Il processo diagnostico dell Alzheimer dalla clinica al neuroimaging Giovanni B. Frisoni M.D.

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1 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

2 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

3 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

4 Why differential diagnosis? Frontotemporal Lobar Degeneration Diagnosis of FTLD advises against the use of cholinesterase inhibitors and memantine Dementia with Lewy Bodies Diagnosis of DLB strongly advises against the use of neuroleptics for their potentially devastating effects Vascular Dementia The efficacy of cholinesterase inhibitors and memantine in pure VD is not proven. Mendes 2007; Archiniegas 2013 Boxer 2013 Piggott 1998 Erkinjuntti 2002

5 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:

6 Rate of progression from mild cognitive impairment to Alzheimer's Disease (AD) in the donepezil-vit E trial No degenerative pathology Non AD degenerative dementias AD dementias Petersen RC et al. N Engl J Med 2005;352:

7 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

8 Symptoms, biology and biomarkers for Alzheimer s disease Cerebral Amyloid deposition PET amyloid % Abnormality of biomarkers CSF Ab42 Asymptoma tic phase Early neurodegeneration (synaptic dysfunction) Mild Cognitive Impairment (MCI) phase Dementia phase Connect ivity in fmri Cortical hypometabolism on PET Frisoni GB et al. Nat Rev Neurol 2010 Late neurodegeneration (neuronal loss, atrophy) Hippocampal CSF Tau athropy in MRI Years after diagnosis of dementia

9 Biomarkers in the clinical practice: Hepatitis B example Asymptomatic phase Sympto matic phase Chronic or healing phase

10 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

11 Clinical features in progressive and stable MCI patients from BS, AMS,and STK pmci smci p N Age (years) 67.6± ± Gender (females) 18 (62%) 23 (52%) 0.41 Follow-up time (months) 23.3± ± Baseline MMSE 26.7± ± MMSE yearly change -4.6± ±0.8 < ApoE ε4 genotype 15 (58%) 21 (51%) 0.61 Prestia, Scheltens, Nordberg, et al., Neurology 2013

12 Progression to dementia is more frequent with increasing marker positivity 100% 4% Prestia, Scheltens, Nordberg, et al., Neurology 2013

13 Independent confirmation with 97 ADNI MCIs Shaffer et al., Radiology 2013;266:583-91

14 Independent confirmation in a multricentre study with MCI patients Vos et al., Brain 2015

15 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 Bocchetta et al. for the Disease Markers Special Interest Group of the European Alzheimer s Disease Consortium. Alzheimers Dement 2014

16 INDIA-FBP Incremental diagnostic value of 18F Florbetapir imaging in patients with cognitive impairment EARLY RESULTS

17 AMYLOID LIGANDS 11C PIB 18F florbetapir Wong et al JNM F flutemetamol Mathis et al., JNM 2007 Cyclotron required Half life 20 Production & injection must be very close 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 18F florbetaben Barthel et al Lancet Neurol 2011 Produced by Piramal Same as above

18 Imaging-pathological association Clark et al., JAMA 2011;305:275-83

19 Imaging-pathological association

20 Aim Evaluate the incremental diagnostic value of 18 F Florbetapir PET (FBP-PET) on top of routine assessment for diagnosis of cognitive impairment in a naturalistic population of patients with cognitive impairment

21 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.

22 Results Scan readouts agreement Rate of concordance of 215/246 (87.4%) Cohen s Kappa = 0.74 (good agreement)

23 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%)

24 Increase of diagnostic confidence in patients with no change of diagnosis +10.7%, p< %, p<.05

25 Change of diagnosis in 132 AD and 35 FTD before PET 132 AD 35 FTD Diagnosis after PET Aβ+ FBP-PET Aβ Same (AD) * FTD 1 8 VD 1 12 LBD 1 - SMI 1 1 Depression - 5 Total Diagnosis after PET Aβ FBP-PET Aβ+ AD - 12 Same (FTD) 17 2 VD 3 - PDD 1 - Total *SNAP

26 Conclusions Based on preliminary results, 18 F Florbetapir PET impacts significantly on diagnosis and improves diagnostic confidence of dementia experts.

27 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

28 HOW TO TRANSFER BIOMARKERS IN CLINICAL PRACTICE? An Italian pathway for the transfer of biomarkers to clinical practice 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

29 Acknowledgements Alessandro Padovani Ugo P Guerra Barbara Paghera Boccardi Marina Paghera Barbara Pizzocaro Claudio Festari Cristina Tarallo Anna Muscio Cristina Altomare Daniele Pievani Michela co-pi Nuclear Medic Nuclear Medic Study coordinator Nuclear medicine physicians Nuclear medicine physicians Project management Project management Project management Data processing Data processing and the INDIA-FBP WORKING GROUP*. *Full list of INDIA-FBP participants: Project link:

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33 Thank you for your attention