2010community Lecture

Treatment of Alzheimer’s Disease Treatment of Alzheimer’s Disease and Related Dementiasand Related Dementias

Treatment of Alzheimer’s Disease Treatment of Alzheimer’s Disease and Related Dementiasand Related Dementias

Diana R. Kerwin, M.D.Diana R. Kerwin, M.D.Assistant ProfessorAssistant Professor

Department of Medicine,Division of GeriatricsDepartment of Medicine,Division of Geriatrics

Neurobehavior Clinic-CNADCNeurobehavior Clinic-CNADC

Northwestern University Feinberg School of MedicineNorthwestern University Feinberg School of Medicine

Chicago, ILChicago, IL

CME 2010CME 2010CME 2010CME 2010

Alzheimer’s Disease: 100 Alzheimer’s Disease: 100 Years AgoYears Ago

Alzheimer’s Disease: 100 Alzheimer’s Disease: 100 Years AgoYears Ago

Dr. Alois Alzheimer, Dr. Alois Alzheimer, a German neuropathologist, in a German neuropathologist, in 1906 presented a clinical 1906 presented a clinical case at a pathology case at a pathology conferenceconference

Auguste D. 51-year-old female Auguste D. 51-year-old female

patient with memory loss, patient with memory loss, disorientation and disorientation and hallucinationshallucinations

Amyloid Plaques Neurofibrillary Tangles

AD NeuropathologyAD NeuropathologyAD NeuropathologyAD Neuropathology

The ProblemThe ProblemThe ProblemThe Problem

Prevalence of AD has been Prevalence of AD has been updated Recently from 4 million updated Recently from 4 million to 5.3 million to 5.3 million

Rising prevalence is due to Rising prevalence is due to aging of the populationaging of the population

Cognitive decline is a leading Cognitive decline is a leading cause of disability in the cause of disability in the elderly and loss of independenceelderly and loss of independence

Prevalence and Prevalence and Treatment RatesTreatment RatesPrevalence and Prevalence and Treatment RatesTreatment Rates

0200400600800

100012001400160018002000

Mild Moderate Severe

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Prevalence1

Diagnosed2

Treated with AChEI3

Sources: 1. Hebert LE, Scherr PA, Bienias J, et al. Arch Neurol. 2003;60:1119-1122. 2. Datamonitor AD Treatment Algorithms. 2002. 3. Market Measures. 2003.

Alzheimer’s Disease:Alzheimer’s Disease:Course, Prevention, Treatment Course, Prevention, Treatment

StrategiesStrategies

Alzheimer’s Disease:Alzheimer’s Disease:Course, Prevention, Treatment Course, Prevention, Treatment

StrategiesStrategies

Disease ProgressionDisease Progression

No DiseaseNo DiseaseNo SymptomsNo Symptoms

Early BrainEarly BrainChangesChangesNo No SymptomsSymptoms

AD Brain AD Brain ChangesChangesMild Mild SymptomsSymptoms

Mild,Mild,Moderate, orModerate, orSevere Severe ImpairmentImpairment

NormalNormal ADADPre-Pre-

symptomatic symptomatic ADAD

Mild Mild Cognitive Cognitive ImpairmentImpairment

Clinical Clinical StateState

BrainBrainPathologic Pathologic StateState

““Prevention”Prevention”StudiesStudies

AChE

AcetylCoA

CholineACh

Presynaptic neuron

Synaptic cleft

Postsynapticneuron Acetate

CholineCholine+

+

ACh

AChE

ChAT

Normal Cholinergic Normal Cholinergic FunctionFunction

Normal Cholinergic Normal Cholinergic FunctionFunction

MR NR

MR NR

Glial cell

BuChE

BuChE

ACh

ACh = acetylcholine; AChE = acetylcholinesterase;BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor.

Adapted from Adem, 1992.

Amyloid Production and Accumulation

Oxidation, Excitotoxicity, Inflammation,Tau Hyperphosphorylation

Cognitive and Behavioral Deterioration

Neurotoxicity

The Amyloid Hypothesis The Amyloid Hypothesis The Amyloid Hypothesis The Amyloid Hypothesis

Cummings JL. New Engl J Med. 2004; 351:56-67.

•NINCDS-ARD

Clinical Diagnosis of Probable Clinical Diagnosis of Probable Alzheimer’s DiseaseAlzheimer’s Disease

Clinical Diagnosis of Probable Clinical Diagnosis of Probable Alzheimer’s DiseaseAlzheimer’s Disease

Dementia Dementia established by exam established by exam and cognitive test and cognitive test (MMSE) and (MMSE) and confirmed by confirmed by neuropsychological neuropsychological teststests

Deficits in >2 Deficits in >2 areas of cognitionareas of cognition

Onset ages 40-90 Onset ages 40-90 yrsyrs

Absence of Absence of systemic systemic disorder or disorder or brain disease brain disease that could that could account for account for cognitive cognitive deficitsdeficits

Diagnostic EvaluationDiagnostic EvaluationDiagnostic EvaluationDiagnostic Evaluation

Focused history: progressive decline in Focused history: progressive decline in cognitive function, family/friend informantscognitive function, family/friend informants

Review all medications, r/o depressionReview all medications, r/o depression

Physical examination, focused to neuroPhysical examination, focused to neuro

Mental status testing: MMSE, MoCA, Animal Mental status testing: MMSE, MoCA, Animal Fluency, Clock draw, depression screenFluency, Clock draw, depression screen

Laboratory studiesLaboratory studies TSH, B12, syphilis only if suspectedTSH, B12, syphilis only if suspected Blood count, kidney and liver function is normalBlood count, kidney and liver function is normal

NeuroimagingNeuroimaging

Case Study 1Case Study 1Case Study 1Case Study 1

75 yo man presents with a 2 yr h/o decline 75 yo man presents with a 2 yr h/o decline in STM, dtr notices difficulty remembering in STM, dtr notices difficulty remembering phone conversations, forgets appointments, phone conversations, forgets appointments, difficulty with finances, dtr now manages difficulty with finances, dtr now manages

Family h/o ?dementia in fatherFamily h/o ?dementia in father

PE normal, TSH, B12, labs WNLPE normal, TSH, B12, labs WNL

MMSE 21/30MMSE 21/30

MRI scattered white matter changesMRI scattered white matter changes

Cognitive TestingCognitive TestingCognitive TestingCognitive Testing

Folstein MMSEFolstein MMSE Test of orientation, registration, attention, memory, Test of orientation, registration, attention, memory,

language, used most often in clinical practicelanguage, used most often in clinical practice Good tool for assessing mild-moderate dementiasGood tool for assessing mild-moderate dementias Good tool for following disease progression and Good tool for following disease progression and

treatment efficacytreatment efficacy Sensitivity 80-90%; Specificity 80% (<24 cutoff)Sensitivity 80-90%; Specificity 80% (<24 cutoff) Adjustments must be made for education levelAdjustments must be made for education level

• College education Score < 29 abnormalCollege education Score < 29 abnormal

• 8th grade education Score <23 abnormal8th grade education Score <23 abnormal

9/25/00Pre-treatmentMMSE 21/30

DIFFERENTIAL DIAGNOSIS DIFFERENTIAL DIAGNOSIS OF DEMENTIAOF DEMENTIA

DIFFERENTIAL DIAGNOSIS DIFFERENTIAL DIAGNOSIS OF DEMENTIAOF DEMENTIA

•Small GW et al. JAMA. 1997;278:1363-1371.

•American Psychiatric Association. Am J Psychiatry. 1997;154(suppl):1-39.

•Morris JC. Clin Geriatr Med. 1994;10:257-276.

•AD

•Vascular dementias•Multi-infarct dementia•Binswanger’s disease

•Vascular dementias•and AD

•AD and Lewybody dementias

•Lewy body dementias•Parkinson’s disease

Diffuse Lewy body diseaseLewy body variant of AD

•

•Other dementias•Frontal lobe dementia

•Creutzfeldt-Jakob disease•Corticobasal degeneration

•Progressive supranuclear palsy•Many others

•5% •10% •65% •5% •7% •8%

AD: Pathology and AD: Pathology and Metabolic Imaging (PET)Metabolic Imaging (PET)

AD: Pathology and AD: Pathology and Metabolic Imaging (PET)Metabolic Imaging (PET)

Cummings J, Cole G. JAMA. 2002:287:2335-2338.

                                                                                                                         <>

FDDNP PET as a FDDNP PET as a Biological Biological

Marker for ADMarker for AD

FDDNP PET as a FDDNP PET as a Biological Biological

Marker for ADMarker for AD

Shoghi-Jadid K et al. Am J Geriatr Psychiatry. 2002;10:24-35.

ManagementManagementManagementManagement

Diagnosed with ADDiagnosed with AD

Education and resources for Education and resources for daughterdaughter

SafetySafety Medications, driving, supervisionMedications, driving, supervision

Treatment discussionTreatment discussion Cholinesterase inhibitorCholinesterase inhibitor

FDA Approved therapies for FDA Approved therapies for Alzeimer’s diseaseAlzeimer’s disease

FDA Approved therapies for FDA Approved therapies for Alzeimer’s diseaseAlzeimer’s disease

Mild-moderate stage diseaseMild-moderate stage disease Cholinesterase inhibitorsCholinesterase inhibitors

• Tacrine Tacrine • DonepezilDonepezil• RivastigmineRivastigmine• GalantamineGalantamine

Moderate-severe stage diseaseModerate-severe stage disease• Donepezil (FDA approval 2007)Donepezil (FDA approval 2007)

Other:Moderate-severe stage diseaseOther:Moderate-severe stage disease• MemantineMemantine

Parkinson’s disease dementiaParkinson’s disease dementia• Rivastigmine (FDA approval 2007)Rivastigmine (FDA approval 2007)

Published Cholinesterase Published Cholinesterase Use GuidelinesUse Guidelines

Published Cholinesterase Published Cholinesterase Use GuidelinesUse Guidelines

ACP-AAFP(2008)ACP-AAFP(2008) Trial of AChI in ADTrial of AChI in AD

Weak recommendationWeak recommendation

ACOVE-3 (2007)ACOVE-3 (2007) AChIs shown to slow AChIs shown to slow progression (AD, VaD, progression (AD, VaD, LBD)LBD)

Document discussionDocument discussion

AAGP (2006)AAGP (2006) Supports efficacySupports efficacy

Recommends consideration Recommends consideration of AChIs in mild-moderate of AChIs in mild-moderate ADAD

AGS (2006)AGS (2006) AChIs use in mild-AChIs use in mild-moderate ADmoderate AD

Standard practiceStandard practice

AAN (2001)AAN (2001)

**Update pending****Update pending**

Does not support use AChIDoes not support use AChI

Small treatment effect Small treatment effect sizesize

6/14/01Tx with Exelon 6 BIDMMSE 22/30

MMSE Scores Correlate MMSE Scores Correlate With Functional AbilityWith Functional AbilityMMSE Scores Correlate MMSE Scores Correlate

With Functional AbilityWith Functional Ability

Adapted with permission from Galasko et al. Eur J Neurol. 1998;5:S9-S17.

Keep AppointmentsTelephone

Obtain Meal/SnackTravel Alone

Use Home ApplianceFind Belongings

Select ClothesDress

GroomMaintain Hobby

Dispose LitterClear Table

WalkEat

Loss of Optimal(Independent) Performance

25% 75%

Act

ivit

ies

of

Dai

ly L

ivin

g

25 20 15 10 5 0

MMSE ScoreProgressive Loss of Function

ACOVE-3 QI Dementia GuidelinesACOVE-3 QI Dementia GuidelinesACOVE-3 QI Dementia GuidelinesACOVE-3 QI Dementia GuidelinesAChI discussionAChI discussion

-AD, VaD and dLB-AD, VaD and dLB

AChIs slow progression AChIs slow progression of cognitive and of cognitive and functional declinefunctional decline

Stroke prophylaxisStroke prophylaxis

-VaD, mixed -VaD, mixed dementiadementia

*AAGP 2006 *AAGP 2006

AntihypertensivesAntihypertensives

Lipid-loweringLipid-lowering

aspirinaspirin

Caregiver support Caregiver support

Patient safetyPatient safety

Diagnosis, prognosis, Diagnosis, prognosis, behaviors, home behaviors, home safety, community safety, community resourcesresources

Delay NH placementDelay NH placement

Links between Pathology of Links between Pathology of AD and Vascular Risk AD and Vascular Risk

Links between Pathology of Links between Pathology of AD and Vascular Risk AD and Vascular Risk

Several previous studies have Several previous studies have found an increased risk of AD found an increased risk of AD associated classic VRFsassociated classic VRFs HypertensionHypertension Diabetes mellitusDiabetes mellitus HypercholesterolemiaHypercholesterolemia

At least 1/3 of patients with AD At least 1/3 of patients with AD have some vascular pathologyhave some vascular pathology

Vascular pathology appears to Vascular pathology appears to lower the threshold of the lower the threshold of the clinical symptoms clinical symptoms

ACOVE-3: Depression in ACOVE-3: Depression in DementiaDementia

ACOVE-3: Depression in ACOVE-3: Depression in DementiaDementia

Occurs in 25% of dementia patientsOccurs in 25% of dementia patients

Independent risk factor for NHPIndependent risk factor for NHP

Sertraline effective for reducing Sertraline effective for reducing depression, behavioral symptoms and depression, behavioral symptoms and improving ADLs (Lyketsos, 2003)improving ADLs (Lyketsos, 2003)

Recommendation for screening in Recommendation for screening in newly diagnosed/initial periodnewly diagnosed/initial period

ACOVE-3: Behavioral ACOVE-3: Behavioral Symptoms in dementiaSymptoms in dementiaACOVE-3: Behavioral ACOVE-3: Behavioral Symptoms in dementiaSymptoms in dementia

Annual screening for behaviorsAnnual screening for behaviors

Up to 90% of NH patients have Up to 90% of NH patients have behavioral symptomsbehavioral symptoms

Treatment: 1Treatment: 1stst line-behavioral line-behavioral

Pharmacotherapy concurrently or 1Pharmacotherapy concurrently or 1stst line if severe or safety concernsline if severe or safety concerns

Document risk-benefit discussion Document risk-benefit discussion if using antipsychoticif using antipsychotic

ACOVE-3: Driving and ACOVE-3: Driving and dementiadementia

ACOVE-3: Driving and ACOVE-3: Driving and dementiadementia

Advise not to driveAdvise not to drive

Refer to Department of Motor Refer to Department of Motor Vehicles or driver safety courseVehicles or driver safety course

Know state lawsKnow state laws

Evidence: 2.5-4.7 increased risk Evidence: 2.5-4.7 increased risk of MVA in persons with dementiaof MVA in persons with dementia

Reger, 2004Reger, 2004

Risk Factors and Risk Factors and InterventionsInterventions

Risk Factors and Risk Factors and InterventionsInterventions

AgeAge Family historyFamily history Apoe4Apoe4 Down’s syndromeDown’s syndrome EducationEducation Midlife Midlife BPBP Midlife Midlife

cholesterolcholesterol HomocysteineHomocysteine -macroglobulin-macroglobulin CYP46CYP46 Family Hx of Family Hx of Down’sDown’s

StatinsStatins HRTHRT NSAIDSNSAIDS AlcoholAlcohol SeafoodSeafood CaffeineCaffeine Vitamin EVitamin E Vitamin CVitamin C B12, folateB12, folate GinkgoGinkgo FatsFats Other genesOther genes

Leisure Leisure activityactivity

Cognitive Cognitive activityactivity

Physical Physical activityactivity

DepressionDepression

DiabetesDiabetes

Head injuryHead injury

EM fieldsEM fields

Active/passive Active/passive immunizationimmunizationFrom Brodaty, 2003From Brodaty, 2003From Brodaty, 2003From Brodaty, 2003

Current UnknownsCurrent UnknownsCurrent UnknownsCurrent Unknowns

Lifestyle factors that reduce riskLifestyle factors that reduce risk DietDiet

• Omega-3, DHA, folic acid, Vitamin E, COmega-3, DHA, folic acid, Vitamin E, C ExerciseExercise AlcoholAlcohol

• Moderate intake studies, red wineModerate intake studies, red wine

Reduction in Risk Through Vascular risk Reduction in Risk Through Vascular risk controlcontrol Blood pressureBlood pressure Cholesterol Cholesterol DiabetesDiabetes Ideal Body WeightIdeal Body Weight

Closing RemarksClosing RemarksClosing RemarksClosing Remarks

QuestionsQuestions