2 Optimizing Neurotherapy and Emerging Paradigm for Alzheimer’s Disease Investigations • Innovation • Clinical ApplicationOptimizing Neurotherapy and Emerging Paradigmfor Alzheimer’s DiseaseThe Current Foundation Role of Cholinergic Stimulation of Alzheimer’s Disease—Focus on Evidence-Based Management of Moderate and Severe ADProgram ChairmanMURRAY A. RASKIND, MDProfessor and Vice-ChairmanDepartment of Psychiatry and Behavioral SciencesUniversity of Washington School of MedicineDirector of the University of Washington Alzheimer’s Disease Research CenterDirector of the VA Northwest Network Mental IllnessResearch, Education and Clinical Center (MIRECC)
3Program Faculty Program Chairman MURRAY A. RASKIND, MD Professor and Vice-ChairmanDepartment of Psychiatry and BehavioralSciencesUniversity of Washington School ofMedicineDirector of the University of WashingtonAlzheimer’s Disease Research CenterDirector of the VA Northwest NetworkMental IllnessResearch, Education and Clinical CenterSeattle, WASANDRA E. BLACK, MD, FRCPCBrill Chair in NeurologyUniversity of Toronto, SunnybrookHealth Sciences CentreToronto, Ontario CanadaJAMES E. GALVIN, MD, MPHProfessor of Neurology and PsychiatryDirector of Clinical OperationsCenter of Excellence on Brain AgingDirector Pearl Barlow Center forMemory Evaluation and TreatmentNew York University Langone School ofMedicineNew York, NYSERGE GAUTHIER, MDDirector of the Alzheimer’s DiseaseResearch UnitMcGill Centre for Studies in AgingProfessor of Neurology and Neurosurgery,Psychiatry and MedicineMcGill UniversityMontreal, Quebec Canada
4Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseAdvances in Alzheimer’s Disease Diagnostics and Therapeutics: A Clinician’s PerspectiveProgram ChairmanMURRAY A. RASKIND, MDProfessor and Vice-ChairmanDepartment of Psychiatry and Behavioral SciencesUniversity of Washington School of MedicineDirector of the University of Washington Alzheimer’s Disease Research CenterDirector of the VA Northwest Network Mental IllnessResearch, Education and Clinical Center (MIRECC)
5QuestionsHow 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?
6Keeping 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.
7Why 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.
8AD BiomarkersPET imaging of brain beta-amyloid protein in aggregated form.Cerebrospinal fluid Aβ and tau concentrations.
9“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
10Beta 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.
11Alzheimer’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: , 2010.
12A Treatment Relevance Question Does a drug that reduces [C-11] PIB-measured Aβ load slow cognitive decline?If so, do beneficial cognitive effects reflect Aβ load reductions?
13The “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.
14Would 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.
15Estimated Mean Change from Baseline on ADAS-COG ADAS-COG mITTADAS-COG Completers2-2-4-6-8-10-122-2-4-6-8-10-12PlaceboBapineuzumabRx difference at week 78 = 2.3P=0.078Rx difference at week 78 = 4.3P=0.003Salloway S, et al. Neurology 2009; 73:
16Bapineuzumab 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.
17Estimated Change from Baseline in Mean C-PiB PET WeekEstimated mean change from baseline in mean C-PiBBaseline0.40.30.20.1-0.1-0.2PlaceboBapineuzumabRinne JO , et al. Lancet Neurol 2010;9:
18Potential Utility of CSF Biomarkers 3/27/2017Potential Utility of CSF BiomarkersA, Total Tau, and Phosphorylated Tau - in Alzheimer’s DiseaseImproving diagnostic accuracy.Predictive value.Monitoring treatment:Alzheimer’s disease (AD)Mild cognitive impairment (MCI)Primary preventionCSF biomarkers/EP 1-07
203/27/2017A42 is the Initiator and Main Culprit in Amyloid Deposition, and Implicated in AD PathogenesisA42 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.CSF biomarkers/EP 1-07
21What Does Decreased CSF A42 Mean? 3/27/2017What 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 et al., J Neurosci 21: , 2001.2Fagan et al., Ann Neurol 59: , 2006.CSF biomarkers/EP 1-07
22Mean Cortical PIB Binding Inverse Relation Between in vivo Amyloid Imaging Load and CSF A42 in Humans1000750500250CSF Aß42 (pg/mL)Mean Cortical PIB Binding(Binding Potential)Fagan AM, et al., Ann Neurol 59: , 2006.
23CSF Total Tau in the Diagnosis of AD 3/27/2017CSF Total Tau in the Diagnosis of ADCSF total tau is measured by a sensitive ELISA.Meta-analysis of AD versus controls:135 studies, 2315 AD; 1126 controlsIn all studies, CSF T-tau in AD > normal controls2-3 fold increase in ADEffect size = 1.31 (95% CI )No correlation with age, dementia duration or severityIncreases slightly with aging in normals1Sunderland T, et al., JAMA 289: , 2003.CSF biomarkers/EP 1-07
24Summary of CSF Biomarkers 3/27/2017Summary of CSF BiomarkersCSF 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.CSF biomarkers/EP 1-07
25Use of CSF Biomarkers for Preclinical Diagnosis: Where Do We Stand 3/27/2017Optimizing Neurotherapy and Emerging Paradigms forAlzheimer's DiseaseUse of CSF Biomarkers for Preclinical Diagnosis: Where Do We StandCSF biomarkers/EP 1-07
26Optimizing Neurotherapy and Emerging Paradigms for 3/27/2017Optimizing Neurotherapy and Emerging Paradigms forAlzheimer's DiseaseCSF Tau: A42 Ratio for Increased Risk of Mild Cognitive Impairment: A Follow-up StudyLi G, et al., Neurology 69: , 2007.CSF biomarkers/EP 1-07
273/27/2017MethodsSubjects:129 controls aged12 MCI21 probable AD12 other neurodegenerative diseaseCSF collected between hours after overnight fast.Li G, et al., Neurology 69: , 2007.CSF biomarkers/EP 1-07
29High CSF T/A42 Ratio and Conversion to MCI in 42 month F/U 3/27/2017Conversion to MCI over 42-months of follow-up in:4/17 persons with high CSF T/A42 ratio0/26 persons with normal CSF T/A42 ratioLogrank test for survival curve, p<0.05Li G, et al., Neurology 69: , 2007.CSF biomarkers/EP 1-07
30Implications of High CSF T/A42 Ratio 3/27/2017Implications of High CSF T/A42 RatioThe 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: , 2007.CSF biomarkers/EP 1-07
31Optimizing Neurotherapy and Emerging Paradigms for 3/27/2017Optimizing Neurotherapy and Emerging Paradigms forAlzheimer's DiseaseCross-sectional Lifespan Study Suggests CSF A42 Concentration is Altered in APOE*4 Carriers.Peskind ER, et al., Arch Neurol 63: , 2006.CSF biomarkers/EP 1-07
32CSF A42 and A40 in 184 Normal Controls Aged 21-88 3/27/2017Peskind ER, et al., Arch Neurol 63: , 2006.CSF biomarkers/EP 1-07
333/27/2017A Sobering FindingCSF 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: , 2006.CSF biomarkers/EP 1-07
34Persistent treatment slows clinical progression. Cholinesterase Inhibitor Clinical Experience and Clinical Trials Support Reduction of AD ProgressionPersistent 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.
35Persistent 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
36Galantamine Shows Sustained Cognitive Benefits in AD Over 12 months (including a delayed start time)Double-blindOpen-extension- 4- 3- 2- 11234567*p < 0.05 vs placebo/ Galantamine 24 mg/day# not significantly different from baseline*#in ADAS-Cog from baselineMean ( SE) changeGalantamine 24 mg/dayPlacebo/ Galantamine 24 mg/dayData from historical placebo groupBaseline36912Raskind M et al., Neurology 54:2261–8, 2000
37Long-term Data: Change from Baseline in ADAS-Cog/11 scores Clinical Improvement-44Mean change from baseline± SE in ADAS-Cog/1181216Placebo comparisonEstimation of decline – Stern EquationClinical Decline20Galantamine 24–32 / 24 mg24Baseline3691218243036Months of TreatmentRaskind MA et al. Arch Neurology 61: , 2004.
38Donepezil Significantly Better Compared to Calculated Change by Stern Equation over 3 Years Wallin AK, et al. Dement Geriatr Disord 2007:23:
3936-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.”
40We Compared Slopes of ADAS-cog Decline Between Dropouts and Completers -11234Change from baseline in ADAS-Cog/1156789Galantamine patients who completed treatment10Galantamine patients who discontinued1110203040Time (months)Raskind MA, et al., Arch Neurol 61: , 2004.
41If ChEIs Delay Disease Progression, What are the Candidate Mechanisms? Nicotinic cholinergic stimulation in vitro:Protects against A-induced neuronal death1Muscarinic cholinergic stimulation in vitro:Inhibits A production from amyloid precursor protein (APP)2Reduces phosphorylation of tau21Arias E et al., Neuropharmacology 46: , 2004.2Fisher A et al., J Mol Neurosci 20: , 2003.
42Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors Role of Alpha-4 and Alpha-7 Receptors in NeuroprotectionAn excellent reviewHighlights: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: , 2010
43Loss 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 deficitsHippocampal and cholinergic neurodegenerationSoluble oligomer (neurotoxic) beta-amyloidHernandez CM, et al. J Neuroscience 30: , 2010.
44Disruptive Agitation: What is it? Distressing behaviors that often cluster togetherIrritabilityAnger outbursts, aggressionSleep disruptionPressured pacing and restlessnessUncooperativeness with necessary careMajor cause of long-term care placement.
45Commonly 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-respondersAdverse effects: pseudoparkinsonism, sedationIncreased 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?
46The 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?
47Noradrenergic System Pathology in Alzheimer’s Disease Despite loss of noradrenergic locus coeruleus neurons there is:Increased cerebrospinal fluid (CSF) norepinephrine (NE) in AD1Increased agitation response to NE in AD2Compensatory upregulation of surviving LC neurons3Increased alpha-1 adrenoreceptors in locus ceruleus target areas41Elrod et al., Am J Psychiatry 154:25-30, 1997.2Peskind, et al., Arch Gen Psychiatry, 1995.3Szot, et al., J Neuroscience, 2006.4Szot, et al., J Neuroscience, 2007.
48CSF Norepinephrine: Effects of Aging and AD *significantly higher than young subjects**significantly higher than all other subject groups500Advanced AD (n=25)**400Old (n=42)*300Mild-Moderate AD (n=49)*CSF norepinephrine (pg/ml)200Young (n=54)100Elrod et al., Am J Psychiatry 154:25-30,
49Postsynaptic 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 disorderWould prazosin be helpful in AD?Raskind MA, et al., Am J Psychiatry 160: , 2003.
50Prazosin 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 brainInexpensive, generic, used for BPH and hypertension by millions of older persons for decades.Clinically effective for AD agitation in open label pilot study.50
51Placebo-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.
52Placebo-Controlled Trial of Prazosin for Disruptive Agitation in Dementia: NPI Wang L, et al., Am J Geriatr Psych 17:744-75, 2009.
53Where 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.
54Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseasePathophysiology of AD: Foundation Role of Cholinergic Dysregulation and Emerging Perspectives on the Pathobiology of AD JAMES E. GALVIN, MD, MPHProfessor of Neurology and PsychiatryDirector of Clinical OperationsCenter of Excellence on Brain AgingDirector Pearl Barlow Center for Memory Evaluation and TreatmentNew York University Langone School of MedicineNew York, NY
55Objectives Pathophysiology of AD Beta-amlyoid hypothesis Cholinergic HypothesisClinical and therapeutic implications of Cholinergic hypothesisIntersection of cholinergic and amyloid-based pathobiologyApproaches to therapyImplications for multi-modal therapies for AD
56Pathophysiology of AD Neuropathologic hallmarks of AD Senile plaques – Amyloid b-protein (Ab)Neurofibrillary tangle – tau proteinLargely a sporadic, late-life cause of dementia, early-onset and familial forms existMutations in APP, PS-1 and PS-2Mutations increase production of AbLate-onset disease is associated with presence of the e4 allele of Apolipoprotein EMore than 40 other genes have been associated with AD
57Amyloid Hypothesis First proposed in 1991 Initiating molecule in AD, ultimately leading to ADMutations in familial AD encode substrate (APP) and enzyme (Presenilin) for Ab productionInfusions of Ab cause neuronal degeneration and cognitive deficitsHarmful form of Ab is small, diffusable aggregates or oligomersPakasi and Kalman 2008, Hardy and Allsop 1991, Kowall et al 1991, McDonald et al 1994, Dahlgren et al 2002
58A is Derived After Cleavage of APP PlaquebC99(b-stub)sAPPaC83(a-stub)sAPPAPPgAbAICDgp3AICD(Ab50-Cter)Lumen/ExtracellularACytosolAPP = amyloid precursor protein; sAPP = soluble form of APP; AICD = APP intracellular domain
59Acetylcholine ACh activity known since turn of 20th century Nobel prize to Henry Dales and Otto LoewiSynthesized de novo by the brainTwo types of receptorsMuscaricNicotinicIn the CNS, largely produced in collection of neurons in basal forebrain and pons with wide-range projections
60Cholinergic Projections From: Cooper, Roth and Bloom, Biochemical Basis of Neuropharmacology, 7th Ed, 1996
61Cholinergic Hypothesis Dysfunction of cholinergic system contributes to memory declineDrachman and Leavitt (1974)Link between cholinergic dysfunction and memory impairmentScopolamine in young adults caused impairmentCorroborated by primate, canine and rodent studiesReduced choline acetyl transferase (ChAT) activity in cortex, hippocampus and amygdala of AD patientsActivity correlated with level of cognitive impairmentSelective loss of cholinergic cells in basal forebrainDavies and Maloney, 1976, Perry et al 1978, Wilcock et al 1982, Whitehouse et al 1981.
62Neuropathological Signaling: Cholinergic Hypothesis AcetylCoA + CholineGlial CellPresynapticNeuronCholineChATBuChEAChBuChESynaptic CleftAChCholine +AcetatePostsynaptic NeuronAChEAChEPurpose:To review the schematic of the cholinergic hypothesisKey Points:If you’re going to try to boost function in a system as demonstrated above, you can do it in3 ways:You can give a building block or a precursor like choline.You could block the breakdown of the neurotransmitter once it’s left the presynaptic neuron; use a cholinesterase inhibitor (ChEI) to delay the breakdown and prolong its physiological effect.Or you could use a false messenger or agonist to tickle the postsynaptic receptor and give a message.Cholinergic ReceptorACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase;ChAT = choline acetyltransferase; CoA = coenzyme A.Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl 139):69-74.
63Cholinergic Hypothesis Basal forebrain and rostral brainstem cholinergic pathways converge to serve important functional rolls in awareness, attention, working memory and mnemonic processesLoss of cholinergic function contributes to cognitive decline associated with ADPerry et al 1999, Bartus 2000,
64Cholinergic Receptors and AD Two classesNicotinic ionic channelsResponsible for fast transmissionReduction in a4 nAChR in ADUp-regulation of a7 nAChR in AD compared with MCI and controlsa7 receptors down-regulated in DLBPossible compensatory response to maintain basal forebrain-cortical cholinergic activitya7 nAChR interacts with APP and Ab peptides which could lead to aberrant functionMuscarinic G protein-coupled receptorsPreserved during progression of ADIn triple transgenic mice, M1 agonists improved cognitive and reduced Ab and tau pathologyHypothesis: activation of TACE/ADAM17, decreased BACE1 levels and/or inhibition of GSK3bMufson et al 2009, Nagele et al 2002, Counts et al, 2007, Caccamo et al 2006
65Role of Cholinergic Deficits in Behavioral Symptoms of AD Temporal and frontal lobe dysfunction implicated in psychosis of ADRegional cholinergic deficits—apathy and indifferenceCholinergic-monoaminergic imbalance hypothesized in mood disordersCholinesterase inhibitors (ChEIs) have shown behavioral benefits in several clinical trialsLanari A, et al 2006; Cummings JL. 2000
66Clinical and Therapeutic Implications of Cholinergic hypothesis Recent functional MRI study demonstrated MCI treated with donepezil demonstrated increased frontal cortex activation relative to untreated controlCorrelated with task performanceAChE does not show decline until late stages of diseaseOnly mild losses in MCI and mild ADVesicular Ach transporter is not severely altered in ADCholinergic neurons appear then to shrink and become dysfunctional rather than degenerate early in diseaseSuggest cholinergic neurons may be viable, however dysfunctional early in disease and thus amenable to manipulationsChanges in neurotrophic gene expression may provide targets of intervention for dysregulation of cholinergic neuronsNGF (trk) receptors down-regulation may be a molecular marker for transition from MCI to frank ADSaykin et al, 2004, Bierer et al 1995, Rinne et al, 2003, Gilmor et al, 1999, Rinne et al 1987, Mufson et al, 2009
67Challenges to Cholinergic Hypothesis Studies of post-mortem tissueLevels of AChE and ChAT are not reduced in very mild ADLevels of ChAT may be upregulated in MCI and very mild ADSince neither ChAT nor AChE are rate-limiting cholinergic enzymes, they are unlikely to accurately reflect cholinergic function in a living patientOther factors may be involvedAlterations in high-affinity choline transport (rate-limiting step)Deficits in nicotinic and muscarinic receptorsDysfunctional neurotrophic supportNeurochemical analyses of autopsy tissue maybe unreliableDependent on length of agonal state and post-mortem intervalMore recent in vivo imaging studies support amyloid hypothesis11C N-methylpiperidine-4-yl proprianate (AChE activity)Nicotine-based ligandsNon-selective muscarinic ligands123I 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
68Recent Developments Extension of studies to early, prodromal stages Religious Orders StudyVery mild cases did not show decreases in ChAT but actually increasesImmunochemistry of brain with very mild AD/MCIChAT or vesicular ACh transporter not reducedMarkers of NGF receptors markedly reducedPossible that other pre- or post-synaptic mechanisms may be compromisedPerhaps down-regulation of retrograde transmission of NGF from hippocampus/frontal cortex to basal forebrainAltered neurotrophic receptors may mark early stage of disease with initial increases in ChAT activityDecreased connectivity between hippocampus and entorhinal cortexDavis 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
69Interactions Between Amyloid and Cholinergic Hypotheses Regulation of Ab by stimulation of muscarinic or nicotinic receptorsPartial M1 agonists increase aAPPs, decrease Ab and decrease tau phosphorylationNicotine may increase downstream synthesis of neurotropinsCholinergic deficits could be secondary to amyloid toxicityBidirectional interaction between cholinergic function and processing of amyloid precursor proteinHigh affinitity a7 receptors can serve as high affinity binding sites for Ab peptidesAmyloid peptides inhibit uptake of choline and decrease endogenous Ach release without exhibiting effects on ChAT activityAb block functional interaction between nicotinic agonists and receptors on hippocampal neuronsCourt 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
70Interactions Between Ab and ACh Toxicity of Ab on the cholinergic systemAch synthesis and release reduced by solubilized AbLoss of cholinergic fibers without loss of cholinergic neuronsReduction of binding to vesicular Ach transporterInhibition of fast axonal transportAb 42 binds with higher affinity to a7 nAChR than Ab 40Ab 42 reduced downstream events in mAChR signal transductionCholinergic system and APP processing via a-secretasemAChRa7nAChR agonistsAChEIAuld 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
71Mechanisms of AChE Inhibitors on the Release of sAPPα ChangeCholinergic mechanismOther mechanismReferenceTacrineDecrease−?Lahiri et al. (1994); Lahiri et al. (1996)MetrifonateIncrease+(Pakaski et al., 2000) and (Pakaski et al., 2001); Racchi et al. (2001)AmbenoniumPakaski et al. (2001)GanstigmineMazzucchelli et al. (2003)LadostigilMAP-kinase or tyrosin kinase-dependent pathwayYogev-Falach et al. (2002)DonepezilEnhancing trafficking and activity of ADAM 10Zimmermann et al. (2004)PhenserineInhibition of APP mRNA translationLahiri et al. (2000); Shaw et al. (2001)GalantamineLenzken et al. (2007)Pakaski and Kalman 2008
74Is There Evidence of Disease-Modifying Effects? From clinical trials, functional imaging and basic science studies, anti-cholinesterase drugs may:Reduce circulating AbAlter APP processingPrevent Ab deposition in cholinergic projection sitesPromote non-amyloidogenic APP processingIf changes in cholinergic transmission alters APP processing, appropriate cholimimetic therapeutics might provide both symptomatic benefit and modify AD pathogenesisLopez et al 2002, Krishman et al 2003, Francis et al 2005, Nordberg 2006, Inestrosa et al 1996, Rogers et al 2000
75Amyloid-Based Approaches Barten and Albright 2008
76Immunization Reduces Ab burden Holmes et al 2008
77Immunization Does not rRduce Disease Burden Time to severe dementiaTime to deathHolmes et al 2008
78Neurotransmitter-Based Approaches Barten and Albright 2008
79Model of Multi-Modal Approach MildModerateSevereDisease-modifying RxPerformanceCombining Symptomatic andDisease-modifying RXSymptomatic RxTime
80SummaryAb as the likely culprit leading to AD is a logical target for anti-AD therapies but to date, Phase III trials have not been successfulAch provides targets for symptomatic benefitDysfunction/degeneration of the cholinergic projection neurons is a later stage event in ADDysregulation of the cholinergic system is an early eventMufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002
81Summary (cont.)There is a bidirectional relationship between the amyloid and cholinergic hypothesesDisease-modifying therapies will likely be more effective when used earlier in disease processClear need for improve detection of AD at earliest, even preclinical stagesMulti-modal approaches offer the best potential to provide treatment throughout the spectrum of diseaseMufson et al 2009,Davis et al 1999, DeKosky et al 2002, Mufson et al 200, Mufson et al 2002
82Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseEvidence-based Role of Cholinesterase Inhibition Across the Severity Spectrum in ADSANDRA E. BLACK, MD, FRCPCBrill Chair in NeurologyUniversity of Toronto, SunnybrookHealth Sciences CentreToronto, Ontario Canada
83Learning ObjectivesReview evidence for cholinesterase inhibitors as cognitive enhancers in mild-moderate Alzheimer’s DiseaseSummarize evidence for utility in earlier and later stages of ADConsider evidence for longer term useSee Canadian Consensus on Dementia Diagnosis and Treatment:Hogan et al, CMAJ 2008; Alzheimer’s and Dementia special issue 2007
84The Cholinergic Deficit in AD Progressive loss of cholinergic neuronsProgressive decrease in available AChImpairment in ADL, behavior and cognitionN. basalis MeynertHippocampusCortexSlide 9: The cholinergic deficit in AD underlies the clinical symptomatologyAcetylcholine (ACh) is needed in sufficient amounts for maintaining proper neurotransmission. Reduction in ACh is the most predominant neurotransmitter deficit found in AD.The progressive loss of ACh available for neurotransmission has been correlated with the cognitive deficits found in AD patients (Perry et al.,1978).These findings have led to the formulation of the cholinergic hypothesis of AD (Bartus et al., 1982), which proposes that the cognitive deficits of AD are related to the observed decrease in central cholinergic activity and that increasing intrasynaptic ACh could enhance cognitive function and clinical well being.Furthermore, cholinergic deficits in the limbic and paralimbic structures may contribute to the development of certain behavioral abnormalities seen in AD (Cummings and Back, 1998).Bartus et al., 1982; Cummings and Back, 1998, Perry et al., 1978
85Cholinesterase Inhibitors: Mechanisms of Action N = nicotinicM = muscarinicACh = acetylcholinePresynaptic nerve terminalAChAstrocyteBuChEN receptorGalantamineM receptorAChDonepezil Rivastigmine GalantamineRivastigmineIn the normal human brain, an electrical nerve impulse travels to the end of the pre-synaptic neuron. This triggers acetylcholine (ACh)-containing vesicles to fuse with the synaptic knob. ACh is released into the synaptic cleft and diffuses towards the post-synaptic neuron. ACh is hydrolyzed by the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to acetic acid and choline. Choline is taken up into the pre-synaptic neuron and used as a substrate for ACh re-synthesis, which is finally stored again in the pre-synaptic vesicles. The pre-synaptic neuron is then ready for further transmitter release.This cycle ensures normal cholinergic transmission, normal development of the central nervous system (CNS), and survival. The biological role of AChE and BuChE in this cycle is the termination of impulse transmissions at cholinergic synapses by rapid hydrolysis of the neurotransmitter ACh.Donepezil is a selective AChE inhibitor, while rivastigmine is a dual AChE and BuChE inhibitor. Studies have shown that galantamine is a weak AChE inhibitor but it is also an allosteric nicotinic receptor modulator.Reference:Adem A: Putative mechanisms of action of tacrine in Alzheimer's disease. Acta Neurol Scand 1992; 85(suppl 139):69-74.ButyrylcholinesteraseAcetylcholinesterasePostsynaptic nerve terminalIncreased availability of ACh at synapse (AChE and BuChE inhibition)
86Efficacy-Cognitive Improvement benefitno benefitheterogeneousBased on 2419 subjectsResponders defined as >/=4 points on ADAS10% [4%, 17%] of patients show significant benefit over placeboLanctot et al, CMAJ, 2003
87Efficacy Clinical Global Impression benefitno benefitHomogeneousBased 4468 subjectsResponder defined as improved on CGIC or CIBIC9% [6%, 12%] of patients show significant benefit over placeboLanctot et al, CMAJ, 2003
88Number Needed to Treat for Benefit Numbers needed to treat to benefit7 (CI95%: 6, 9) for stabilization or better12 (CI95%: 9, 16) for minimal improvement or better42 (CI95%: 26, 114) for marked improvementNNT for clinically benefit are low.Homogeneous-all 3 ChEI similarLanctot et al, CMAJ, 2003
89Tolerability Caveat Galantamine above recommended doses, heterogeneity 8% [5,11]8% [5,12]7% [3,10]Lanctot et al CMAJ, 2003
90SafetyNumber needed to harm (ie to cause AE in 1 patient) = (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’sSyncope vs 18.6/ HR 1.76Bradycardia 6.9 vs 4-4/ HR 1.69Pacemaker needed 4.7 vs 3.3/1000 HR 1.49Hip fracture 22.4 vs 19.8/ HR 1.18Gill et al Arch Int Med 2009
91Limitations of Drug Trials to Date Benefits in cognition, behavior and function have been for 6 months- only a few 1-year placebo-controlled studiesLonger term benefits derived from open label extensions, limited by large dropouts and bias from self-selectionMost clinical trials have been pharma-sponsored without independent analyses, except for AD 2000Differential 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 domainsPlacebo trials may no longer be feasible or ethicalRecent review of RCTs highlight methodological flaws (e.g., no corrections for multiple comparisons, LOCF method) and questions utility of drugs in clinical practiceKaduszkiewicz et al., BMJ, 2005
92Use in Early and Later Disease Stages Optimizing Neurotherapy and Emerging Paradigms forAlzheimer's DiseaseUse in Early and Later Disease Stages
93Nursing home placement Natural History of AD: early5101520253012346789MMSEYearsEarlyCognitive symptomsLoss of functionalindependenceMild-moderateBehavioural problemsNursing home placementSevereDeathFeldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.
94Conversion of Normal and MCI Subjects to Dementia (AD Cooperative Study) 0.00.51.01.52.02.53.03.5102030405060708090100Follow-up Time (Years)Proportion Free of Dementia (%)NormalsMCI45%Key PointsThis graph demonstrates the conversion rate from MCI to dementia next to the conversion rate of normal (non-MCI) to dementia.The conversion to dementia is much more common in patients with MCI than in normals.In fact, by the 3.5-year mark, >50% of MCI sufferers will have converted to dementia.ReferencesDeKosky ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc 2003;51(5 Suppl):S314-S320.Grundman M et al. Rate of dementia of Alzheimer type (DAT) in subjects with mild cognitive impairment? The Alzheimer's Disease Cooperative Study. Neurology 1996;46:A403.Retrospective analysis of 687 subjects with MCI Mean age 72.2 yrsDeKosky ST. J Am Geriatr Soc, 2003; Adapted from Grundman M et al, Abstract in Neurology, 1996.
95ADCS: 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 MCI2) slow the decline of symptomsDesign: 3-year, randomized, double-blind, placebo-controlled, parallel group study60 sites in the US and 9 sites in CanadaPatients were randomized to receive donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placeboSubjects: 769 patients with MCIOutcome measures:Primary: Conversion to ADSecondary: MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, Neuropsychological batteryKey PointsThe objective of this study was to determine whether daily doses of vitamin E or donepezil given over a 3-year period can:delay or prevent the onset of AD in people who have MCIslow the decline of symptomsThis long-term, randomized, double-blind, placebo-controlled parallel group study included 769 patients with MCI from 60 sites in the US and 9 sites in Canada.Patients received donepezil 10 mg/day, vitamin E 1,000 IU b.i.d., or placebo.The primary outcome measures used to evaluate this population of patients was the rate of conversion to AD, based on the clinical criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer’s Disease and related Disorders Association (NINCDS-ARDRA).The secondary outcome measures used to evaluate the symptoms of AD included the MMSE, ADAS-cog, CDR, CDR-SB, ADCS, GDS, and a neuropsychological battery.ReferencePetersen RC et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352.Petersen et al. N Engl J Med, 2005
96Survival Analysis: Donepezil vs. Placebo 6 mo1 yr18 mo1.00.90.8Probability of notconverting to AD0.70.6DonepezilPlaceboKey Points: Survival with P-Value Reference from Pointwise Z-Test: Donepezil vs. PlaceboAt study endpoint (3 years) the risk of progression was the same in all three treatment groupsDonepezil reduced the risk of progressing from MCI to AD vs. placebo for up to 12 monthsThe effects of donepezil treatment lasted longer (up to 2-3 years) in patients with the Apo E4 genotypeThe mean difference in time to conversion between donepezil and placebo-treated patients was 6 months, with mean times of 661 days and 484 days, respectivelyVitamin E had no effect on progression to ADDonepezil had an effect on overall function, memory and language for up to 18 monthsVitamin E had a minor effect on secondary outcomesAmnestic MCI strongly predicted progression to AD – 99% of converters converted to ADReferencePetersen RC et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352.p<0.0010.5p<0.009p<0.0350.42004006008001,0001,200Time on MCI study (days)Petersen RC et al. N Engl J Med, 2005
97Summary of MCI StudiesNIH 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 conversionMore deaths noted with galantamine 1.4% vs 0.3% in placebo MCI subjects leading to product label warningSee Raschetti et al Cochrane Review PLoS Med 2007Key PointsAlthough the symptomatic MCI studies with donepezil failed to reach statistical significance on their primary endpoints, results were promising and warrant further investigation.As such, there are other currently ongoing trials are examining the role of donepezil treatment in MCI further.Further investigation using longer study duration, flexible dosing, and other efficacy measures is also warranted, and is currently underway with donepezil.
98Safety and Tolerability of Donepezil (10mg/d) in aMCI Study DesignSafety 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 aMCIKey Results57.4% in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AEMost 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 groupBackgroundIt has been suggested that aMCI may be an early clinical manifestation of AD in many individualsThus, treatments for AD may be expected to benefit patients with aMCI and possibly delay the progression to ADTo this date, studies have not demonstrated a delay to onset and there are significant safety risks associated with use in this population.ConclusionsDonepezil in aMCI appeared to be safe, but patients with AD seem to tolerate it better than patients with MCIDoody, et al., Am J of AD & Other Dem. 2010
99Higher Rate of Progression to AD in Patients with aMCI and Depressive Symptoms Study Design756 aMCI from the three year NIH study drug trial of donepezil and vitamin EDepressive symptoms assessed at baseline using the Beck Depression Inventory (BDI)Key ResultsOn regression analysis higher BDI scores were associated with progression to ADDepressive 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 yearsNondepressive subjects: no difference between the three treatment groupsStudy DesignPatients were followed either to the end of the study or to the endpoint of progression to probable or possible AD.ConclusionsThe study suggests that donepezil modulates the increased risk of progressing to AD by the presence of depressive symptomsConclusionsDepressive symptoms may be predictive of progression from aMCI to ADTreatment with donepezil delayed progression to AD in depressive subjects with aMCILu, et al., Neurology 2009
100Survival Lu, et al., Neurology 2009 Conclusions - The study suggests that donepezil modulates the increased risk of progressing to AD by the presence of depressive symptomsLu, et al., Neurology 2009
101Nursing home placement Natural History of AD:Moderate to severe stage5101520253012346789MMSEYearsEarlyCognitive symptomsLoss of functionalindependenceMild-moderateBehavioural problemsNursing home placementSevereDeathFeldman H and Gracon S in: Clinical Diagnosis and Management of Alzheimer’s Disease 1998.
102Mean Change From Baseline Donepezil vs Placebo in Nursing Home Study in Severe AD (MMSE 1-10): Cognition (SIB)SIBp=0.003*6p=0.008†Clinicalimprovementp=0.008*42Mean Change From Baselinein SIB ScoreBaseline-2Donepezil-4PlaceboClinicaldecline-636ITT LOCF*OC analysis; †LOCF analysis.MonthsWinblad et al. Lancet, 2006.
103Functional Abilities Also Showed Less Decline ClinicalImprovementP = 0.086*P = 0.031*P = 0.029†Mean Change From Baselinein ADCS-ADLBaselineMulticenter, randomized, double-blind, parallel-group trial of ARICEPT versus placeboPatients residing in assisted-care facilities in Sweden (equivalent to skilled nursing facilities)248 subjects with severe ADBaseline MMSE = 5.8 for ARICEPT; 6.3 for placeboDiagnosisPatients with severe AD consistent with DSM-IV and NINCDS-ADRDA criteriaMain criteria for inclusionMMSE 1-10Functional Assessment Staging (FAST) 5-7cClinicalDecline36ITT LOCFMonths*OC analysis; †LOCF analysis.Winblad et al Lancet, 2006
104Less Cognitive Decline in Community Dwelling Severe AD (MMSE1-12) -8-6-4-22468p =ClinicalimprovementSIB scores: LS mean change frombaseline (SE)Raw data required to completedClinicaldecline10mg/dDonepezilPlacebo81624ITT LOCFStudy weekBlack et al Neur 2007
105Cholinesterase Inhibitor Use in Other Dementias Level 1 evidence for different compounds according to studies undertakenDonepezil in vascular dementiaRivastigmine in parkinson/diffuse lewy body dementiaGalantamine in mixed vascular dementia(Memantine also shows efficacy in moderate to severe AD)
106Use of Higher Doses, New Formulations Optimizing Neurotherapy and Emerging Paradigms forAlzheimer's DiseaseUse of Higher Doses, New Formulations
107Once Daily Formulations Galantamineextended release8mg od –16mg od– 24mg odRivastigmine patch4.6-mg od –9.5mg odGI tolerability better than oralformulation(eg nausea: oral 23 vs patch 7%vs placebo 5%)Skin sensitivity (erythema, edema,pruritus, pain)Recent caution due to additive dose effectsif patch not removed daily before new one appliedExposure levels and Cmax are highest when the patch is applied to the upper back, chest or upper arm (Lefevre et al. J Clin Pharmacol 2007;47:471-8). Taking the upper back as the reference point, the relative bioavailabilities with other body sites are 100% for the chest, 92% for the upper arm, 80% for the abdomen, and 71% for the thigh. It is recommended that the Patch be applied to the upper or lower back, chest or upper arm. The patch is kept on for 24 hrs and should be applied to a new site every day. It is recommended that the patch not be applied to the same site for 14 days to minimize the risk of any skin irritation.Winblad et al. Int J Geri Psych. 2007107
108Safety & Tolerability of Higher Dose Donepezil (20mg) PurposeTo evaluate the safety and tolerability of donepezil at doses of 15 and 20mg/dayStudy DesignA 24-week, randomized, double-blind, placebo controlled, pilot study31 patients (male and female) aged yearsAll patients had been treated with 10mg/day donepezil for months prior to enrollmentPrimary 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 parametersStudy Design- diagnosed mild to moderate probable AD (MMSE 10-26)Doody, et al., Drugs Aging 2008
109Safety & Tolerability of higher dose Donepezil (20mg) Key ResultsHigher-dose group:15 of 16 patients tolerated the maximum 20 mg/day dose by week 24Standard-dose group:14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the studyAdverse events possibly related to treatment were reported by 3 patients in the standard-dose group and 6 patients in the higher-dose groupNo difference between groups on psychometric measuresResultsNo patients withdrew from the study and there were no serious adverse events or deaths1 patient in the higher-dose group had a permanent dose reduction to donepezil 15 mg/day1 patient in the standard-dose group had a permanent dose reduction to donepezil 10 mg/plus placebo 5 mg/dayTemporary dose reductions occurred in two patients (one in each group)Adverse events were mild to moderate as expectedIncreased donepezil dose was associated with an increase in donepezil plasma concentrationsConclusionsDoses of 15 and 20 mg/day of donepezil appeared to be safe and well toleratedMay justify larger clinical trials for the safety and efficacy of donepezil at higher doses in patients with AD.Doody, et al., Drugs Aging 2008
110Purpose Design Results High Dose (23mg/d) vs Standard 10mg Dose Donepezil in Moderate to Severe Stage ADPurposeTo determine effectiveness, safety and tolerability of 23 mg vs 10mg donepezil in mod-severe AD already on 10 mg donepezilDesign1467 patients (465 US) in 209 sites randomized to 23mg (n=972) vs 10mg (n= 479)MMSE: 76%: 0-16; 34%: 17-20Approx 36% also on memantine (75% in US)ResultsDiscontinuation higher for 23 mg vs 10mg:30% (18% for AE’s vs 18% (8% for AE’s)
111Effectiveness analysis:Cognition Severe Impairment BatteryMMSELess decline from baseline on SIBP<0.001Farlow et al. Clinical Therapeutics 2010.
112Frequency Distribution of CIBIC Scores at Week 24No difference in ADL scoresAdverse Events: vs 10Nausea % vs 3.4Vomiting % vs 2.5Diarrhea % vs 5.3Anorexia %SAE % vs 9.6Farlow et al. Clinical Therapeutics2010.
113Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseIs There Any Evidence for Longer Term Use of Cholinesterase Inhibitors?
114Rivastigmine-Placebo Group Does not Catch Up to Treated Group 6–12 mg/day rivastigmine1–4 mg/day rivastigminePlaceboProj. placeboDose optimization withrivastigmine (6-12 mg/day)*2–2–4–6–8ADAS-Cog mean changefrom baselineSlide 38: Rivastigmine on Cognition: greater long-term benefits when therapy starts earlierThese results represent the first evidence showing that rivastigmine is effective in the long-term treatment of mild to moderately-severe AD patients. Furthermore, they suggest rivastigmine treatment should be started as early as possible in order to gain the maximum benefit (Messina et al., 2000).Patients who participated in Study B352 were followed through week 52 in the open-label extension Study B353. This figure illustrates the mean change in ADAS-Cog scores over time, from baseline through the end of the double-blind study (week 26), and through a total of 52 weeks in the study. At week 26, all patients were restarted on rivastigmine and adjusted to their optimal dose (up to 6 mg b.i.d.).Due to the open-label design of Study B353, a placebo-control group was no longer available after week 26. Therefore, a model was created based on data from the first 26 weeks for the original placebo group, to estimate the expected change in cognition in the placebo group through 52 weeks. The change in this projected placebo group is depicted by the dashed line. The decline of 7 points in the projected placebo group is consistent with the cognitive decline observed after 1 year in untreated community-based patients with AD (Stern et al., 1994).In the extension study, the original 6–12 mg/day group remained above baseline on the ADAS-Cog through 38 weeks. The original 1–4 mg/day and placebo groups improved after restarted on rivastigmine, but did not reach the level of cognitive improvement observed in the original 6–12 mg/day group. Compared with the projected placebo group, all three randomization groups showed a statistically significant improvement in cognition at week 52 versus projected placebo.Although all patients were re-adjusted to their optimal rivastigmine dose (up to 6 mg b.i.d.) in the extension phase, patients originally randomized to placebo did not catch up to the original rivastigmine groups. Of interest, the decline seen in the original 6–12 mg/day group after 52 weeks was less than the decline seen in the placebo group after 26 weeks. The results suggest that although patients who start treatment later demonstrate cognitive improvement, they may not attain the level of cognitive benefit seen in patients who begin therapy earlier.All patientsrestarted on rivastigmine26Study weekB352 patients in Study B353 (OC) at week 52 *p<0.05 vs projected placeboMessina et al., 2000
115Mean change from baseline Mean Change in ADAS-Cog Score from Baseline: Open Label Galantamine Over 4 Years–448Mean change from baseline(±SE) in ADAS-Cog/111212-month placeboExpected decline in untreated patients of 6–9 points/year162024Galantamine 24–32/24 mg28Baseline36912243648(n)(322)(309)(310)(233)(298)(228)(140)(103)Time (months)Database and from Raskind et al Arch Neurol 2004.
1161-year Preservation of Function Study with Donepezil Design1-year, randomized, placebo-controlled, double-blindSubjects431 patients with mild-to-moderate ADAged 49-94, mean MMSE 17.1Primary OutcomeTime to clinically evident functional decline’, defined by:Decline in 1 basic ADL present at baselineDecline of 20% of the instrumental ADL present at baselineIncrease 1 point from baseline in global CDR score (Clinical Dementia Rating scale)Mohs et al. Neurology. 2001
117Time to Clinically Evident Functional Decline*0.10.20.30.220.127.116.11.80.9161218243036424854Duration of treatment (weeks)Probability of survivalDonepezil 10 mg/dayPlaceboKaplan-Meier survival estimatesThe probability of survival (maintaining functional ability) at 48 weeks was:51% for donepezil35% for placeboSurvival curve comparison:p=0.002 (log-rank test)p=0.005 (Wilcoxon test)*As judged by investigator, ITT populationMohs et al. Neurology. 2001
118Longer-Term Effects: Non-Pharmaceutical Sponsored StudyTwo-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 washoutc) 51% of total sample had CVD
119Other 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 donepezil1Compared 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 yearIn this general Alzheimer’s disease population, symptomatic benefits were observed in cognition, activities of daily living and behaviour for up to 2 years in both treatment groups.1 No placebo group was used for ethical reasons, but historical data for all outcome measures suggest that untreated patients would have shown a more marked decline than that observed with cholinesterase inhibitor-treated patients in this study.When compared with data on placebo or untreated AD populations,2,3 the decline on SIB in the study population (9 points over 2 years) suggests that cholinesterase inhibitor treatment might have delayed decline on this measure by about a year. In addition, the current study indicates that cholinesterase inhibition has the potential for stabilization of symptoms, as performance on the SIB was stable (no change or improvement) in approximately 50% of patients after 1 year and 35% of patients after 2 years. Similarly, compared with historical data on MMSE decline,4–6 ADCS-ADL decline,7 and NPI decline,7 the results of this study suggest that cholinesterase inhibitor therapy may delay the advance of cognitive and functional decline and the progression or emergence of neuropsychiatric symptoms by up to a year.1Bullock R et al. CMRO 2005;21:1317–27; 2Schmitt FA et al. Alzheimer Dis Assoc Disord 1997;11(Suppl 2):S51–6; 3Feldman H et al. Neurology 2001;57:613–20; 4Winblad B et al. Neurology 2001;57:489–95; 5Klatte ET et al. Alzheimer Dis Assoc Disord 2003;17:113–6; 6Small G et al. Int J Clin Pract 2005;59:473–7; 7Aisen PS et al. JAMA 2003;289:2819–26.1Bullock R et al. CMRO 20052Schmitt et al. Alzheimer Dis Assoc Disord 19973 Feldman et al. Neurology 20014Winblad et al. Neurology 2001;5Klatte et al. Alzheimer Dis Assoc Disord 20036Small et al Int J Clin Pract 20057Aisen et al. JAMA 2003
120Patients on ChEI’s Had Less Decline in Multiple Cognitive Domains over 1 YearN= 65 in each of treated vs untreated group, well-matched on age, edcuation, severity, comorbidities, vasc risk factors and medicationsLess decline in:Overall cognitionNamingVisuospatial and visuoconstructive skillsExecutive functionsDementia Rating Scalep<0.0001Effect size d = 0.7Behl et al Dem Ger Cog Dis 2006
121Treated patients showed less decline on: Patients on ChEI’s Continued to Show Less Declineon Select Cognitive Domains at Two YearsVerbal MemoryTreated patients showed less decline on:Overall cognitionMemoryNamingExecutive functionsp=0.007ES: d1 =0.8; d2 = 0.4Behl et al Dem Ger Cog Dis 2006
122Instrumental Basic Overall DAD Patients on ChEI’s also showed less decline in functional abilities over 2 years, especially in initiation (DAD)InstrumentalBasicOverall DADPyear1=0.04; Pyear2=0.001ES 1 =0.6; ES 2= 0.9Pyear1=0.08 ; Pyear2=0.001ES 1= 0.4; ES 2 = 0.7Pyear1=0.036; Pyear2=0.001ES 1= 0.5; ES 2= 0.8Behl et al, Int Psychoger 2008
123Also Planning and Organization BasicOverall DADPyear1=0.039; Pyear2=0.001ES 1 = 0.7; ES = 1.0Pyear1= 0.038; Pyear2=0.006ES 1=0.8; ES 2 =1.0Behl et al, Int Psychoger 2008
124Does Persistent Use of Antidementia Drugs Slow Clinical Progression of AD over 20 Years? Study Design641 probable AD patients were followed for 20 years in a single centreCumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptomsMeasures: annual change in slope of neuropsychological and functional tests as predicted by follow up time, PI, and the interaction between these variablesKey ResultsPI was associated with significantly slower rates of decline on MMSE, Physical Self-Maintenance Scale (PSMS), IADL, CDR-SBResults suggest that PI (cumulative drug exposure) slowed ADAS-Cog decline for 3.3 years, with effect then lostBackgroundObservational studies suggest that antidementia drugs may benefit cognition in AD patients for a year and/or slow time to dementia related nursing home placement.No studies have evaluated the optimal duration of treatment, or whether greater persistency of antidementia drug therapy affects patient outcomes.The authors hypothesize that greater cumulative exposure to the Cholinesterase Inhibitors (ChEIs) or memantine or both would be associated with slower rates of decline on cognitive and functional measures in AD patients over the long term.Study DesignThe authors did not quantify dosage or distinguish between outcomes on monotherapy with ChEI or combination therapy with a ChEI and glutamate modulator.Results43% of patients had been exposed to drug before the initial visit and 43% began treatment within 2 years following the new patient visit12% never used medication over the entire period of follow upIncluding all visits, there were equal proportions of patients on a ChEI alone (n=1623) or combination therapy of a ChEI and memantine (n=1627), but only few taking memantine alone (n=169)Greater antidementia drug use was associated with slower rate of decline on the ADAS-Cog for the first 3.3 years, followed by a diminished positive effect.The treatment effect was clinically significant in magnitudeConclusionsPersistent drug treatment had a positive impact on AD progression in terms of cognitive, functional, and global outcome measuresPositive treatment effects extended to those at more advanced stages of diseaseRountree, et al., Alzheimer’s Res. & Ther. 2009
125ConclusionsCholinesterase 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 fallsTheir benefits are also seen in more advanced stages, but are not evident in MCI though some MCI subgroups may be more responsiveDuration 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 obtainCognitive benefits are likely selective to the processes most affected by acetylcholine (attention/executive, initiation and social engagement)
126Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseTranslating Advances in Biomarker-based Detection into Clinical Practice Implications for Current Therapies and BeyondSERGE GAUTHIER, MDDirector of the Alzheimer’s Disease Research UnitMcGill Centre for Studies in AgingProfessor of Neurology and Neurosurgery, Psychiatry and MedicineMcGill UniversityMontreal, Quebec Canada
127OutlineCase histories of persons at riskCase history of person with MCICase histories of persons with ADConclusions
128Young Person with Strong Family History of AD Age: 40Cognitive symptoms: noneFamily history of AD: mother d55, sister d53Biomarkers: genetic (PS, APP); neuro-imaging (FDG-PET)Current Rx: enroll in DIANFuture Rx: anti-amyloid
130Middle-age Person with Concern About Family History of AD Cognitive symptoms: noneFamily history of AD: mother d85Biomarkers: genetic (apoE); neuro-imaging (MRI)Current Rx: assess risk using mid-life risk scoreFuture Rx: enhance protective factors
131CAIDE Dementia Risk Score Age< 47 years47-53 years>53 years0 3 4Formal education≥10 years 7-9 years 0-6 years0 2 3SexWomen Men0 1Systolic BP 140 mm Hg > 140 mm Hg0 2BMI 30 kg/m2 > 30 kg/m2Total cholesterol 6.5 mmol/l > 6.5 mmol/lPhysical activityActive Inactive1The Dementia Risk Score was composed as the sum of the individual score; can vary between 0-15.Kivipelto et al., Lancet Neurol 2006131
132The overall occurrence of dementia 4.4% Probability of Dementia in Late-life According to the Risk Score Category in Middle AgeThe overall occurrence of dementia 4.4%SCOREAll /Demented, n% Risk (95% CI)0-5401 / 41.0 ( )6-7270 / 51.9 ( )8-9312 / 134.2 ( )10-11245 / 187.4 ( )12-15122 / 2016.4 ( )The probability of dementia increased as the risk score became greater. The increase was especially clear in the highest categories.Kivipelto et al., Lancet Neurology 2006132
133Older Person with Concern About Family History of ADAge: 76Cognitive symptoms: noneFamily history of AD: mother d93Biomarkers: genetic (apoE); neuro-imaging (MRI)Current Rx: assess risk using late-life dementia risk indexFuture Rx: enhance protective factors, reduce risk factors
134The Late-Life Dementia Risk Index Barnes DE, et al. Neurology 2009;73; ;
135OutlineCase histories of persons at riskCase history of person with MCICase histories of persons with ADConclusions
136Older Person with MCI Age: 70 Cognitive symptoms: mild Family history of AD: mother d87Biomarkers: genetic (apoE); CSF (ß42, total tau, phospho tau); neuro-imaging (MRI, FDG-PET)Current Rx: follow over timeFuture Rx: anti-amyloid
138Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseDubois et al., Lancet Neurology 2007
139Optimizing Neurotherapy and Emerging Paradigms for Alzheimer's DiseaseDubois et al., Lancet Neurology 2007
140Slope Analyses According to AD CSF Profile at Baseline Visser PJ, et al. Lancet Neurol 2009; 8: 619–27
141OutlineCase histories of persons at riskCase history of person with MCICase histories of persons with ADConclusions
142Older Person with Mild AD Age: 75Cognitive symptoms: mild dementiaFamily history of AD: noneBiomarkers: neuro-imaging (MRI)Current Rx: ChEIFuture Rx: anti-amyloid
143Older Person with AD and High Tau Levels in CSFAge: 75Cognitive symptoms: early dementiaFamily history of AD: noneBiomarkers: Neuro-imagimg (MRI); CSF low ß42, very high phospho tauCurrent Rx: ChEIFuture Rx: anti-amyloid and anti-tau
144Distribution of CSF total tau, phosphorylated tau (P-tau), and ß-amyloid 1-42 (Aß42) levels Wallin AK, et al. Neurology 2010;74;
145Five-Year Survival in the Three Clusters Wallin AK, et al. Neurology 2010;74;
146Pathology by Clinical Status Proximate to DeathSchneider JA, et al. Ann Neurol 2009;66:200–208
147OutlineCase histories of persons at riskCase history of person with MCICase histories of persons with ADConclusions
148Biomarkers for the Diagnosis and Management of AD Assessment of risk is possible using mid-life and late-life risk profiles, including apoE genotypingEarlier diagnosis of AD is now possible using neuro-imaging and CSF analysisBetter selection of disease-modifying treatments may be possible using CSF analysis and neuro-imaging, knowing the relative weight of each pathological component