quale costrutto nella diagnosi clinica di demenza...
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Giancarlo Logroscino MD PhDNeurodegenerative Diseases UnitDepartment 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
Quale costrutto nella diagnosi clinica di Demenza/ Malattia di Alzheimer?
1984
1993
2007
2010
2011
2013
2015
1980 1990 2000 2010 2020
The Future: Reshaping The Natural History of a Disease
Gordis L, Epidemiology 2000 W. B. Saunders Company Philadelphia, PA
BiologicalOnset
PathologicalEvidence
Signs and Symptomsof Disease
MedicalCare
sought
Diagnosis Treatment
Outcome
(A) (P) (S) (M) (D) (T)
Preclinical Phase Clinical Phase
time
How early could/should be the Diagnosis?MCI
EarlyAD
Preclinical phase SMC
Sequence of Pathological, Clinical, and Radiologic Changes from Normal Aging to Early AD
Mayeux R. NEJM 2010; 362:2194-201
Clinical diagnosis of Probable AD NICDS-ADRDA Criteria
• 1984 NINCDS ADRDA Clinical Criteria
• The disease was caused
by proven AD pathology
What isthe Gold Standard?
Validity of current clinical criteria for AD, VAD, LBDThe Camberwell Dementia Case Register
Holmes C. British Journal of Psychiatry 1999; 174: 45-500,
76
0,92
0,76
1,00
1,00
1,00
0,64
0,17
0,64
0,78
0,91
0,91
0,75
0,70 0,75
1,00
1,00
1,00
0,66
0,50
0,66
0,30
0,22
0,16
0,00
0,10
0,20
0,30
0,40
0,50
0,60
0,70
0,80
0,90
1,00
NINCDS Neurplaque
NINCDS Neurplaque+ Pat
AIREN Infarctionsalone
AIREN Infarctions+Pat
DLB Lewy Body+NP.
DLB Lewy Body+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 decadesCasserly 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:c3584
Increasing 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
DiagnosticCriteria(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 therapy
The egffect of different Classification Systemson the Prevalence of Dementia
Erkinjuntti et al NEJM 1997 ;337:1667-74.
How early could/should be the Diagnosis?MCI
EarlyAD
Preclinical phase SMC
Sequence of Pathological, Clinical, and Radiologic Changes from Normal Aging to Early AD
Mayeux R. NEJM 2010; 362:2194-201
• “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 Biomarker
AD 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 al
Disease 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 NondementedOlder Persons: Results From the Kungsholmen Project
Palmer K et al Am J Psychiatry 2002;159:436-442
Differential Evolution of Cognitive Impairment in NondementedOlder Persons: Results From the Kungsholmen Project
Palmer K et al Am J Psychiatry 2002;159:436-442
Conversion 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
Copyright restrictions may apply.
Petersen, R. C. et al. Arch Neurol 2009;66:1447-1455.
Prevalence Studies of Mild Cognitive Impairment (MCI)
Individuals and Populations
Normal Individuals
17%
Amiloidosis 59%42%+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 vita
What is the gold standard?
• Neuropathology
• Decline/Conversion
• Biomarkers/ Neuropathology in vivo
• The demonstration of clinical improvementwill be enough for symptomatique effects
• The changes in biomarkersis neededto have a diseasemodifying effect
European Medicine Agency (EMA) 2008
Prevalence of Pathological Lesions According to AgeAge, 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 LifeC.Brayne Nature Reviews in Neuroscience 2007;8:233-239
Physical Frailty accounts for22% of AD pathology
Disappointing Results from AD Trials: Hope is Still There?
Possible Type of Interventions
time
UK US
Dementia Incidence is declining in Europe and US ?
GBD 2010:
Risk Factors are more Dangerous than DiseasesComparison of the 10 leading diseases and injures and the 10 risk factors
based on the percentage of Global Deaths and Global DALY
The Lancet vol 380, December, 2012
High Blood Pressure
Smoking
Alcohol Use
Diet Low in Fruit Ischemic Heart Disease
CerebroVascular Disease
Estimated Percent and Number of AD cases Attributableto Potentially Modifiable Risk Factors
Barnes&Jaffe Lancet Neurology 2011;10: 819-28
Good health flows from population levels to the individualrather than the other way around
Geoffry Rose
ADVANCED NEUROLOGICAL
RESEARCH
3T MRIPET
SCAN
NEURODEGENERATIVE MARKERS LAB
NEUROPSYCOLOGY
NEURODEGENERATIVE DISEASE UNIT
Card. G. Panico Hospital Tricase ( LE)University of Bari
Prevalence 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.