Quale costrutto nella diagnosi clinica di Demenza/ Malattia di Alzheimer? - ISS
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Quale costrutto nella diagnosi clinica di
Demenza/ Malattia di Alzheimer?
Giancarlo Logroscino MD PhD
Neurodegenerative Diseases Unit
Department of Basic Medicine Neuroscience and Sense Organs
Department of Clinical Research in Neurology of the University of Bari
at “Pia Fondazione Card G. Panico“ Hospital Tricase (Le)
University Aldo Moro Bari Italy
2015
2013
2011
2010
2007
1993
1984
1980 1990 2000 2010 2020
The Future:
Reshaping The Natural History of a Disease
Gordis L, Epidemiology 2000 W. B. Saunders Company Philadelphia, PA
Preclinical Phase Clinical Phase
Outcome
(A) (P) (S) (M) (D) (T)
Biological Pathological Signs and Medical Diagnosis Treatment
Onset Evidence Symptoms Care
of Disease sought
time
Sequence of Pathological, Clinical, and Radiologic
Changes from Normal Aging to Early AD
Mayeux R. NEJM 2010; 362:2194-201
Preclinical Early
phase
SMC MCI
AD
How early could/should be the Diagnosis?
Clinical diagnosis of Probable AD NICDS-ADRDA Criteria
What is the Gold Standard? • 1984 NINCDS ADRDA Clinical Criteria • The disease was caused by proven AD pathology
Validity of current clinical criteria for AD, VAD, LBD
The Camberwell Dementia Case Register
Holmes C. British Journal of Psychiatry 1999; 174: 45-50
1,00
0,90
0,80
0,70
0,60
1,00
1,00
1,00
1,00
1,00
1,00
0,50
0,92
0,91
0,91
0,78
0,40
0,76
0,76
0,75
0,75
0,70
0,66
0,66
0,64
0,64
0,30
0,50
0,20
0,30
0,22
0,17
0,16
0,10
0,00
NINCDS Neur NINCDS Neur AIREN Infarctions AIREN Infarctions DLB Lewy Body DLB Lewy Body
plaque plaque+ Pat alone +Pat +NP. +Pat.
PPV NPV SPECIFICITY SENSITIVITY
Dementia and Alzheimer’s disease:
Diagnosis and Disease
Last A dictionary of Epidemiology IEA 1988
• The process of determining health status and
define the identity of the condition from which a
patient suffer.
• Identified by a phenotype or a test or a battery of
test or on an opinion based on pattern ricognition.
Mortality from leading causes of death over the past five decades
Casserly I. et al Lancet 2004; 363:1139-46.
Incidence across 3 Studies:
GP do not diagnose Dementia
Rait G et al BMJ. 2010 5;341:c3584Increasing the Grey Area/ Uncertainties of the Case/Control approach
Dementia Diagnosis Determinants • The reference system is key (in vivo / postmortem) • The diagnosis is culturally/socially influenced • The real use of the diagnostic system may rapidly change over time • Measures of Brain Functioning have a wider distribution around the point estimate in older age groups
Clinical diagnosis of Probable AD NICDS-ADRDA Criteria
Diagnostic Criteria (Operational Criteria)
• Provide clear and reproducibile applications of
definition ( based on clinical/test characteristics)
• Provide homogeneous groups of cases
• Possible identification of subgroups
• Starting point to predict prognosis and choose a
therapyThe egffect of different Classification Systems
on the Prevalence of Dementia
Erkinjuntti et al NEJM 1997 ;337:1667-74.Sequence of Pathological, Clinical, and Radiologic
Changes from Normal Aging to Early AD
Mayeux R. NEJM 2010; 362:2194-201
Preclinical Early
phase
SMC MCI
AD
How early could/should be the Diagnosis?• “A biomarker that is
intended to substitute for
a clinical endpoint.
• It is expected to predict
clinical benefit (or lack of
benefit) based on
epidemiologic,
therapeutic,
pathophysiologic or other
scientific evidence.”
Definition of Clinical Endpoint BiomarkerAD Biomarker:
A combined Multimodal Approach
• Diagnostic biomarkers
– Used to enrich,select stratify subject with AD
• Endpoint biomarkers
– To monitor disease progression and therapy effect
• Pathophysiology biomarkers
– To identify pathophysiology at preclinical stage
Cavedo et alDisease Modifying Treatment • Able to slow or halt the disease progression • Permanent effect should be present – (no transient effect like in symptomatique treatments) • Modify the underlying pathological process
Primary Outcome Measures of the Study • How Many subjects with AD at MCI stage progressed to AD Dementia based on DSM-IV criteria and/or NINDS- NIA-McKahn 1984 criteria?
IWG1; IWG2, NIA- AA AD criteria: Differences in Survival Probability
What is the Prognosis of the SNAP group ?
20%Clinical (tertiary center) vs population-based setting
Differential Evolution of Cognitive Impairment in Nondemented
Older Persons: Results From the Kungsholmen Project
Palmer K et al Am J Psychiatry 2002;159:436-442Differential Evolution of Cognitive Impairment in Nondemented
Older Persons: Results From the Kungsholmen Project
Palmer K et al Am J Psychiatry 2002;159:436-442Conversion Patterns from MCI to Dementia between the clinic- and community-based samples
Conclusions: • A substantial proportion of CIND develop dementia in a three years period • There is a sobstantial proportion of CIND who improve • The absence of subjective memory complaint is the only reliable predictor of improvement • Setting is important to determine the clinical features including prognosis
Prevalence Studies of Mild Cognitive Impairment
(MCI)
Petersen, R. C. et al. Arch Neurol 2009;66:1447-1455.
Copyright restrictions may apply.Individuals and Populations
Normal IndividualsAmiloidosis 59%
42%+17%
17%
Jack CR et al• Numero di casi di demenza incrementa in maniera
esponenziale in tutto il mondo
• La diagnosi è inadeguata
• Le demenze (AD in particolare) sono la più
probabile causa di disabilità nella fase avanzata
della vitaWhat is the gold standard? • Neuropathology • Decline/Conversion • Biomarkers/ Neuropathology in vivo
• The demonstration of
clinical improvement
will be enough for
symptomatique effects
• The changes in
biomarkers is needed
to have a disease
modifying effect
European Medicine Agency
(EMA) 2008Prevalence of Pathological Lesions According to Age
Age, Neuropathology, and Dementia
Savva et al 2009; 360:2302-2309
.Neuropathology in the Latest Part of Life • With increasing age there is a decrease in the ability to predict dementia on the basis of the burden – Neuritic placques in the hippocampus and neocortex – Neurofibrilary tangles in the hippocampus • Loss of validity of neuropathology in the oldest old
Health States during Later Stages of Life C.Brayne Nature Reviews in Neuroscience 2007;8:233-239
Physical Frailty accounts for 22% of AD pathology
Disappointing Results from AD Trials: Hope is Still There?
Possible Type of Interventions
timeDementia Incidence is declining in Europe and US ?
UK USGBD 2010:
Risk Factors are more Dangerous than Diseases
Comparison of the 10 leading diseases and injures and the 10 risk factors
based on the percentage of Global Deaths and Global DALY
High Blood Pressure
Smoking
Alcohol Use
Diet Low in Fruit Ischemic Heart Disease
CerebroVascular Disease
The Lancet vol 380, December, 2012Estimated Percent and Number of AD cases Attributable
to Potentially Modifiable Risk Factors
Barnes&Jaffe Lancet Neurology 2011;10: 819-28Geoffry Rose
Good health flows from population levels to the individual
rather than the other way aroundNEURODEGENERATIVE DISEASE
UNIT
Card. G. Panico Hospital Tricase ( LE)
University of Bari NEURODEGENERATIVE MARKERS LAB
ADVANCED
3T NEUROLOGICAL
PETMRI RESEARCH
SCAN
NEUROPSYC
OLOGYPrevalence of different types of dementia in a population based study
in Southern Italy: The GreatAGE study.
R Tortelli, MR Barulli, R Capozzo, A Leo, M Tursi, A Grasso, R Chiloiro, M Giannini, M Lozupone, F Veneziani, M Casulli,
F Coppola, C Bonfiglio, V Guerra, A Osella, D Seripa, F Panza, V Solfrizzi, N Quaranta, C Sabbà, G Logroscino.You can also read
