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Transcript of Il processo diagnostico - psicogeriatria.it · Il processo diagnostico dell’Alzheimer dalla...
Il processo diagnostico
dell’Alzheimer dalla clinica al neuroimaging
Giovanni B. Frisoni M.D.
Professor of Clinical Neurosciences, University of Geneva
Médecin Responsable, Memory Clinic, Hôpitaux Universitaires de Genève
Scientific Director, IRCCS Fatebenefratelli, Brescia, Italy
Disclosures
♦ Sources of Research Support: Wyeth Int.l, Lilly Int.l, Lundbeck Italia,
Roche, Alzheimer’s Association
♦ Consulting Relationships: Piramal, Lilly, BMS, Bayer, Lundbeck, Elan,
Astra Zeneca, Pfizer, Taurx, Wyeth, GE,
Baxter, Envivo
♦ Editorial Boards:
• The Lancet Neurology
• NeuroBiology of Aging
• Alzheimer’s Diseases & Associated
Disorders
• Neurodegenerative Diseases
• Aging Clinical & Experimental Research
♦ Industry-Sponsored Trials: • Florbetapir in Clinical Practice, Lilly
• Flutemetamol in Delirium, GE
• Addedd value of florbetaben, Piramal
♦ Fees > $10,000: None
♦ Stock Equity: • CEREBRO SaRL, Genève
♦ Speaker’s Bureaus: None
Summary
♦ Why early and accurate differential diagnosis?
♦ Biomarkers for early and accurate differential
diagnosis of AD: the concept
♦ Biomarkers for early diagnosis of AD: results from an
Italian multicentre study w/ amyloid PET
Why differential diagnosis?
Frontotemporal Lobar
Degeneration
Dementia with Lewy
Bodies
Vascular Dementia
Diagnosis of FTLD advises
against the use of
cholinesterase inhibitors
and memantine
Diagnosis of DLB strongly
advises against the use of
neuroleptics for their
potentially devastating
effects
The efficacy of
cholinesterase inhibitors
and memantine in pure VD
is not proven.
• Mendes 2007;
Archiniegas 2013
• Boxer 2013
• Piggott 1998 • Erkinjuntti 2002
Rate of progression from mild cognitive impairment to Alzheimer's Disease (AD) in the donepezil-vit E trial
Petersen RC et al. N Engl J Med 2005;352:2379-2388.
Rate of progression from mild cognitive impairment to Alzheimer's Disease (AD) in the donepezil-vit E trial
Petersen RC et al. N Engl J Med 2005;352:2379-2388.
Non AD
degenerative
dementias
AD dementias
No degenerative
pathology
Summary
♦ Why early and accurate differential diagnosis?
♦ Biomarkers for early and accurate differential
diagnosis of AD: the concept
♦ Biomarkers for early diagnosis of AD: results from an
Italian multicentre study w/ amyloid PET
Frisoni GB et al. Nat Rev Neurol 2010
-20 -15 -10 -5 0 5 10 15 20
Years after diagnosis of dementia
Asymptoma
tic phase
Mild Cognitive
Impairment
(MCI)
phase
Dementia
phase
% Abnormality
of biomarkers
Symptoms, biology and
biomarkers for Alzheimer’s disease
Cerebral Amyloid deposition
PET amyloid CSF Ab42
Early neurodegeneration
(synaptic dysfunction)
Connectivity in
fMRI
Cortical hypometabolism
on PET
Late neurodegeneration
(neuronal loss, atrophy) CSF Tau Hippocampal
athropy in MRI
Asymptomatic
phase
Sympto
matic
phase
Chronic or healing phase
Biomarkers in the clinical practice: Hepatitis B example
Summary
♦ Why early and accurate differential diagnosis?
♦ Biomarkers for early and accurate differential
diagnosis of AD: the concept
♦ Biomarkers for early diagnosis of AD: results from an
Italian multicentre study w/ amyloid PET
Clinical features in progressive and
stable MCI patients from BS, AMS,and STK
pMCI sMCI p
N 29 44
Age (years) 67.6±8.9 65.3±9.4 0.31
Gender (females) 18 (62%) 23 (52%) 0.41
Follow-up time (months) 23.3±16.3 31.8±16.5 0.033
Baseline MMSE 26.7±1.6 27.5±1.8 0.053
MMSE yearly change -4.6±5.4 0.1±0.8 <0.0001
ApoE ε4 genotype 15 (58%) 21 (51%) 0.61
Prestia, Scheltens, Nordberg, et al., Neurology 2013
Progression to dementia is more
frequent with increasing marker positivity
4%
100%
Prestia, Scheltens, Nordberg, et al., Neurology 2013
Independent confirmation with 97 ADNI MCIs
Shaffer et al., Radiology 2013;266:583-91
Independent confirmation in a multricentre
study with 1.697 MCI patients
Vo
s e
t a
l., B
rain
20
15
Bocchetta et al. for the Disease Markers Special Interest Group
of the European Alzheimer’s Disease Consortium. Alzheimers Dement 2014
Clinical vignette: answers
At least ONE abnormal amyloid +
ONE abnormal neuronal injury marker
At least ONE
abnormal
amyloid +
ONE
abnormal
neuronal
injury marker,
n = 36
INDIA-FBP
Incremental diagnostic value of
18F‐Florbetapir imaging in patients with
cognitive impairment
EARLY RESULTS
11C PIB
18F florbetapir Wong et al JNM 2010
18F flutemetamol Mathis et al., JNM 2007
18F florbetaben Barthel et al Lancet Neurol 2011
• Cyclotron required
• Half life 20’
• Production & injection must be
very close
AMYLOID LIGANDS
• Produced by Avid/Lilly®
• Approved by FDA and EMA
• Half life 110’
• Production & injection can be
as far as 400 km
• Produced by GE®
• Under evaluation by FDA and
EMA
• Same as above
• Produced by Piramal®
• Same as above
Imaging-pathological association
Cla
rk e
t al.,
JA
MA
2011;3
05:2
75
-83
Imaging-pathological association
Aim
Evaluate the incremental diagnostic value of 18F Florbetapir PET (FBP-PET) on top of
routine assessment for diagnosis of
cognitive impairment in a naturalistic
population of patients with cognitive
impairment
Methods
Patients: investigated for cognitive impairment in 21 memory
clinics (UVA) and with a diagnostic probability of AD between
15% and 85%.
Total group size: 246 patients, 27 healthy volunteers
Preliminary results on: 191 patients, 26 healthy volunteers
Physicians in charge formulated diagnosis and diagnostic
confidence before (15-85%) and after (0-100%) FBP-PET.
FBP-PET images were visually examined by 2 nuclear
physicians and reported as Amy pos or Amy neg. In case of
disagreement the images were evaluated by a third expert.
Results
Scan readouts agreement
• Rate of concordance of 215/246 (87.4%)
• Cohen’s Kappa = 0.74 (good agreement)
Results
Inconsistent amy results
AD: 39/132 amy neg (30%)
FTD: 14/35 amy+ (40%)
LBD: 3/4 amy+ (75%)
VD: 2/7 amy+ (29%)
HC: 4/15 amy+ (15%)
Increase of diagnostic confidence in
patients with no change of diagnosis
+10.7%, p<.05 +12.5%, p<.05
Change of diagnosis in
132 AD and 35 FTD before PET
Diagnosis
after PET
FBP-PET
Aβ+ Aβ–
Same (AD) 89 11+2*
FTD 1 8
VD 1 12
LBD 1 -
SMI 1 1
Depression - 5
Total 93 39
132 AD
*SNAP
Diagnosis
after PET
FBP-PET
Aβ– Aβ+
AD - 12
Same (FTD) 17 2
VD 3 -
PDD 1 -
Total 21 14
35 FTD
Conclusions
Based on preliminary results, 18F Florbetapir PET impacts
significantly on diagnosis and
improves diagnostic confidence
of dementia experts.
Alzheimer’s biomarkers in the clinic:
issues to be addressed
- Standard operational procedures
- Guidelines for biomarker use in the clinic
- Incremental diagnostic value
- Naturalistic studies on health outcomes
- Development of national plans to enhance
access to the biomarker-based diagnosis
Alessandro Padovani – SINDEM, Italian Neurological Society
Stefano Bastianello, Andrea Falini – Italian Association of Neuroradiology
Gaetano Bernardi, Giuseppe Castaldo – Italian Society of Laboratory Medicine
(Biochimica Clinica)
Daniela Perani, Giovanni Lucignani – Italian Association of Nuclear Medicine
Corinna Porteri – Study Group of Bioethics of the Italian Neurological Society
Marco Trabucchi – Italian Psychogeriatrics Association
HOW TO TRANSFER BIOMARKERS IN CLINICAL PRACTICE?
An Italian pathway for the transfer of biomarkers to clinical practice
Acknowledgements
Alessandro Padovani co-PI
Ugo P Guerra Nuclear Medic
Barbara Paghera Nuclear Medic
Boccardi Marina Study coordinator
Paghera Barbara Nuclear medicine physicians
Pizzocaro Claudio Nuclear medicine physicians
Festari Cristina Project management
Tarallo Anna Project management
Muscio Cristina Project management
Altomare Daniele Data processing
Pievani Michela Data processing
and the INDIA-FBP WORKING GROUP*.
*Full list of INDIA-FBP participants:
http://www.centroalzheimer.org/sito/contenuti/ip_lilly_publications/INDIA-FBP_WORKING_GROUP.pdf
Project link: http://www.centroalzheimer.org/sito/ip_lilly.php
Thank you for your attention