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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
Nu
mb
er o
f P
atie
nts
(th
ou
san
ds
)
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