Presentazione di PowerPointMild Cognitive Impairment Ten Years Later Ronald C. Petersen, et al.,...

Indice

Introduzione

Quale diagnosi precoce

Quali gli strumenti e le aree di valutazione

Il Ruolo dei Biomarcatori Vantaggi e limiti

La popolazione bersaglio

Quale rete assistenziale?

Mild Cognitive ImpairmentPetersen RC , 1995

Memory complaint corroborated by

an informant

Normal general cognitive function

Normal activities of daily living

Memory impairment in relation to

age and education

Not demented

Mild Cognitive Impairment

Normal MCI Dementia

Cognitive Performance

‘MCI refers to the state of cognition and

functional ability between normal aging and

very mild AD’

(Petersen, 2001)

Revised Petersen Criteria (2006)

Proposes a parallel set of procedures to those for diagnosing AD

Includes clinical judgement for assessment of cognitive performance and ADL performance (no specific instruments or cut-off scores)

Clinical judgement particularly relevant when assessing people of either high intellect (where performance may now be average) or of low education (where below average performance may not represent cognitive decline)


4 subsets of MCI now included:

1. aMCI (single domain)

2. aMCI (multiple domains)

3. Non-amnestic MCI (single domain)

4. None-amnestic MCI (multiple domains)

Mild Cognitive ImpairmentTen Years LaterRonald C. Petersen, et al., Arch Neurol. 2009;66(12):1447-1455

While the construct of MCI has engendered a great

deal of attention, it has also raised a great deal of

controversy.

Much of the concern about the construct pertains to

its heterogeneity, lack of specific ability to predict

outcome, and vagueness of the criteria, eg, the

degree of cognitive impairment in nonmemory

cognitive domains and the degree of functional

impairment.

Mild Cognitive ImpairmentTen Years LaterRonald C. Petersen, et al., Arch Neurol. 2009;66(12):1447-1455

While the construct of MCI has engendered a great

deal of attention, it has also raised a great deal of

controversy.

Much of the concern about the construct pertains to

•its heterogeneity,

•lack of specific ability to predict outcome,

•vagueness of the criteria, eg, the degree of cognitive

impairment in nonmemory cognitive domains and the degree

of functional impairment.

The pressure of the Society:Survey Summary

1. Nearly 89% of Americans say that if they were exhibiting confusion and memory loss, they would want to know if the cause of the symptoms was AD.

2. Of those aged 60 years and older, 95% say they would want to know if they had AD.

3. More than 97% say that if they had a family member exhibiting problems with memory loss, they would want him or her to see a doctor to determine whether the cause was AD.

4. The convergence of evidence from numerous sources indicates that as many as half of people with dementia have never received a diagnosis.

5. A formal diagnosis allows individuals and their caregivers to have access to available treatments, build a care team, participate in support services, and enroll in clinical trials.

6. Participating in planning early in the disease process allows individuals with AD to create advance directives regarding their care and finances so that their wishes can be carried out when they are no longer cognitively able to make such decisions.

7. Early diagnosis also allows individuals with the disease and their caregivers to manage medications more effectively, receive counseling, and address driving and safety issues in advance.

8. Undertaking the diagnostic process early potentially allows cognitive impairment to be reversed in some people. For nearly one in every four individuals who reported to a memory clinic with cognitive problems, their cognitive impairment was the result of a reversible cause, such as depression or a vitamin B12 deficiency.

Alzheimer Disease (AD) Incidence by High or Low Physical Activity Levels

and Mediterranean-Type Diet Adherence Scores

Scarmeas, N. et al. JAMA 2009;302:627-637

Copyright restrictions may apply.

• Application of advanced technologies for screening of candidate therapies. These include the use of induced neurons from skin fibroblasts of carriers of disease-causing alleles of genes associated with dementia• Application of molecular neuroimaging and advanced MRI and PET imagingmethods including ligand development for inflammation and tau deposits• Advanced cognitive neuroscience for the design of novel tests for cognitive impairment• Expertise in characterising cognitive deficits in terms of intermediate phenotypes that support translation between animal model systems and clinical populations• Expertise in the epidemiology of dementia in the community and the implications of new findings for public health• The development and validation of novel imaging technologies including radiopharmaceuticals for PET, amyloid plaque imaging• The identification of novel genes associated with dementia.

In order to early diagnosis, we need:

Genetics Diagnostics

TherapeuticsDisease

Management

Health

Outcomes

Molecular

Diagnostics

In Vitro

Diagnostics

Imaging

Monitoring

Devices

Predisposition

ProfilingGene Therapy

Population

Stratification

VaccinesProteins

Small

MoleculesPharmacoeconomics

Compliance

Therapeutic

Intervention

Non-Therapeutic

Intervention

Potential areas of interest in the realm of

Alzheimer Disease

Le questioni aperte

Quale paziente?Quale medico?Quali indagini?

Quale organizzazione?


Diagnosi precoce di AD in corso di demenza

Diagnosi precoce di AD in corso di MCI

Diagnosi precoce di AD in soggetti normali





…..ma come?

Alzheimer’s disease exists on a spectrum from

minimal symptoms to dementia

No symptomsMild cognitive

symptomsDementia

Increasing Alzheimer’spathology

Time

• Increasingly severe phenotype• Biomarkers assist in identifying the underlying pathology• Biomarker changes may precede clinically detectable changes

© JL Cummings, 2008

AGE

30

40

50

60

70

80

90

100

Deposizione di -amiloide

AttivazioneMicrogliale Grovigli

neurofibrillariPerdita neuronale/

alterazioni neurochimiche

DEMENZA

Treating AD: The Amyloid Cascade Hypothesis

1984 Neurology

2007 LancetNeurology

2010 LancetNeurology

2011 Alzheimer’s & Dementia

AD PROGRESSION USING BIOMARKERS

Abnormal

Normal TimePresymptomatic eMCI LMCI Dementia

CSF Aβ42

Amyloid imagingFDG-PETMRI hippocampal volumeCSF TauCognitive performanceFunction (ADL)

FDG-PET

MRI hippocampal volume

CSF Aβ42

Amyloid imaging

Cognitive performance

Function (ADL)

CSF Tau

Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

Experimental evidence of validity

Revised NIA-AA diagnostic criteria

NINCDS-ADRDA (1984)

• Cognitive impairment (multi

domain)

• Progressive

• With disability

• Not due to other causes

ETIOLOGY

• Agnostic

DUBOIS-FELDMAN (2007) NIA-AA (2011)

• Cognitive deficit

+

• Medial temporal atrophy

• Amyloid- and tau-related biochem.

changes in CSF

• Metabolic changes in temporoparietal cx

• Brain amyloid deposition by PET

ETIOLOGY

• Beta amyloid

• Tau-related neurodegeneration

Traditional and new criteria for the

diagnosis of Alzheimer’s Dementia

Preclinical Stages AD

Prodromal AD

The evolution of the lexical-semantics of Alzheimer Disease

Preclinical ADProdromal AD (included

mild cognitive impairment category)

AD dementia

AD pathophysiological process (AD-P)

AD clinical (AD-C) (including AD dementia and MCI due to AD)

Preclinical AD

MCI (MCI due to AD) Probable AD dementia (included

probable AD with increased level of certainty)

Possible AD dementia

Probable or possible AD dementia with evidence of the AD phatophysiological process (for research purposes)

Phatophysiologically proved AD

Dubois et al, Lancet Neurol, 2007 NIA-AA, JAD, 2011

Mild Cognitive Impairment (MCI)

This diagnostic label is now applied when patients

do not fulfill the criteria for the clinico-biological phenotype of prodromal AD because:

they have memory symptoms that are not characteristic of AD;

or they are biomarker negative.

Revised definition of MCI within the framework of the New

Criteria

AD specific

symptoms present

AD specific

symptoms absent

Biomarkers positive Prodromal AD MCI

Biomarkers negative

or not performed

MCI MCI

MCI Due to Alzheimer’s Disease

Cognition Likelihood of AD Biomarker Evidence

MCI High likelihood (+) amyloid-β biomarker AND (+) neuronal

injury biomarker*

MCI Intermediate likelihood (+) amyloid-β biomarker OR (+) neuronal

injury biomarker*

MCI Uninformative situation Biomarkers fall in ambiguous ranges, conflict,

have not be obtained

MCI Unlikely due to AD Demonstrated absence of AD-type molecular

marker and possible presence of marker

suggestive of non-AD disorder

*hippocampal or medial temporal atrophy on MRI; AD pattern on PET or SPECT; elevated CSF tau or p-tau

(Albert M, et al, 2011)

AD Diagnosis Marching Leftward

Standard

diagnosis

Dubois

research criteria:

“early AD”

Modified

Dubois criteria:

“earlier AD”

Presymptomatic

= Preclinical AD

No symptoms,

biomarker

evidence

of amyloid

dysregulation

Very mild

symptoms

+ amyloid

biomarker

Episodic

memory

impairment

+ any

biomarker

Dementia

Onset of ADpath

Aisen PS, Alzheimers Res Ther, 2009

SECONDARY PREVENTION

Staging Framework for Preclinical AD

Sperling et al., 2011

2011

La valutazione di MCI

Quali gli elementi utili per identificare la M. Alzheimer

Interpretare i risultati

dei test di valutazione

dello stato mentale e

funzionale

risultati normali:

non deficit cognitivi,

non perdita funzionalerisultati patologici:

deficit cognitivi,

perdita funzionale

Resta il

sospetto?

Valutazione di secondo livello

(clinica e strumentale):

test neruopsicologici

esami di laboratorio

neuroimaging

risultati misti:

noRassicurare

(suggerire

un folllow-

up a 6-12

mesi) si

Evidenza

di

demenza

?

- Valutare e trattare i

sintomi non cognitivi

- Considerare la

possibilità di interventi

riabilitativi

- Prescrivere farmaci

specifici

- Pianificare gli

interventi sociali e per

di supposrto ai

caregiver

Follow-up ogni 3-6 mesi

Definire

l'etiologia

Problem with memory impairment

What is impairment? No specific cut-offs

No standard memory tests prescribed

Standard practice is to define 1.5 SD below population norms corrected for age, education

BUT criterion then based on clinician judgement this is not operationalised but allows flexibility

eg to allow for high intelligence, low education

Recenti studi sulla frequenza della Mild Cognitive

Impairment (MCI) in Malattia di Parkinson (MP)

MCI

Affidabilità caregivers

Affidabilità degli strumenti di valutazione cognitiva e funzionale

Affidabilità dei dati normativi

Il ruolo della comorbidità somatica

Il ruolo della comorbidità psichiatrica

Invecchiamento Cognitivo Normale

Anche persone normali si possono lamentare di un cambiamento della memoria

I problemi sono: Difficoltà di concentrazione in presenza di distrazioni

Diminuita capacità di processare informazoni provenienti da canali diversi

Difficoltà in compiti multi-tasking

Rallentamento dei tempi di reazione

Lieve diminuizione della memoria verbale ritardata

Jonker C et al. J Am Geriatr Soc, 1996; Derouesne C et al. Arch Gerontol Geriatr Suppl, 1989.

Episodic Memory Trajectories

Cognitively Normal Community Recruits

Mungas et al., In Press, Psychology & Aging

Depression & cognitive impairmentParticipants with depressive Sx performed worse

on memory and executive function

Artero et al (2008). JNNP; 79:979-984

Instability of MCI

Normal cognition

at baseline

(n=4010; 58%)

MCI at baseline

(n=2882; 42%)

Back to normal at 4yr

follow-up (n=1067; 37%)

MCI

(n=1626;

56%)

Dementia at 4yr

follow-up (n=189; 7%)

Come Identificarli

precocemente?

MMSE total raw score of 150 MCI subjects classified in four group on the basis

of their clinical diagnosis at 12 and 24 months follow-up: progressed MCI (39%),

stable MCI (47%), reverted MCI (9%), temporary reverted MCI (5%).

time follow up

321

MM

SE

to

tal ra

w s

co

re

28,0

26,0

24,0

22,0

progressed

partially reversible

reversible

stable mci

mcievol

Dati Personali

Come intercettare i soggetti a

rischio di conversione a

demenza?

Neuropsychological characteristics of 150 MCI subjects classified in four

group on the basis of their clinical diagnosis at 12 and 24 months follow-

up: progressed MCI (39%), stable MCI (47%), temporary reverted MCI

(5%), reverted MCI (9%).

Progressed MCI

Stable

MCI

Temporary

reverted MCI Reverted MCI

58 (39%) 71 (47%) 8 (5%) 13 (9%)

Mean SD Mean SD Mean SD Mean SD

Rey's words list Immediate Recall 30.1 a 5.9 33.1 6.5 37.1 9.4 38.2 a 6.9

Rey's words list Delayed Recall 3.6 a,b,c 2.9 5.4 b 2.7 7.1 c 2.6 7.7 a 1.9

Short story 6.7 c 3.7 7.3 3.8 7.8 4.7 9.8 c 3.7

Short story immediate recall* 5.2 a 3.2 5.6 3.1 7.1 4.2 8.3 a 2.8

Short story delayed recall* 5.1 a 4.2 5.2 b 4.4 6.5 c 4.8 11.1 a,b,c 4.1

Clock drawing 5.9 b,c,d 2.4 7.5 b 2.4 8.6 c 1.1 8.4 d 2.2

Rey's figure recall 9.4 6.6 9.2 6.1 13.2 6.1 12.9 5.6

“a variety of episodic memory tests that are useful for identifying those MCI patients who have a high likelihood of progressing to AD dementia within a few years…Examples of such tests include (but are not limited to): the Free and Cued Selective Reminding Test, the Rey Auditory Verbal Learning Test,and the California Verbal Learning Test. Other episodic memory measures include:immediate and delayed recall of a paragraph such as the Logical Memory I and II of the Wechsler Memory Scale Revised (or other versions) and immediateand delayed recall of nonverbal materials, such as the Visual Reproduction subtestsof the Wechsler Memory Scale-Revised I and II.”

The Free and Cued Selective Reminding

Task

(orginally, Grober and Buschke, 1987)

C’e’ un animale?

SCORES

Immediate free recall (range 0-36)

Immediate free and cued recall (range 0-36)

INDEX OF SENSITIVITY TO CUEING (range 0-1)

Immediate free recall– Immediate free and cued recall _______________________________________________________

Immediate free recall– 36

Delayed free recall (range 0-12)

Delayed free and cued recall (range 0-12)

Number of intrusions (range 0-∞)

1Sarazin M et al . Neurology 2007; 69 (19): 1859-1867

Validity

FCSRT: PREDICTION OF MCI

PROGRESSION TOWARDS AD IN

CLINICAL PRACTICE

135 MCI subjects

Outcome: AD

Follow-up: 22±10 months

Baseline characteristics of the MCI sample by outcome at follow-up*

MCI at follow-up

N 93

AD at follow-up

N 42

p

Age yrs, mean ± SD 74.83 ± 6.86 76.70 ± 6.76 ns

Female, n (%) 54 (58) 27 (64) ns

Education yrs, mean ± SD 7.23 ± 3.74 7.76 ± 3.81 ns

MMSE score, mean ± SD 26.13 ± 2.18 24.12 ± 2.80 0.049

GDS score <11, n (%) 56 (60.2) 26 (61.9) ns

APOE 4* at least 1 allele, n (%) 19 (29.7) 7 (34.3) ns

Under-threshold FCSRT IFR, n (%) 31 (33.3) 31 (73.8) <0.0001

Under-threshold FCSRT ITR, n (%) 47 (50.5) 37 (88.1) <0.0001

Under-threshold FCSRT DFR, n (%) 33 (35.5) 34 (81.0) <0.0001

Under-threshold FCSRT DTR, n (%) 33 (35.5) 33 (78.6) <0.0001

Under-threshold FCSRT ISC, n (%) 25 (26.9) 32 (76.2) <0.0001

Under-threshold FCSRT intrusion, n (%) 14 (15.1) 21 (50.0) <0.0001

* follow-up (mean±SD): 22±10 months

Vanacore, Cappa, Mariani, Clerici,

5/9/13

OR and 95% CI for AD according to baseline characteristics : follow-up 22±10 months

Characteristic OR 95% CI

age 1,03 0.98-1.07

Sex 1.30 0.66-2.58

MMSE 0.93 0.83-1.05

IFR 0.86 0.34-2.32

ITR 0.51 0.14-1.91

DFR 3.31 1.06-10.36

DTR 2.24 0.73-6.91

ISC 2.48 0.99-6.20

Intrusion 0.67 0.32-1.45


5/9/13

ROC analyses: FCSRT subitems

IFR

IFR corretto

ITR

DFR

DFR corretto

DTR

Intrusioni

ISC


5/9/13

FCSRT: PREDICTION OF MCI

PROGRESSION TOWARDS AD IN

CLINICAL PRACTICE

82 MCI subjects

Outcome: AD

Follow-up ≥ 24 months

OR and 95% CI for AD according to baseline characteristics:

follow-up 24 months

Characteristic OR 95% CI

age 1,04 0.99-1.09

Sex 1.02 0.45-2.32

MMSE 0.93 0.83-1.06

IFR 0.56 0.18-1.69

ITR 0.81 0.17-4.00

DFR 7.70 1.84-32.18

DTR 1.28 0.30-5.44

ISC 3.36 1.13-9.99

Intrusion 0.73 0.32-1.66


5/9/13

Naturalmente, non è il solo test con

elevato valore predittivo…

Date of download: 5/30/2013Copyright © 2012 American Medical

Association. All rights reserved.

From: Heterogeneity of Brain Glucose Metabolism in Mild Cognitive Impairment and Clinical Progression to

Alzheimer Disease

Arch Neurol. 2005;62(11):1728-1733. doi:10.1001/archneur.62.11.1728

Distribution of amnesic mild cognitive impairment (aMCI) converters and aMCI nonconverters according to California Verbal

Learning Test–Long Delay Free Recall (CVLT-LDFR) scores and regional cerebral glucose metabolism ratios (rCGM-r). California

Verbal Learning Test–Long Delay Free Recall scores of 7 or higher accurately predict stable aMCI, while the rCGM-r can

discriminate the outcome in subjects with CVLT-LDR scores less than 7. Circles indicate aMCI nonconverters; diamonds, aMCI

converters; the 3 ringed symbols, subjects with a misdiagnosis.

Figure Legend:

Other candidates

PAL (Fowler et al., 2002)

Short-term memory (STM) binding (Parra et al., 2009, 2010)

“entorhinal-perirhinal cortex” tests:

DMS48 (Barbeau et al., 2004)

familiarity-recollection (Wolk et al., 2011).

topographical memory (Hartley et al, 2007)

Short-term memory binding early-onset familial Alzheimer’s disease carriers (sensitivity = 77%, PPV = 77%, NPV =

83%) asymptomatic carriers (sensitivity = 73%, PPV = 81%, NPV = 76%) separating them from healthy controls (specificity = 83%).

Paired Associates Learning early-onset familial Alzheimer’s disease (sensitivity = 82%, PPV = 72%, NPV = 85%) asymptomatic carriers (sensitivity = 40%, PPV = 63%, NPV = 56%) less specific than the short-term memory binding task (specificity = 77%).

Recall of the Rey–Osterrieth Complex Figure sensitive to detect early-onset familial Alzheimer’s disease carriers (sensitivity = 77%,

PPV = 94%, NPV = 85%) insensitive to detect asymptomatic carriers (sensitivity = 23.3%, PPV = 86%, NPV =

55%) high specificity (96%).

Raccomandazioni AIP/SINDEM

La valutazione cognitiva è fondamentale per la diagnosi precoce e

la gestione della MA e dovrebbe essere eseguita obbligatoriamente

in tutti i pazienti che riferiscono un declino cognitivo prima di

indagare i biomarcatori

La valutazione cognitiva nei soggetti con il declino cognitivo e

soggetti con esordio atipico deve essere quantitativa e deve

includere misure cognitive globali e una valutazione approfondita

dei principali ambiti cognitivi (memoria, apprendimento, linguaggio,

funzioni esecutive, abilità visuo-spaziali, attenzione)

Nei pazienti con disturbi di memoria, test come il FCRST e il

RAVLT sono fortemente raccomandati per misurare

oggettivamente le prestazioni mnesiche e per identificare i soggetti

Raccomandazioni

Gli autori raccomandano di ottenere valutazioni longitudinali

della cognitività, ove possibile, per aumentare l’accuratezza

della diagnosi

Per monitorare il declino cognitivo, comportamentale e

funzionale, si raccomanda che i pazienti che soddisfano i

criteri per MCI o che lamentano persistentemente deficit

cognitivi tornino per una nuova valutazione neuropsicologica e

per la prosecuzione dell’iter diagnostico almeno dopo sei mesi

Il ruolo dei Disturbi del

Comportamento

Prevalence of

Neuropsychiatric

Symptoms in

Dementia and Mild

Cognitive

Impairment

(JAMA. 2002;288:1475-1483)

2013 Aug 20. [Epub ahead of print]

Differential Impact of Apathy and Depression in the

Development of Dementia in Mild Cognitive

Impairment patients.

Vicini Chilovi B et al. Dementia & GCD, 2009

Aim of this study was to evaluate the role of apathy and depression in the conversion to dementia among MCI subjects.

0

10

20

30

40

50

60

Normal Depressed Apathetic

Prevalence of Progressors patients

(developing Dementia within two years

from baseline) in a sample of 124

outpatients with Mild Cognitive

Impairment, subgrouped by presence of

depression presence of apathy without

depression, absence of depression and

apathy.

Conclusion: These findings demonstrate a differential role of

apathy and depression in the development of dementia, and

argue for the need of dissecting in MCI patients apathy and

depression symptoms in the reading of mood disorders.

Differential Impact of Apathy and Depression in the Development of Dementia in Mild Cognitive Impairment patients.Vicini Chilovi B et al. Dementia & GCD, 2009

OR 95 % C.I. p.

Age 1,10 1,02 1,19 .01

Barthel index 0,83 0,71 0,97 .02

ADAS-Cog ( > 9.5)^ 7,85 2,54 24,29 .000

Depression° 0,10 0,02 0,39 .001

Apathy* 7,07 1,99 25,17 .003

E le attività della vita

quotidiana?

La punta dell’Iceberg

72.3% individuals with aMCI have 1 or more deficits in daily functioning compared with 97.4% with mild AD and 7.9% of self-reported healthy controls.

1.8% to 21.3% of individuals with aMCI require assistance or were dependent per the IADLs assessed; 12.4% to 66.3% of patients with mild AD required assistance or were dependent per most of the IADLs assessed

Functionally impaired individuals with aMCI had greater medial temporal atrophy and deficits in memory and processing speed compared with functionally intact individuals with aMCI.

These findings show that even mild disruptions in daily functioning may be an important clinical indicator of disease and represent the latter phases of disease progression within the MCI classification system for cognitive impairment

IADL deficits were greater in amnestic than nonamnestic MCI, but within these subgroups, did not differ between those with single or multiple domains of cognitive impairment.

FAQ indices correlated significantly with memory and processing speed/executive function.

These cross-sectional findings support previous longitudinal reports suggesting that cognitive and functional impairments in MCI may be independently associated with dementia risk.

MCI

IS it Prodromal Alzheimer Disease?

Are biomarkers reliable enough to predict Alzheimer Disease in preclinical/prodromal stage?

An emerging dilemma

….we suggest that neurologists and other clinicians carefully

consider the potential risks and benefits of PET scans in dementia

diagnosis before ordering them. While clinicians and patients have

many legitimate reasons for greater diagnostic certainty, currently

available options including PET and APOE4 testing have not been

proven to improve upon the opinion of astute clinicians and may

instead result in ethical or clinical quandaries.

Neuroimaging Professional Interest Association of ISTAART, Neurology 2013

Accuracy rates of diagnostic tools

Indici di accuratezza

Clin Chem Lab Med 2010;48(5):603–607 2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2010.131

2010/586

Article in press - uncorrected proof

Minireview

Inter-laboratory variation in cerebrospinal fluid biomarkers

for Alzheimer’s disease: united we stand, divided we fall

Niklas Mattsson*, Kaj Blennow and Henrik

Zetterberg

Institute of Neuroscience and Physiology, Department of

Psychiatry and Neurochemistry, The Sahlgrenska Academy,

University of Gothenburg, Goteborg and Molndal, Sweden

Abstract

Several drug candidates for Alzheimer’s disease are being

evaluated in clinical trials, with the goal of finding a drug

with disease-modifying effects. When such a drug finally

reaches the market, there will be a demand for accurate diag-

nostic tools useful for early detection of disease and for mon-

itoring biochemical effects. The core cerebrospinal fluid

(CSF) biomarkers amyloid peptides (Ab42), total-tau and

phospo-tau are promising in this respect. However, inter-cen-

ter variation (caused by pre-analytical, analytical and post-

analytical factors), and inter-laboratory variation (caused by

analytical factors), particularly for CSF Ab42, lowers their

utility in multicenter studies. Here, we discuss the causes of

these variations, and present a global quality control program

to overcome them.

Clin Chem Lab Med 2010;48:603–7.

Keywords: Alzheimer’s disease; amyloid; cerebrospinal flu-

id; quality control; variations.

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative

disease affecting millions of individuals world-wide (1). The

prevalence is expected to rise dramatically in the next dec-

ades as a result of increased life expectancy. Despite intense

research efforts, the disease mechanisms are still not fully

understood. The two pathological hallmarks are extracellular

plaques, mainly composed of amyloid peptides (Ab42), and

intraneuronal neurofibrillary tangles, composed primarily of

hyperphosphorylated tau protein (P-tau) (1, 2). The amyloid

cascade hypothesis is supported by experimental data and

appreciated by many AD researchers, although they not are

in complete agreement (3–6). The hypothesis states that the

*Corresponding author: Dr. Niklas Mattsson, ClinicalNeurochemistry Laboratory, Sahlgrenska University Hospital/Molndal, 431 80 Molndal, SwedenPhone: q 46 31 3432377, Fax: q 46 31 3432426,E-mail: [email protected] November 6, 2009; accepted January 8, 2010;previously published online March 5, 2010

amyloid pathology occurs early in the disease process and is

a causative factor, with tau pathology being a down stream

event. No available treatment halts disease progression, but

several drug candidates are in clinical trials (7, 8). Most of

these drugs are directed against amyloid, and include

enzyme-modulators and -inhibitors, anti-aggregation agents,

and vaccination regimes. If any drug halts disease progres-

sion, there will be an increased demand for diagnostic tools

enabling accurate diagnosis of AD. In addition, since drugs

are likely to be most effective if administered before signif-

icant damage has been inflicted on the brain, a valuable diag-

nostic tool should be accurate early in the course of the

disease; when a clinical diagnosis is difficult or impossible

to make. Such tools will also be valuable in clinical trials,

to enrich study populations with incipient AD patients and

avoid inclusion of patients with other diseases that might blur

significant drug effects. Finally, there is a need for markers

to monitor the biochemical effects of drugs, especially in

slow progressive conditions, such as AD, where a beneficial

effect may not be clinically evident for several years. Such

markers would make small pilot studies feasible, for selec-

tion of drugs for continuation to large scale clinical trials.

Cerebrospinal fluid biomarkers for AD

Cerebrospinal fluid (CSF) is the focus of much AD biomar-

ker research (9). Molecular changes in the extracellular envi-

ronment of the brain are reflected in CSF, since the sin-

gle-cell layer epithelium separating the two compartments

allows an essentially unhindered flow of molecules from the

brain towards the CSF (10). This research has established the

core CSF biomarkers Ab42, total-tau (T-tau) and P-tau for

the diagnosis of fully developed AD. Ab42 is a biomarker

for deposition of Ab in the brain. T-tau is a biomarker for

axonal degeneration, while P-tau reflects tau hyperphospho-

rylation, which appears to be a relatively AD-specific phe-

nomenon in the adult brain. A multitude of studies confirm

a decrease in CSF Ab42 and an increase in CSF T-tau and

P-tau in AD patients when compared with healthy controls

(11). Furthermore, these biomarkers are stable over time in

AD, suggesting that they may be used for early diagnosis

and monitoring of biochemical effects of drugs (12, 13). AD

is often preceded by mild cognitive impairment (MCI),

defined as cognitive decline adjusted for age and education,

but not yet fulfilling the criteria for dementia (14, 15). MCI

provides a challenge to the clinical physician, since only

; 50% of MCI patients will eventually receive a diagnosis

of AD, with an annual conversion rate of 10%–15%. The

remaining MCI patients are diagnosed with other dementias

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Mattsson N, Clin Chem Lab Med, 2010Verwey NA, Clin Chem Lab Med, 2010

Clin Chem Lab Med 2010;48(5):603–607 2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2010.131

2010/586

Article in press - uncorrected proof

Minireview

Inter-laboratory variation in cerebrospinal fluid biomarkers

for Alzheimer’s disease: united we stand, divided we fall

Niklas Mattsson*, Kaj Blennow and Henrik

Zetterberg

Institute of Neuroscience and Physiology, Department of

Psychiatry and Neurochemistry, The Sahlgrenska Academy,

University of Gothenburg, Goteborg and Molndal, Sweden

Abstract

Several drug candidates for Alzheimer’s disease are being

evaluated in clinical trials, with the goal of finding a drug

with disease-modifying effects. When such a drug finally

reaches the market, there will be a demand for accurate diag-

nostic tools useful for early detection of disease and for mon-

itoring biochemical effects. The core cerebrospinal fluid

(CSF) biomarkers amyloid peptides (Ab42), total-tau and

phospo-tau are promising in this respect. However, inter-cen-

ter variation (caused by pre-analytical, analytical and post-

analytical factors), and inter-laboratory variation (caused by

analytical factors), particularly for CSF Ab42, lowers their

utility in multicenter studies. Here, we discuss the causes of

these variations, and present a global quality control program

to overcome them.

Clin Chem Lab Med 2010;48:603–7.

Keywords: Alzheimer’s disease; amyloid; cerebrospinal flu-

id; quality control; variations.

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative

disease affecting millions of individuals world-wide (1). The

prevalence is expected to rise dramatically in the next dec-

ades as a result of increased life expectancy. Despite intense

research efforts, the disease mechanisms are still not fully

understood. The two pathological hallmarks are extracellular

plaques, mainly composed of amyloid peptides (Ab42), and

intraneuronal neurofibrillary tangles, composed primarily of

hyperphosphorylated tau protein (P-tau) (1, 2). The amyloid

cascade hypothesis is supported by experimental data and

appreciated by many AD researchers, although they not are

in complete agreement (3–6). The hypothesis states that the

*Corresponding author: Dr. Niklas Mattsson, ClinicalNeurochemistry Laboratory, Sahlgrenska University Hospital/Molndal, 431 80 Molndal, SwedenPhone: q 46 31 3432377, Fax: q 46 31 3432426,E-mail: [email protected] November 6, 2009; accepted January 8, 2010;previously published online March 5, 2010

amyloid pathology occurs early in the disease process and is

a causative factor, with tau pathology being a down stream

event. No available treatment halts disease progression, but

several drug candidates are in clinical trials (7, 8). Most of

these drugs are directed against amyloid, and include

enzyme-modulators and -inhibitors, anti-aggregation agents,

and vaccination regimes. If any drug halts disease progres-

sion, there will be an increased demand for diagnostic tools

enabling accurate diagnosis of AD. In addition, since drugs

are likely to be most effective if administered before signif-

icant damage has been inflicted on the brain, a valuable diag-

nostic tool should be accurate early in the course of the

disease; when a clinical diagnosis is difficult or impossible

to make. Such tools will also be valuable in clinical trials,

to enrich study populations with incipient AD patients and

avoid inclusion of patients with other diseases that might blur

significant drug effects. Finally, there is a need for markers

to monitor the biochemical effects of drugs, especially in

slow progressive conditions, such as AD, where a beneficial

effect may not be clinically evident for several years. Such

markers would make small pilot studies feasible, for selec-

tion of drugs for continuation to large scale clinical trials.

Cerebrospinal fluid biomarkers for AD

Cerebrospinal fluid (CSF) is the focus of much AD biomar-

ker research (9). Molecular changes in the extracellular envi-

ronment of the brain are reflected in CSF, since the sin-

gle-cell layer epithelium separating the two compartments

allows an essentially unhindered flow of molecules from the

brain towards the CSF (10). This research has established the

core CSF biomarkers Ab42, total-tau (T-tau) and P-tau for

the diagnosis of fully developed AD. Ab42 is a biomarker

for deposition of Ab in the brain. T-tau is a biomarker for

axonal degeneration, while P-tau reflects tau hyperphospho-

rylation, which appears to be a relatively AD-specific phe-

nomenon in the adult brain. A multitude of studies confirm

a decrease in CSF Ab42 and an increase in CSF T-tau and

P-tau in AD patients when compared with healthy controls

(11). Furthermore, these biomarkers are stable over time in

AD, suggesting that they may be used for early diagnosis

and monitoring of biochemical effects of drugs (12, 13). AD

is often preceded by mild cognitive impairment (MCI),

defined as cognitive decline adjusted for age and education,

but not yet fulfilling the criteria for dementia (14, 15). MCI

provides a challenge to the clinical physician, since only

; 50% of MCI patients will eventually receive a diagnosis

of AD, with an annual conversion rate of 10%–15%. The

remaining MCI patients are diagnosed with other dementias

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Amyloid Imaging: Achilles' Heel(s)

• PiB-PET may peak early in the disease course

Jack CR, Brain, 2009Engler H, Brain, 2006

Evidence of incremental accuracy of

biomarkers

CSF Ab42

FDG PET

Hippo vol

100%

4%

Prestia Nordberg Scheltens et al., Neurology 2013

Evi

dence

of i

ncrem

enta

l

diagnost

ic v

alue

Dev

elopm

ent o

f clin

ical

guidel

ines

Sta

ndard O

perat

ing

Pro

cedure

s

Exp

erim

enta

l evi

dence

of

valid

ity

TIME

Quale i grado di correlazione tra i

biomarker

Tutti i biomarkers insieme o step by step?

So, do they work?

In general, yes, but...

Cut points, normal/abn

Temporal ordering

Conflicting markers

Imaging vs. CSF

Cost

Need more data

Need to validate in the general population





…..ma a tutti?

Questioni aperte nella diagnosi precoceChi deve essere indagato e quando?Chi sostiene le spese per le indagini e perché?Solo ricerca o anche clinica?Cosa comunicare alle persone a rischio?E’ ragionevole indagare pazienti per i quali non vi sono rimedi?

A tal fine sarà inevitabile:Rendere le indagini più accurate mediante standardizzazione, soglie di cut-

off, e referti quantitativi automatizzati quando possibileCombinare studi di biomarker per stratificare il rischio e predire il corso di

declinoIntegrare i dati genetici nell’algoritmo di rischioAumentare l’accettabilità delle indagini strumentaliEducare il personale coinvolto all’uso dei registri, dei tests e dei criteri cliniciPromuovere la formazione specialistica e integrativaPromuovere rapporti integrati con la Medicina Territoriale

Dovremo prevenire e diagnosticare precocemente

la M. Alzheimer negli ultra-ottantenni?

Screening mirato della popolazione a

rischio?

Seguire nel tempo anche soggetti con SMI/SCI

MAC-Q o altro (es., Questionario di screening per lamentele di memoria da validare per la popolazione italiana)

Vannier-Nitenberg et al. BMC Geriatrics 2013, 13:55

Memory Assessment Clinic Questionnaire

(MAC-Q, soglia 25)

108642COMPLESSIVAMENTE LA VOSTRA

MEMORIA DI ADESSO RISPETTO A QUELLA

DEL PASSATO VI SEMBRA

54321RICORDARE LE COSE DA COMPERARE

QUANDO ENTRATE IN UN NEGOZIO O

FARMACIA

54321RICORDARE EVENTI PRECISI CHE AVETE

APPENA LETTO NEL GIORNALE OD IN

RIVISTE

54321RICORDARE DOVE AVETE POSTO GLI

OGGETTI (OCCHIALI, CHIAVI, ECC.) IN

CASA OD IN ALTRO LUOGO

54321RICORDARE I NUMERI DI TELEFONO CHE

USATE TUTTI I GIORNI OD ALMENO 1

VOLTA LA SETTIMANA

54321RICORDARE I NOMI DI PERSONE CHE VI

SONO APPENA STATE PRESENTATE

MOLTO

PEGGIO

ORA

UN PO’

PEGGIO

ORA

PIU’ O

MENO

UGUALE

UN PO’

MEGLIO

ORA

MOLTO

MEGLIO

ORA

Crook TH, et al. Int Psychogeriatrics, 1992; 4:165-175





…..ma dove?

SOP

Criteri Qualità

Indicatori Efficienza

Aspetti Futuri: L’organizzazione dei Servizi

MCI Atipico

MCI persistente o

progressivo non

interpretabile

MCI ad esordio presenile

Pazienti con diagnosi di

possibile AD

Pazienti con MCI/AD

presenile

Pazienti con Familiarità

Una possibile propostaUVA/Centri della

Memoria

Valutazione clinica Standardizzata

Valutazione Cognitiva e Comportamentale di base

Indagini Strumentali (CT, MRI)

Registro

Centri di II Livello

Valutazione Clinica Multidisciplinare standardizzata

Valutazione Cognitiva e Comportamentale Estesa

Counselling Genetico Biomarker Strumentali e

di Laboratorio (FDG-PET, AMY-PET, LIQUOR, fMRI, MRI Morfometria, DATSCAN)

Registro

Qualche numero per riflettere

Ogni anno in Italia 150.000 nuovi pazienti con Demenza o con Decadimento Cognitivo Lieve

Di questi, non più del 50% giungono tempestivamente ad un’UVA o Centro Memoria

Di questi 75.000, 2/3 hanno età superiore a 70 anni e il 50% lamenta una significativa comorbidità somatica

Solo il 25% di questi NON manifesta patologia cerebrovascolare

In pratica sono circa 15000 i soggetti che ogni anno potrebbero necessitare di indagini di 2° livello e che potrebbero essere trattati con terapie anti-amiloide se disponibili, che porterebbe a circa 250 pazienti per centro (ipotizzando 1 centro specializzato per 1 milione di abitanti)

“In the future, when doctors can truly prescribe the right treatment, to the right person, at the right time, we will have a new level of precision and effectiveness that will provide the knowledge-driven power that is necessary to achieve our highest goals in healthcare reform”

HHS Secretary Kathleen Sebelius

Senate confirmation hearings, April 2, 2009

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