Investigations • Innovation • Clinical Application Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease The Current Foundation Role of Cholinergic Stimulation of Alzheimer’s Disease—Focus 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 Alzheimer’s Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Program Faculty 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 Alzheimer’s Disease Research Center Director of the VA Northwest Network 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 New York University Langone School of Medicine New York, NY SERGE GAUTHIER, MD Director of the Alzheimer’s 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 Advances in Alzheimer’s Disease Diagnostics and Therapeutics: A Clinician’s 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 Alzheimer’s Disease Research Center Director of the VA Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC) Questions ► How can biomarkers help us diagnose AD and estimate treatment response? ► Do “disease modifying” anti-beta-amyloid (Aβ) therapeutics modify AD progression? ► Are cholinesterases “simply” symptomatic drugs? ► Can we find rational pharmacotherapies for AD agitation/aggression? Keeping Expectations Modest ► If your primary goal is cure, switch to ophthalmology or orthopedics. ► Maintain quality of life and function and relieving distress are important accomplishments. ► Slowing disease progression is a primary goal. Why Biomarkers? ► Earlier diagnosis. ► More precise monitor of the effect of anti-amyloid therapeutics. ► However, cognitive testing may still be most sensitive measure of disease progression. AD Biomarkers ► PET imaging of brain beta-amyloid protein in aggregated form. ► Cerebrospinal fluid Aβ and tau concentrations. “Promise Seen for Detection of Alzheimer’s” Headline – New York Times June 23, 2010 This front page article discusses the development and potential of PET Aβ imaging Beta Amyloid PET Imaging Ligands [11C] Pittsburgh Compound B (PIB) Currently available, but short half-life (20 minutes), requires close proximity to cyclotron. [18F] –AV-45 Approaching availability. Longer half-life (10 minutes), enhances availability. Alzheimer’s Disease Neuroimaging Initiative (ADNI) ► PIB distinguishes AD from MCI from normals. ► PIB highly correlated with CSF Aβ42. ► But PIB and CSF Aβ42 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. ► However, some individuals had apparently meaningful Aβ load increases. Jagust WJ et al, Alzheimer’s and Dementia 6:221-229, 2010. A Treatment Relevance Question ► Does a drug that reduces [C-11] PIBmeasured Aβ load slow cognitive decline? ► If so, do beneficial cognitive effects reflect Aβ load reductions? The “Anti-Amyloid Antibody” Approach to the Treatment of Alzheimer’s Disease ► 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. 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. Estimated Mean Change from Baseline on ADAS-COG ADAS-COG mITT ADAS-COG Completers 2 2 0 Placebo Bapineuzumab 0 -2 -2 -4 -4 -6 -6 -8 -8 -10 -12 Rx difference at week 78 = 2.3 P=0.078 0 11 24 37 50 63 Salloway S, et al. Neurology 2009; 73:2061-2070 -10 78 -12 Rx difference at week 78 = 4.3 P=0.003 0 11 24 37 50 63 78 Bapineuzumab Decreases 11C-PIB Aβ Load ► 28 AD patients assigned to bapineuzumab (n=20) or placebo (n=8). ► Treatment with bapineuzumab for 78 weeks reduced cortical 11C-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. Estimated mean change from baseline in mean C-PiB Estimated Change from Baseline in Mean C-PiB PET 0.4 Placebo Bapineuzumab 0.3 0.2 0.1 0 -0.1 -0.2 Baseline 20 45 Week Rinne JO , et al. Lancet Neurol 2010;9:363-72. 78 Potential Utility of CSF Biomarkers A, Total Tau, and Phosphorylated Tau in Alzheimer’s Disease ► Improving diagnostic accuracy. ► Predictive value. ► Monitoring treatment: ● ● ● Alzheimer’s disease (AD) Mild cognitive impairment (MCI) Primary prevention Neurochemical Changes in Alzheimer’s Disease phospho-tau Neurofibrillary tangles tau Axonal damage oxidation? isoprostanes inflammation?? Amyloid A42 A deposition/metabolism/clearance? A42 is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD Pathogenesis ► ► ► ► ► A42 is the initial amyloid species deposited in brain. A42 exceeds A40 in amyloid deposits. Toxicity and amyloid fibril formation: A42>A 40. in trisomy 21 and almost all APP mutations. Selectively in presenilin mutations. What Does Decreased CSF A42 Mean? ► In Tg 2576 (APP-Swedish mutation) mice, decreases in CSF A42 parallel increases in brain A421. ► In humans, inverse relation between in vivo brain amyloid load (PIB binding) and CSF A42, even in cognitively normal subjects2. 1Kawarabayashi 2Fagan et al., J Neurosci 21:372-381, 2001. et al., Ann Neurol 59:512-519, 2006. Inverse Relation Between in vivo Amyloid Imaging Load and CSF A42 in Humans CSF Aß42 (pg/mL) 1000 750 500 250 0 0.0 0.5 Mean Cortical PIB Binding (Binding Potential) Fagan AM, et al., Ann Neurol 59:512-519, 2006. 1.0 CSF Total Tau in the Diagnosis of AD CSF total tau is measured by a sensitive ELISA. ► Meta-analysis of AD versus controls:1 ► ● ► 35 studies, 2315 AD; 1126 controls In all studies, CSF T-tau in AD > normal controls ● ● ● ● 1Sunderland 2-3 fold increase in AD Effect size = 1.31 (95% CI 1.23-1.39) No correlation with age, dementia duration or severity Increases slightly with aging in normals T, et al., JAMA 289:2094-2103, 2003. Summary of CSF Biomarkers ► CSF A42 is decreased and CSF tau increased in 75-85% of patients with AD. ► Changes in CSF A42 and tau are present, but are less marked, in MCI than AD. Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use of CSF Biomarkers for Preclinical Diagnosis: Where Do We Stand Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease CSF Tau: A42 Ratio for Increased Risk of Mild Cognitive Impairment: A Follow-up Study Li G, et al., Neurology 69:631-639, 2007. Methods ► Subjects: ● ● ● ● ► 129 controls aged 21-100 12 MCI 21 probable AD 12 other neurodegenerative disease CSF collected between 0900-1100 hours after overnight fast. Li G, et al., Neurology 69:631-639, 2007. Subject Characteristics and CSF Biomarker Concentrations Controls < 65 yr Controls ≥ 65 yr MCI AD Other 81 48 12 21 12 M:F 41:40 22:26 8:4 10:11 7:5 Age 40 ± 15* (21 – 64) 73 ± 7 (65 – 100) 71 ± 13 (49 – 82) 69±9 (52 – 87) 63 ± 11 18 14 50 72 --- RBC/l 7 ± 22 (0 – 176) 10 ± 28 (0 – 163) 10 ± 21 (0 – 58) 14 ± 39 (0 – 180) 8 ± 18 (0 – 83) CSF A42 (pg/ml) 313 ± 14 386 ± 34 245 ± 41 225 ± 27* 332 ± 35 CSF tau (pg/ml) 487 ± 24* 784 ± 49 1117 ± 115 1535 ± 131 769 ± 111 CSF P-tau181 (pg/ml) 97 ± 16* 248 ± 33 676 ± 125 936 ± 120 --- n % APOE*4+ Li G, et al., Neurology 69:631-639, 2007. High CSF T/A42 Ratio and Conversion to MCI in 42 month F/U ► Conversion to MCI over 42-months of followup in: ● ● ● 4/17 persons with high CSF T/A42 ratio 0/26 persons with normal CSF T/A42 ratio Logrank test for survival curve, p<0.05 Li G, et al., Neurology 69:631-639, 2007. Implications of High CSF T/A42 Ratio ► The high CSF T/A42 subgroup of controls had significantly increased risk of conversion to MCI during 42 months of follow-up. ► Suggests that high CSF T/A42 individuals had “latent” AD at time of CSF collection. Li G, et al., Neurology 69:631-639, 2007. Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Cross-sectional Lifespan Study Suggests CSF A42 Concentration is Altered in APOE*4 Carriers. Peskind ER, et al., Arch Neurol 63:936-939, 2006. CSF A42 and A40 in 184 Normal Controls Aged 21-88 Peskind ER, et al., Arch Neurol 63:936-939, 2006. A Sobering Finding ► CSF A42 findings consistent with acceleration by the APOE*4 allele of pathogenic A42 deposition starting in later middle life in persons with normal cognition. Peskind ER, et al., Arch Neurol 63:936-939, 2006. Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Reduction of AD Progression ► Persistent treatment slows clinical progression. ► 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. ► Sounds like disease modification to me. 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. ► 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 Galantamine Shows Sustained Cognitive Benefits in AD Over 12 months (including a delayed start time) -4 Double-blind Open-extension in ADAS-Cog from baseline Mean ( SE) change -3 -2 -1 *# *p < 0.05 vs placebo/ Galantamine 24 mg/day # not significantly different from baseline 0 1 2 3 4 Galantamine 24 mg/day Placebo/ Galantamine 24 mg/day 5 6 7 Baseline Data from historical placebo group 3 6 Raskind M et al., Neurology 54:2261–8, 2000 9 12 Mean change from baseline ± SE in ADAS-Cog/11 Long-term Data: Change from Baseline in ADAS-Cog/11 scores Clinical Improvement -4 0 4 8 12 16 20 24 Baseline 3 Placebo comparison Estimation of decline – Stern Equation Clinical Decline Galantamine 24–32 / 24 mg 6 9 12 18 24 Months of Treatment Raskind MA et al. Arch Neurology 61:252-246, 2004. 30 36 Donepezil Significantly Better Compared to Calculated Change by Stern Equation over 3 Years Wallin AK, et al. Dement Geriatr Disord 2007:23:150-160 36-Month Galantamine Trial ► 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.” We Compared Slopes of ADAS-cog Decline Between Dropouts and Completers Change from baseline in ADAS-Cog/11 -1 0 1 2 3 4 5 6 7 8 9 Galantamine patients who completed treatment Galantamine patients who discontinued 10 11 0 10 20 Time (months) Raskind MA, et al., Arch Neurol 61:252-256, 2004. 30 40 If ChEIs Delay Disease Progression, What are the Candidate Mechanisms? ► Nicotinic cholinergic stimulation in vitro: ● ► Muscarinic cholinergic stimulation in vitro: ● ● 1Arias Protects against A-induced neuronal death1 Inhibits A production from amyloid precursor protein (APP)2 Reduces phosphorylation of tau2 E et al., Neuropharmacology 46:103-114, 2004. A et al., J Mol Neurosci 20:349-356, 2003. 2Fisher Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors Role of Alpha-4 and Alpha-7 Receptors in Neuroprotection ► An excellent review ► Highlights: ● ● 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. Akaike A, et al. J Mol Neurosci 40:211-216, 2010 Loss of Alpha-7 Nicotinic Receptors Enhances Beta-amyloid Oligomer Accumulation in a Mouse Model of Alzheimer’s Disease ► “Alzheimer’s” transgenic mice with deletion of the alpha-7 nicotinic receptor have increased: ● ● ● Learning and memory deficits Hippocampal and cholinergic neurodegeneration Soluble oligomer (neurotoxic) beta-amyloid Hernandez CM, et al. J Neuroscience 30:2442-2453, 2010. Disruptive Agitation: What is it? Distressing behaviors that often cluster together • • • • • Irritability Anger outbursts, aggression Sleep disruption Pressured pacing and restlessness Uncooperativeness with necessary care Major cause of long-term care placement. Commonly Used Psychotropic Medications for Disruptive Agitation in AD ► Antipsychotics: haloperidol, risperidone, olanzapine, aripiprazole, quetiapine. All show modest efficacy in some placebo-controlled trials. ● ● ● Frequent non-responders Adverse effects: pseudoparkinsonism, sedation 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? The Brain Noradrenergic System ► The noradrenergic system is the brain “adrenaline” system for attention and arousal. ► Excessive noradrenergic reactivity produces anxiety and agitation. ► Does excessive noradrenergic activity contribute to agitation in AD? Noradrenergic System Pathology in Alzheimer’s Disease ► Despite loss of noradrenergic locus coeruleus neurons there is: ● ● ● ● 1Elrod Increased cerebrospinal fluid (CSF) norepinephrine (NE) in AD1 Increased agitation response to NE in AD2 Compensatory upregulation of surviving LC neurons3 Increased alpha-1 adrenoreceptors in locus ceruleus target areas4 et al., Am J Psychiatry 154:25-30, 1997. et al., Arch Gen Psychiatry, 1995. 3Szot, et al., J Neuroscience, 2006. 4Szot, et al., J Neuroscience, 2007. 2Peskind, CSF norepinephrine (pg/ml) CSF Norepinephrine: Effects of Aging and AD 500 *significantly higher than young subjects **significantly higher than all other subject groups ** 400 * 300 * 200 100 0 Young (n=54) Old (n=42) Elrod et al., Am J Psychiatry 154:25-30, 1997.4 Mild-Moderate Advanced AD (n=49) AD (n=25) Postsynaptic Adrenergic Receptor Antagonists in AD ► Would reducing brain responsiveness to NE by blocking adrenergic receptors reduce agitation in AD? ► Alpha-1 receptor antagonist: prazosin. ● ● Long lasting benefits in posttraumatic stress disorder Would prazosin be helpful in AD? Raskind MA, et al., Am J Psychiatry 160:371-373, 2003. Prazosin as a Novel Pharmacologic Approach to Agitation in AD ► Prazosin is an alpha-1 receptor antagonist. ● Only one that crosses from the blood into the brain ► Inexpensive, generic, used for BPH and hypertension by millions of older persons for decades. ► Clinically effective for AD agitation in open label pilot study. 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. ► 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). ► Primary outcome measures: BPRS, NPI, CGIC. Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia: NPI Wang L, et al., Am J Geriatr Psych 17:744-75, 2009. 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. ► 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. Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease 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 Objectives ► Pathophysiology of AD ► Beta-amlyoid hypothesis ► Cholinergic Hypothesis ► Clinical and therapeutic implications of Cholinergic hypothesis ► Intersection of cholinergic and amyloid-based pathobiology ► Approaches to therapy ► Implications for multi-modal therapies for AD Pathophysiology of AD ► Neuropathologic hallmarks of AD ● Senile plaques – Amyloid b-protein (Ab) ● Neurofibrillary tangle – tau protein ► Largely a sporadic, late-life cause of dementia, early-onset and familial forms exist ● Mutations in APP, PS-1 and PS-2 ● Mutations increase production of Ab ► Late-onset disease is associated with presence of the e4 allele of Apolipoprotein E ● More than 40 other genes have been associated with AD Amyloid Hypothesis ► First proposed in 1991 ► Initiating molecule in AD, ultimately leading to AD ► Mutations in familial AD encode substrate (APP) and enzyme (Presenilin) for A production ► Infusions of A cause neuronal degeneration and cognitive deficits ► 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 A is Derived After Cleavage of APP sAPP Plaque sAPPa APP Ab a g p3 g A Lumen/ Extracellular Cytosol AICD C99 C83 AICD (-stub) (a-stub) (A50-Cter) APP = amyloid precursor protein; sAPP = soluble form of APP; AICD = APP intracellular domain Acetylcholine ► ACh activity known since turn of 20th century ● Nobel prize to Henry Dales and Otto Loewi ► Synthesized de novo by the brain ► Two types of receptors ● ● ► Muscaric Nicotinic In the CNS, largely produced in collection of neurons in basal forebrain and pons with widerange projections Cholinergic Projections From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7th Ed, 1996 Cholinergic Hypothesis ► ► Dysfunction of cholinergic system contributes to memory decline Drachman and Leavitt (1974) ● ● ● ► Link between cholinergic dysfunction and memory impairment Scopolamine in young adults caused impairment Corroborated by primate, canine and rodent studies Reduced choline acetyl transferase (ChAT) activity in cortex, hippocampus and amygdala of AD patients ● ● Activity correlated with level of cognitive impairment Selective loss of cholinergic cells in basal forebrain Davies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981. Neuropathological Signaling: Cholinergic Hypothesis Presynaptic Neuron Acetyl CoA + Choline Glial Cell Choline ChAT BuChE ACh Synaptic Cleft Postsynaptic Neuron ACh AChE Choline + Acetate AChE Cholinergic Receptor ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A. Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl 139):69-74. BuChE Cholinergic Hypothesis ► 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 Perry et al 1999, Bartus 2000, Cholinergic Receptors and AD ► Two classes ● Nicotinic ionic channels • Responsible for fast transmission • Reduction in a4 nAChR in AD • Up-regulation of a7 nAChR in AD compared with MCI and controls – a7 receptors down-regulated in DLB • Possible compensatory response to maintain basal forebrain-cortical cholinergic activity • a7 nAChR interacts with APP and A peptides which ● could lead to aberrant function Muscarinic G protein-coupled receptors • Preserved during progression of AD • 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 Mufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006 Role of Cholinergic Deficits in Behavioral Symptoms of AD ► Temporal and frontal lobe dysfunction implicated in psychosis of AD ► Regional cholinergic deficits—apathy and indifference ► Cholinergic-monoaminergic imbalance hypothesized in mood disorders ► Cholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trials Lanari A, et al 2006; Cummings JL. 2000 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 ● ► AChE does not show decline until late stages of disease ● ► Only mild losses in MCI and mild AD Vesicular Ach transporter is not severely altered in AD ● ● ► Correlated with task performance 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 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 Saykin et al, 2004, Bierer et al 1995, Rinne et al, 2003, Gilmor et al, 1999, Rinne et al 1987, Mufson et al, 2009 Challenges to Cholinergic Hypothesis ► Studies of post-mortem tissue ● ● ► ► 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 ● ● ● ► Levels of AChE and ChAT are not reduced in very mild AD Levels of ChAT may be upregulated in MCI and very mild AD Alterations in high-affinity choline transport (rate-limiting step) Deficits in nicotinic and muscarinic receptors Dysfunctional neurotrophic support Neurochemical analyses of autopsy tissue maybe unreliable ● ● Dependent on length of agonal state and post-mortem interval More recent in vivo imaging studies support amyloid hypothesis • 11C N-methylpiperidine-4-yl proprianate (AChE activity) • Nicotine-based ligands • Non-selective muscarinic ligands • 123I 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 Recent Developments ► Extension of studies to early, prodromal stages ● ● ● Religious Orders Study Very mild cases did not show decreases in ChAT but actually increases Immunochemistry of brain with very mild AD/MCI • ChAT or vesicular ACh transporter not reduced • Markers of NGF receptors markedly reduced • 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 • Altered neurotrophic receptors may mark early stage of disease with initial increases in ChAT activity • 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 Interactions Between Amyloid and Cholinergic Hypotheses ► Regulation of A by stimulation of muscarinic or nicotinic receptors ● ● Partial M1 agonists increase aAPPs, decrease A and decrease tau phosphorylation Nicotine may increase downstream synthesis of neurotropins ► Cholinergic deficits could be secondary to amyloid toxicity ► Bidirectional interaction between cholinergic function and processing of amyloid precursor protein ● ● ● High affinitity a7 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 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 Interactions Between Ab and ACh ► Toxicity of A on the cholinergic system ● ● ● ● ● ● ► Ach synthesis and release reduced by solubilized Ab Loss of cholinergic fibers without loss of cholinergic neurons Reduction of binding to vesicular Ach transporter Inhibition of fast axonal transport A 42 binds with higher affinity to a7 nAChR than A 40 A 42 reduced downstream events in mAChR signal transduction Cholinergic system and APP processing via a-secretase ● ● ● mAChR a7nAChR agonists 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 Mechanisms of AChE Inhibitors on the Release of sAPPα AchE inhibitor Change Tacrine Metrifonate Cholinergic mechanism Other mechanism Reference Decrease − ? Lahiri et al. (1994); Lahiri et al. (1996) Increase + ? (Pakaski et al., 2000) and (Pakaski et al., 2001); Racchi et al. (2001) Ambenonium Increase + ? Pakaski et al. (2001) Ganstigmine Increase + ? Mazzucchelli et al. (2003) Ladostigil Increase + Donepezil Increase + Phenserine Decrease − Galantamine Increase + Pakaski and Kalman 2008 MAP-kinase or tyrosin Yogev-Falach et al. (2002) kinase-dependent pathway Enhancing trafficking and Zimmermann et al. (2004) activity of ADAM 10 Inhibition of APP mRNA Lahiri et al. (2000); Shaw et al. (2001) translation ? Lenzken et al. (2007) Linking Ab and ACh Pakaski and Kalman 2008 Discrimination Between Disease Modification and Symptomatic Benefit Withdrawal design Randomized phase Placebo phase Active Disease-modifying effect Placebo Performance Performance Randomized phase Staggered-start design Placebo phase Active Placebo Symptomatic effect Symptomatic effect Disease-modifying effect Time Time Is There Evidence of DiseaseModifying Effects? ► From clinical trials, functional imaging and basic science studies, anti-cholinesterase drugs may: ● ● ● ● ► Reduce circulating A Alter APP processing Prevent A deposition in cholinergic projection sites 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 Lopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000 Amyloid-Based Approaches Barten and Albright 2008 Immunization Reduces Ab burden Holmes et al 2008 Immunization Does not rRduce Disease Burden Time to severe dementia Holmes et al 2008 Time to death Neurotransmitter-Based Approaches Barten and Albright 2008 Model of Multi-Modal Approach Performance Mild Moderate Severe Disease-modifying Rx Combining Symptomatic and Disease-modifying RX Symptomatic Rx Time 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 ► Ach provides targets for symptomatic benefit ● ● Dysfunction/degeneration of the cholinergic projection neurons is a later stage event in AD 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 Summary (cont.) ► 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 ● ► 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 Mufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Evidence-based Role of Cholinesterase Inhibition Across the Severity Spectrum in AD SANDRA E. BLACK, MD, FRCPC Brill Chair in Neurology University of Toronto, Sunnybrook Health Sciences Centre Toronto, Ontario Canada Learning Objectives ► Review evidence for cholinesterase inhibitors as cognitive enhancers in mild-moderate Alzheimer’s Disease ► Summarize evidence for utility in earlier and later stages of AD ► Consider evidence for longer term use See Canadian Consensus on Dementia Diagnosis and Treatment: Hogan et al, CMAJ 2008; Alzheimer’s and Dementia special issue 2007 The Cholinergic Deficit in AD – Progressive loss of cholinergic neurons – Progressive decrease in available ACh N. basalis Meynert – Impairment in ADL, behavior and cognition Cortex Hippocampus Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978 Cholinesterase Inhibitors: Mechanisms of Action Presynaptic nerve terminal ACh N = nicotinic M = muscarinic ACh = acetylcholine Astrocyte BuChE N receptor Galantamine M receptor Donepezil Rivastigmine Galantamine Acetylcholinesterase Rivastigmine ACh Butyrylcholinesterase Postsynaptic nerve terminal Increased availability of ACh at synapse (AChE and BuChE inhibition) Efficacy-Cognitive Improvement benefit Rogers, 1998b no benefit Rosler, 1999 Wilcock, 2000 heterogeneous Rockwood, 2001 Wilkinson, 2001 Meta-analytic difference 30% 20% 10% 0% -10% 10% [4%, 17%] of patients show significant benefit over placebo Lanctot et al, CMAJ, 2003 Efficacy Clinical Global Impression Rogers, 1998a Rogers, 1998b Burns, 1999 Rosler, 1999 Raskind, 2000 Wilcock, 2000 Rockwood, 2001 Wilkinson, 2001 Meta-analytic difference 30% 20% benefit no benefit Homogeneous 10% 0% -10% 9% [6%, 12%] of patients show significant benefit over placebo Lanctot et al, CMAJ, 2003 Number Needed to Treat for Benefit ► Numbers needed to treat to benefit ● ● ● 7 (CI95%: 6, 9) for stabilization or better 12 (CI95%: 9, 16) for minimal improvement or better 42 (CI95%: 26, 114) for marked improvement ►NNT for clinically benefit are low. ►Homogeneous-all 3 ChEI similar Lanctot et al, CMAJ, 2003 Tolerability 14 Caveat ChEI placebo diff 12 Galantamine above recommended doses, heterogeneity 10 8 6 donepezil rivastigmine galantamine 4 2 0 DO 8% [5,11] Lanctot et al CMAJ, 2003 AE DO d/t AE 8% [5,12] 7% [3,10] Safety ► 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) ► 19,803 treated with cholinesterase inhibitors vs 61,499 not on CHEI’s ● ● ● ● Syncope 31.5 vs 18.6/1000 Bradycardia 6.9 vs 4-4/1000 Pacemaker needed 4.7 vs 3.3/1000 Hip fracture 22.4 vs 19.8/1000 Gill et al Arch Int Med 2009 HR 1.76 HR 1.69 HR 1.49 HR 1.18 Limitations of Drug Trials to Date ► ► Benefits in cognition, behavior and function have been for 6 monthsonly a few 1-year placebo-controlled studies 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 ► 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 ► Recent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practice Kaduszkiewicz et al., BMJ, 2005 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use in Early and Later Disease Stages Natural History of AD: early 30 25 Loss of functional independence 20 MMSE Early Cognitive symptoms Mild-moderate Behavioural problems 15 10 Nursing home placement 5 Severe Death 0 1 2 3 4 5 6 7 8 Years Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998. 9 Proportion Free of Dementia (%) Conversion of Normal and MCI Subjects to Dementia (AD Cooperative Study) 100 90 80 70 60 50 40 30 20 10 0 0.0 Normals MCI 45% 0.5 1.0 1.5 2.0 2.5 Follow-up Time (Years) 3.0 3.5 Retrospective analysis of 687 subjects with MCI Mean age 72.2 yrs DeKosky ST. J Am Geriatr Soc, 2003; Adapted from Grundman M et al, Abstract in Neurology, 1996. ADCS: MCI Study Design Objectives ► 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 ► 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: Secondary: Conversion to AD MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, Neuropsychological battery Petersen et al. N Engl J Med, 2005 Survival Analysis: Donepezil vs. Placebo 6 mo 1 yr 18 mo Probability of not converting to AD 1.0 0.9 0.8 0.7 0.6 Donepezil Placebo p<0.001 0.5 p<0.009 p<0.035 0.4 0 200 400 600 800 Time on MCI study (days) Petersen RC et al. N Engl J Med, 2005 1,000 1,200 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) ► Recent 48 wk study of donepezil in 821 aMCI patients likewise found nsd in 1o and 2o 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 ► 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 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 Key Results • 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) • 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 Doody, et al., Am J of AD & Other Dem. 2010 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 • 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 • 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 Conclusions • Depressive symptoms may be predictive of progression from aMCI to AD • Treatment with donepezil delayed progression to AD in depressive subjects with aMCI Lu, et al., Neurology 2009 Survival Lu, et al., Neurology 2009 Natural History of AD: Moderate to severe stage 30 Early Cognitive symptoms 25 Loss of functional independence MMSE 20 Mild-moderate 15 Behavioural problems 10 Nursing home placement 5 Severe Death 0 1 2 3 4 5 6 7 8 9 Years Feldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998. Donepezil vs Placebo in Nursing Home Study in Severe AD (MMSE 1-10): Cognition (SIB) 6 Mean Change From Baseline in SIB Score p=0.003* SIB p=0.008* p=0.008† Clinical improvement 4 2 Baseline 0 -2 Donepezil Placebo -4 Clinical decline -6 0 3 6 ITT LOCF Months Winblad et al. Lancet, 2006. *OC analysis; †LOCF analysis. Mean Change From Baseline in ADCS-ADL Functional Abilities Also Showed Less Decline 4 Donepezil Placebo 3 Clinical Improvement 2 1 P = 0.086* P = 0.031* P = 0.029† Baseline 0 -1 -2 -3 Clinical Decline -4 0 3 6 Months *OC analysis; †LOCF analysis. Winblad et al Lancet, 2006 ITT LOCF SIB scores: LS mean change from baseline (SE) Less Cognitive Decline in Community Dwelling Severe AD (MMSE1-12) 8 6 p =0 .0001 4 Clinical improvement 2 0 -2 d Clinical decline -4 Donepezil 10mg/d Placebo -6 -8 0 8 16 Study week Black et al Neur 2007 24 ITT LOCF Cholinesterase Inhibitor Use in Other Dementias ► Level 1 evidence for different compounds according to studies undertaken ● ● ● ● Donepezil in vascular dementia Rivastigmine in parkinson/diffuse lewy body dementia Galantamine in mixed vascular dementia (Memantine also shows efficacy in moderate to severe AD) Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Use of Higher Doses, New Formulations 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) Winblad et al. Int J Geri Psych. 2007 Recent caution due to additive dose effects if patch not removed daily before new one applied Safety & Tolerability of Higher Dose Donepezil (20mg) Purpose • 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 • 31 patients (male and female) aged 50-86 years •All patients had been treated with 10mg/day donepezil for 12-30 months prior to enrollment • Primary outcome measures: • Tolerability (discontinuations, dose modifications, and adverse events) • Safety (monitored by adverse events, physical examinations, clinical lab tests, and ECGs) • Secondary outcome measures: • Psychometric measures: ADAS-Cog, MMSE, CIBIC+, pharmacokinetic/pharmacodynamic parameters Doody, et al., Drugs Aging 2008 Safety & Tolerability of higher dose Donepezil (20mg) Key Results •Higher-dose group: •15 of 16 patients tolerated the maximum 20 mg/day dose by week 24 • Standard-dose group: •14 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 • No difference between groups on psychometric measures Conclusions • 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. Doody, et al., Drugs Aging 2008 High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage AD Purpose ► To determine effectiveness, safety and tolerability of 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezil Design ► 1467 patients (465 US) in 209 sites randomized to 23mg (n=972) vs 10mg (n= 479) ► MMSE: 76%: 0-16; 34%: 17-20 ► Approx 36% also on memantine (75% in US) Results ► Discontinuation higher for 23 mg vs 10mg: ● 30% (18% for AE’s vs 18% (8% for AE’s) Effectiveness analysis:Cognition Severe Impairment Battery Less decline from baseline on SIB P<0.001 Farlow et al. Clinical Therapeutics 2010. MMSE Frequency Distribution of CIBIC Scores at Week 24 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 % Farlow et al. Clinical Therapeutics2010. 8.6 vs 9.6 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Is There Any Evidence for Longer Term Use of Cholinesterase Inhibitors? Rivastigmine-Placebo Group Does not Catch Up to Treated Group 6–12 mg/day rivastigmine Placebo Proj. placebo ADAS-Cog mean change from baseline 2 1–4 mg/day rivastigmine Dose optimization with rivastigmine (6-12 mg/day) * 0 * –2 * * * * * –4 –6 * * All patients restarted on rivastigmine –8 0 10 Messina et al., 2000 20 26 30 Study week 40 50 B352 patients in Study B353 (OC) at week 52 *p<0.05 vs projected placebo Mean Change in ADAS-Cog Score from Baseline: Open Label Galantamine Over 4 Years Mean change from baseline (±SE) in ADAS-Cog/11 –4 0 4 8 12 16 12-month placebo 20 Expected decline in untreated patients of 6–9 points/year 24 Galantamine 24–32/24 mg 28 Baseline 3 6 9 12 (n) (322) (309) (310) (233) (298) 24 36 48 (228) (140) (103) Time (months) Database and from Raskind et al Arch Neurol 2004. 1-year Preservation of Function Study with Donepezil Design ► 1-year, randomized, placebo-controlled, double-blind Subjects ► 431 patients with mild-to-moderate AD ► Aged 49-94, mean MMSE 17.1 Primary Outcome ► Time to clinically evident functional decline’, defined by: ● Decline in 1 basic 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) Mohs et al. Neurology. 2001 Time to Clinically Evident Functional Decline* 1 Kaplan-Meier survival estimates Probability of survival 0.9 The probability of survival (maintaining functional ability) at 48 weeks was: 51% for donepezil 35% for placebo 0.8 0.7 0.6 0.5 0.4 Donepezil 10 mg/day Placebo 0.3 0.2 Survival curve comparison: p=0.002 (log-rank test) p=0.005 (Wilcoxon test) 0.1 0 0 6 12 18 24 30 36 42 48 54 Duration of treatment (weeks) *As judged by investigator, ITT population Mohs et al. Neurology. 2001 Longer-Term Effects: Non-Pharmaceutical Sponsored Study 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) Issues: 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 c) 51% of total sample had CVD Other Studies Suggesting Symptomatic Stabilization over Longer Periods ► 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 donepezil1 ► 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 1Bullock R et al. CMRO 2005 et al. Alzheimer Dis Assoc Disord 1997 3 Feldman et al. Neurology 2001 4Winblad et al. Neurology 2001; 5Klatte et al. Alzheimer Dis Assoc Disord 2003 6Small et al Int J Clin Pract 2005 7Aisen et al. JAMA 2003 2Schmitt Patients on ChEI’s Had Less Decline in Multiple Cognitive Domains over 1 Year Less decline in: • • • • Overall cognition Naming Visuospatial and visuoconstructive skills Executive functions Dementia Rating Scale 125 120 Mean DRS scores N= 65 in each of treated vs untreated group, wellmatched on age, edcuation, severity, comorbidities, vasc risk factors and medications untreated treated 115 110 105 100 95 90 baseline follow-up p<0.0001 Effect size Behl et al Dem Ger Cog Dis 2006 d = 0.7 Patients on ChEI’s Continued to Show Less Decline on Select Cognitive Domains at Two Years Verbal Memory Mean CVLT acquisition Treated patients showed less decline on: • Overall cognition • Memory • Naming • Executive functions 30 25 untreated treated 20 15 10 5 0 baseline follow-up1 follow-up2 p=0.007 ES: d1 =0.8; d2 = 0.4 Behl et al Dem Ger Cog Dis 2006 Patients on ChEI’s also showed less decline in functional abilities over 2 years, especially in initiation (DAD) Instrumental 80 70 60 50 40 untreated 30 treated 20 10 0 baseline follow-up1 follow-up2 Basic 80 mean basic ADLs initiation Mean overall DAD initiation 90 Mean Instrumental initiation scores Overall DAD 70 60 50 40 untreated 30 treated 20 10 0 baseline follow-up1 follow-up2 120 100 80 60 untreated 40 treated 20 0 baseline follow-up1 follow-up2 Pyear1=0.036; Pyear2=0.001 Pyear1=0.04; Pyear2=0.001 Pyear1=0.08 ; Pyear2=0.001 ES 1= 0.5; ES 1 =0.6; ES 2= 0.9 ES 1= 0.4; ES 2= 0.8 Behl et al, Int Psychoger 2008 ES 2 = 0.7 Also Planning and Organization Basic Overall DAD 120 mean basic ADLs planning Mean overall DAD planning 90 80 70 60 50 40 untreated 30 treated 20 10 100 80 60 untreated 40 treated 20 0 0 baseline follow-up1 follow-up2 Pyear1= 0.038; Pyear2=0.006 ES 1=0.8; ES 2 =1.0 Behl et al, Int Psychoger 2008 baseline follow-up1 Pyear1=0.039; Pyear2=0.001 ES 1 = 0.7; ES = 1.0 follow-up2 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 • 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 Key Results • PI was associated with significantly slower rates of decline on MMSE, Physical SelfMaintenance Scale (PSMS), IADL, CDR-SB • 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 • Positive treatment effects extended to those at more advanced stages of disease Rountree, et al., Alzheimer’s Res. & Ther. 2009 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 ► 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 ► Cognitive benefits are likely selective to the processes most affected by acetylcholine (attention/executive, initiation and social engagement) Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Translating Advances in Biomarker-based Detection into Clinical Practice Implications for Current Therapies and Beyond SERGE GAUTHIER, MD Director of the Alzheimer’s Disease Research Unit McGill Centre for Studies in Aging Professor of Neurology and Neurosurgery, Psychiatry and Medicine McGill University Montreal, Quebec Canada Outline ► Case histories of persons at risk ► Case history of person with MCI ► Case histories of persons with AD ► Conclusions Young Person with Strong Family History of AD ► Age: 40 ► Cognitive symptoms: none ► Family history of AD: mother d55, sister d53 ► Biomarkers: genetic (PS, APP); neuro-imaging (FDG-PET) ► Current Rx: enroll in DIAN ► Future Rx: anti-amyloid FDG-PET IN AD Middle-age Person with Concern About Family History of AD ► Age: 50 ► Cognitive symptoms: none ► Family history of AD: mother d85 ► Biomarkers: genetic (apoE); neuroimaging (MRI) ► Current Rx: assess risk using mid-life risk score ► Future Rx: enhance protective factors CAIDE Dementia Risk Score CAIDE Dementia Risk Score < 47 years 47-53 years >53 years 0 3 4 ≥10 years 7-9 years 0-6 years 0 2 3 Women Men 0 1 140 mm Hg > 140 mm Hg 0 2 BMI 30 kg/m2 > 30 kg/m2 0 2 Total cholesterol 6.5 mmol/l > 6.5 mmol/l 0 2 Physical activity Active Inactive 0 1 Age Formal education Sex Systolic BP Kivipelto et al., Lancet Neurol 2006 Probability of Dementia in Late-life According to the Risk Score Category in Middle Age The overall occurrence of dementia 4.4% SCORE All /Demented, n % Risk (95% CI) 0-5 401 / 4 1.0 (0.0-2.0) 6-7 270 / 5 1.9 (0.2-3.5) 8-9 312 / 13 4.2 (1.9-6.4) 10-11 245 / 18 7.4 (4.1-10.6) 12-15 122 / 20 16.4 (9.7-23.1) Kivipelto et al., Lancet Neurology 2006 Older Person with Concern About Family History of AD ► Age: 76 ► Cognitive symptoms: none ► Family history of AD: mother d93 ► Biomarkers: genetic (apoE); neuroimaging (MRI) ► Current Rx: assess risk using late-life dementia risk index ► Future Rx: enhance protective factors, reduce risk factors The Late-Life Dementia Risk Index Barnes DE, et al. Neurology 2009;73;173-179; Outline ► Case histories of persons at risk ► Case history of person with MCI ► Case histories of persons with AD ► Conclusions Older Person with MCI ► Age: 70 ► Cognitive symptoms: mild ► Family history of AD: mother d87 ► Biomarkers: genetic (apoE); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET) ► Current Rx: follow over time ► Future Rx: anti-amyloid Dubois et al., Lancet Neurology 2007 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Dubois et al., Lancet Neurology 2007 Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's Disease Dubois et al., Lancet Neurology 2007 Slope Analyses According to AD CSF Profile at Baseline Visser PJ, et al. Lancet Neurol 2009; 8: 619–27 Outline ► Case histories of persons at risk ► Case history of person with MCI ► Case histories of persons with AD ► Conclusions Older Person with Mild AD ► 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 AD and High Tau Levels in CSF ► Age: 75 ► Cognitive symptoms: early dementia ► Family history of AD: none ► Biomarkers: Neuro-imagimg (MRI); CSF low ß42, very high phospho tau ► Current Rx: ChEI ► Future Rx: anti-amyloid and anti-tau Distribution of CSF total tau, phosphorylated tau (Ptau), and ß-amyloid 1-42 (Aß42) levels Wallin AK, et al. Neurology 2010;74;1531-1537 Five-Year Survival in the Three Clusters Wallin AK, et al. Neurology 2010;74;1531-1537 Pathology by Clinical Status Proximate to Death Schneider JA, et al. Ann Neurol 2009;66:200–208 Outline ► Case histories of persons at risk ► Case history of person with MCI ► Case histories of persons with AD ► Conclusions Biomarkers for the Diagnosis and Management of AD ► 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 ► Better selection of disease-modifying treatments may be possible using CSF analysis and neuro-imaging, knowing the relative weight of each pathological component