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.