Alzheimer Centennial 1907-2007 - PowerPoint PPT Presentation

Loading...

PPT – Alzheimer Centennial 1907-2007 PowerPoint presentation | free to download - id: 3c79d8-NGE5M



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Alzheimer Centennial 1907-2007

Description:

MCI: A Risk Management Model Charles Yanofsky, MD Susquehanna Health Alzheimer Centennial 1907-2007 Principles of Risk factor model Identify Risks: Retrospectoscope ... – PowerPoint PPT presentation

Number of Views:72
Avg rating:3.0/5.0
Slides: 51
Provided by: susqneuro
Learn more at: http://www.susqneuro.com
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Alzheimer Centennial 1907-2007


1
MCI A Risk Management Model
Charles Yanofsky, MD Susquehanna Health
Alzheimer Centennial 1907-2007
2
MCI
Delirium
Dementia
3
Principles of Risk factor model
  • Identify Risks Retrospectoscope
  • Synergistic risk factors
  • Identify persons of highest risk
  • Prospective clinical trials
  • Reduce disease occurrence

We are here
Goal Recognize (high risk pt e.g. MCI), then
Prevent
4
MCI Risk Factor Model
  • Non-Modifiable
  • Age
  • Female
  • Apo E
  • Heredity
  • Nun study Young age
  • Modifiable
  • Atherosclerotic
  • diabetes
  • Inflammation
  • Hormonal
  • Homocysteine
  • Head trauma
  • Education
  • Inertia
  • Physical
  • Mental

5
Atherosclerotic Risks, Diabetes
Other Genetic Syndromes
APO E4
MILD COGNITIVE IMPAIRMENT
Advanced Age
Low Education
Delirium
Alzheimer (or other) Dementia
Where Can we intervene??
6
Neurologist Savior of the brain.
7
MCINeuro-claudication
  • Limping brain
  • Episodic decompensation
  • Family noting problems
  • delirium
  • Then permanent brain failure

8
MCI
  • 6-25 progress to Alzheimers disease per year.
  • Recent Memory impairment
  • Word finding impairment
  • Early cognitive slippage
  • Memory or language problem not yet evidence in
    2nd cognitive area
  • Autopsy similar findings but lower numbers of
    Alzheimer neuropath changes

9
(No Transcript)
10
MCI
  • Prevalence ranges from 12-15 among those over
    65
  • amnestic v. non-amnestic
  • 26-30 on MMS
  • Progression to AD10-15 per year v. population
    incidence of 1-2
  • Increased risk for delirium

11
Amnestic v. non-amnestic MCI
  • Amnestic
  • Alzheimer Disease
  • Depression
  • Vascular dementia
  • Non-Amnestic
  • Picks fronto-temporal dementia
  • Ravel Bolero
  • Primary progressive aphasia
  • Diffuse Lewy Body disease
  • VaD
  • NPH
  • Cortico-basal degen
  • Alien hand
  • Subcortical e.g. MS

12
Dementia
  • Multi-modal (DSM-IV)
  • Amnesia
  • Aphasia
  • Agnosia
  • Apraxia
  • Query as to tasks
  • Clock drawing, dressing, directions, hobbies,
    occupations, driving, checkbook, interests,
    ADLs, reliability

13
4.5 million Americans
14
MCI Problem
  • We will diagnose it with certainty - before we
    have definitive therapy
  • Dx based on
  • Clinical suspicion
  • MMS, Clock drawing
  • Exclusion of other diagnosis

15
Neurologic Diseases biochemical model esp
protein deposition
  • Alzheimer disease Aß42
  • Amyloid Angiopathy Aß42
  • Huntington Disease Huntingtin
  • Trinucleotide repeat diseases
  • Prion Disease PrP sc
  • Tauopathies Picks, FT dementia, PSP,
    corticobasal Degen
  • Parkinson Disease, Lewy body Dementia (alpha
    synuclein)
  • Spino-cerebellar Degenerations Ataxins
  • ALS Neurofilament, SOD
  • Macular Degeneration A2E (drusen)
  • Tay-Sachs Family of diseases e.g.
    sphingolipidoses
  • So Definitive therapy awaits method to decrease
    neurotoxin accumulation.

16
Evidence that Ab42 causes Alzheimer disease
  • Widespread accumulation in A. brains
  • Genetically engineered mice that increase Ab42
    cause dementia
  • Mutations in g-secretase cause disease
  • Downs pts who have increase APP yield disease
  • Mutations in genes encoding for APP and gamma
    secretin (Presenilin 1) that promote beta amyloid
    production or Ab42 cause familial A.s disease
  • APO e4 which increases Ab accumulation trebles
    the risk for late onset disease.
  • PET scans using amyloid binding ligands
    demonstrate amyloid deposition prior to memory
    loss in pts who develop As disease
  • Ab42 which aggregates more rapidly than other Ab
    subspecies is predominant in amyloid plaques.

17
  • Alpha and Beta secretase alternate pathways.

18
End Run Against Alzheimer Disease
  • Shunt to a secretase
  • Inhibit b and g secretase
  • Immune removal vaccine
  • Decrease deposition e.g. statin
  • Inhibit inflammatory response flubiprofen
  • Inhibit tau or PHF formation

19
(No Transcript)
20
Plaques and tangles
21
Cascade of eventsIntervening mechanisms still
defy explanation
  • Extracellular Ab42 accumulation
  • Microglia ? AChE, BChE
  • Amyloid Plaque
  • Binding to membrane a7 nicotinic receptor
  • Tau misfolding, PHF tangle accumulation
  • Phosphorylation of actin protein remodeling
    cytoskeleton
  • Destruction of Synapses and cells
  • Atrophy
  • Dementia

22
Will MCI progress? The answer
  • APO-E status
  • Hippocampal atrophy
  • ?CSF tau and ab levels, isoprostanes
  • FDG PET temporoparietal hypometabolism
  • ? Positive amyloid imaging on PET scan

23
Hippocampal Atrophy
24
Amyloid imaging
25
Functional MRI in patients at risk to have
Alzheimer Disease. E4 positive persons Activate
wider areas of brain for same verbal task.
26
Concept of Cerebral Reserve
Normal PET scan
Pet in Advanced AD loss of Orange yellow green
(metabolic Activity)
Brain is more likely to fail if partially failing
already
27
Xu, G. et al. Neurology 2007691650-1656
28
APO E4
  • One copy trebles the risk, 2 copies 15 X risk of
    developing AD
  • E4 less effective than E2, E3 suppressing brain
    inflammation and microglia
  • E4 Pts have increased inflammatory response after
    cardiac bypass
  • E4 is associated not only with Alzheimer disease
    but poor response to injury e.g. post ICU
    deficits
  • Apolipoprotein E 4 Allele Increases the Risk of
    Early Postoperative Delirium in Older Patients
    Undergoing Noncardiac Surgery. Clinical
    Investigations
  • Anesthesiology. 107(3)406-411, September
    2007.Leung, Jacqueline M.

29
(No Transcript)
30
MCI and Donepezil
  • NEJM Petersen et al 2005
  • aMCI 769 subjects multinational
  • Donepezil decreased the risk of developing AD for
    first 12 mos.
  • Donepezil decreased transition to AD for 24 mos
    in E4 positive subjects.
  • Vitamin E at 2000 units NO EFFECT
  • Of 214 conversions, 212 had AD.

31
(No Transcript)
32
Rivastigmine in Lewy Body Dementia
  • McKeith et al. Lancet 9247 2031-36 (2000)
  • Behavior and cognitive assessment improved on
    Exelon. Reversed when drug was D/C
  • FDA approved for Lewy Body Dementia
  • New Patch available

33
Galantamine (Razadyne)
  • Common snowdrop (Galanthus nivalis)
  • Binds AChE
  • Modulator of Nicotinic Receptors
  • ?Enhanced Sexual Fxn
  • Mythology
  • Iliad, Circe, Atropine, Jimsonweed

34
Statins and Alzheimers
  • 2 small Studies in Arch Neurology Seemed to have
    positive effect
  • Some epidemiologic studies find lowering of AD
    risk in patients taking statins
  • NIH study CLASP cholest lowering agent to slow
    progression underway simvastatin
  • Pfizer study atorvastatin donepezil underway

35
Estrogen
  • 2/3 of Alzheimer Patients are women
  • Onset After Menopause
  • May increase cholinergic transmission
  • Neurotrophic effects
  • Anti-amyloidogenic properties
  • Association with Neurotrophins
  • Regulates synapse formation in hippocampus

36
Estrogen
  • 3 studies in Neurology 200054 show no effect in
    women already Diagnosed e.g. premarin
  • Baltimore Long. Study After adjusting for
    education, the relative risk for AD in ERT users
    as compared with nonusers was 0.46
  • Analysis of data of WHIMS implies pre-menopausal
    estrogen use halves Alz risk. JAMA 298 No. 2,
    July 11, 2007
  • Tang MX et al. Effect of estrogen during
    menopause on risk and age at onset of Alzheimer's
    disease. Lancet 1996348429-432
  • Prospective treatment trials PREPARE

37
Womens Health Initiative Memory Study (WHIMS)
  • May 2003 Women's Health Initiative Memory Study
    (WHIMS reported of health risks for women over
    age 65 using a type of combined estrogen plus
    progestin known as Prempro. JAMA. 2003 May
    28289(20)2651-62
  • WHIMS the number of women over age 65 who began
    having symptoms of dementia while using Prempro
    was twice as high as those not taking any
    hormones.

38
Exercise and AD
  • Swedish study 2005 decr incidence by 50 Oct 2005
    Lancet Neurology
  • Asian Study Similar
  • Increase brain volume
  • Observational not prospective
  • Cause of Effect

39
cognitive activity
  • Engagement, chess, theatre, friends etc decrease
    occurrence of MCI, dementia RRapprox .5
  • 900 persons prospective clinical, pathological
    study at Rush, Chicago
  • But pathology in engaged and non-engaged brains
    about the same.
  • Education, Brain activity engagement allows you
    to get around or compensate for brain pathology
    longer.
  • NEUROLOGY 2007691911-1920, ALSO NEUROLOGY
    200666821-827 Many others

40
NSAIDs
  • Prospective, population-based cohort study of
    6989 subjects 55 years of age or older who were
    free of dementia at base line.
  • Relative risk of Alzheimer's disease was 0.95 in
    subjects with short-term use of NSAIDs
  • RR 0.83 with intermediate-term use
  • RR 0.20 with long-term use.
  • Risk did not vary according to age
  • Use of NSAIDs was not associated with a reduction
    in the risk of vascular dementia.
  • Bas A. in 't Veld, N Engl J Med 2001
    3451515-1521, Nov 22, 2001

41
NSAIDs Baltimore Longitudinal Study of Aging
  • Relative risk of Alzheimer's disease of 0.50
    among regular users of NSAIDs, as compared with
    nonusers
  • Stewart et al Neurology 199748626-632

42
NSAIDs and AD
  • NEJM 3451515-1521 (2001)
  • NSAIDs decr risk with strength of effect based
    on length of use. Longterm use (gt24 mos) RR0.20
  • ADAPT 2500 pts Celecoxib, Naproxen to prevent
    AD. NIH funded stopped early, no findings.

43
NSAID prospective studies
  • Alsen et al JAMA 2892819-2826, 2003 rofecoxib or
    naproxen v. placebo No effect.
  • Reines et al Neurology 6266-71, 2004 Rofecoxib.
    No effect, Thal et al 2005 R. increased
    occurrence over placebo
  • R-Flurbiprofen (Ansaid is s-enantiomere) at high
    dosage may modulate gamma secretase. Being
    studied.
  • Phase II clinical trial positive. Phase III sched
    for completion in 2/2008. R-flurbi is a non-NSAID

44
Homocysteine
  • Eight years
  • RR 1.4 for each increase of 1 SD in the
    log-transformed homocysteine value either at base
    line or eight years earlier
  • RR of Alzheimer's disease was 1.8 per increase of
    1 SD at base line
  • RR1.6 per increase of 1 SD eight years before
    base line.
  • Plasma homocysteine level greater than 14 µmol
    per liter doubled the risk of Alzheimer's
    disease.
  • Seshadri et al. N Engl J Med 346476-483 February
    14, 2002

45
Homocysteine
  • Does this mean that lowering H. levels will
    prevent As Disease?
  • No one knows

46
Homocysteine
  • 50 Mg pyridoxine
  • Up to 4 mg. of Folate
  • 500 mcg of B12
  • Foltx 1mg B12, 2.5 mg folate, 25 mg pyridoxine
  • Results disappointing for atherosclerosis
    endpoints.

47
Evaluation
  • Thorough Hx/Pex
  • Mental Function Evaluation
  • CBC, Chems, RPR, LFTs,Thyroid, B12
  • HIV testing in selected cases
  • Imaging (CT or MRI)
  • Advanced imaging
  • Hippocampus, fMRI, Ab Pittsburg, PET
  • Neuropsych testing if dx is uncertain
  • LP in doubtful cases
  • Tau and amyloid beta
  • Apolipoprotein genotype??

48
Once MCI diagnosed
  • Foltx
  • AChE
  • Statin
  • Atherosclerotic/diabetic risk factors
  • Physical exercise
  • Mental Exercise

49
Strategies forAvoiding Decrepitude
  • Avoid Atherosclerotic Anathemas use statins
  • Aerobic Exercise
  • Mental Challenge Change, Striving, education
  • Helpful Chemicals? Statins, ASA, NSAIDs,
    Folate,B12, Omega-3s???
  • Avoid Injury Trauma, cigs, gluttony
  • No Surprise General Physical and Mental Health
  • Purpose driven life

50
(No Transcript)
About PowerShow.com