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)
Revised Petersen Criteria (2006)
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)
Revised Petersen Criteria (2006)
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?
Quale diagnosi precoce
Diagnosi precoce di AD in corso di demenza
Diagnosi precoce di AD in corso di MCI
Diagnosi precoce di AD in soggetti normali
Quale diagnosi precoce
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
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
0
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
Vanacore, Cappa, Mariani, Clerici,
5/9/13
ROC analyses: FCSRT subitems
IFR
IFR corretto
ITR
DFR
DFR corretto
DTR
Intrusioni
ISC
Vanacore, Cappa, Mariani, Clerici,
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
Vanacore, Cappa, Mariani, Clerici,
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
Quale diagnosi precoce
Diagnosi precoce di AD in corso di demenza
Diagnosi precoce di AD in corso di MCI
Diagnosi precoce di AD in soggetti normali
…..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
Quale diagnosi precoce
Diagnosi precoce di AD in corso di demenza
Diagnosi precoce di AD in corso di MCI
Diagnosi precoce di AD in soggetti normali
…..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