DEMENTIA& ALZHEIMER’S!

Dr. Mohamad Shaikhani.

Dementia:• An acquired syndrome of intellectual impairment

• Interferes with social & vocational function

• Associated with impairment in at least 3 of the following:

– Language, visuospatial skills, Memory, Personality & cognition (abstraction mathematics, judgment)

Dementia is a clinical syndrome characterised by a loss of previously acquired intellectual function in the absence of impairment of arousal.

Alzheimer's disease &diffuse vascular disease are the most common causes.

The distinction of senile from pre-senile dementia is unhelpful. Rarer causes should be more actively sought in younger patients

&those with short histories

Dementia:

CAUSES OF DEMENTIA

Type Common Unusual Rare

Vascular Diffuse small-vessel disease Amyloid angiopathyMultiple emboli

Cerebral vasculitis

Degenerative/inherited Alzheimer's disease LeucodystrophiesHuntington's diseaseWilson's diseasePick's diseaseDystrophia myotonicaCortical Lewy body diseaseProgressive supranuclear palsyOthers (e.g. cortico-basal degeneration)

Mitochondrial encephalopathies

Neoplastic Secondary deposits Primary cerebral tumour Paraneoplastic syndrome (limbic encephalitis)

Inflammatory Multiple sclerosis Sarcoidosis

Traumatic Chronic subdural haematomaPost-head injury

Punch-drunk syndrome

Hydrocephalus Communicating/non-communicating'Normal pressure' hydrocephalus

Toxic/nutritional Alcohol Thiamin deficiency B12 deficiency Anoxia/carbon monoxide poisoningHeavy metal poisoning

Infective SyphilisHIV

Post-encephaliticWhipple's diseaseSubacute sclerosing panencephalitis

Prion diseases Sporadic Creutzfeldt-Jakob disease (CJD) Variant CJD Kuru Gerstmann-Sträussler-Scheinker disease

Geriatric Psychiatry: A Review & Update

Differential Diagnosis: Top Ten Differential Diagnosis: Top Ten

1.1. AAlzheimer Disease (pure ~40%, + mixed~70%)lzheimer Disease (pure ~40%, + mixed~70%)2.2. VVascular Disease, MID (5ascular Disease, MID (5--20%)20%)3.3. DDrugs, rugs, DDepression, epression, DDeliriumelirium4.4. EEthanolthanol (5(5--15%)15%)5.5. MMedical / edical / MMetabolic Systemsetabolic Systems6.6. EEndocrine (thyroid, diabetes), ndocrine (thyroid, diabetes), EEars, ars, EEyes, yes, EEnviron.nviron.7.7. NNeurologic (other primary degenerations, etc.)eurologic (other primary degenerations, etc.)8.8. TTumor, umor, TToxin, oxin, TTraumarauma9.9. IInfection, nfection, IIdiopathic, diopathic, IImmunologicmmunologic10. 10. AAmnesia, mnesia, AAutoimmune, utoimmune, AApnea, pnea, AAAMIAMI

Reversible DEMENTIA:– D= Drugs, Delirium– E= Emotions (depression)& Endocrine Dis– M= Metabolic Disturbances– E= Eye & Ear Impairments– N= Nutritional Disorders– T= Tumors, Toxicity, Trauma to Head– I= Infectious Disorders– A Alcohol, Arteriosclerosis(Dick-Mulheke- Overview of Alzheimer's Disease)

Irreversible DEMENTIA:– Alzheimer’s– Lewy Body Dementia– Pick’s Disease (Frontotemperal Dementia)– Parkinson’s– Heady Injury– Huntington’s Disease– Jacob-Cruzefeldt Disease

DIAGNOSIS OF DEMENTIA:

• Behaviorally defined - no lab test provides diagnosis of dementia

• Dementia is a disease process

• Not a normal part of aging

Anatomical substrates of memoryin Dementia?

• A. Medial temporal lobes & hippocampus (also fornix, mamillary bodies of limbic system)

• B. Medial thalamus - especially dorsal median nucleus

• C. Nucleus basalis of Meynert

• D. Need bilateral damage to have memory loss

Five most general classifications for Dementia

• Pure memory loss

• Cortical dementias

• Subcortical dementias

• Mixed Dementias

• Reversible / Treatable Dementias

Pure memory loss: causes• Herpes encephalitis sequelae - bilateral medial temporal lobe

lesions

• Korsakoffs amnesia - bilateral dorsal median nuclei & mamillary body damage due to chronic thiamine deficiency

• Vertebral - basilar infarcts - if result in bilateral temporal lobe lesions

• Transient global amnesia – TIA/migrainous?

• Limbic encephalitis - damage to hippocampus/ limbic pathway

Two subtypes of Cortical dementias

• Alzheimer’s disease

• Pick’s disease

Alzheimer’s Disease (AD) Most common neurodegenerative disease of aging. 65% of demented patients Affects 10% > 65 Uncommon up to 65 ys, but up to 20% of those >80 ys. Deficits in Memory Forgetfulness, disorientation, speed of performance, problem solving, language,

perception & judgment Mental functions become progressively more impaired leading to profound

dementia AD Diagnosis:

Neurological exam & neuropsychological testingBrain imaging: brain atrophy due to extensive neuronal loss Diagnosis confirmed by histology of post-mortem brain

‘Plaques’ & ‘tangles’ in hippocampus & cerebral cortex

AD/DAT: Epidemiology Prevalence slightly higher in women than men AD subdivided into:

Early-onset AD (<65) or late-onset AD (>65) 75% of AD patients have disease onset after 60 60% of AD patients have no family history of disease DAT is Amyloid Protein Aggregation Formation

RELATIVE RISK FACTORS • Family history of dementia 3.5 (2.6 - 4.6)

• Family history – Downs 2.7 (1.2 - 5.7)

• Family history - Parkinson’s 2.4 (1.0 - 5.8)

• Maternal age > 40 years 1.7 (1.0 - 2.9)

DIAGNOSIS OF DAT: A clinical diagnosis"diagnosis by exclusion," There is no exact clinical test or finding that makes

Alzheimer's disease unique. Initial deterioration can be simulate many disorders, so each

disorder must be systematically excluded or ruled out before

a diagnosis can be made.

DIAGNOSTIC CRITERIA FOR DEMENTIA OF THE ALZHEIMER TYPE(DSM-IV, APA, 1994)

• A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS

• 1. MEMORY IMPAIRMENT

• 2, OTHER COGNITIVE IMPAIRMENT

• B. THESE IMPAIRMENTS CAUSE DYSFUNCTION IN

• IN SOCIAL OR OCCUPATIONAL ACTIVITIES

• C. COURSE SHOWS GRADUAL ONSET AND DECLINE

• D. DEFICITS ARE NOT DUE TO:

• 1. OTHER CNS CONDITIONS

• 2. SUBSTANCE INDUCED CONDITIONS

• F. DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM

• G. ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER

Histopathology of Alzheimer’s Disease• Generalized cortical neuronal dropout

• Neurofibrillary tangles & senile plaques (with amyloid composed of -A4 protein), granulovacuolar degeneration

• Neuronal loss in nucleus basalis of Meynert

AD: Pathology

• Abnormalities & loss of neurons in hippocampus, cortex, basal forebrain (ACh)– Marked decrease in

cortical ChAT & AChE

– Degree of cholinergic deficit correlates with

degree of dementia

Senile Plaques

• Extracellular deposits of amyloid-b peptide forming plaque core surrounded by axons/dendrites & glia– Small number of plaques found

in normal aging brain• Amyloid-b peptide derived from

amyloid precursor protein (APP)– APP gene is located on

chromosome 21 – Mutations in APP gene give

rise to some familial forms of AD

Neurofibrillary Tangles• Intraneuronal fibers composed of

paired helical filaments of tau protein hyperphosphorylated – Normally found in axons

associated with microtubules– In AD: tau protein self-

aggregates & is found throughout the neuron

• Clinical symptoms & severity of AD correlate best with density & distribution of tangles (& not with amyloid-b deposition)

clinical diagnosis of Alzheimer’s Disease

A)Definite Alzheimer’s Disease

B) Probable Alzheimer’s Disease

C) Possible Alzheimer’s Disease

• Definite Alzheimer’s Disease

• Clinical criteria present

• +

• Histopathologic evidence from brain biopsy

Probable Alzheimer’s Disease

Documentation of cognitive impairment with screening mental status examination, confirmed by neuropsychological testing

Deficits in two or more areas of cognition

Progressive worsening of memory & other cognitive function No disturbance of consciousness Onset between ages 40 - 90, most often after 65 Absence of other disorders.

• Possible Alzheimer’s Disease There are variations in the onset, presentation, or clinical course

of a dementing illness that are unusual in DAT but for which there is no alternative explanation

There is a second systemic or brain disease capable of producing a dementia syndrome that is not considered to be the cause of the dementia in this case.

There is a single gradually progressive deficit

staging of Alzheimer’s Disease• Mild - although work or social activities are significantly

impaired, the capacity for independent living remains, with adequate personal hygiene & relatively intact judgment (~1 -3 yrs)

• Moderate - Independent living is hazardous& some degree of supervision is necessary (~2-8 yrs)

• Severe: Activities of daily living are so impaired that continuous supervision is required, e.g., unable to maintain minimal personal hygiene; largely incoherent or mute.

MILD COGNITIVE IMPAIRMENT CRITERIA (Amer. Acad. Neurology)

(Petersen et al., 2001 – Neurology 56:1133)

• Memory complaint, preferably corroborated by an informant• Objective memory impairment• Normal general cognitive function• Intact activities of daily living• Not demented.• Consider age &APOE genotype to differentiate from age-

related cognitive dysfunction.

MILD COGNITIVE IMPAIRMENT progression:

Study Mean Age

Criteria Annual conversion rate to AD %

Mayo 81 MCI 12

Toronto 74 Memory Impairment 14

Columbia 66 Questionable dementia 15

MGH 72 CDR 0.5 6

Seattle 74 Isolated memory loss 12

NYU 71 GDS 3 25

Pick’s disease• An uncommon type of cortical dementia

• Clinically similar to Alzheimer’s in the late stages

• Early, extravagant personality changes & stereotyped language output (repetitive joke telling) may help differentiate

• Pathologically there is focal atrophy of the frontal &/or anterior lobes

Hallmarks of Subcortical dementias Psychomotor retardation

Slowed speech& cognition, motor sequencing problems, abnormal posture & gait

Forgetfulness Characterized by difficulty retrieving information- recall

often improves if provide a clue

Disorders are associated with subcortical dementia

a. Parkinson’s disease

b. Huntington’s disease

c. Progressive supranuclear palsy

d. Wilson’s disease

e. AIDS dementia

Pathology of subcortical dementia

• Pathologically involves

– Basal ganglia

– Thalamus

– Rostral brainstem

“Distinguishing Features of Cortical & Subcortical Dementia”

Cortical Subcortical

Intellectual Functions

Aphasia-

Amnesia

Visuospatial disorder

Poor abstraction

Aculculia

Apraxia

Agnosia-loss of the power to recognize the import of sensory stimulus.

Psychomotor retardation

Forgetfulness

Cognitive dilapidation

Impaired insight

Poor strategy formulation

“Distinguishing Features of Cortical & Subcortical Dementia”

Cortical Subcortical

Personality/Emotions

Indifference Depression(rarely, mania)

“Distinguishing Features of Cortical & Subcortical Dementia”

Cortical Subcortical

Speech Normal (until late) Dysarthria

“Distinguishing Features of Cortical & Subcortical Dementia”

Cortical Subcortical

Motor Normal (until late) Abnormal (parkinsonian, chorea, dystonia, etc.)

“Distinguishing Features of Cortical & Subcortical Dementia”

Cortical Subcortical

Anatomy Neocortical association areas&hippocampus

Thalamus

basal ganglia

rostral brainstem

Mixed dementias cortical & subcortical structures

are involved

Causes:• 1. Multi-infarct

• 2. Slow virus

• 3. General Paresis (Neurosyphilis)

Factors involved in Multi-infarct

Dementia(vascular dementia)

Step-wise progression is hallmark

Abrupt onset, focal signs

By treating stroke risk factors may prevent progression

Factors involved in Slow virus Dementia

• Ex: Jacob Creutzfeldt Disease

• Rare, associated with myoclonus

Three important facts about Dementia syndrome or

pseudodementia:

It reverses with antidepressant therapy (“pseudodementia”)

It occurs in up to 10% of depressed elderly

Many of these (elderly) will later develop irreversible dementia, but benefit from treatment of depression

regardless

3 important effects of depression

• Decreases:

– concentration

– response time

– motivation

Differentiate primary depression & primary dementia by History!

• Depression – acute onset– family awareness– short symptom duration– rapid progression– history of depression in patient and/or family– Dementia– slow onset– vague family awareness– long symptom duration– slow progression

Differentiate Depression & Dementia by clinical testing

• depression

– little effort on tasks– “don’t know” answers– absence of dyspraxia, agnosia, language problems

• dementia – – struggles to complete tasks– attempts answers but incorrect– presence of dyspraxias, agnosias, and language problems

2 facts of Normal Pressure hydrocephalus

• Clinical triad: ataxia, incontinence, dementia

• Difficult to identify those who may improve with shunt, high morbidity

High risk for Subdural Hematoma

• Elderly

• Alcoholics

Symptoms of Subdural H

• Fluctuating symptoms

• Headaches

• may have focal signs

Workup of the demented patient

• A. History - important to interview family

• B. Physical and Neurologic examination

• C. Mental status

Test to examine the mental status

• Folstein’s mini-mental status examination

• Widely used at bedside for brief assessment (not specific or very sensitive)

Age-specific norms for the MMSE

• 60s – 28

• 70s – 28

• 80s –26

Test that performs a more in depth Psychological testing

• WAIS (Wechsler Adult Intelligence Scale)

Discrepancy of 15 points between verbal & performance scores associated with acquired brain dysfunction

Available Screening Tests• MMSE 10 -- 15 min

• Too long

• 7-Minute Screen 7 – 10 min• Too complex

• Clock Drawing Test 2 – 4 min• Not sensitive

• Mini-cog 3 – 5 min• Complex scoring, unclear adequacy

• Memory Impairment Screen 4 min• Need for slightly shorter, easier test

• (a suitably accurate test that takes less than 2 minutes is not available)

13 lab and other studies used to diagnose demented patients!

• Electrolytes, BUN, creatinine, CA++• CBC• Thyroid studies• ESR• B 12• Folate• VDRL/FTA-Ab, ANA, Anti DsDNA.• EKG• CXR• CT• LP if suspicion of infectious etiology• HIV Ab.• drug screen if appropriate• Brain biopsy.

Management of irreversible dementias Provide structured safe environment

Close supervision when indicated

Frequent orientation

Familiar surroundings provide important cues - deteriorate rapidly when moved (hospitalization)

If sudden worsening, evaluate for infection or side effect of new medication

Caregiver support

AD: TreatmentNo cure for ADLimited therapy to help symptoms or to slow progressionTherapies to improve symptoms:Enhancement of cholinergic systemIncrease dietary choline: little effect on cognition AChE inhibitors: small cognitive enhancing effect

Anticholinesterases, such as donepezil, rivastigmine & galantamine, or NMDA (N-methyl-D-aspartate receptor antagonists (memantine) appear to improve cognitive

function to some extent in Alzheimer's disease

Tacrine (Cognex)

• for Alzheimer’s Disease of mild-to-moderate severity

• Appears to improve or slow the decline in some test scores in a minority of patients (response is dose-related)

• Associated with an elevation in liver enzyme (SGPT) in nearly 50% of patients (25% 3 x nl); reverses after D/C

Areas of investigation

• Eldepryl (Selegiline) - anti-oxidant therapy

• NSAIDs

• ApoE

• Nerve growth factors

• Herbal remedies available.

• Ginkgo biloba.