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©2011 MFMER | slide-1
Alzheimer Disease:Update
Neill R. Graff-Radford, MBBCh, FRCPProfessor of Neurology
Mayo College of Medicine
©2011 MFMER | slide-2
Disclosures
• Dr Graff-Radford is part of multicenter treatment studies funded by Medivation, Allon, Janssen, Forrest
• He is chair of the DSMB for a Baxter study using IGIV
• He is on the Scientific Advisory Board of Codman
• He has funding from several NIH and State grants
• He is on the Editorial Board of the Neurologist and Alzheimer Research and Therapy journals
©2011 MFMER | slide-3
Case One
• In 2001 a 71 year old women complained of some memory difficulty and was diagnosed with Mild Cognitive Impairment but her MMSE was 29/30
• In 2004 her MMSE was 27/30 and she still met criteria for MCI
• In 2007 she declined and was diagnosed with Probable AD. MMSE 22/30
• In 2009 her MMSE was 16/30 but she played 2 recitals monthly lasting 40 minutes including 9 pieces
©2011 MFMER | slide-4
Knowing how but not knowing what
©2011 MFMER | slide-5
Why do AD patients know how but not what?
1. It is the anatomy
2. It is a fluke in this patient
3. It is easier to remember what makes you happy
4. Alzheimer patients have excellent remote memory
©2011 MFMER | slide-6
Topographic Distribution of AD Lesions
Arnold et al., Cerebral Cortex 1991
©2011 MFMER | slide-7
Alzheimer Disease Update
• New Diagnostic Criteria
• May Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE 4 patients
• AV45 PET scan
©2011 MFMER | slide-8
R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13
Normal Preclinical MCI Dementia
Clinical Disease Stage
Abnormal
Amyloid- accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/sMRI)
Tau-mediated neuronal injury (CSF)
Brain structure (volumnetric MRI)
Cognition
Clinical function
©2011 MFMER | slide-9
Staging Categories forPreclinical AD Research
NegativeNegativePositiveAsymptomaticcerebralamyloidosis
Stage 1
PositivePositivePositive
Amyloidosis +neuronal injury + subtlecognitive/behavioral decline
Stage 3
Evidence of Subtle
Cognitive Change
Markers of Neuronal
Injury (tau, FDG, sMRI
A(PET or CSF)DescriptionStage
NegativePositivePositive
Asymptomaticamyloidosis +“downstream” neuro-degeneration
Stage 2
R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13
©2011 MFMER | slide-10
©2011 MFMER | slide-11Rowe et.al. Neurobiol. of Aging 2010;3`:1275-83
60
50
40
30
20
10
030 40 50 60 70 80 90 100
Age (years)
Pre
vale
nce
(%
)
Prevalenceof PiB+ve PETin HC
Prevalence of plaquesin HC
Prevalenceof AD
~15 yrs
(Davies, 1988, n=110)(Braak, 1996, n=551)(Sugihara, 1995, n=123)
(Tobias, 2008)
©2011 MFMER | slide-12
Alzheimer Disease Update
• New Diagnostic Criteria
• Mayo Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE 4 patients
• AV45 PET scan
©2011 MFMER | slide-13
©2011 MFMER | slide-14
Staging Categories for Preclinical AD Research
PositivePositivePositive
Amyloidosis + neuronal injury + subtle cognitive/behavioral decline
Stage 3
NegativeNegativePositiveAsymptomatic cerebral amyloidosis
Stage 1
Evidence of Subtle
Cognitive Change
Markers of Neuronal
Injury (tau, FDG, sMRI)
A(PET or CSF)DescriptionStage
NegativePositivePositive
Asymptomiatic amyloidosis + “downstream” neurodegeneration
Stage 2
R.A. Sperling et al. Alzheimer’s & Dementia;(2011) 1-13
©2011 MFMER | slide-15
©2011 MFMER | slide-16
An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease
Annals of Neurologypages n/a-n/a, 9 APR 2012 DOI: 10.1002/ana.22628
©2011 MFMER | slide-17
New Diagnostic Alzheimer Disease Criteria (7 changes)
• AD path seen in normals, MCI and AD so ‘pathophysiological process = +ve A biomarkers (in CSF or with PET)
• Takes into account criteria for LBD, FTD and VD
• Includes structural change on MR or PET
• May not present with memory loss e.g. PCA, logopenic aphasia, FTD
• Includes known genes
• Includes persons below age 40
• Possible AD before included MCI today
Mckhann, Knopman and colleagues AD and Dementia 2011;7:263-6
©2011 MFMER | slide-18
Alzheimer Disease Update
• New Diagnostic Criteria
• May Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE 4 patients
• AV45 PET scan
©2011 MFMER | slide-19
Protective Gene
Nature Published on line July 11, 2012
T Jonsson et al. Nature 000, 1-4 (2012) doi:10.1038/nature11283
A673T reduces BACE1 cleavage of APP.
©2011 MFMER | slide-21
Findings in this study
• A coding mutation (A673T) in the APP gene protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease.
• This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro.
• The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease.
• Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.
©2011 MFMER | slide-22
BACE Inhibitors in Clinical Trials
• LY2886721 – Phase 2
• Merck has one as well but not in clinicaltrials.gov
©2011 MFMER | slide-23
Lancet Neurology 2010, 9:702-16
©2011 MFMER | slide-24
Alzheimer Disease Update
• New Diagnostic Criteria
• May Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE 4 patients
• AV45 PET scan
©2011 MFMER | slide-25
NEJM July 23, 2012
©2011 MFMER | slide-26
©2011 MFMER | slide-27
DIAN Study
• CSF A42 begins to decline 25 years before onset
• PIB PET 15 years before symptom onset
• Brain atrophy and increase CSF tau 15 years
• Hypometabolism on PET and anterograde memory 10 years
• Global cognitive decline (MMSE) 5 years
• Met dementia criteria 3 years before expected onset
©2011 MFMER | slide-28
Alzheimer Disease Update
• New Diagnostic Criteria
• May Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE4 patients
• AV45 PET scan
©2011 MFMER | slide-29
Lancet Neurol. 2010 Apr;9(4):363-72
©2011 MFMER | slide-30
News Release July 23, 2012
• In the 302 study ApoE4 +ve mild to moderate AD patients did not improve using bapineuzumab
©2011 MFMER | slide-31
Alzheimer Disease Update
• New Diagnostic Criteria
• May Study of Aging and Diagnostic Criteria
• APP mutation
• DIAN biomarkers
• Bapineuzumab results for ApoE4 patients
• AV45 PET scan
©2011 MFMER | slide-32
Patient information
• Amyvid is a radioactive diagnostic agent for PET imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline.
• The scan is interpreted as either positive or negative
• A positive Amyvid PET scan indicates moderate to frequent amyloid neuritic plaques
• The cost of performing and interpreting an Amyvid PET scan is approximately $5000.
©2011 MFMER | slide-33
Indications
• In a patient with a dementia syndrome or mild cognitive impairment when greater certainty of amyloid deposition in the brain, and hence probable Alzheimer’s disease, would:
• help establish a diagnosis
• better determine treatment/management and prognosis
• defend discontinuation of work and defend documentation of full and permanent disability
©2011 MFMER | slide-34
Contraindications
• Any person who:
• is cognitively normal
• will not have their treatment or prognosis altered with the increased confidence of a probable AD diagnosis (positive result) or a non-AD diagnosis (negative result)
• is not mentally prepared to handle a positive or negative result
• has limited financial means to pay for the scan (at least until third party payers and Medicare provides preauthorization)
©2011 MFMER | slide-35
In Cognitively Normal Persons
• Physicians at Mayo Clinic strongly discourage cognitively normal subjects from Amyvid PET scan.
• At present, few Mayo Clinic physicians will agree to order an Amyvid PET for cognitively normal persons.
• A +ve scan means that a person has amyloid deposition in the brain.
• It does NOT mean a person currently has Alzheimer’s disease, or ever will develop Alzheimer’s disease
• It may impact a person’s psychological well-being and ability to secure some forms of insurance
• A –ve scan means that a person has no significant amyloid deposition but does NOT mean that a person will never develop Alzheimer’s disease
• It does not exclude the possibility of developing a non-Alzheimer disorder such as Lewy body disease or frontotemporal lobar degeneration