with normal cognition (Panel A) has no tracer retention whereas the patient with amnestic mild cognitive impair-

ment has an intermediate amount of tracer retention (Panel B) and the patient with Alzheimerrsquos disease has promi-

nent tracer retention (Panel C)

The New England Journal of Medicine

Downloaded from nejmorg at UECE on July 24 2016 For personal use only No other uses without permission

Copyright copy 2011 Massachusetts Medical Society All rights reserved

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 16: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Outros Marcadores

bull Liacutequor

bull Dosagem de TAU (decaacuteda de 90)

bull Dosagem de AB-42

bull Growdon 1999 (AB-42 e TAU na DA)

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 17: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Mattsson N et al 2009 JAMA

bull 750 pacientes com Comprometimento Cognitivo Leve

bull Seguimento por 2 anos

bull 271 evoluiram para DA

bull 59 apresentaram outras demecircncias

bull Baixos niacuteveis de Aβ-42 e altos de Fosfo-Tau com maior

acuraacutecia para evoluccedilatildeo para DA

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 18: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

bull 74 pacientes com Doenccedila de Alzheimer x 142 com

Comprometimento Cognitivo Leve e 82 controles

bull Hipometabolismo

- Precuneos

- Ciacutengulo Posterior

- Coacutertex Temporo-parietal

- Coacutertex Frontal

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 19: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Koivunen et al Neurology 2011

bull 29 pacientes acompanhados por 2 anos

bull Avaliaccedilatildeo de PET com PIB e RM (Atrofia de

hipocampo)

bull 1729 converteram

bull Maior depoacutesito de PIB Ciacutengulo Posterior frontal lateral

temporal e putamem com maior atrofia

bull Pouca modificaccedilao no PIB em 2 anos

bull Aumento da atrofia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 20: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Hipoacutetese da Evoluccedilatildeo Temporal

dos processos fisiopatoloacutegicos

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 21: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Biomarcador e CCL

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 22: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Criteacuterios para Pesquisa DA

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 23: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Porque utilizar biomarcador empacientes com quadros cognitivos

bull O paciente vai piorar dos sintomas cognitivos

bull Existe um processo patoloacutegico jaacute conhecido

bull Existe dano neuronal Topografia

bull Falsos positivos o que fazer

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 24: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Ressonacircncia Magneacutetica de Cracircnio

bull Atrofia hipocampal

bull Casos leves ou assintomaacuteticos

bull Avaliaccedilatildeo de espessura cortical (Walhovd K et al 2010)

bull DTI (Sexton C et al 2011)

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 25: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Ressonacircncia Magneacutetica

Vantagens

bull Disponibilidade

bull Visualizaccedilatildeo de atrofia

bull Possibilidade de vaacuterias mediccedilotildees

Limitaccedilotildees

bull Teacutecnicas habituaispoucos sensiacuteveis paraquadros leves

bull Reflete somente o danoneuronal

bull Teacutecnicas especiaispouca disponibilidade

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 26: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso

bull RM laudo normal

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 27: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

PET-FDG

Vantagens

bull Sensibilidade

bull Reflete dano neuronal

Limitaccedilotildees

bull Custo

bull Sem ponto de corte

bull Natildeo especiacutefico do dano patoloacutegico

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 28: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso

bull PET-FDG hipometabolismo FTP esquerdo e leve a Direita frontal e parietal

bull O que esse laudo mostra

bull Que eu consegui examinar e topografar direito

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 29: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

PET Amiloide

bull Dificuldades Iniciais

bull Marcador a base de Fluor

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 30: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

PET Tau and Amyloid-β Burden in Mild Alzheimers Disease Divergent Relationshipwith Age Cognition and Cerebrospinal Fluid BiomarkersKoychev I1 Gunn RN23 Firouzian A2 Lawson J1 Zamboni G1 Ridha B4 Sahakian BJ5 Rowe JB6 Thomas A7 Rochester L7 Ffytche D8 Howard R9 Zetterberg H9101112 MacKay C1 Lovestone S1 Deep and Frequent Phenotyping study team

J Alzheimers Dis 2017 Aug 8

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 31: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

PET Marcador Amiloacuteide

Vantagens

bull Refletem o processo patoloacutegico

bull Conseguem detectar indiviacuteduos assintomaacuteticos em risco

bull Predizem piora cliacutenica

Limitaccedilotildees

bull Custo

bull Disponibilidade

bull Normalizaccedilatildeo de pontos de corte

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 32: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso

bull PET-Amiloacuteide

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 33: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

241 Estudos

11341 Pacientes

7086 Pacientes

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 34: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Entatildeo vamos coletar Liacutequor para todos

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory ClinicPatients in a Prospective CohortHandels RL12 Joore MA23 Vos SJ1 Aalten P1 Ramakers IH1 Rikkert MO4 Scheltens P5 Jansen WJ1 Visser PJ15 van Berckel BM5 van Domburg P6 Smid M7 Hoff E8 Hoogmoed J910 Bouwman F5 Claassen J4 Leentjens AF1 Wolfs CA1 Severens JL11 Verhey FR1Author information

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 35: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

bull 200 DA

bull 16 DA prodromica

bull 69 DFT

bull 59 DCB

bull 16 PSP

bull 44 DCL

bull 22 ACP

bull 41 Demecircncia Semacircntica

bull 52 Afasias logopecircnicas

bull 11 Afasias natildeo fluentes

bull 71 Depressatildeo

bull 49 Queixa subjetiva de memoacuteria

bull DA -100

bull DA prodromica-100

bull 439 dos outros pacientes tbpositivos

bull 818 ACP

bull 788 Afasia logopecircnica

bull 50 DCL

bull 458 DCB

bull 454 afasias natildeo fluentes

bull 366 demecircncia semacircnticas

bull 145 das DFT

bull 117 (Depressatildeo e QSM)

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 36: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

E o teste de Memoacuteria

bull Sensibilidade100

bull Especificidade de 748

bull Intrusotildees Sensibilidade de 83 e Especificidade72

bull 273 tinham deacuteficit hipocampal

bull 366 dos deprimidos

bull 40 DCL

bull 375 PSP

bull 319 DFT

bull 273 Afasia natildeo fluente

bull 227 ACP

bull 22 Demecircncia Semacircntica

bull 22 DCB

bull 58 Afasia logopecircnica

Existiu uma correlaccedilatildeo desempenho com os marcadores

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 37: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Liacutequor

Vantagens

bull Possibilidade de dosagem de vaacuterios marcadores

bull Predizem quem podem evoluir

bull Podem ajudar no diferencial

bull Avalia carga amiloide e dano neuronal

Limitaccedilotildees

bull Invasivo

bull Erros preacute-analiacuteticos

bull Natildeo padronizaccedilatildeo

bull Custo (+-)

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 38: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso

bull Liacutequor AB 453 TAU250 Fosfo TAU82

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 39: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Biomarcador Ideal

bull Alta Sensibilidade e Especificidade

bull Faacutecil Realizaccedilatildeo

bull Baixo Custo

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 40: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

E agora

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 41: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Sangue

bull Perfil lipiacutedico no sangue

bull TAU

bull AB (inicial mais promissor)

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 42: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

E A NOSSA PACIENTE

bull DA X DCB

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 43: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Mov Disords 2015

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 44: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Caso

bull Mutaccedilatildeo no Gen da Presenilina 1

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 45: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 46: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

ABN Recomendaccedilotildees examescomplementares

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 47: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

ABN Recomendaccedilotildees examescomplementares

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 48: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Conclusotildees

bull Noacutes pacientes com CCL eles conseguem predizer que corre maiorrisco (intervenccedilotildees futuras)

bull Confirmaccedilatildeo de formas atiacutepicas

bull PETSPECT e RM padrotildees de atrofia que satildeo bastantes sugestivos

bull Sua normalidade estaacute relacionada a melhor prognoacutestico

bull Disponibilidade custos operacionais e pouco influecircncia no curso da doenccedila limitam sua aplicaccedilatildeo de rotina

Obrigado pela atenccedilatildeonaffrotayahoocombr

Page 49: Biomarcadores na Doença de Alzheimer - neurosong.org · Doença de Alzheimer Norberto Anizio Ferreira Frota Prof. Curso de Medicina da UNIFOR Coordenador da Residência em Neurologia

Obrigado pela atenccedilatildeonaffrotayahoocombr