I NUOVI CRITERI DIAGNOSTICI PER LA MALATTIA DI ALZHEIMER ... · La sequenza di eventi nella malattia di Alzheimer comprende deposizione di amiloide, neurodegenerazione e sintomi

LE UNITA’ DI VALUTAZIONE ALZHEIMER: DALLA COMPLESSITA’ ALLA PIANIFICAZIONE DEI PERCORSI.

UNO SGUARDO AL FUTURO.

Lamezia Terme, 16 aprile 2012

I NUOVI CRITERI DIAGNOSTICI PER LA MALATTIA DI ALZHEIMER:

PERCORSI INTEGRATI PER LA DIAGNOSI

GB Frisoni Vice Direttore Scientifico

LENITEM - Laboratorio di Neuroimmagine e UITRR - Unità per il Trasferimento della Ricerca

IRCCS Fatebenefratelli. Brescia

www.centroAlzheimer.org

The Pathophysiological Model of Alzheimer’s

Evidence of validity of the model

Biological markers in the context of the new diagnostic criteria

Instances of clinical application in MCI

Future challenges

The amyloid cascade from plaques to tangles, neurodegeneration, and symptoms

AMYLOID NEURODEGE-

NERATION ATROPHY SYMPTOMS PLAQUES TANGLES

Encoding episodic & spatial

memories

Encoding semantic memories ?

Smell

discrim.

Aphasia

Apraxia

Agnosia

Spared SM

and visual

functions

Braak & Braak , Courtesy of Frisoni et al., Frisoni et al., Acta Neuropath 1991 P. Giannakopoulos J Neurol 2009 J Neurol 2009

THE DYNAMIC MARKER HYPOTHESIS

Amyloidosis- and Neurodegeneration-associated markers change over time in a stereotyped fashion

Markers of amyloid

deposition

Markers of cortical

Entorhinal hypometabolism Cortex atrophy & synaptic

dysfunction Hippocampal

& post cing. atrophy

Temporal

Neocortex atrophy

Whole brain atrophy

-20 -15 -10 -5 0 5 10 15 20

Years from AD diag..





Future challenges

The course of atrophy is non linear…

Frisoni et al., J Neurol 2009 6

…and its slope differs from that of other markers

CSF Abeta42 Hippocampal volume

Caroli, Frisoni, et al., Neurobiol Aging 2010, ADNI issue 7

Up stream

AMYLOID NEURODEGENERATION TANGLES ATROPHY SYMPTOMS

PLAQUES

Down stream

EVIDENCE OF VALIDITY

Atrophy maps downstream onto symptoms…

Late onset Alzheimer’s Early onset Alzheimer’s

Frisoni et al., Brain 2007 9

EVIDENCE OF VALIDITY

…and upstream onto pathology

Murray et al., Lancet Neurol 2011

Amyloid markers predict dementia and cognitive deterioration in healthy elderly persons

N Desig F-U Pre- Outcome Associa- n dictor tion

Skoog et al., DGCD 35 Popu- 3 yrs Ab42 Dementia OR 8.2 2003 lation

Hansson et al., 53 Volunt 4-6 Ab42 Conversion to Sens 91% Lancet Neurol 2006 eers yrs MCI Spec 81%

Stomrud et al. 57 Volun- 3 Ab42 Subj mem imp + Sens 71% DGCD 2007 teers +tau decreased QoL Spec 76%

Gustafson et al., 55 Popu- 10 yrs Ab42 MMSE -5 pts OR 2.2 JNNP 2007 lation or dementia ♀

Fagan et al., Arch 61 Popu- 1-8 Tau/ CDR 0 gg 0.5+ OR 5.2 Neurol 2007 lation yrs Ab42

Li et al., Neurology 129 Volun- 42 Tau/ Conversion to OR 4.5 2007 teers mos Ab42 MCI

EVIDENZA DI VALIDITA’ DEL MODELLO FISIOPATOLGICO

Specificity to AD of cortical atrophy pattern





Future challenges


Marker combination predicts dementia in MCI

587 persons with no

cognitive impairment @ baseline

211 persons with MCI

@ baseline

Bennett et al., Neurology 2002;59:198-205


Marker combination predicts dementia in MCI

MCI-NC MCI-AD p

n=51 n=24

Age 70.9+7.1 72.2+7.1 .57

Sex (female) 28 (55%) 17 (71%) .38

Education 7.7+3.6 8.8+4.6 .39

MMSE 26.3+1.9 26.4+1.6 .24

In vivo β amyloid imaging with PET





Future challenges

Patient R.F.

Clinical & demograph. features

● Age 78, educ 13, onset 6 mos ● Lives alone, no relatives ● MMSE 29/30

● Fails ONLY 1 memory test ● Fully functional in daily life

● Asks whether she has Alzheimer`s

Frisoni et al., Alzheimer Dis Assoc Disord. 2010;24:108-14. Porteri et al., Can J Neurol Sci. 2010;37:67-75

Patient F.C.

Clinical & demograph. features

● Age 75, educ 18, onset 18 mos ● Lives alone, 1+1 daughters ● MMSE 29/30

● Poor performance ONLY in memory tests

● Fully functional in daily life

● Daughters ask whether she has Alzheimer`s to arrange future care


Pazienti RF e FC La biologia

RF FC

Cognitività MMSE 29/30 29/30

CDR 0.5 0.5

Disabilità IADL, funz perse 0/8 0/8

Barthel 100/100 100/100

consapevolezza GRAD 4/4 4/4

(piena consapevol.) (piena consapevol.)

CIRS 0/8 0/8

(piena consapevol.) (piena consapevol.)

Umore Depressione (BSI) 0.33/4 0.33/4

(assente) (assente)

Ansia (BSI) 0.04/4 0.33/4

(assente) (assente)


RF FC

Raw Perc. Raw Perc.

LEARNING

3 objects 3 places (Prestia 2006) 8/9 -- 7/9 --

Logical memory (Spinnler 1987) 1.5/28 <5th 15.5/28 >50th

Rey figure del. recall (Caffarra 2002) 8.5/36 10-25th 8/36 25-50th

SHORT TERM MEMORY

Digit span 5 25-50th 6 >50th

Spatial span (Spinnler 1987) 4 10-25th 4 10-25th

LANGUAGE

Token test (Spinnler 1987) 30/36 10-25th 33/36 >50th

Letter fluency (Novelli 1986) 27/3 min 25-50th 26/3 min 25-50th

Semantic fluency (Spinnler 1987) 22/3 min 10-25th 24/3 min <10th

VISUO-SPATIAL ABILITIES

Rey figure copy (Caffarra 2002) 34/36 >50th 28/36 <10th

FRONTAL/EXEC

Raven's coloured PM (O.S. 1985) 26/36 25-50th 33/36 >50th

TMT B-A (Giovagnoli, 1996) 132 sec 10-25th 40 sec >50th

Pazienti RF, FC, e anziano normale

Risonanza magnetica

FC Control SM

Pazienti RF, FC, e anziano normale

Volumetria ippocampale

4.000 4.000

3.500 3.500

3.000 3.000

2.500 2.500

2.000 2.000

RF

FC 1.500 1.500

20,00 40,00 60,00 80,00 100,00 20,00 40,00 60,00 80,00 100,00

Le linee rappresentano i percentili: 1°, 5°, 25°, 50°, 75°, 95°, 99°

Pazienti RF e FC Metabolismo cerebrale con FDG PET"

SM FC


Pazienti RF e FC

Profilo liquorale 750

700

650

600 FC 550 SM

500

450

400

350

300

250

200

150

100

50

0

200 250 300 350 400 450 500 550 600 650 700 750 800 850

Abeta 42 (pg/ml)


Pazienti RF e FC La comunicazione

• R.F.: lQualche segno di invecchiamento cerebrale

accelerato, potrebbe diventare Alzheimer, ma non

sappiamo quandoz. Terapia: donepezil 10 mg.

Rivalutazioni cliniche e npsy semestrali •

F.C.:

Paziente: lQualche segno di invecchiamento

cerebrale accelerato, facciamo cura per cercare

di arrestare la progressione, poi ci si rivedez.

Familiari: lQuasi certezza che si tratti di

Alzheimer, peggiorerà nel giro di mesi/

pochissimu anni, terapia solo sintomatica,

decorso disabilitante in 10 anni circaz. Terapia

donepezil 10 mg.

ETHICS

Related to clinical issues

• Was it justified to answer patient`s and

relatives` requests for early diagnosis? •

Was it justified to diagnose an almost

asymptomatic disease when therapy is

poorly effective?

• What should have patients been told?

Whole truth or almost so?

• Should have relatives been told

anything at all?

Cognitività dopo 1 anno I numeri indicano la variazione % rispetto alla prima valutazione clinica

VISUO- FRONTAL- LEARNING WORKING

20 SPATIAL EXECUTIVE MEMORY LANGUAGE

0

-20

SM -40

FC

-60

-80

-100





Future challenges

Development of diagnostic markers

Validation in pilot diagnostic studies

Translational Outpatient Memory Clinic

PATIENTS: MCIs, demented with uncertain features

CLINICAL DATA COLLECTION Clinical and Drug History, Neurol exam, Cogn & Mood screen (MMSE, BSI)

MARKER COLLECTION

HIGH RESOLUTION NEUROPSYCHOL 18F-FDG PET LUMBAR TAP

MR TESTING

PROCESSING OF DATA/MARKERS

Hppocampal volume T-sum for TP Age- and educ-

Subcortical micro- Abeta42, tau, p-tau hypometabolism corrected scores

vascular damage scale

DIAGNOSTIC REPORT to physician-in-charge

Frisoni et al., Alzheimer Dementia 2009

Development of diagnostic markers

Development of Standard Operating Procedures for Biomarker Assessment

Modality Measurement

Hippocampal 3D T1 MR

volume

Temporo- parietal FDG PET

hypometabolism

CSF Ab42 and Lumbar tau puncture

Cortical amyloid Amyloid SOPs developed by ligand manufacturers

deposition PET

NEXT STEPS TOWARDS TRANSLATION

Challenges to translation


Challenges to translation

1. Clinical factors: evidence on efficacy of combined

markers, SOPs, normative population and abnormality

thresholds, estimates of biomarker predictivity 2.

Health-care organization-related factors: primary

secondary tertiary care, panel/stand alone biomarkers;

3. Reimbursement-related factors 4. Market-related factors

5. Incremental diagnostic value

6. Cost/benefit ratio: cost/risk/feasibility/invasiveness 7. Patient/caregiver preferences: “wish to know”


Challenges to translation: understanding patient needs and wishes

CONCLUSIONI

La sequenza di eventi nella malattia di Alzheimer comprende deposizione di amiloide, neurodegenerazione e sintomi.

I biomarcatori diventano anomali secondo una sequenza precisa: prima di amiloidosi, poi funzionali, metabolici, strutturali, e infine cognitivi.

L’atrofia mappa a monte sulla

neurodegenerazione e a valle sui sintomi.

I marcatori di amiloidosi e di

neurodegenerazione permettono di riconoscere i pazienti MCI con neuropatologia Alzheimer.

Per essere utilizzati su larga scala, i biomarcatori devono essere standardizzati.

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I NUOVI CRITERI DIAGNOSTICI PER LA MALATTIA DI ALZHEIMER ... · La sequenza di eventi nella malattia di Alzheimer comprende deposizione di amiloide, neurodegenerazione e sintomi