©2011 MFMER | slide-1 Alzheimer Disease: Update Neill R. Graff-Radford, MBBCh, FRCP Professor of...

©2011 MFMER | slide-1

Alzheimer Disease:Update

Neill R. Graff-Radford, MBBCh, FRCPProfessor of Neurology

Mayo College of Medicine


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


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


Knowing how but not knowing what


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


Topographic Distribution of AD Lesions

Arnold et al., Cerebral Cortex 1991


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


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


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


©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)




• Mayo Study of Aging and Diagnostic Criteria

• APP mutation

• DIAN biomarkers


• AV45 PET scan


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



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


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





• APP mutation

• DIAN biomarkers


• AV45 PET scan


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.


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.


BACE Inhibitors in Clinical Trials

• LY2886721 – Phase 2

• Merck has one as well but not in clinicaltrials.gov


Lancet Neurology 2010, 9:702-16





• APP mutation

• DIAN biomarkers


• AV45 PET scan


NEJM July 23, 2012


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





• APP mutation

• DIAN biomarkers

• Bapineuzumab results for ApoE4 patients

• AV45 PET scan


Lancet Neurol. 2010 Apr;9(4):363-72


News Release July 23, 2012

• In the 302 study ApoE4 +ve mild to moderate AD patients did not improve using bapineuzumab





• APP mutation

• DIAN biomarkers

• Bapineuzumab results for ApoE4 patients

• AV45 PET scan


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.


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


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)


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

©2011 MFMER | slide-1 Alzheimer Disease: Update Neill R. Graff-Radford, MBBCh, FRCP Professor of...

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