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Alzheimer Centennial 1907-2007 MCI: A Risk Management Model Charles Yanofsky, MD Susquehanna Health.

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Presentation on theme: "Alzheimer Centennial 1907-2007 MCI: A Risk Management Model Charles Yanofsky, MD Susquehanna Health."— Presentation transcript:

1 Alzheimer Centennial 1907-2007 MCI: A Risk Management Model Charles Yanofsky, MD Susquehanna Health

2 MCI Delirium Dementia

3 Principles of Risk factor model Identify Risks: Retrospectoscope Identify Risks: Retrospectoscope Synergistic risk factors Synergistic risk factors Identify persons of highest risk Identify persons of highest risk Prospective clinical trials Prospective clinical trials Reduce disease occurrence Reduce disease occurrence We are here Goal: Recognize (high risk pt e.g. MCI), then Prevent

4 MCI: Risk Factor Model Non-Modifiable Non-Modifiable AgeAge FemaleFemale Apo EApo E HeredityHeredity Nun study: Young ageNun study: Young age Modifiable Modifiable Atherosclerotic diabetes Inflammation Hormonal Homocysteine Head trauma Education Inertia Physical Mental

5 MILD COGNITIVE IMPAIRMENT Alzheimer (or other) Dementia APO E4 Other Genetic Syndromes Advanced Age Low Education Delirium Atherosclerotic Risks, Diabetes Where Can we intervene??

6 Neurologist: Savior of the brain.

7 MCI=Neuro-claudication Limping brain Limping brain Episodic decompensation Episodic decompensation Family noting problemsFamily noting problems deliriumdelirium Then: permanent brain failure Then: permanent brain failure

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

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10 MCI Prevalence ranges from 12%-15% among those over 65 Prevalence ranges from 12%-15% among those over 65 “amnestic” v. “non-amnestic” “amnestic” v. “non-amnestic” 26-30 on MMS 26-30 on MMS Progression to AD=10-15% per year v. population incidence of 1-2% Progression to AD=10-15% per year v. population incidence of 1-2% Increased risk for delirium Increased risk for delirium

11 Amnestic v. non-amnestic MCI Amnestic Amnestic Alzheimer DiseaseAlzheimer Disease DepressionDepression Vascular dementiaVascular dementia Non-Amnestic Non-Amnestic Pick’s 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) Multi-modal (DSM-IV) AmnesiaAmnesia AphasiaAphasia AgnosiaAgnosia ApraxiaApraxia Query as to tasks Query as to tasks Clock drawing, dressing, directions, hobbies, occupations, driving, checkbook, interests, ADL’s, reliabilityClock drawing, dressing, directions, hobbies, occupations, driving, checkbook, interests, ADL’s, reliability

13 4.5 million Americans

14 MCI Problem We will diagnose it with certainty - before we have definitive therapy We will diagnose it with certainty - before we have definitive therapy Dx based on: Dx based on: Clinical suspicionClinical suspicion MMS, Clock drawingMMS, Clock drawing Exclusion of other diagnosisExclusion of other diagnosis

15 Neurologic Diseases: biochemical model esp protein deposition Alzheimer disease: Aβ42 Alzheimer disease: Aβ42 Amyloid Angiopathy: Aβ42 Amyloid Angiopathy: Aβ42 Huntington Disease: Huntingtin Huntington Disease: Huntingtin Trinucleotide repeat diseases Trinucleotide repeat diseases Prion Disease: PrP sc Prion Disease: PrP sc “Tauopathies: Pick’s, FT dementia, PSP, corticobasal Degen “Tauopathies: Pick’s, FT dementia, PSP, corticobasal Degen Parkinson Disease, Lewy body Dementia (alpha synuclein) Parkinson Disease, Lewy body Dementia (alpha synuclein) Spino-cerebellar Degenerations: Ataxins Spino-cerebellar Degenerations: Ataxins ALS: Neurofilament, SOD ALS: Neurofilament, SOD Macular Degeneration: A2E (drusen) Macular Degeneration: A2E (drusen) Tay-Sachs Family of diseases e.g. sphingolipidoses Tay-Sachs Family of diseases e.g. sphingolipidoses So Definitive therapy awaits method to decrease neurotoxin accumulation.

16 Evidence that  42 causes Alzheimer disease Widespread accumulation in A. brains Widespread accumulation in A. brains Genetically engineered mice that increase 42 cause dementia Genetically engineered mice that increase 42 cause dementia Mutations in secretase cause disease Mutations in secretase cause disease Down’s pts who have increase APP yield disease Down’s pts who have increase APP yield disease Mutations in genes encoding for APP and gamma secretin (Presenilin 1) that promote beta amyloid production or A42 cause familial A.’s disease Mutations in genes encoding for APP and gamma secretin (Presenilin 1) that promote beta amyloid production or A42 cause familial A.’s disease APO 4 which increases A accumulation trebles the risk for late onset disease. APO 4 which increases A 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 A’s disease PET scans using amyloid binding ligands demonstrate amyloid deposition prior to memory loss in pts who develop A’s disease A42 which aggregates more rapidly than other A subspecies is predominant in amyloid plaques. A42 which aggregates more rapidly than other A subspecies is predominant in amyloid plaques.

17 Alpha and Beta secretase alternate pathways. Alpha and Beta secretase alternate pathways.

18 End Run Against Alzheimer Disease Shunt to  secretase Shunt to  secretase Inhibit  and  secretase Inhibit  and  secretase Immune removal – vaccine Immune removal – vaccine Decrease deposition e.g. statin Decrease deposition e.g. statin Inhibit inflammatory response – flubiprofen Inhibit inflammatory response – flubiprofen Inhibit tau or PHF formation Inhibit tau or PHF formation

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20 Plaques and tangles

21 Cascade of events Intervening mechanisms still defy explanation Extracellular A42 accumulation Extracellular A42 accumulation Microglia: ? AChE, BChE Microglia: ? AChE, BChE Amyloid Plaque Amyloid Plaque Binding to membrane 7 nicotinic receptor Binding to membrane 7 nicotinic receptor Tau misfolding, PHF tangle accumulation Tau misfolding, PHF tangle accumulation Phosphorylation of actin protein remodeling cytoskeleton Phosphorylation of actin protein remodeling cytoskeleton Destruction of Synapses and cells Destruction of Synapses and cells Atrophy Atrophy Dementia Dementia

22 Will MCI progress? The answer:: APO-E status APO-E status Hippocampal atrophy Hippocampal atrophy ?CSF tau and a levels, isoprostanes ?CSF tau and a levels, isoprostanes FDG PET temporoparietal hypometabolism FDG PET temporoparietal hypometabolism ? Positive amyloid imaging on PET scan ? 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 Normal PET scan Pet in Advanced AD loss of Orange yellow green (metabolic Activity) Concept of “Cerebral Reserve” Brain is more likely to fail if partially failing already

27 Xu, G. et al. Neurology 2007;69:1650-1656

28 APO E4 One copy trebles the risk, 2 copies 15 X risk of developing AD 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 less effective than E2, E3 suppressing brain inflammation and microglia E4 Pts have increased inflammatory response after cardiac bypass 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 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 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. Anesthesiology. 107(3):406-411, September 2007. Leung, Jacqueline M.

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

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32 Rivastigmine in Lewy Body Dementia McKeith et al. Lancet 9247: 2031-36 (2000) McKeith et al. Lancet 9247: 2031-36 (2000)9247 Behavior and cognitive assessment improved on Exelon. Reversed when drug was D/C Behavior and cognitive assessment improved on Exelon. Reversed when drug was D/C FDA approved for Lewy Body Dementia FDA approved for Lewy Body Dementia New Patch available New Patch available

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

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

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

36 Estrogen 3 studies in Neurology 2000;54 show no effect in women already Diagnosed e.g. premarin 3 studies in Neurology 2000;54 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” 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 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 1996;348:429-432 Tang MX et al. Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429-432 Prospective treatment trials: PREPARE Prospective treatment trials: PREPARE

37 Women’s 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 28;289(20):2651-62 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 28;289(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. 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 Swedish study 2005 decr incidence by 50% Oct 2005 Lancet Neurology Asian Study: Similar Asian Study: Similar Increase brain volume Increase brain volume Observational not prospective Observational not prospective Cause of Effect Cause of Effect

39 “cognitive activity” Engagement, chess, theatre, friends etc decrease occurrence of MCI, dementia RR=approx.5 Engagement, chess, theatre, friends etc decrease occurrence of MCI, dementia RR=approx.5 900 persons prospective clinical, pathological study at Rush, Chicago 900 persons prospective clinical, pathological study at Rush, Chicago But pathology in engaged and non- engaged brains about the same. 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. Education, Brain activity engagement allows you to “get around” or compensate for brain pathology longer. NEUROLOGY 2007;69:1911-1920, ALSO NEUROLOGY 2006;66:821-827 Many others NEUROLOGY 2007;69:1911-1920, ALSO NEUROLOGY 2006;66:821-827 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. 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 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= 0.83 with intermediate-term use RR= 0.20 with long-term use. RR= 0.20 with long-term use. Risk did not vary according to age Risk did not vary according to age Use of NSAIDs was not associated with a reduction in the risk of vascular dementia. 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; 345:1515-1521, Nov 22, 2001Bas A. in 't Veld, N Engl J Med 2001; 345:1515-1521, Nov 22, 2001

41 NSAID’s:: 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 1997;48:626-632

42 NSAID’s and AD NEJM 345:1515-1521 (2001) NEJM 345:1515-1521 (2001) NSAID’s decr risk with strength of effect based on length of use. Longterm use (>24 mos) RR=0.20NSAID’s decr risk with strength of effect based on length of use. Longterm use (>24 mos) RR=0.20 ADAPT: 2500 pts Celecoxib, Naproxen to prevent AD. NIH funded stopped early, no findings. ADAPT: 2500 pts Celecoxib, Naproxen to prevent AD. NIH funded stopped early, no findings.

43 NSAID prospective studies Alsen et al JAMA 289:2819-2826, 2003 rofecoxib or naproxen v. placebo: No effect. Alsen et al JAMA 289:2819-2826, 2003 rofecoxib or naproxen v. placebo: No effect. Reines et al Neurology 62:66-71, 2004 Rofecoxib. No effect, Thal et al 2005 R. increased occurrence over placebo Reines et al Neurology 62:66-71, 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. 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-NSAIDPhase II clinical trial positive. Phase III sched for completion in 2/2008. R-flurbi is a non-NSAID

44 Homocysteine Eight years 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= 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 RR of Alzheimer's disease was 1.8 per increase of 1 SD at base line RR=1.6 per increase of 1 SD eight years before base line. RR=1.6 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. Plasma homocysteine level greater than 14 µmol per liter doubled the risk of Alzheimer's disease. Seshadri et al. N Engl J Med 346:476-483 February 14, 2002Seshadri et al. N Engl J Med 346:476-483 February 14, 2002

45 Homocysteine Does this mean that lowering H. levels will prevent A’s Disease? Does this mean that lowering H. levels will prevent A’s Disease? No one knows No one knows

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

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

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

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

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