ROLE OF AMYLOID IMAGING IN THE REVISED CRITERIA FOR THE DIAGNOSIS OF ALZHEIMER DISEASE

1. ROLE OF AMYLOID IMAGING IN THE REVISED CRITERIA FOR THE DIAGNOSIS OF ALZHEIMER DISEASE Serge Gauthier, MD, FRCPC McGill Center for Studies in Aging Douglas Mental Health University Institute, Montreal, Canada

2. DISCLOSURES Member of advisory board, DSM, speaker or investigator with Affiris, Astellas, Astra-Zeneca, Bayer, Baxter, BMS, Elan, Epix, ExonHit, GE Health Care, Janssen-Cilag, Lundbeck, Lilly, Merz, Myriad, Neurochem, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, Servier, Sonexa, UBC, Wyeth

3. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

4. PROGRESSION OF SYMPTOMS IN ALZHEIMER’S DISEASE Lovestone & Gauthier 2000

6. AD Progression CSF Aβ42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL) Abnormal FDG-PET MRI hippocampal volume CSF Aβ42 Cognitive performance Amyloid imaging Function (ADL) CSF Tau Normal Time Presymptomatic eMCI LMCI Dementia Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

7. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

8. DIAGNOSTIC CRITERIA FOR PROBABLE AD IN 1984 Dementia established clinically, eg deficit in memory and one or more areas or cognition, interfering with daily life, progressing gradually No disturbance of consciousness Onset between 40 and 90 (below 65: early onset) Absence of other brain or systemic disease that could account for the dementia

9. DIAGNOSTIC CRITERIA FOR PROBABLE AD IN 2011 Dementia established clinically, eg deficit in two or more areas or cognition, interfering with daily life, progressing gradually No disturbance of consciousness Any age Absence of other brain or systemic disease that could account for the dementia Optional evidence of AD pathophysiology using biomarkers

10. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

11. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

12. SPINAL FLUID (CSF) IN AD Total tau in neuronal axons Phosphorylated tau in tangles A1-42 in senile plaques

13. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

14. PIB -ve

15. PIB +ve

16. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

17. SPINAL FLUID (CSF) IN AD Total tau in neuronal axons Phosphorylated tau in tangles A1-42 in senile plaques

18. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

19. MRI IN AD 0 1 2 Rated area 3 4

20. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

21. [18F]FDG normal vs AD

22. BIOMARKERS IN AD • Biomarkers of Aß deposition * spinal fluid Aß levels (low) * PET amyloid imaging (high) • Biomarkers of neuronal injury * spinal fluid tau levels (high) * MRI looking at hippocampus, temporal lobe or whole brain (smaller) * FDG-PET (areas of reduced metabolism) * SPECT (areas of reduced blood flow)

23. SPECT scan of normal control vs AD Normal Control Alzheimer’s Disease Sandra E. Black-S&W-U of T

24. AD Progression CSF Aβ42 Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL) Abnormal FDG-PET MRI hippocampal volume CSF Aβ42 Cognitive performance Amyloid imaging Function (ADL) CSF Tau Normal Time Presymptomatic eMCI LMCI Dementia Aisen PS, Petersen RC, Donohue MC, et al. Alzheimers Dement. 2010;6:239-246.

25. DIAGNOSTIC CRITERIA FOR PROBABLE AD USING BIOMARKERS(Modified from McKhann et al, 2011) Aß Neuronal injury • Probable AD with++ high likelihood • Probable AD with + or untested untested or + intermediate likelihood • Probable AD dementia untested or conflicting results • Possible AD dementia + + (atypical clinical presentation) * Unlikely AD dementia - -

26. PERSON WITH EARLY ONSET DEMENTIA(from Kadir et al, 2011) • 53 year old woman practicing nursing • Two year history of cognitive problems at home and at work, confirmed by relatives • No family history of AD; ApoE 4/4 carrier • MMSE 27 down to 13 over five years

27. Longitudinal changes in cerebral glucose metabolism with progression of AD 27/30 21/30 13/30 Kadir, Marutle et al Brain 2010.

28. Kadir, Marutle et al Brain 2010

29. New Amyloid-Binding PET Tracers • 11C-labeled PiB was the 1st PET ligand to bind amyloid in living patients. It has a short half-life (20 min) so is difficult to use • Ligands under study (florbetaben, florbetapir and flumetamol) are labeled with 18F and provide a wider window for scanning.

30. Status of new PET tracers • One product (florbetapir) has been submitted for approval in the US • An FDA advisory committee meeting (Jan 20, 2011) showed interest in moving forward with the approval of this compound for PET imaging of β-amyloid but raised issues to be resolved before FDA approval

31. Amyloid deposition Bielschowsky F-19 Florbetaben Neuritic/ cored Non-neuritic/ Diffuse vascular Florbetaben detects all types of β-amyloid deposits in the brain • Florbetaben binds to all aggregated forms of β-amyloid

32. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

33. PATTERNS OF SYMPTOMS IN TYPICAL AD Lovestone & Gauthier 2000

34. MCI AMNESTIC TYPE * Memory complaint, preferably confirmed by an informant * Memory impairment relative to age- and education-matched normal subjects • Relatively normal general cognitive function • Largely intact activities of daily living • Not demented

35. PERSON WITH MCI • 62 year old man practicing law • Came alone complaining of difficulties at work (remembering jurisprudence and preparing his speeches for the court) • Wife reached on the phone says he has no problems at home • MMSE 30, MoCA 26, Boston Naming 13/15

36. MoCA ►One-page ► 30-point scale ► 10 minutes to administer www.mocatest.org

37. DIAGNOSTIC CRITERIA FOR MCI DUE TO AD USING BIOMARKERS(Modified from Albert et al, 2011) Aß Neuronal injury • MCI due to AD + + high likelihood • MCI due to AD + untested intermediate likelihood untested + • MCI possibly due to AD untested or conflicting • MCI unlikely due to AD - -

38. PERSON WITH MCI • Told he has MCI likely due to AD -> early retirement from law practice and chose to start a cholinesterase inhibitor • Interested in studies to delay progression towards dementia

39. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

40. PERSON CONCERNED ABOUT RISK OF AD • 55 year old woman consulting because she took care of her mother, dying at 85 with AD • No cognitive symptoms • MMSE 30, MoCA 30

41. DIAGNOSTIC CRITERIA FOR PRECLINICAL AD USING BIOMARKERS(Modified from Sperling et al, 2011) Aß Neuronal Symptoms injury • Asymptomatic + - - cerebral amyloidosis (ACA) • ACA + evidence of neuronal + + - injury (NI) • ACA + NI + subtle cognitive + + + decline

42. PERSON CONCERNED ABOUT RISK OF AD • Told he has a higher risk of developing AD in later life, as she suspected from her family history. • No specific test results given or put in medical file. • Interested in studies to delay progression towards MCI and Dementia

43. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

44. USE OF AMYLOID SCAN IN CLINICAL TRIALS FOR AD • Help to confirm the diagnosis of AD at any stage • Proof of concept of the amyloid-lowering effects of medications

45. With the Advent of Disease Modifiers Early Detection of AD Becomes Even More Important Eisai GSI GSK/Affiris AB Antibody Hoffmann-LaRoche AB Active Vaccination Pfizer AB GSK AB Gamma Secretase Inhibitor Merck vac Other mechanisms not related to Aβ Roche AB Astellas/Comentis ßSI BMS GSI Elan Aß-aggreg inhib. Pfizer RAGE Wyeth GSI Elan/Wyeth vac Novartis vac Allon Peptide Prana MPAC Lilly AB Pfizer / Medivation Ahist TauRx MTC Baxter IVIg Lilly GSI Elan/Wyeth AB 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Adapted from E. Siemers ICAD 2008

46. PIB PET SCAN IN AD BEFORE AND AFTER IMMUNOTHERAPY

47. OUTLINE • Natural history of AD • NIA-AA revised diagnostic criteria for dementia caused by AD • NIA-AA criteria for MCI due to AD • NIA-AA criteria for pre-clinical AD • Use of biomarkers in therapeutic studies • Issues for application in clinical practice

48. WHY AN EARLIER DIAGNOSIS OF AD? • Pragmatic need of individual patients for a medical diagnosis (early retirement where appropriate) • Relief from uncertainty about nature of symptoms • Allow for better planning for financial affairs, for medical care, for participation in research • Break current deadlock on disease modification

49. Unresolved issues with very early diagnosis of AD • Risk of false positive diagnosis (need to follow-up longitudinally) • Risk of catastrophic reaction • No proven long-term treatments • Additional costs for tests • Can this be done in primary care practice?

50. CONCLUSIONS • The revised diagnostic criteria for AD will facilitate research on new treatments • Biomarkers are an essential component of the diagnosis of AD in very early stages • Ethical considerations are important for the person undergoing assessment and for society as a whole