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Optimizing Neurotherapy and Emerging Paradigm for Alzheimers Disease The Current Foundation Role of Cholinergic Stimulation of Alzheimers DiseaseFocus.

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Presentation on theme: "Optimizing Neurotherapy and Emerging Paradigm for Alzheimers Disease The Current Foundation Role of Cholinergic Stimulation of Alzheimers DiseaseFocus."— Presentation transcript:

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2 Optimizing Neurotherapy and Emerging Paradigm for Alzheimers Disease The Current Foundation Role of Cholinergic Stimulation of Alzheimers DiseaseFocus on Evidence-Based Management of Moderate and Severe AD Program Chairman MURRAY A. RASKIND, MD Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Director of the University of Washington Alzheimers Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Research, Education and Clinical Center (MIRECC) Investigations Innovation Clinical Application

3 Program Faculty Program Chairman MURRAY A. RASKIND, MD Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences Sciences University of Washington School of Medicine Medicine Director of the University of Washington Alzheimers Disease Research Center Alzheimers Disease Research Center Director of the VA Northwest Network Mental Illness Mental Illness Research, Education and Clinical Center Seattle, WA SANDRA E. BLACK, MD, FRCPC Brill Chair in Neurology University of Toronto, Sunnybrook Health Sciences Centre Toronto, Ontario Canada JAMES E. GALVIN, MD, MPH Professor of Neurology and Psychiatry Director of Clinical Operations Center of Excellence on Brain Aging Director Pearl Barlow Center for Memory Evaluation and Treatment Memory Evaluation and Treatment New York University Langone School of Medicine Medicine New York, NY SERGE GAUTHIER, MD Director of the Alzheimers Disease Research Unit Research Unit McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Medicine Psychiatry and Medicine McGill University Montreal, Quebec Canada

4 Advances in Alzheimers Disease Diagnostics and Therapeutics: A Clinicians Perspective Program Chairman MURRAY A. RASKIND, MD Professor and Vice-Chairman Department of Psychiatry and Behavioral Sciences University of Washington School of Medicine Director of the University of Washington Alzheimers Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Research, Education and Clinical Center (MIRECC) Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

5 Questions How can biomarkers help us diagnose AD and estimate treatment response? How can biomarkers help us diagnose AD and estimate treatment response? Do disease modifying anti-beta-amyloid (Aβ) therapeutics modify AD progression? Do disease modifying anti-beta-amyloid (Aβ) therapeutics modify AD progression? Are cholinesterases simply symptomatic drugs? Are cholinesterases simply symptomatic drugs? Can we find rational pharmacotherapies for AD agitation/aggression? Can we find rational pharmacotherapies for AD agitation/aggression?

6 Keeping Expectations Modest If your primary goal is cure, switch to ophthalmology or orthopedics. If your primary goal is cure, switch to ophthalmology or orthopedics. Maintain quality of life and function and relieving distress are important accomplishments. Maintain quality of life and function and relieving distress are important accomplishments. Slowing disease progression is a primary goal. Slowing disease progression is a primary goal.

7 Why Biomarkers? Earlier diagnosis. Earlier diagnosis. More precise monitor of the effect of anti-amyloid therapeutics. More precise monitor of the effect of anti-amyloid therapeutics. However, cognitive testing may still be most sensitive measure of disease progression. However, cognitive testing may still be most sensitive measure of disease progression.

8 AD Biomarkers PET imaging of brain beta-amyloid protein in aggregated form. PET imaging of brain beta-amyloid protein in aggregated form. Cerebrospinal fluid Aβ and tau concentrations. Cerebrospinal fluid Aβ and tau concentrations.

9 Promise Seen for Detection of Alzheimers Headline – New York Times June 23, 2010 This front page article discusses the development and potential of PET Aβ imaging

10 Beta Amyloid PET Imaging Ligands [ 11 C] Pittsburgh Compound B (PIB) Currently available, but short half-life (20 minutes), requires close proximity to cyclotron. [ 18 F] –AV-45 Approaching availability. Longer half-life (10 minutes), enhances availability.

11 Alzheimers Disease Neuroimaging Initiative (ADNI) PIB distinguishes AD from MCI from normals. PIB distinguishes AD from MCI from normals. PIB highly correlated with CSF Aβ 42. PIB highly correlated with CSF Aβ 42. But PIB and CSF Aβ 42 not significantly correlated with MMSE cognitive measure. But PIB and CSF Aβ 42 not significantly correlated with MMSE cognitive measure. In 17 normal, 50 MCI, and 13 AD one-year follow-up subjects: small, nonsignificant changes in Aβ load. In 17 normal, 50 MCI, and 13 AD one-year follow-up subjects: small, nonsignificant changes in Aβ load. However, some individuals had apparently meaningful Aβ load increases. However, some individuals had apparently meaningful Aβ load increases. Jagust WJ et al, Alzheimers and Dementia 6: , 2010.

12 A Treatment Relevance Question Does a drug that reduces [C-11] PIB- measured Aβ load slow cognitive decline? Does a drug that reduces [C-11] PIB- measured Aβ load slow cognitive decline? If so, do beneficial cognitive effects reflect Aβ load reductions? If so, do beneficial cognitive effects reflect Aβ load reductions?

13 The Anti-Amyloid Antibody Approach to the Treatment of Alzheimers Disease Transgenic AD mice show marked reduction in amyloid plaque deposition when actively immunized against beta amyloid. Transgenic AD mice show marked reduction in amyloid plaque deposition when actively immunized against beta amyloid. Active beta amyloid immunization in humans produced apparent reduction of amyloid plaque density; but no clear cognitive benefits. 6% incidence of meningo-encephalitis. Active beta amyloid immunization in humans produced apparent reduction of amyloid plaque density; but no clear cognitive benefits. 6% incidence of meningo-encephalitis.

14 Would Passive Monoclonal Anti-Amyloid Antibody Approaches be More Effective and Less Toxic? Bapineuzumab: N terminus-directed beta amyloid monoclonal antibody in clinical trials. Primary efficacy outcomes in Phase 2 trial not significant. Significant effect on ADAS-Cog in completers. Signal for efficacy in E4 negative subjects. Solanezumab: Mid domain-directed beta amyloid monoclonal antibody in clinical trials. No human trial results available. Antibody design targets soluble beta amyloid.

15 Estimated Mean Change from Baseline on ADAS-COG Salloway S, et al. Neurology 2009; 73: ADAS-COG mITT ADAS-COG Completers Rx difference at week 78 = 2.3 P=0.078 Rx difference at week 78 = 4.3 P=0.003 PlaceboBapineuzumab

16 Bapineuzumab Decreases 11 C-PIB A β Load 28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8). 28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8). Treatment with bapineuzumab for 78 weeks reduced cortical 11 C-PIB amyloid load compared to baseline and placebo. Treatment with bapineuzumab for 78 weeks reduced cortical 11 C-PIB amyloid load compared to baseline and placebo. But, in this small subsample, effects on clinical endpoints were disappointing and did not appear related to effects on Aβ binding. But, in this small subsample, effects on clinical endpoints were disappointing and did not appear related to effects on Aβ binding.

17 Estimated Change from Baseline in Mean C-PiB PET Rinne JO, et al. Lancet Neurol 2010;9: Week Estimated mean change from baseline in mean C-PiB Baseline PlaceboBapineuzumab

18 Potential Utility of CSF Biomarkers Improving diagnostic accuracy. Improving diagnostic accuracy. Predictive value. Predictive value. Monitoring treatment: Monitoring treatment: Alzheimers disease (AD) Alzheimers disease (AD) Mild cognitive impairment (MCI) Mild cognitive impairment (MCI) Primary prevention Primary prevention A, Total Tau, and Phosphorylated Tau - in Alzheimers Disease

19 tau Axonal damage phospho-tau Neurofibrillary tangles Amyloid A 42 A deposition/metabolism/clearance? oxidation ? isoprostanes inflammation ?? Neurochemical Changes in Alzheimers Disease Neurochemical Changes in Alzheimers Disease

20 A 42 is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD Pathogenesis A 42 is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD Pathogenesis A 42 is the initial amyloid species deposited in brain. A 42 is the initial amyloid species deposited in brain. A 42 exceeds A 40 in amyloid deposits. A 42 exceeds A 40 in amyloid deposits. Toxicity and amyloid fibril formation: A 42 >A 40. Toxicity and amyloid fibril formation: A 42 >A 40. in trisomy 21 and almost all APP mutations. in trisomy 21 and almost all APP mutations. Selectively in presenilin mutations. Selectively in presenilin mutations.

21 What Does Decreased CSF A 42 Mean? In Tg 2576 (APP-Swedish mutation) mice, decreases in CSF A 42 parallel increases in brain A In Tg 2576 (APP-Swedish mutation) mice, decreases in CSF A 42 parallel increases in brain A In humans, inverse relation between in vivo brain amyloid load (PIB binding) and CSF A 42, even in cognitively normal subjects 2. In humans, inverse relation between in vivo brain amyloid load (PIB binding) and CSF A 42, even in cognitively normal subjects 2. 1 Kawarabayashi et al., J Neurosci 21: , Fagan et al., Ann Neurol 59: , 2006.

22 Inverse Relation Between in vivo Amyloid Imaging Load and CSF A 42 in Humans Fagan AM, et al., Ann Neurol 59: , Mean Cortical PIB Binding (Binding Potential) CSF Aß 42 (pg/mL)

23 CSF Total Tau in the Diagnosis of AD CSF total tau is measured by a sensitive ELISA. CSF total tau is measured by a sensitive ELISA. Meta-analysis of AD versus controls: 1 Meta-analysis of AD versus controls: 1 35 studies, 2315 AD; 1126 controls 35 studies, 2315 AD; 1126 controls In all studies, CSF T-tau in AD > normal controls In all studies, CSF T-tau in AD > normal controls 2-3 fold increase in AD 2-3 fold increase in AD Effect size = 1.31 (95% CI ) Effect size = 1.31 (95% CI ) No correlation with age, dementia duration or severity No correlation with age, dementia duration or severity Increases slightly with aging in normals Increases slightly with aging in normals 1 Sunderland T, et al., JAMA 289: , 2003.

24 Summary of CSF Biomarkers CSF A 42 is decreased and CSF tau increased in 75-85% of patients with AD. CSF A 42 is decreased and CSF tau increased in 75-85% of patients with AD. Changes in CSF A 42 and tau are present, but are less marked, in MCI than AD. Changes in CSF A 42 and tau are present, but are less marked, in MCI than AD.

25 Use of CSF Biomarkers for Preclinical Diagnosis: Where Do We Stand Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

26 CSF Tau: A 42 Ratio for Increased Risk of Mild Cognitive Impairment: A Follow-up Study Li G, et al., Neurology 69: , Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

27 Methods Subjects: Subjects: 129 controls aged controls aged MCI 12 MCI 21 probable AD 21 probable AD 12 other neurodegenerative disease 12 other neurodegenerative disease CSF collected between hours after overnight fast. CSF collected between hours after overnight fast. Li G, et al., Neurology 69: , 2007.

28 Subject Characteristics and CSF Biomarker Concentrations Controls < 65 yr < 65 yrControls 65 yr 65 yrMCIADOther n M:F41:4022:268:410:117:5 Age 40 ± 15* (21 – 64) 73 ± 7 (65 – 100) 71 ± 13 (49 – 82) 69±9 (52 – 87) 63 ± 11 % APOE* RBC/ l 7 ± 22 (0 – 176) 10 ± 28 (0 – 163) 10 ± 21 (0 – 58) 14 ± 39 (0 – 180) 8 ± 18 (0 – 83) CSF A 42 (pg/ml) 313 ± ± ± ± 27*332 ± 35 CSF tau (pg/ml) 487 ± 24*784 ± ± ± ± 111 CSF P-tau 181 (pg/ml) 97 ± 16*248 ± ± ± Li G, et al., Neurology 69: , 2007.

29 High CSF T/A 42 Ratio and Conversion to MCI in 42 month F/U Conversion to MCI over 42-months of follow- up in: Conversion to MCI over 42-months of follow- up in: 4/17 persons with high CSF T/A 42 ratio 4/17 persons with high CSF T/A 42 ratio 0/26 persons with normal CSF T/A 42 ratio 0/26 persons with normal CSF T/A 42 ratio Logrank test for survival curve, p<0.05 Logrank test for survival curve, p<0.05 Li G, et al., Neurology 69: , 2007.

30 Implications of High CSF T/A 42 Ratio The high CSF T/A 42 subgroup of controls had significantly increased risk of conversion to MCI during 42 months of follow-up. The high CSF T/A 42 subgroup of controls had significantly increased risk of conversion to MCI during 42 months of follow-up. Suggests that high CSF T/A 42 individuals had latent AD at time of CSF collection. Suggests that high CSF T/A 42 individuals had latent AD at time of CSF collection. Li G, et al., Neurology 69: , 2007.

31 Peskind ER, et al., Arch Neurol 63: , Cross-sectional Lifespan Study Suggests CSF A 42 Concentration is Altered in APOE*4 Carriers. Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

32 CSF A 42 and A 40 in 184 Normal Controls Aged Peskind ER, et al., Arch Neurol 63: , 2006.

33 A Sobering Finding CSF A 42 findings consistent with acceleration by the APOE*4 allele of pathogenic A 42 deposition starting in later middle life in persons with normal cognition. CSF A 42 findings consistent with acceleration by the APOE*4 allele of pathogenic A 42 deposition starting in later middle life in persons with normal cognition. Peskind ER, et al., Arch Neurol 63: , 2006.

34 Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Reduction of AD Progression Persistent treatment slows clinical progression. Persistent treatment slows clinical progression. Delayed start design: persons first on placebo than switched to a cholinesterase inhibitor do not catch up. Delayed start design: persons first on placebo than switched to a cholinesterase inhibitor do not catch up. Increasingly divergent clinical status in long-term trials favoring cholinesterase inhibitors. Increasingly divergent clinical status in long-term trials favoring cholinesterase inhibitors. Sounds like disease modification to me. Sounds like disease modification to me.

35 Persistent Treatment with Cholinesterase Inhibitors and/or Memantine Slows Progression of AD 641 AD patients followed at Baylor College of Medicine for over 20 years. 641 AD patients followed at Baylor College of Medicine for over 20 years. Persistent treatment with donepezil, other cholinesterase inhibitors, and memantine slowed AD progression assessed by multiple cognitive, functional and global measures. Persistent treatment with donepezil, other cholinesterase inhibitors, and memantine slowed AD progression assessed by multiple cognitive, functional and global measures. Rountree SD, et al. Alzheimers Res Ther 1(2):7, 2009

36 *# Data from historical placebo group Raskind M et al., Neurology 54:2261–8, 2000 *p < 0.05 vs placebo/ Galantamine 24 mg/day # not significantly different from baseline Galantamine 24 mg/day Placebo/ Galantamine 24 mg/day Mean ( SE) change in ADAS-Cog from baseline Baseline 126 Double-blindOpen-extension Galantamine Shows Sustained Cognitive Benefits in AD Over 12 months (including a delayed start time)

37 Long-term Data: Change from Baseline in ADAS-Cog/11 scores Mean change from baseline ± SE in ADAS-Cog/11 ± SE in ADAS-Cog/11 Raskind MA et al. Arch Neurology 61: , Baseline Months of Treatment Placebo comparison Galantamine 24–32 / 24 mg Estimation of decline – Stern Equation Clinical Improvement Clinical Decline

38 Donepezil Significantly Better Compared to Calculated Change by Stern Equation over 3 Years Wallin AK, et al. Dement Geriatr Disord 2007:23:

39 36-Month Galantamine Trial Does a greater rate of cognitive decline in dropouts than 36 month completers explain results? Does a greater rate of cognitive decline in dropouts than 36 month completers explain results? No! Rate of decline prior to galantamine discontinuation in dropouts was the same as in completers. No! Rate of decline prior to galantamine discontinuation in dropouts was the same as in completers.

40 We Compared Slopes of ADAS-cog Decline Between Dropouts and Completers Time (months) Galantamine patients who completed treatment Galantamine patients who discontinued Change from baseline in ADAS-Cog/ Raskind MA, et al., Arch Neurol 61: , 2004.

41 If ChEIs Delay Disease Progression, What are the Candidate Mechanisms? Nicotinic cholinergic stimulation in vitro: Nicotinic cholinergic stimulation in vitro: Protects against A -induced neuronal death 1 Protects against A -induced neuronal death 1 Muscarinic cholinergic stimulation in vitro: Muscarinic cholinergic stimulation in vitro: Inhibits A production from amyloid precursor protein (APP) 2 Inhibits A production from amyloid precursor protein (APP) 2 Reduces phosphorylation of tau 2 Reduces phosphorylation of tau 2 1 Arias E et al., Neuropharmacology 46: , Fisher A et al., J Mol Neurosci 20: , 2003.

42 Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors An excellent review An excellent review Highlights: Highlights: Stimulation of nicotinic receptors (particularly alpha-7) by nicotine or galantamine or donepezil prevents glutamate neurotoxicity. Stimulation of nicotinic receptors (particularly alpha-7) by nicotine or galantamine or donepezil prevents glutamate neurotoxicity. These effects of cholinesterase inhibitors appear independent of their inhibition of cholinesterase activity. These effects of cholinesterase inhibitors appear independent of their inhibition of cholinesterase activity. Akaike A, et al. J Mol Neurosci 40: , 2010 Role of Alpha-4 and Alpha-7 Receptors in Neuroprotection

43 Loss of Alpha-7 Nicotinic Receptors Enhances Beta-amyloid Oligomer Accumulation in a Mouse Model of Alzheimers Disease Alzheimers transgenic mice with deletion of the alpha-7 nicotinic receptor have increased: Alzheimers transgenic mice with deletion of the alpha-7 nicotinic receptor have increased: Learning and memory deficits Learning and memory deficits Hippocampal and cholinergic neurodegeneration Hippocampal and cholinergic neurodegeneration Soluble oligomer (neurotoxic) beta-amyloid Soluble oligomer (neurotoxic) beta-amyloid Hernandez CM, et al. J Neuroscience 30: , 2010.

44 Disruptive Agitation: What is it? Distressing behaviors that often cluster together Irritability Irritability Anger outbursts, aggression Anger outbursts, aggression Sleep disruption Sleep disruption Pressured pacing and restlessness Pressured pacing and restlessness Uncooperativeness with necessary care Uncooperativeness with necessary care Major cause of long-term care placement. Major cause of long-term care placement.

45 Commonly Used Psychotropic Medications for Disruptive Agitation in AD Antipsychotics: haloperidol, risperidone, olanzapine, aripiprazole, quetiapine. All show modest efficacy in some placebo-controlled trials. Antipsychotics: haloperidol, risperidone, olanzapine, aripiprazole, quetiapine. All show modest efficacy in some placebo-controlled trials. Frequent non-responders Frequent non-responders Adverse effects: pseudoparkinsonism, sedation Adverse effects: pseudoparkinsonism, sedation Increased risk of stroke and death caused FDA to issue Black Box Warning. Increased risk of stroke and death caused FDA to issue Black Box Warning. All antipsychotics are antagonists of the Alpha-1 Adrenoreceptor: Does this contribute to efficacy for agitation?

46 The Brain Noradrenergic System The noradrenergic system is the brain adrenaline system for attention and arousal. The noradrenergic system is the brain adrenaline system for attention and arousal. Excessive noradrenergic reactivity produces anxiety and agitation. Excessive noradrenergic reactivity produces anxiety and agitation. Does excessive noradrenergic activity contribute to agitation in AD? Does excessive noradrenergic activity contribute to agitation in AD?

47 Noradrenergic System Pathology in Alzheimers Disease Despite loss of noradrenergic locus coeruleus neurons there is: Despite loss of noradrenergic locus coeruleus neurons there is: Increased cerebrospinal fluid (CSF) norepinephrine (NE) in AD 1 Increased cerebrospinal fluid (CSF) norepinephrine (NE) in AD 1 Increased agitation response to NE in AD 2 Increased agitation response to NE in AD 2 Compensatory upregulation of surviving LC neurons 3 Compensatory upregulation of surviving LC neurons 3 Increased alpha-1 adrenoreceptors in locus ceruleus target areas 4 Increased alpha-1 adrenoreceptors in locus ceruleus target areas 4 1 Elrod et al., Am J Psychiatry 154:25-30, Peskind, et al., Arch Gen Psychiatry, Szot, et al., J Neuroscience, Szot, et al., J Neuroscience, 2007.

48 Young (n=54) CSF norepinephrine (pg/ml) Old (n=42) * Mild-Moderate AD (n=49) * Advanced AD (n=25) ** *significantly higher than young subjects **significantly higher than all other subject groups Elrod et al., Am J Psychiatry 154:25-30, CSF Norepinephrine: Effects of Aging and AD

49 Postsynaptic Adrenergic Receptor Antagonists in AD Would reducing brain responsiveness to NE by blocking adrenergic receptors reduce agitation in AD? Would reducing brain responsiveness to NE by blocking adrenergic receptors reduce agitation in AD? Alpha-1 receptor antagonist: prazosin. Alpha-1 receptor antagonist: prazosin. Long lasting benefits in posttraumatic stress disorder Long lasting benefits in posttraumatic stress disorder Would prazosin be helpful in AD? Would prazosin be helpful in AD? Raskind MA, et al., Am J Psychiatry 160: , 2003.

50 Prazosin as a Novel Pharmacologic Approach to Agitation in AD Prazosin is an alpha-1 receptor antagonist. Prazosin is an alpha-1 receptor antagonist. Only one that crosses from the blood into the brain Only one that crosses from the blood into the brain Inexpensive, generic, used for BPH and hypertension by millions of older persons for decades. Inexpensive, generic, used for BPH and hypertension by millions of older persons for decades. Clinically effective for AD agitation in open label pilot study. Clinically effective for AD agitation in open label pilot study.

51 Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia Twenty-one persons (mean age 80 years) with DSM-IV dementia (possible or probable AD) and frequent disruptive agitation. Twenty-one persons (mean age 80 years) with DSM-IV dementia (possible or probable AD) and frequent disruptive agitation. Randomized to prazosin (n = 10) or placebo (n = 11) for 8 weeks. Randomized to prazosin (n = 10) or placebo (n = 11) for 8 weeks. Prazosin dose range 2-6 mg/day (mean dose 5.6 ± 1.2 mg/day). Prazosin dose range 2-6 mg/day (mean dose 5.6 ± 1.2 mg/day). Primary outcome measures: BPRS, NPI, CGIC. Primary outcome measures: BPRS, NPI, CGIC.

52 Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia: NPI Wang L, et al., Am J Geriatr Psych 17:744-75, 2009.

53 Where Are We Now? AD biomarkers will be increasingly valuable, but do not under-estimate the importance of a careful history and longitudinal cognitive/ functional assessment. AD biomarkers will be increasingly valuable, but do not under-estimate the importance of a careful history and longitudinal cognitive/ functional assessment. The primacy of Aβ in AD pathogenesis and therapeutics remains in question. The primacy of Aβ in AD pathogenesis and therapeutics remains in question. Improving treatments for behavioral disturbances in AD will have major impacts on patients and caregiver quality of life and health care costs. Improving treatments for behavioral disturbances in AD will have major impacts on patients and caregiver quality of life and health care costs.

54 Pathophysiology of AD: Foundation Role of Cholinergic Dysregulation and Emerging Perspectives on the Pathobiology of AD Pathophysiology of AD: Foundation Role of Cholinergic Dysregulation and Emerging Perspectives on the Pathobiology of AD JAMES E. GALVIN, MD, MPH Professor of Neurology and Psychiatry Director of Clinical Operations Center of Excellence on Brain Aging Director Pearl Barlow Center for Memory Evaluation and Treatment New York University Langone School of Medicine New York, NY Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

55 Objectives Pathophysiology of AD Pathophysiology of AD Beta-amlyoid hypothesis Beta-amlyoid hypothesis Cholinergic Hypothesis Cholinergic Hypothesis Clinical and therapeutic implications of Cholinergic hypothesis Clinical and therapeutic implications of Cholinergic hypothesis Intersection of cholinergic and amyloid-based pathobiology Intersection of cholinergic and amyloid-based pathobiology Approaches to therapy Approaches to therapy Implications for multi-modal therapies for AD Implications for multi-modal therapies for AD

56 Pathophysiology of AD Neuropathologic hallmarks of AD Neuropathologic hallmarks of AD Senile plaques – Amyloid b-protein (Ab) Senile plaques – Amyloid b-protein (Ab) Neurofibrillary tangle – tau protein Neurofibrillary tangle – tau protein Largely a sporadic, late-life cause of dementia, early-onset and familial forms exist Largely a sporadic, late-life cause of dementia, early-onset and familial forms exist Mutations in APP, PS-1 and PS-2 Mutations in APP, PS-1 and PS-2 Mutations increase production of Ab Mutations increase production of Ab Late-onset disease is associated with presence of the e4 allele of Apolipoprotein E Late-onset disease is associated with presence of the e4 allele of Apolipoprotein E More than 40 other genes have been associated with AD More than 40 other genes have been associated with AD

57 Amyloid Hypothesis First proposed in 1991 First proposed in 1991 Initiating molecule in AD, ultimately leading to AD Initiating molecule in AD, ultimately leading to AD Mutations in familial AD encode substrate (APP) and enzyme (Presenilin) for A production Mutations in familial AD encode substrate (APP) and enzyme (Presenilin) for A production Infusions of A cause neuronal degeneration and cognitive deficits Infusions of A cause neuronal degeneration and cognitive deficits Harmful form of A is small, diffusable aggregates or oligomers Harmful form of A is small, diffusable aggregates or oligomers Pakasi and Kalman 2008, Hardy and Allsop 1991, Kowall et al 1991, McDonald et al 1994, Dahlgren et al 2002

58 A is Derived After Cleavage of APP Lumen/Extracellular Cytosol C83 ( -stub) sAPP sAPP p3AICD (A 50 -Cter) C99 ( -stub) sAPP sAPP APP Ab AbAICD A Plaque APP = amyloid precursor protein; sAPP = soluble form of APP; AICD = APP intracellular domain

59 Acetylcholine ACh activity known since turn of 20 th century ACh activity known since turn of 20 th century Nobel prize to Henry Dales and Otto Loewi Nobel prize to Henry Dales and Otto Loewi Synthesized de novo by the brain Synthesized de novo by the brain Two types of receptors Two types of receptors Muscaric Muscaric Nicotinic Nicotinic In the CNS, largely produced in collection of neurons in basal forebrain and pons with wide- range projections In the CNS, largely produced in collection of neurons in basal forebrain and pons with wide- range projections

60 Cholinergic Projections From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7 th Ed, 1996

61 Cholinergic Hypothesis Dysfunction of cholinergic system contributes to memory decline Dysfunction of cholinergic system contributes to memory decline Drachman and Leavitt (1974) Drachman and Leavitt (1974) Link between cholinergic dysfunction and memory impairment Link between cholinergic dysfunction and memory impairment Scopolamine in young adults caused impairment Scopolamine in young adults caused impairment Corroborated by primate, canine and rodent studies Corroborated by primate, canine and rodent studies Reduced choline acetyl transferase (ChAT) activity in cortex, hippocampus and amygdala of AD patients Reduced choline acetyl transferase (ChAT) activity in cortex, hippocampus and amygdala of AD patients Activity correlated with level of cognitive impairment Activity correlated with level of cognitive impairment Selective loss of cholinergic cells in basal forebrain Selective loss of cholinergic cells in basal forebrain Davies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981.

62 AChEAChE Acetyl CoA + Choline Choline + Acetate ACh PresynapticNeuron Synaptic Cleft Postsynaptic Neuron Cholinergic Receptor Choline AChEAChE ChATChAT Glial Cell BuChEBuChE BuChEBuChE Neuropathological Signaling: Cholinergic Hypothesis ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A. Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl 139): ACh

63 Cholinergic Hypothesis Basal forebrain and rostral brainstem cholinergic pathways converge to serve important functional rolls in awareness, attention, working memory and mnemonic processes Basal forebrain and rostral brainstem cholinergic pathways converge to serve important functional rolls in awareness, attention, working memory and mnemonic processes Loss of cholinergic function contributes to cognitive decline associated with AD Loss of cholinergic function contributes to cognitive decline associated with AD Perry et al 1999, Bartus 2000,

64 Cholinergic Receptors and AD Two classes Two classes Nicotinic ionic channels Nicotinic ionic channels Responsible for fast transmission Responsible for fast transmission Reduction in 4 nAChR in AD Reduction in 4 nAChR in AD Up-regulation of 7 nAChR in AD compared with MCI and controls Up-regulation of 7 nAChR in AD compared with MCI and controls – 7 receptors down-regulated in DLB Possible compensatory response to maintain basal forebrain-cortical cholinergic activity Possible compensatory response to maintain basal forebrain-cortical cholinergic activity 7 nAChR interacts with APP and A peptides which could lead to aberrant function 7 nAChR interacts with APP and A peptides which could lead to aberrant function Muscarinic G protein-coupled receptors Muscarinic G protein-coupled receptors Preserved during progression of AD Preserved during progression of AD In triple transgenic mice, M1 agonists improved cognitive and reduced A and tau pathology In triple transgenic mice, M1 agonists improved cognitive and reduced A and tau pathology Hypothesis: activation of TACE/ADAM17, decreased BACE1 levels and/or inhibition of GSK3 Hypothesis: activation of TACE/ADAM17, decreased BACE1 levels and/or inhibition of GSK3 Mufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006

65 Role of Cholinergic Deficits in Behavioral Symptoms of AD Temporal and frontal lobe dysfunction implicated in psychosis of AD Temporal and frontal lobe dysfunction implicated in psychosis of AD Regional cholinergic deficitsapathy and indifference Regional cholinergic deficitsapathy and indifference Cholinergic-monoaminergic imbalance hypothesized in mood disorders Cholinergic-monoaminergic imbalance hypothesized in mood disorders Cholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trials Cholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trials Lanari A, et al 2006; Cummings JL. 2000

66 Clinical and Therapeutic Implications of Cholinergic hypothesis Recent functional MRI study demonstrated MCI treated with donepezil demonstrated increased frontal cortex activation relative to untreated control Recent functional MRI study demonstrated MCI treated with donepezil demonstrated increased frontal cortex activation relative to untreated control Correlated with task performance Correlated with task performance AChE does not show decline until late stages of disease AChE does not show decline until late stages of disease Only mild losses in MCI and mild AD Only mild losses in MCI and mild AD Vesicular Ach transporter is not severely altered in AD Vesicular Ach transporter is not severely altered in AD Cholinergic neurons appear then to shrink and become dysfunctional rather than degenerate early in disease Cholinergic neurons appear then to shrink and become dysfunctional rather than degenerate early in disease Suggest cholinergic neurons may be viable, however dysfunctional early in disease and thus amenable to manipulations Suggest cholinergic neurons may be viable, however dysfunctional early in disease and thus amenable to manipulations Changes in neurotrophic gene expression may provide targets of intervention for dysregulation of cholinergic neurons Changes in neurotrophic gene expression may provide targets of intervention for dysregulation of cholinergic neurons NGF (trk) receptors down-regulation may be a molecular marker for transition from MCI to frank AD NGF (trk) receptors down-regulation may be a molecular marker for transition from MCI to frank AD Saykin et al, 2004, Bierer et al 1995, Rinne et al, 2003, Gilmor et al, 1999, Rinne et al 1987, Mufson et al, 2009

67 Challenges to Cholinergic Hypothesis Studies of post-mortem tissue Studies of post-mortem tissue Levels of AChE and ChAT are not reduced in very mild AD Levels of AChE and ChAT are not reduced in very mild AD Levels of ChAT may be upregulated in MCI and very mild AD Levels of ChAT may be upregulated in MCI and very mild AD Since neither ChAT nor AChE are rate-limiting cholinergic enzymes, they are unlikely to accurately reflect cholinergic function in a living patient Since neither ChAT nor AChE are rate-limiting cholinergic enzymes, they are unlikely to accurately reflect cholinergic function in a living patient Other factors may be involved Other factors may be involved Alterations in high-affinity choline transport (rate-limiting step) Alterations in high-affinity choline transport (rate-limiting step) Deficits in nicotinic and muscarinic receptors Deficits in nicotinic and muscarinic receptors Dysfunctional neurotrophic support Dysfunctional neurotrophic support Neurochemical analyses of autopsy tissue maybe unreliable Neurochemical analyses of autopsy tissue maybe unreliable Dependent on length of agonal state and post-mortem interval Dependent on length of agonal state and post-mortem interval More recent in vivo imaging studies support amyloid hypothesis More recent in vivo imaging studies support amyloid hypothesis 11 C N-methylpiperidine-4-yl proprianate (AChE activity) 11 C N-methylpiperidine-4-yl proprianate (AChE activity) Nicotine-based ligands Nicotine-based ligands Non-selective muscarinic ligands Non-selective muscarinic ligands 123 I Benzovesamacol (vesicular Ach transporter) 123 I Benzovesamacol (vesicular Ach transporter) Terry and Buccafusco 2003, Slotkin 1990, Auld et al 2002, Kuhl et al 1999, Norberg 2001, Zubieta et al 2001, Kuhl et al 1996

68 Recent Developments Extension of studies to early, prodromal stages Extension of studies to early, prodromal stages Religious Orders Study Religious Orders Study Very mild cases did not show decreases in ChAT but actually increases Very mild cases did not show decreases in ChAT but actually increases Immunochemistry of brain with very mild AD/MCI Immunochemistry of brain with very mild AD/MCI ChAT or vesicular ACh transporter not reduced ChAT or vesicular ACh transporter not reduced Markers of NGF receptors markedly reduced Markers of NGF receptors markedly reduced Possible that other pre- or post-synaptic mechanisms may be compromised Possible that other pre- or post-synaptic mechanisms may be compromised Perhaps down-regulation of retrograde transmission of NGF from hippocampus/frontal cortex to basal forebrain Perhaps down-regulation of retrograde transmission of NGF from hippocampus/frontal cortex to basal forebrain Altered neurotrophic receptors may mark early stage of disease with initial increases in ChAT activity Altered neurotrophic receptors may mark early stage of disease with initial increases in ChAT activity Decreased connectivity between hippocampus and entorhinal cortex Decreased connectivity between hippocampus and entorhinal cortex Davis et al, 1999, Dekosky et al, 2002, Gilmor et al, 2000, Mufson et al, 2002, Terry et al, 2003, Counts and Mufson, 2005, Ikonomovic et al, 2003, Kordower et al, 2001

69 Interactions Between Amyloid and Cholinergic Hypotheses Regulation of A by stimulation of muscarinic or nicotinic receptors Regulation of A by stimulation of muscarinic or nicotinic receptors Partial M1 agonists increase APPs, decrease A and decrease tau phosphorylation Partial M1 agonists increase APPs, decrease A and decrease tau phosphorylation Nicotine may increase downstream synthesis of neurotropins Nicotine may increase downstream synthesis of neurotropins Cholinergic deficits could be secondary to amyloid toxicity Cholinergic deficits could be secondary to amyloid toxicity Bidirectional interaction between cholinergic function and processing of amyloid precursor protein Bidirectional interaction between cholinergic function and processing of amyloid precursor protein High affinitity 7 receptors can serve as high affinity binding sites for A peptides High affinitity 7 receptors can serve as high affinity binding sites for A peptides Amyloid peptides inhibit uptake of choline and decrease endogenous Ach release without exhibiting effects on ChAT activity Amyloid peptides inhibit uptake of choline and decrease endogenous Ach release without exhibiting effects on ChAT activity A block functional interaction between nicotinic agonists and receptors on hippocampal neurons A block functional interaction between nicotinic agonists and receptors on hippocampal neurons Court et al, 1998, Muller et al 1997, Genis et al 1999, Jonnala et al 2002, Roberson et al, 1997, Wang et al 2000, Pakaski and Kalman, 2008, Liu 2001

70 Interactions Between Ab and ACh Toxicity of A on the cholinergic system Toxicity of A on the cholinergic system Ach synthesis and release reduced by solubilized Ab Ach synthesis and release reduced by solubilized Ab Loss of cholinergic fibers without loss of cholinergic neurons Loss of cholinergic fibers without loss of cholinergic neurons Reduction of binding to vesicular Ach transporter Reduction of binding to vesicular Ach transporter Inhibition of fast axonal transport Inhibition of fast axonal transport A 42 binds with higher affinity to 7 nAChR than A 40 A 42 binds with higher affinity to 7 nAChR than A 40 A 42 reduced downstream events in mAChR signal transduction A 42 reduced downstream events in mAChR signal transduction Cholinergic system and APP processing via -secretase Cholinergic system and APP processing via -secretase mAChR mAChR 7nAChR agonists 7nAChR agonists AChEI AChEI Auld et al 1998, Boncristiano et al 2002, Ikeda et al 2000, Kasa et al 2000, Qi et al 2005, Kelly et al 1996, Buxbaum et al 1992, Zimmerman et al 2004

71 Mechanisms of AChE Inhibitors on the Release of sAPP α AchE inhibitor Change Cholinergic mechanism Other mechanismReference TacrineDecrease?Lahiri et al. (1994); Lahiri et al. (1996) MetrifonateIncrease+? (Pakaski et al., 2000) and (Pakaski et al., 2001); Racchi et al. (2001) AmbenoniumIncrease+?Pakaski et al. (2001) GanstigmineIncrease+?Mazzucchelli et al. (2003) LadostigilIncrease+ MAP-kinase or tyrosin kinase-dependent pathway Yogev-Falach et al. (2002) DonepezilIncrease+ Enhancing trafficking and activity of ADAM 10 Zimmermann et al. (2004) PhenserineDecrease Inhibition of APP mRNA translation Lahiri et al. (2000); Shaw et al. (2001) GalantamineIncrease+?Lenzken et al. (2007) Pakaski and Kalman 2008

72 Linking Ab and ACh Pakaski and Kalman 2008

73 Withdrawal design Staggered-start design Time Performance Time Performance Randomized phase Placebo phase Placebo Active Placebo Active Symptomatic effect Disease-modifying effect Symptomatic effect Discrimination Between Disease Modification and Symptomatic Benefit

74 Is There Evidence of Disease- Modifying Effects? From clinical trials, functional imaging and basic science studies, anti-cholinesterase drugs may: From clinical trials, functional imaging and basic science studies, anti-cholinesterase drugs may: Reduce circulating A Reduce circulating A Alter APP processing Alter APP processing Prevent A deposition in cholinergic projection sites Prevent A deposition in cholinergic projection sites Promote non-amyloidogenic APP processing Promote non-amyloidogenic APP processing If changes in cholinergic transmission alters APP processing, appropriate cholimimetic therapeutics might provide both symptomatic benefit and modify AD pathogenesis If changes in cholinergic transmission alters APP processing, appropriate cholimimetic therapeutics might provide both symptomatic benefit and modify AD pathogenesis Lopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000

75 Amyloid-Based Approaches Barten and Albright 2008

76 Immunization Reduces Ab burden Holmes et al 2008

77 Immunization Does not rRduce Disease Burden Time to severe dementia Time to death Holmes et al 2008

78 Neurotransmitter-Based Approaches Barten and Albright 2008

79 Time Performance Mild Combining Symptomatic and Disease-modifying RX Disease-modifying Rx Symptomatic Rx Model of Multi-Modal Approach ModerateSevere

80 Summary Ab as the likely culprit leading to AD is a logical target for anti-AD therapies but to date, Phase III trials have not been successful Ab as the likely culprit leading to AD is a logical target for anti-AD therapies but to date, Phase III trials have not been successful Ach provides targets for symptomatic benefit Ach provides targets for symptomatic benefit Dysfunction/degeneration of the cholinergic projection neurons is a later stage event in AD Dysfunction/degeneration of the cholinergic projection neurons is a later stage event in AD Dysregulation of the cholinergic system is an early event Dysregulation of the cholinergic system is an early event Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

81 Summary (cont.) There is a bidirectional relationship between the amyloid and cholinergic hypotheses There is a bidirectional relationship between the amyloid and cholinergic hypotheses Disease-modifying therapies will likely be more effective when used earlier in disease process Disease-modifying therapies will likely be more effective when used earlier in disease process Clear need for improve detection of AD at earliest, even preclinical stages Clear need for improve detection of AD at earliest, even preclinical stages Multi-modal approaches offer the best potential to provide treatment throughout the spectrum of disease Multi-modal approaches offer the best potential to provide treatment throughout the spectrum of disease Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002

82 SANDRA E. BLACK, MD, FRCPC Brill Chair in Neurology University of Toronto, Sunnybrook Health Sciences Centre Toronto, Ontario Canada Evidence-based Role of Cholinesterase Inhibition Across the Severity Spectrum in AD Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

83 Review evidence for cholinesterase inhibitors as cognitive enhancers in mild-moderate Alzheimers Disease Summarize evidence for utility in earlier and later stages of AD Consider evidence for longer term use Learning Objectives See Canadian Consensus on Dementia Diagnosis and Treatment: Hogan et al, CMAJ 2008; Alzheimers and Dementia special issue 2007

84 –Progressive loss of cholinergic neurons –Progressive decrease in available ACh –Impairment in ADL, behavior and cognition Hippocampus Cortex N. basalis Meynert Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978 The Cholinergic Deficit in AD

85 Butyrylcholinesterase N = nicotinic M = muscarinic ACh = acetylcholine Postsynaptic nerve terminal M receptor N receptor Presynaptic nerve terminal ACh Acetylcholinesterase Increased availability of ACh at synapse (AChE and BuChE inhibition) ACh Astrocyte BuChE Galantamine Donepezil Rivastigmine Galantamine Rivastigmine Cholinesterase Inhibitors: Mechanisms of Action

86 benefitno benefit heterogeneous Efficacy-Cognitive Improvement 10% [4%, 17%] of patients show significant benefit over placebo Lanctot et al, CMAJ, 2003

87 benefitno benefit 9% [6%, 12%] of patients show significant benefit over placebo Homogeneous Lanctot et al, CMAJ, 2003 Efficacy Clinical Global Impression

88 Numbers needed to treat to benefit Numbers needed to treat to benefit 7 (CI 95% : 6, 9) for stabilization or better 7 (CI 95% : 6, 9) for stabilization or better 12 (CI 95% : 9, 16) for minimal improvement or better 12 (CI 95% : 9, 16) for minimal improvement or better 42 (CI 95% : 26, 114) for marked improvement 42 (CI 95% : 26, 114) for marked improvement NNT for clinically benefit are low. NNT for clinically benefit are low. Homogeneous-all 3 ChEI similar Homogeneous-all 3 ChEI similar Lanctot et al, CMAJ, 2003 Number Needed to Treat for Benefit

89 Caveat Galantamine above recommended doses, heterogeneity 8% [5,11] 7% [3,10] 8% [5,12] Lanctot et al CMAJ, 2003 Tolerability

90 Safety Number needed to harm ( ie to cause AE in 1 patient ) = 12 ( Lanctot et al CMAJ 2003 ) Number needed to harm ( ie to cause AE in 1 patient ) = 12 ( Lanctot et al CMAJ 2003 ) Recent study of community-dwelling dementia patients using healthcare database in Ontario, Canada (2002-4) Recent study of community-dwelling dementia patients using healthcare database in Ontario, Canada (2002-4) 19,803 treated with cholinesterase inhibitors vs 61,499 not on CHEIs 19,803 treated with cholinesterase inhibitors vs 61,499 not on CHEIs Syncope 31.5 vs 18.6/1000 HR 1.76 Syncope 31.5 vs 18.6/1000 HR 1.76 Bradycardia 6.9 vs 4-4/1000 HR 1.69 Bradycardia 6.9 vs 4-4/1000 HR 1.69 Pacemaker needed 4.7 vs 3.3/1000 HR 1.49 Pacemaker needed 4.7 vs 3.3/1000 HR 1.49 Hip fracture 22.4 vs 19.8/1000 HR 1.18 Hip fracture 22.4 vs 19.8/1000 HR 1.18 Gill et al Arch Int Med 2009

91 Benefits in cognition, behavior and function have been for 6 months- only a few 1-year placebo-controlled studies Benefits in cognition, behavior and function have been for 6 months- only a few 1-year placebo-controlled studies Longer term benefits derived from open label extensions, limited by large dropouts and bias from self-selection Longer term benefits derived from open label extensions, limited by large dropouts and bias from self-selection Most clinical trials have been pharma-sponsored without independent analyses, except for AD 2000 Most clinical trials have been pharma-sponsored without independent analyses, except for AD 2000 Differential treatment effects on specific cognitive domains are not known as they have not been studied; the tools used may not have sampled the most sensitive domains Differential treatment effects on specific cognitive domains are not known as they have not been studied; the tools used may not have sampled the most sensitive domains Placebo trials may no longer be feasible or ethical Placebo trials may no longer be feasible or ethical Recent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practice Recent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practice Limitations of Drug Trials to Date Kaduszkiewicz et al., BMJ, 2005

92 Use in Early and Later Disease Stages Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

93 MMSE Years Early Mild-moderate Severe Cognitive symptoms Loss of functional independence Behavioural problems Nursing home placement Death Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimers Disease Natural History of AD: early

94 Follow-up Time (Years) Proportion Free of Dementia (%) Normals MCI Retrospective analysis of 687 subjects with MCI Mean age 72.2 yrs 45% DeKosky ST. J Am Geriatr Soc, 2003; Adapted from Grundman M et al, Abstract in Neurology, Conversion of Normal and MCI Subjects to Dementia (AD Cooperative Study)

95 Objectives To determine whether daily doses of vitamin E or donepezil given over a 3-year period can: To determine whether daily doses of vitamin E or donepezil given over a 3-year period can: 1) delay or prevent the onset of AD in people who have MCI 2) slow the decline of symptoms Design: 3-year, randomized, double-blind, placebo-controlled, parallel group study 60 sites in the US and 9 sites in Canada 60 sites in the US and 9 sites in Canada Patients were randomized to receive donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placebo Patients were randomized to receive donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placebo Subjects: 769 patients with MCI Outcome measures: Primary: Conversion to AD Primary: Conversion to AD Secondary:MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, Neuropsychological battery Secondary:MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, Neuropsychological battery ADCS: MCI Study Design Petersen et al. N Engl J Med, 2005

96 Survival Analysis: Donepezil vs. Placebo Probability of not converting to AD Probability of not converting to AD Time on MCI study (days) ,0001, Donepezil Placebo Donepezil Placebo 1 yr 6 mo 18 mo p<0.001 p<0.009 p<0.035 Petersen RC et al. N Engl J Med, 2005

97 Summary of MCI Studies NIH MCI study with donepezil failed statistical significance on primary endpoint, but decline delayed by up to 12 months, and was slower in APOE e4 participants (Petersen et al NEJM 2005) NIH MCI study with donepezil failed statistical significance on primary endpoint, but decline delayed by up to 12 months, and was slower in APOE e4 participants (Petersen et al NEJM 2005) Recent 48 wk study of donepezil in 821 aMCI patients likewise found nsd in 1 o and 2 o outcomes, though patients felt better subjectively ( Doody et al Neurol 2009) Recent 48 wk study of donepezil in 821 aMCI patients likewise found nsd in 1 o and 2 o outcomes, though patients felt better subjectively ( Doody et al Neurol 2009) Other MCI trials with galantamine (Winblad et al Neurol 2008) rivastigmine ( Feldman et al Lancet Neurol 2007) also did not delay conversion Other MCI trials with galantamine (Winblad et al Neurol 2008) rivastigmine ( Feldman et al Lancet Neurol 2007) also did not delay conversion More deaths noted with galantamine 1.4% vs 0.3% in placebo MCI subjects leading to product label warning More deaths noted with galantamine 1.4% vs 0.3% in placebo MCI subjects leading to product label warning See Raschetti et al Cochrane Review PLoS Med 2007

98 Doody, et al., Am J of AD & Other Dem Safety and Tolerability of Donepezil (10mg/d) in aMCI Study Design Safety and tolerability of donepezil (10mg) was evaluated in 145 aMCI patients as an open label 28-week extension study after a 48-week RCT of 821 aMCI Safety and tolerability of donepezil (10mg) was evaluated in 145 aMCI patients as an open label 28-week extension study after a 48-week RCT of 821 aMCI Key Results 57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE 57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE Most frequent treatment related AEs were diarrhea, muscle spasms, insomnia, and nausea (more common early on & mild-moderate in severity) Most frequent treatment related AEs were diarrhea, muscle spasms, insomnia, and nausea (more common early on & mild-moderate in severity) 22.1% in the placebo/donepezil group discontinued donepezil due to an AE compared with 10.3% in the donepezil/donepezil group 22.1% in the placebo/donepezil group discontinued donepezil due to an AE compared with 10.3% in the donepezil/donepezil group Conclusions Donepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it better than patients with MCI Donepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it better than patients with MCI

99 Lu, et al., Neurology 2009 Higher Rate of Progression to AD in Patients with aMCI and Depressive Symptoms Study Design 756 aMCI from the three year NIH study drug trial of donepezil and vitamin E 756 aMCI from the three year NIH study drug trial of donepezil and vitamin E Depressive symptoms assessed at baseline using the Beck Depression Inventory (BDI) Depressive symptoms assessed at baseline using the Beck Depression Inventory (BDI) Key Results On regression analysis higher BDI scores were associated with progression to AD On regression analysis higher BDI scores were associated with progression to AD Depressive subjects: proportion progressing to AD was lower in donepezil group than combined vitamin E and placebo groups at 1.7 years, 2.2 years, and marginally lower at 2.7 years Depressive subjects: proportion progressing to AD was lower in donepezil group than combined vitamin E and placebo groups at 1.7 years, 2.2 years, and marginally lower at 2.7 years Nondepressive subjects: no difference between the three treatment groups Nondepressive subjects: no difference between the three treatment groups Conclusions Depressive symptoms may be predictive of progression from aMCI to AD Depressive symptoms may be predictive of progression from aMCI to AD Treatment with donepezil delayed progression to AD in depressive subjects with aMCI Treatment with donepezil delayed progression to AD in depressive subjects with aMCI

100 Lu, et al., Neurology 2009 Survival

101 MMSE Years Early Mild-moderate Severe Cognitive symptoms Loss of functional independence Behavioural problems Nursing home placement Death Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimers Disease Natural History of AD: Moderate to severe stage

102 Donepezil Placebo Donepezil vs Placebo in Nursing Home Study in Severe AD (MMSE 1-10): Cognition (SIB) 36 ITT LOCF Clinical improvement Clinical decline Baseline Months Mean Change From Baseline in SIB Score *OC analysis; LOCF analysis. p=0.003* p=0.008* p= SIB Winblad et al. Lancet, 2006.

103 Functional Abilities Also Showed Less Decline 36ITT LOCF Months Mean Change From Baseline in ADCS-ADL Clinical Improvement Clinical Decline Baseline P = 0.031*P = P = 0.086* *OC analysis; LOCF analysis. 0 Winblad et al Lancet, 2006

104 Study week SIB scores: LS mean change from baseline (SE) Donepezil Placebo d Clinical improvement Clinical decline 0 Less Cognitive Decline in Community Dwelling Severe AD (MMSE1-12) 24 ITT LOCF 8 p = mg/d Black et al Neur 2007

105 Level 1 evidence for different compounds according to studies undertaken Level 1 evidence for different compounds according to studies undertaken Donepezil in vascular dementia Donepezil in vascular dementia Rivastigmine in parkinson/diffuse lewy body dementia Rivastigmine in parkinson/diffuse lewy body dementia Galantamine in mixed vascular dementia Galantamine in mixed vascular dementia (Memantine also shows efficacy in moderate to severe AD) (Memantine also shows efficacy in moderate to severe AD) Cholinesterase Inhibitor Use in Other Dementias

106 Use of Higher Doses, New Formulations Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

107 Once Daily Formulations Galantamine extended release 8mg od –16mg od– 24mg od Rivastigmine patch 4.6-mg od –9.5mg od GI tolerability better than oral formulation (eg nausea: oral 23 vs patch 7% vs placebo 5%) Skin sensitivity (erythema, edema, pruritus, pain) Recent caution due to additive dose effects if patch not removed daily before new one applied Winblad et al. Int J Geri Psych. 2007

108 Doody, et al., Drugs Aging 2008 Purpose To evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/day To evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/day Study Design A 24-week, randomized, double-blind, placebo controlled, pilot study A 24-week, randomized, double-blind, placebo controlled, pilot study 31 patients (male and female) aged years 31 patients (male and female) aged years All patients had been treated with 10mg/day donepezil for months prior to enrollmentAll patients had been treated with 10mg/day donepezil for months prior to enrollment Primary outcome measures: Primary outcome measures: Tolerability (discontinuations, dose modifications, and adverse events) Tolerability (discontinuations, dose modifications, and adverse events) Safety (monitored by adverse events, physical examinations, clinical lab tests, and ECGs) Safety (monitored by adverse events, physical examinations, clinical lab tests, and ECGs) Secondary outcome measures: Secondary outcome measures: Psychometric measures: ADAS-Cog, MMSE, CIBIC+, pharmacokinetic/pharmacodynamic parameters Psychometric measures: ADAS-Cog, MMSE, CIBIC+, pharmacokinetic/pharmacodynamic parameters Safety & Tolerability of Higher Dose Donepezil (20mg)

109 Key Results Higher-dose group:Higher-dose group: 15 of 16 patients tolerated the maximum 20 mg/day dose by week 2415 of 16 patients tolerated the maximum 20 mg/day dose by week 24 Standard-dose group: Standard-dose group: 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study Adverse events possibly related to treatment were reported by 3 patients in the standard-dose group and 6 patients in the higher-dose group Adverse events possibly related to treatment were reported by 3 patients in the standard-dose group and 6 patients in the higher-dose group No difference between groups on psychometric measures No difference between groups on psychometric measures Conclusions Doses of 15 and 20 mg/day of donepezil appeared to be safe and well tolerated Doses of 15 and 20 mg/day of donepezil appeared to be safe and well tolerated May justify larger clinical trials for the safety and efficacy of donepezil at higher doses in patients with AD. May justify larger clinical trials for the safety and efficacy of donepezil at higher doses in patients with AD. Doody, et al., Drugs Aging 2008 Safety & Tolerability of higher dose Donepezil (20mg)

110 Purpose To determine effectiveness, safety and tolerability of 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezil To determine effectiveness, safety and tolerability of 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezilDesign 1467 patients (465 US) in 209 sites randomized to 23mg (n=972) vs 10mg (n= 479) 1467 patients (465 US) in 209 sites randomized to 23mg (n=972) vs 10mg (n= 479) MMSE: 76%: 0-16; 34%: MMSE: 76%: 0-16; 34%: Approx 36% also on memantine (75% in US) Approx 36% also on memantine (75% in US)Results Discontinuation higher for 23 mg vs 10mg: Discontinuation higher for 23 mg vs 10mg: 30% (18% for AEs vs 18% (8% for AEs) 30% (18% for AEs vs 18% (8% for AEs) High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage AD

111 Effectiveness analysis:Cognition Farlow et al. Clinical Therapeutics Severe Impairment Battery MMSE Less decline from baseline on SIB P<0.001

112 Frequency Distribution of CIBIC Scores at Week 24 Farlow et al. Clinical Therapeutics2010. No difference in ADL scores Adverse Events: 23 vs 10 Nausea % 11.8 vs 3.4 Vomiting % 9.3 vs 2.5 Diarrhea % 8.3 vs 5.3 Anorexia % SAE % 8.6 vs 9.6

113 Is There Any Evidence for Longer Term Use of Cholinesterase Inhibitors? Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

114 Proj. placeboDose optimization with rivastigmine (6-12 mg/day) * * * * * * * * * –2 –4 –6 –8 ADAS-Cog mean change from baseline Study week 6–12 mg/day rivastigmine 1–4 mg/day rivastigmine Placebo All patients restarted on rivastigmine B352 patients in Study B353 (OC) at week 52 *p<0.05 vs projected placebo 26 Messina et al., 2000 Rivastigmine-Placebo Group Does not Catch Up to Treated Group

115 Mean change from baseline (±SE) in ADAS-Cog/11 (±SE) in ADAS-Cog/11 Time (months) –4– Baseline Galantamine 24–32/24 mg (103) (322) (140) (309) (310) (233) (298) (228) 12-month placebo Expected decline in untreated patients of 6–9 points/year Database and from Raskind et al Arch Neurol (n)(n) Mean Change in ADAS-Cog Score from Baseline: Open Label Galantamine Over 4 Years

116 Design 1-year, randomized, placebo-controlled, double-blind 1-year, randomized, placebo-controlled, double-blindSubjects 431 patients with mild-to-moderate AD 431 patients with mild-to-moderate AD Aged 49-94, mean MMSE 17.1 Aged 49-94, mean MMSE 17.1 Primary Outcome Time to clinically evident functional decline, defined by: Time to clinically evident functional decline, defined by: Decline in 1 basic ADL present at baseline Decline in 1 basic ADL present at baseline Decline of 20% of the instrumental ADL present at baseline Decline of 20% of the instrumental ADL present at baseline Increase 1 point from baseline in global CDR score (Clinical Dementia Rating scale) Increase 1 point from baseline in global CDR score (Clinical Dementia Rating scale) Mohs et al. Neurology year Preservation of Function Study with Donepezil

117 *As judged by investigator, ITT population Mohs et al. Neurology Kaplan-Meier survival estimates The probability of survival (maintaining functional ability) at 48 weeks was: 51% for donepezil 35% for placebo Survival curve comparison: p=0.002 (log-rank test) p=0.005 (Wilcoxon test) Time to Clinically Evident Functional Decline*

118 Two-year, double blind, RCT in AD of donepezil versus placebo in a family practice setting in the UK sponsored by local health authority (AD2000) Two-year, double blind, RCT in AD of donepezil versus placebo in a family practice setting in the UK sponsored by local health authority (AD2000) Small improvements shown but not considered clinically significant since no delay in NHP, loss of milestones or decrease in caregiver costs (AD 2000, Courtney et al., Lancet, 2004) (AD 2000, Courtney et al., Lancet, 2004)Issues: a) Large dropout (40% 1-year, 77% 2-year) a) Large dropout (40% 1-year, 77% 2-year) b) Not clear if samples used for analyses were matched after run in; also used washout b) Not clear if samples used for analyses were matched after run in; also used washout c) 51% of total sample had CVD c) 51% of total sample had CVD Longer-Term Effects: Non-Pharmaceutical Sponsored Study

119 Potential for symptom stabilization – 50% of patients with no change or improvement on SIB after 1 year, and 35% after 2 years in head to head trial of rivastigmine and donepezil 1 Potential for symptom stabilization – 50% of patients with no change or improvement on SIB after 1 year, and 35% after 2 years in head to head trial of rivastigmine and donepezil 1 Compared with placebo or untreated populations, 2– 7 ChE-I therapy may delay cognitive and functional decline and the progression of neuropsychiatric symptoms by up to a year Compared with placebo or untreated populations, 2– 7 ChE-I therapy may delay cognitive and functional decline and the progression of neuropsychiatric symptoms by up to a year 1 Bullock R et al. CMRO Schmitt et al. Alzheimer Dis Assoc Disord Feldman et al. Neurology Winblad et al. Neurology 2001; 5 Klatte et al. Alzheimer Dis Assoc Disord Small et al Int J Clin Pract Aisen et al. JAMA 2003 Other Studies Suggesting Symptomatic Stabilization over Longer Periods

120 N= 65 in each of treated vs untreated group, well- matched on age, edcuation, severity, comorbidities, vasc risk factors and medications N= 65 in each of treated vs untreated group, well- matched on age, edcuation, severity, comorbidities, vasc risk factors and medications Less decline in: Less decline in: Overall cognition Overall cognition Naming Naming Visuospatial and visuoconstructive skills Visuospatial and visuoconstructive skills Executive functions Executive functions p< Effect size d = 0.7 Dementia Rating Scale Behl et al Dem Ger Cog Dis 2006 Patients on ChEIs Had Less Decline in Patients on ChEIs Had Less Decline in Multiple Cognitive Domains over 1 Year Multiple Cognitive Domains over 1 Year

121 Treated patients showed less decline on: Treated patients showed less decline on: Overall cognition Overall cognition Memory Memory Naming Naming Executive functions Executive functions p=0.007 ES: d1 =0.8; d2 = 0.4 Verbal Memory Behl et al Dem Ger Cog Dis 2006 Behl et al Dem Ger Cog Dis 2006 Patients on ChEIs Continued to Show Less Decline on Select Cognitive Domains at Two Years

122 P year1 =0.036; P year2 =0.001 ES 1= 0.5; ES 2= 0.8 Overall DAD Instrumental P year1 =0.04; P year2 =0.001 ES 1 =0.6; ES 2= 0.9 Basic P year1 =0.08 ; P year2 =0.001 ES 1= 0.4; ES 2 = 0.7 Behl et al, Int Psychoger 2008 Patients on ChEIs also showed less decline in functional abilities over 2 years, especially in initiation (DAD)

123 P year1 = 0.038; P year2 =0.006 ES 1=0.8; ES 2 =1.0 Overall DAD Basic P year1 =0.039; P year2 =0.001 ES 1 = 0.7; ES = 1.0 Behl et al, Int Psychoger 2008 Also Planning and Organization

124 Rountree, et al., Alzheimers Res. & Ther Does Persistent Use of Antidementia Drugs Slow Clinical Progression of AD over 20 Years? Study Design 641 probable AD patients were followed for 20 years in a single centre 641 probable AD patients were followed for 20 years in a single centre Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms Measures: annual change in slope of neuropsychological and functional tests as predicted by follow up time, PI, and the interaction between these variables Measures: annual change in slope of neuropsychological and functional tests as predicted by follow up time, PI, and the interaction between these variables Key Results PI was associated with significantly slower rates of decline on MMSE, Physical Self- Maintenance Scale (PSMS), IADL, CDR-SB PI was associated with significantly slower rates of decline on MMSE, Physical Self- Maintenance Scale (PSMS), IADL, CDR-SB Results suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for 3.3 years, with effect then lost Results suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for 3.3 years, with effect then lost Conclusions Persistent drug treatment had a positive impact on AD progression in terms of cognitive, functional, and global outcome measures Persistent drug treatment had a positive impact on AD progression in terms of cognitive, functional, and global outcome measures Positive treatment effects extended to those at more advanced stages of disease Positive treatment effects extended to those at more advanced stages of disease

125 Conclusions Cholinesterase inhibitors have modest symptomatic benefits in cognition, function, and behavior in mild-moderate AD and remain the only proven therapy for these disease stages after 20 years. They may be associated with increase risk of syncope and falls Cholinesterase inhibitors have modest symptomatic benefits in cognition, function, and behavior in mild-moderate AD and remain the only proven therapy for these disease stages after 20 years. They may be associated with increase risk of syncope and falls Their benefits are also seen in more advanced stages, but are not evident in MCI though some MCI subgroups may be more responsive Their benefits are also seen in more advanced stages, but are not evident in MCI though some MCI subgroups may be more responsive Duration of benefits may go beyond the 6 months used in the pivotal trials but Level 1 evidence for this is scarce and ethically difficult to obtain Duration of benefits may go beyond the 6 months used in the pivotal trials but Level 1 evidence for this is scarce and ethically difficult to obtain Cognitive benefits are likely selective to the processes most affected by acetylcholine (attention/executive, initiation and social engagement) Cognitive benefits are likely selective to the processes most affected by acetylcholine (attention/executive, initiation and social engagement)

126 Translating Advances in Biomarker-based Detection into Clinical Practice Implications for Current Therapies and Beyond SERGE GAUTHIER, MD Director of the Alzheimers Disease Research Unit McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Medicine McGill University Montreal, Quebec Canada Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

127 Outline Case histories of persons at risk Case histories of persons at risk Case history of person with MCI Case history of person with MCI Case histories of persons with AD Case histories of persons with AD Conclusions Conclusions

128 Age: 40 Age: 40 Cognitive symptoms: none Cognitive symptoms: none Family history of AD: mother d55, sister d53 Family history of AD: mother d55, sister d53 Biomarkers: genetic (PS, APP); neuro-imaging (FDG-PET) Biomarkers: genetic (PS, APP); neuro-imaging (FDG-PET) Current Rx: enroll in DIAN Current Rx: enroll in DIAN Future Rx: anti-amyloid Future Rx: anti-amyloid Young Person with Strong Family History of AD

129 FDG-PET IN AD

130 Age: 50 Age: 50 Cognitive symptoms: none Cognitive symptoms: none Family history of AD: mother d85 Family history of AD: mother d85 Biomarkers: genetic (apoE); neuro- imaging (MRI) Biomarkers: genetic (apoE); neuro- imaging (MRI) Current Rx: assess risk using mid-life risk score Current Rx: assess risk using mid-life risk score Future Rx: enhance protective factors Future Rx: enhance protective factors Middle-age Person with Concern About Family History of AD

131 CAIDE Dementia Risk Score Age < 47 years years >53 years Formal education 10 years 7-9 years 0-6 years Sex Women Men 0101 Systolic BP 140 mm Hg > 140 mm Hg 0202 BMI 30 kg/m2 > 30 kg/m Total cholesterol 6.5 mmol/l > 6.5 mmol/l 0202 Physical activity Active Inactive 0101 Kivipelto et al., Lancet Neurol 2006 CAIDE Dementia Risk Score

132 SCORE All /Demented, n % Risk (95% CI) / ( ) / ( ) / ( ) / ( ) / ( ) The overall occurrence of dementia 4.4% Kivipelto et al., Lancet Neurology 2006 Probability of Dementia in Late-life According to the Risk Score Category in Middle Age

133 Age: 76 Age: 76 Cognitive symptoms: none Cognitive symptoms: none Family history of AD: mother d93 Family history of AD: mother d93 Biomarkers: genetic (apoE); neuro- imaging (MRI) Biomarkers: genetic (apoE); neuro- imaging (MRI) Current Rx: assess risk using late-life dementia risk index Current Rx: assess risk using late-life dementia risk index Future Rx: enhance protective factors, reduce risk factors Future Rx: enhance protective factors, reduce risk factors Older Person with Concern About Family History of AD

134 The Late-Life Dementia Risk Index Barnes DE, et al. Barnes DE, et al. Neurology 2009;73; ;

135 Outline Case histories of persons at risk Case histories of persons at risk Case history of person with MCI Case history of person with MCI Case histories of persons with AD Case histories of persons with AD Conclusions Conclusions

136 Age: 70 Age: 70 Cognitive symptoms: mild Cognitive symptoms: mild Family history of AD: mother d87 Family history of AD: mother d87 Biomarkers: genetic (apoE); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET) Biomarkers: genetic (apoE); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET) Current Rx: follow over time Current Rx: follow over time Future Rx: anti-amyloid Future Rx: anti-amyloid Older Person with MCI

137 Dubois et al., Lancet Neurology 2007

138 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease

139 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Dubois et al., Lancet Neurology 2007

140 Slope Analyses According to AD CSF Profile at Baseline Visser PJ, et al. Lancet Neurol 2009; 8: 619–27

141 Outline Case histories of persons at risk Case histories of persons at risk Case history of person with MCI Case history of person with MCI Case histories of persons with AD Case histories of persons with AD Conclusions Conclusions

142 Age: 75 Cognitive symptoms: mild dementia Family history of AD: none Biomarkers: neuro-imaging (MRI) Current Rx: ChEI Future Rx: anti-amyloid Older Person with Mild AD

143 Age: 75 Age: 75 Cognitive symptoms: early dementia Cognitive symptoms: early dementia Family history of AD: none Family history of AD: none Biomarkers: Neuro-imagimg (MRI); CSF low ß42, very high phospho tau Biomarkers: Neuro-imagimg (MRI); CSF low ß42, very high phospho tau Current Rx: ChEI Current Rx: ChEI Future Rx: anti-amyloid and anti-tau Future Rx: anti-amyloid and anti-tau Older Person with AD and High Tau Levels in CSF

144 Distribution of CSF total tau, phosphorylated tau (P- tau), and ß-amyloid 1-42 (Aß42) levels Wallin AK, et al. Wallin AK, et al. Neurology 2010;74;

145 Five-Year Survival in the Three Clusters Wallin AK, et al. Wallin AK, et al. Neurology 2010;74;

146 Pathology by Clinical Status Proximate to Death Schneider JA, et al. Schneider JA, et al. Ann Neurol 2009;66:200–208

147 Outline Case histories of persons at risk Case histories of persons at risk Case history of person with MCI Case history of person with MCI Case histories of persons with AD Case histories of persons with AD Conclusions Conclusions

148 Biomarkers for the Diagnosis and Management of AD Assessment of risk is possible using mid-life and late-life risk profiles, including apoE genotyping Assessment of risk is possible using mid-life and late-life risk profiles, including apoE genotyping Earlier diagnosis of AD is now possible using neuro-imaging and CSF analysis Earlier diagnosis of AD is now possible using neuro-imaging and CSF analysis Better selection of disease-modifying treatments may be possible using CSF analysis and neuro-imaging, knowing the relative weight of each pathological component Better selection of disease-modifying treatments may be possible using CSF analysis and neuro-imaging, knowing the relative weight of each pathological component


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