DEMENTIADEMENTIA

Michael J. Mintzer, MDMichael J. Mintzer, MD

Associate Professor of MedicineAssociate Professor of Medicine

University of Miami School of MedicineUniversity of Miami School of Medicine

Director of Community Academic Director of Community Academic PartnershipsPartnerships

Miami VAMC and GRECCMiami VAMC and GRECC

DementiaDementia

Learning Objectives:Learning Objectives:• Define dementiaDefine dementia• Describe the common dementias in the Describe the common dementias in the

elderlyelderly• Differentiate the issues of reversibility, Differentiate the issues of reversibility,

comorbidity, and arrestabilitycomorbidity, and arrestability• Describe the current dilemmas in the Describe the current dilemmas in the

pharmacological treatment of dementiapharmacological treatment of dementia

DementiaDementiaDefinitionDefinitionA: The development of multiple cognitive deficits manifested A: The development of multiple cognitive deficits manifested

by both:by both:(1)(1) Memory impairment (impaired ability to learn new Memory impairment (impaired ability to learn new information or to recall previously learned information)information or to recall previously learned information)(2)(2) One or more cognitive disturbances:One or more cognitive disturbances:

(a) aphasia (language disturbance)(a) aphasia (language disturbance)(b) apraxia (impaired ability to carry out motor (b) apraxia (impaired ability to carry out motor

activities despite intact motor function)activities despite intact motor function)(c) agnosia (failure to identify objects despite intact (c) agnosia (failure to identify objects despite intact

sensory function)sensory function)(d) disturbance in executive functioning (planning, (d) disturbance in executive functioning (planning,

organizing, sequencing, abstracting, etc.)organizing, sequencing, abstracting, etc.)

DementiaDementiaDefinitionDefinitionB: The cognitive deficits in Criteria A1 and A2 each cause B: The cognitive deficits in Criteria A1 and A2 each cause

significant impairment in social or occupational functioning significant impairment in social or occupational functioning and represent a significant decline from previous level of and represent a significant decline from previous level of functioningfunctioning

C: Features specific to the clinical presentation of (1) C: Features specific to the clinical presentation of (1) Alzheimer's Disease, or (2) vascular disease, or (3) other Alzheimer's Disease, or (2) vascular disease, or (3) other general medical condition, or (4) the persisting effects of a general medical condition, or (4) the persisting effects of a substance, or (5) multiple etiologies or (6) "not otherwise substance, or (5) multiple etiologies or (6) "not otherwise specified.“specified.“

D,E,F: The cognitive deficits in Criteria A1 and A2 are not due D,E,F: The cognitive deficits in Criteria A1 and A2 are not due to a different specific illness (i.e., a different form of to a different specific illness (i.e., a different form of dementia, delirium or psychiatric illness).dementia, delirium or psychiatric illness).

DementiaDementiaEtiologiesEtiologies• Degenerative (Alzheimer’s, Lewy body, Degenerative (Alzheimer’s, Lewy body,

Parkinson’s)Parkinson’s)• Vascular (MID, large stroke, vasculitis, Vascular (MID, large stroke, vasculitis,

Binswanger’s)Binswanger’s)• Metabolic (hypothyroid, B12 deficiency)Metabolic (hypothyroid, B12 deficiency)• Infectious (AIDS, Syphilis, late post TB)Infectious (AIDS, Syphilis, late post TB)• Hypoxic (s/p CPR, s/p anesthesia?, s/p RT?)Hypoxic (s/p CPR, s/p anesthesia?, s/p RT?)• Toxic (heavy metal)Toxic (heavy metal)• Intracranial lesion (mass)Intracranial lesion (mass)• Trauma (dementia pugilistica)Trauma (dementia pugilistica)

DementiaDementiaMost Common Causes of Dementia in Most Common Causes of Dementia in

the Elderlythe Elderly• Alzheimer’s disease (AD)(50-60%)Alzheimer’s disease (AD)(50-60%)**

• Diffuse Lewy body disease (DLBD)(15-Diffuse Lewy body disease (DLBD)(15-20%)20%)

• Vascular dementia (VD)(15-20%)Vascular dementia (VD)(15-20%)• Parkinson’s dementia (1-3%)Parkinson’s dementia (1-3%)• Frontotemporal dementia (1-2%)Frontotemporal dementia (1-2%)• All otherAll other**In the past, DLBD was included in this category. In addition, up to In the past, DLBD was included in this category. In addition, up to

10% of dementias are mixed AD plus VD10% of dementias are mixed AD plus VD

DementiaDementia

Reversible or not!Reversible or not!• The definition does NOT define permanence of The definition does NOT define permanence of

the lesion (pseudodementia?)the lesion (pseudodementia?)• Data suggests there are very few reversible Data suggests there are very few reversible

dementias in the elderly (depression, chronic dementias in the elderly (depression, chronic intoxication by medication, hypothyroidism) intoxication by medication, hypothyroidism) (Larson)(Larson)

• Co-morbid conditions account for most of the Co-morbid conditions account for most of the reversibility in dementia in the elderly (Larson)reversibility in dementia in the elderly (Larson)

• ““Arrestable” or “Remediable” may be better Arrestable” or “Remediable” may be better terms (Maletta)terms (Maletta)

DementiaDementia

Minimum Cognitive Impairment Minimum Cognitive Impairment (MCI)(MCI)

• DefinitionDefinition• What do we do with it?What do we do with it?

DementiaDementia

Clinically helpful Clinically helpful EARLYEARLY clues clues• Alzheimer’sAlzheimer’s MemoryMemory• Diffuse LBDDiffuse LBD Attention, Exec Func, Visio-spatialAttention, Exec Func, Visio-spatial• VascularVascular Focal signs, temporal relationshipFocal signs, temporal relationship• FT / Pick’sFT / Pick’s Behavioral, social skills, hygieneBehavioral, social skills, hygiene• Parkinson’sParkinson’s Dementia does Dementia does NOTNOT occur early in occur early in

Parkinson’s diseaseParkinson’s disease

DementiaDementia

Alzheimer’s diseaseAlzheimer’s disease• Deposition of beta-amyloid in Deposition of beta-amyloid in

senile plaques diffusely in the senile plaques diffusely in the brain, often around blood brain, often around blood vesselsvessels

• Neurofibrillary tanglesNeurofibrillary tangles• Loss of neuronsLoss of neurons• Brain shrinkage especially Brain shrinkage especially

cortexcortex

Alzheimer’s Risk FactorsAlzheimer’s Risk Factors1.1. AgeAge

• Prevalence doubles every 5 years after age 60Prevalence doubles every 5 years after age 60

2.2. Family HistoryFamily History• Fourfold increase risk overall. The presence of Fourfold increase risk overall. The presence of

the ApoE4 allele increases risk but is not the ApoE4 allele increases risk but is not predictive.predictive.

3.3. GenderGender• Woman probably more than menWoman probably more than men

4.4. Head TraumaHead Trauma• Repeated, especially in menRepeated, especially in men

5.5. Down’s SyndromeDown’s Syndrome• Characteristic brain pathology by age 40Characteristic brain pathology by age 40

6.6. Educational Level / Mental ActivityEducational Level / Mental Activity

Risk Factors Risk Factors (continued)(continued)

7.7. Estrogen plus progesteroneEstrogen plus progesterone• Doubles risk of dementiaDoubles risk of dementia

8.8. Environment ?Environment ?

9.9. Hypertension ?Hypertension ?

10.10. Elevated Cholesterol ?Elevated Cholesterol ?

11.11. Depression ?Depression ?

DementiaDementia

Medications for Alzheimer’s diseaseMedications for Alzheimer’s disease• Acetylcholinesterase inhibitors: indicated for mild Acetylcholinesterase inhibitors: indicated for mild

to moderate dementia. Increases acetylcholine to moderate dementia. Increases acetylcholine in synapsesin synapses

• Memantine (NamendaMemantine (Namenda): indicated for moderate ): indicated for moderate to severe dementia and used with ACI. Selective to severe dementia and used with ACI. Selective blocks the excitotoxic effects of glutamate while blocks the excitotoxic effects of glutamate while allowing the physiologic transmission for normal allowing the physiologic transmission for normal cell functioncell function

Acetylcholinesterase Acetylcholinesterase inhibitorsinhibitors

Do they work when they work?Do they work when they work?• Using family – fewer problem Using family – fewer problem

behaviorsbehaviors• Using NH placement – save ~2 yrsUsing NH placement – save ~2 yrs• Using metrics (MMSE) - minimal Using metrics (MMSE) - minimal

incremental improvementincremental improvement

MemantineMemantine

• Works for moderate to severeWorks for moderate to severe• Works aloneWorks alone• Works with ACIWorks with ACI

Alzheimer’s DiseaseAlzheimer’s Disease

What else works?What else works?• Vitamin EVitamin E• Statins?Statins?

Factors Contributing to [AßFactors Contributing to [Aßss]]

[Aß[Aßss]]

24S-OH 24S-OH cholesterolcholesterolcerebrocholestercerebrocholesterolol

cholesterolcholesterol

inflammationinflammation

APPAPPCNS CNS growthgrowth/repair/repair

LRPLRP

AgingAging

ApoEApoE44

Adapted from Hazzard 2004 AGS annual meetingAdapted from Hazzard 2004 AGS annual meeting

Cholesterol & Alzheimer’sCholesterol & Alzheimer’s• In human studies there are more ß-amyloid In human studies there are more ß-amyloid

plaques in patients dying from heart disease plaques in patients dying from heart disease than from other causes (Sparks 1991)than from other causes (Sparks 1991)

• Cholesterol >240 between age 40-50 Cholesterol >240 between age 40-50 predicted higher AD risk 30 years later predicted higher AD risk 30 years later (Notkolo 1998)(Notkolo 1998)

• In animal studies, rabbits fed high cholesterol In animal studies, rabbits fed high cholesterol diet led to plaques that regressed when diet led to plaques that regressed when cholesterol was removedcholesterol was removed

What do we do with our effective What do we do with our effective cholesterol lowering drugs?cholesterol lowering drugs?

Adapted from Hazzard 2004 AGS annual meetingAdapted from Hazzard 2004 AGS annual meeting

Cholesterol & Alzheimer’sCholesterol & Alzheimer’s

• It’s too early to recommend adding It’s too early to recommend adding “statins” for the treatment of “statins” for the treatment of Alzheimer’sAlzheimer’s

• We need well controlled studies We need well controlled studies across the spectrum of dementiaacross the spectrum of dementia

Adapted from Hazzard 2004 AGS annual meetingAdapted from Hazzard 2004 AGS annual meeting

Let’s Add to the ConfusionLet’s Add to the Confusion

• ACI and memantine(?) might work ACI and memantine(?) might work for vascular dementia, too ! ! !for vascular dementia, too ! ! !

SummarySummary

• Dementia is easy to diagnoseDementia is easy to diagnose• There are features that help differentiate There are features that help differentiate

the common dementias in the elderlythe common dementias in the elderly• Reversible dementias are uncommon in Reversible dementias are uncommon in

the elderly but many dementias are the elderly but many dementias are arrestablearrestable

• Treating comorbid conditions allows those Treating comorbid conditions allows those with dementia to function at their best with dementia to function at their best

• Current drugs used for Alzheimer’s may Current drugs used for Alzheimer’s may help vascular dementia as wellhelp vascular dementia as well

• Vitamin E is worth a try but not statinsVitamin E is worth a try but not statins