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The Dementias William S. Woodfin, M.D.

Neurology Specialists of DallasClinical Assoc. Prof. of NeurologyUT Southwestern Medical School

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Definition

Dementia:The development of multiple cognitive deficits suffficiently severe to cause impairment in occupational or social functioning

Mild Cognitive Impairment: usually refers to a single cognitive domain

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Classification

Alzheimer’s Disease: Sporadic v. Familial

Parkinson Syndromes

Fronto-Temporal Lobar

Vascular

Infectious

Metabolic

Pseudodementia

Others

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Differential Diagnosis of Dementia

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DEMENTIA SYNDROMES

Lewy Body Parkinson’s

Disease

MultipleSystem Atrophy

FXTAS

Diffuse Lewy Body

Disease

SupranuclearPalsy

CorticobasalganglionicDegeneration

Alzheimer’sDisease

Fronto-temporalDementia

VascularParkinsonism

TAUOPATHIES α-SYNUCLEINOPATHIES

NormopressureHydrocephalus

Amyloid and Tau

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Alzheimer’sHistory: Alois Alzheimer 1906

Epidemiology: * 4 million pts.

* A disease of advancing age but not normal aging.

Loss vs. shringage of neurons

* Age 60 1%

Age 85 30-50%

* Underdiagnosed

* Women more than men

* Cost $110 billion

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DSM-IV Definition of Alzheimer’s Disease

Development of multiple cognitive deficits manifested by both memory impairment (amnesia) and 1 or more of the following cognitive disturbances: aphasia, apraxia, agnosia, or disturbance in executive functioning (abstractions)

Cognitive deficits cause significant impairment in social functioning and represent a significant decline from a previous level of functioning

Course is gradual in onset with continuingcognitive decline

Deficits are not due to any other CNS disorder, systemic illness, or substance-induced condition

Deficits do not occur exclusively during the courseof delirium

Source: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:85-86.

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Alzheimer’s Disease (AD): More Than Just Memory Loss

AD is a progressive, degenerative disease involving:

A Decline in ability to perform activities of daily living

B Changes in personality and behavior

C Loss of memory and other cognitive functions

D Eventual nursing home placement, death

$ Increases in resource utilization

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0

5

10

15

20

25

30

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9

Years

MM

SE

sc

ore

Early Diagnosis Mild-Moderate Severe

Cognitive Symptoms

Loss of ADLs

Behavioral Problems

Nursing Home Placement

Death

Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer’s Disease. 1996, 239-253.

Progression of Alzheimer's Disease

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Risk Factors for Alzheimer’s Disease

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Apolipoprotein E

ε 4 allele: a “susceptibility gene” on chromosome 19

single copy→ 2-3 x risk, double copy→ 5 x risk

lowers age of onset

may be assoc. c clearing of Aβ- increased plaques,

but no increase in NFTs

ε 2 allele appears protective

“Not necessary or sufficient”- ½ of AD pts. don’t have

the allele, 10-20% of normal older adults carry one or

two

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Gross Pathology

Temporal lobes esp. hippocampus & entorhinal cortex. Olfactory bulbs and tracts

Parietal lobes

Subcortical nuclei that project to the cortex:

Nucleus Basalis of Meynert (AcH)

Locus ceruleus (NE)

Raphae nuclei (Serotonin)

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Neuropathologic ChangesNeuropathologic ChangesCharacteristic of Alzheimer’s DiseaseCharacteristic of Alzheimer’s Disease

Normal

AP = amyloid plaques.NFT = neurofibrillary tangles.Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation.

AD

AP NFT

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EXTRACELLULAREXTRACELLULAR INTRACELLULARINTRACELLULAR

NORMALNORMAL ALZHEIMER’SALZHEIMER’S

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βaptists v Tauists

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Microscopic Pathology

Amyloid (Senile) Plaques: Extraneuronal

Aβ

Dystrophic axons and dendrites

Astrocytes

Microglia

Neurofibrillary Tangles: Intraneuronal- predominantly

axonal, longer axons

Hyperphosphorylated tau protein

Neuronal loss

Vascular change: Cerebral Amyloid Angiopathy

Aβ 40

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Etiology: Amyloid Hypothesis

Cleavage of transmembranous APP by secretases

Aβ 40 & Aβ 42

Insoluble oligomers

Insoluble fibrils

Diffuse plaque

Mature plaque- due to inflammatory reaction with astrocytes and microglia

Neuronal and synaptic injury

NFTs and Neuronal death

Loss of neurotransmitters

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Evidence for the Amyloid Hypothesis

Aβ neurotoxic in vitro

Overexpression of APP in transgenic mice=disease

Mutations in APP = early onset disease

All known mutations= increased Aβ

Downs Syndrome with 3 copies of APP gene

Apolipoprotein E € 4 accelerated Amyloid deposition

Amyloid antibodies in mice and men slows disease

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Familial Alzheimer’s

Chromosome 14 c presenilin 1 gene

Chromosome 1 c presenilin 2 gene

Both code for a portion of γ-secretase

Chromosome 21 c APP mutations

Onset of sxs. In 40s & 50s

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PET Imaging of Amyloid

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Tau Association With Microtubules

Tau bound to microtubule

Microtubule

Hyperphosphorylated tau subunits

PHF composed of tau subunits

PHF = paired helical filaments.

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Prevention

Anti-Inflammatories

Hormones

Vitamins and Herbs

Diet and Antioxidants

Alcohol and Smoking

Exercise

Basic Medical Care

Blood Pressure

Lipids

Homocystine

Specific Agents

Cholinesterase Inhibitors

NMDA Receptor Blockers

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Anti-Inflammatories

Dutch study, NEJM 2001: RR 0.95 < 1 month

0.83 1-24 months

0.20 > 2 years

No benefit with trials of: Prednisone

Diclofenac

Rofecoxib

Naproxen

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Estrogens

Mechanisms: Estrogen receptors associated with NGF receptors

May enhance neurotransmitter function, esp. Ach

May diminish excitatory effect of Aβ

May alter APP resulting in less Aβ

PET shows increased blood flow and glucose metabolism in hippocampus

Early studies mixed: Prior to 1999, 4 impairment, 7 improvement

WHIMS: Estrogen & Progesterone: Mild increase in stroke and dementia

Estrogen alone: stopped this year, risk of dementia about the same

Would earlier institution of estrogens or longer duration of treatment be useful? Cache Co. Utah study

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Vitamins and Herbs

Vitamin E- No help

Potential toxicity: bleeding, HA,N,V,diarrhea, bone pain, hair loss

Vitamin C- No compelling evidence

Folic Acid- Increasing evidence for protection for AD and VaD

Would use more than 400 mcgm/day

Ginko Biloba- several studies suggest some improvement

St. Johns Wort- caution

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Diet & Antioxidants

Fats: Diets high in unsaturated, unhydrogenated fats and low in saturated/transunsaturated fats may protect against dementia and coronary disease.

Cholesterol: Mixed findings. Dietary cholesterol has less impact on serum cholesterol than does saturated fat intake.

Dietary Flavinoids: May diminish risk

Caloric Intake: Animal studies show all degenerative diseases associated with aging diminish with reduced caloric intake.

Increased oxidative stress and accumulation of free radicals.

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Alcohol & Smoking

Red Wine: 250-500 ml/day may protect

May be due to flavanoids, also found in tea,fruit, and vegetables.

Beer: May worsen odds with low intake of thiamine and other B vitamins

Dangers in the elderly: Lean body mass

Trauma

Interactions with medications

Smoking: Accelerates microvascular cerebral disease

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Exercise

Physical: Decreases glucose and LDL levels, raises HDL

Aerobic vs. anaerobic and frontal lobe function

Mental: Educational attainment

Ongoing cognitive efforts: Nun study- Top 10% were 47% less likely than bottom 10% to become demented.

Sensory support: eyeglasses, hearing aids

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Basic Medical Care

Control of blood pressure and glucose

Statins: Inhibit activity of β and γ secretase

May limit effects of APO € 4 allele

Endothelial remodeling

Increase e NOS

Decrease endothelin-1

PROSPER study (Pravastatin)

HPS study (Simvastatin)

Atorvastatin

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Specific Pharmaceutical Intervention

Cholinesterase Inhibitors: Donepezil (Aricept)

Rivistigmine (Exelon)

Galantamine (Reminyl→Razadyne))

NMDA Inhibitors: Memantine (Namenda)

Considerations in their use: Cognition

Behavior

Activities of Daily Living

Efficacy, Safety, Side Effects and Cost (~$140/mo.)

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Parkinson Syndromes

1)Idiopathic PD:

Up to 40% c dementia; 65% by age 85

3rd leading cause overall

Increases c age at dx., early hallucinosis & advanced motor signs, presence of depression

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Pathological changes are those of Alzheimer’s dis. In addition to the typical pathology of Lewy bodies and neuronal loss in the substantia nigra.

Lewy bodies- intraneuronal, eosinophilic inclusions containing misfolded α-synuclein

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2) Diffuse Lewy Body Disease

Motor sxs, dementia c often striking fluctuation and prominent haullucinosis

Lewy bodies are diffusely distributede in the cerebral cortex

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Fronto-Temporal Lobar

1)Fronto-Temporal Dementia: Characterized by behavioral & executive function changes. 40-50% is familial. 10-20% of all dementias. Earlier age of onset. Atrophy of frontal & temporal poles. Pick bodies- argyrophilic round intraneuronal inclusions composed mainly of abnormal tau proteins. Unresponsive to AChI- tret c SSRIs & ? Memantine.

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2) Primary Progressive Aphasia

Predominantly expressive

Other cognitive domains essentially intact

Focal atrophy seen on imaging

Eventual dementia

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3) Semantic Aphasia

Predominantly a receptive aphasia

Atrophy seen more in parietal and posterior temporal regions

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4) Other Tauopathies

Progressive Supranuclear Palsy (Steele-Richardson-Olsewski Syn.)

Corticobasal ganglionic degeneration

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Vascular

2nd leading cause of dementia

Subtypes: Cortical- large vessel & embolic stroke. Stepwise progression. More severe aphasia. Sensoro-motor abnormalities.

Subcortical- small vessel. Pseudobulbar palsy, gait impairment ( marche à petit pas), urinary incontinence

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Treatment of Vascular Dementia

Attempt to limit progression: Hypertension, diabetes, homocysteine, lipids, cardiac

Cognitive: possibly AChIs & memantine

Behavioral: above + SSRIs

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Alzheimer’sDisease

FTD

Dementia withLewy Bodies

Ischemicvasculardementia

NPH

+

+

+

+

+

MemoryLoss

++

±

–

±

–

ImpairedLanguage

+

–

–

±

–

VisuospatialImpairment

Typical Differential Points of Common Dementias at Initial Presentation

MotorSigns

_

AbnormalBehavior

VascularEvent

_

++

+

+

_ _

+_

+

+

_

_

++

_

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Infectious

Cruetzfeldt-Jacob Disease

Familial

Sporadic

New Variant

Fatal familial insomnia

Gerstmann-Sträussler-Scheinker

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Other Infectious

HIV

GPI

Lyme disease

Fungal

Tuberculous

PML

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Metabolic

Thyroid

B 12

Folate

Thiamine

Hepatic

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Other

Huntington’s disease: irritability, apathy, impulsive behavior, poor personal hygeine, psychosis. Etiol. unclear until chorea appears esp. c spontaneous mutation.

HD gene on chrom. 4 contains trinucleotide repeats,CAG, encoding for glutamine preventing normal turnover of protein, huntingtin, in cytoplasm and nuclei. Abn. aggregation of this protein may→ pathology, cortical 7 subcortical

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Other continued

Tumor

Subdural hematoma

Hydrocephalus

Demyelinating

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Pseudodementia

Probably the most common etiology in the 30-60 patient population

Stress

Depressive disorders

Anxiety disorders

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Clinical Evaluation

History

Neurological Exam

N-P testing

Blood work

Imaging & EEG

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Counseling for Patients & Families

Prognosis re. rate of decline & life expectancy

Patient & family goals for treatment

Review of finances & power of attorney

Medical advance directives

Driving

Home safety

Wandering (www.alz.org/Services/SafeReturn.asp)

Long term care

Resources for family and caregiver includ. Alz. Assoc. & ABA Commission on Legal problems for the Elderly

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