DEMENTIA Prof. Abdulkader Daif Consultant Neurologist 2011

DEMENTIA

Prof. Abdulkader Daif

Consultant Neurologist

2011

Cognitive Disorders (DSM-IV)Cognitive Disorders (DSM-IV)

1.1.DementiaDementia

2. Delirium2. Delirium

3. Amnesic Disorder3. Amnesic Disorder

CognitionCognition

Brain functions including:Brain functions including:

AttentionAttention InitiationInitiation

MemoryMemory LanguageLanguage

CalculationCalculation PraxisPraxis

Executive functionsExecutive functions

Visuospatial capacityVisuospatial capacity

Time and space orientationTime and space orientation

Cognitive Disorders: DementiaCognitive Disorders: Dementia

DementiaDementiaDementiaDementia •Clinical condition/syndromeClinical condition/syndrome•Loss of cognitive functionLoss of cognitive function•Interferes with normal activitiesInterferes with normal activities•Interferes with social relationshipsInterferes with social relationships

Common signs

1. Impairment of memory2. Multiple disturbances of cognition3. Impairment of executive function.4. Disorientation.5. Behavioral changes.

Definition of DementiaDefinition of Dementia

Normal cognitive decline vs. DementiaNormal cognitive decline vs. Dementia

Cognitive function declines with age:Cognitive function declines with age:Slower learning curveSlower learning curve

Slower reaction timeSlower reaction time

Decreased/slower working memory and Decreased/slower working memory and frontal functionsfrontal functions

Maintenance of vocabulary and Maintenance of vocabulary and grammatical structuresgrammatical structures

When compared to younger adultsWhen compared to younger adults

Dementia is a complex syndrome

Psychological / psychiatric symptoms

Behavioral

Behavioral disturbances

Amnesia ApraxiaAgnosiaAphasia

Functional

Cognitive

Instrumental ADL Personal ADL

Dementia? Reversible causes?

Depression? Delirium?

MCI ? CIND?

Acute onsetStepwise

Risk factorsGait

Neurological

Gradual onsetMemory loss

Normal examination

HallucinationsFluctuationsVisuospatial

Parkinsonism

BehaviouralLanguageFamily hx

Young onset

Frontotemporal Dementia

Lewy Body Dementia

Alzheimer’sDisease

Vascular Dementia

Dementia: CausesDementia: Causes

1.1.ReversibleReversible

2. Irreversible2. Irreversible

Reversible Dementia (some causes)Reversible Dementia (some causes)

Dementia due to treatable conditionDementia due to treatable condition::•infectionsinfections•toxic effects of drugs (polypharmacy)toxic effects of drugs (polypharmacy)•normal pressure hydrocephalusnormal pressure hydrocephalus•head injuryhead injury•nutritional deficiencies

Korsakoff’s syndrome (vitamin B1)Wernicke’s disease

•metabolic problems (e.g., hypothyroidism)metabolic problems (e.g., hypothyroidism)•mental and sensory deprivationmental and sensory deprivation•Depression (pseudodementia)*Depression (pseudodementia)*•Delirium*Delirium*

Important to Important to treat earlytreat early

Important to Important to treat earlytreat early

Can become Can become irreversibleirreversible

Causes of DementiaCauses of Dementia

65%10%

7%

5%

5%8% Alzheimer's Disease (AD): 65%

AD & Vascular: 10%

Lewy body: 7%

AD and Lewy body: 5%

Vascular: 5%

Other: 8%

WISCONSIN ALZHEIMER’S INSTITUTE

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Prevalence of dementia in Canada: Canadian Prevalence of dementia in Canada: Canadian Study of Health and Aging (1991-1992)Study of Health and Aging (1991-1992)

Female to male ratio is 2:1Female to male ratio is 2:1

2.4 % for 65-74 years2.4 % for 65-74 years

34.5% for those aged 85+34.5% for those aged 85+

Prevalence of Alzheimer’s Disease and Prevalence of Alzheimer’s Disease and Vascular Dementia in CanadaVascular Dementia in Canada

Alzheimer’s Alzheimer’s 5.1%5.1% for 65+ for 65+– 1.0% for 65-74 years1.0% for 65-74 years– 26% for 85+ years26% for 85+ years

Vascular dementia Vascular dementia 1.5%1.5% for 65+ for 65+– 0.6 % for 65-74 years0.6 % for 65-74 years– 4.8 % for 85+ years4.8 % for 85+ years

Vascular Dementia: DiagnosisVascular Dementia: Diagnosis

Diagnostic criteria of memory decline, loss of Diagnostic criteria of memory decline, loss of functioning similar to AD, but:functioning similar to AD, but:Requires presence of focal neurologic deficits Requires presence of focal neurologic deficits reflecting a CVA or multiple cerebrovascular risk reflecting a CVA or multiple cerebrovascular risk factorsfactors

HypertensionHypertensionCoronary artery diseaseCoronary artery diseaseHypercholesterolemiaHypercholesterolemiaObesityObesityType II diabetesType II diabetes

EpidemiologyEpidemiology– Second most common cause of dementia next to AD.Second most common cause of dementia next to AD.

Vascular DementiaVascular Dementia

SymptomsSymptoms– Mood labilityMood lability– Stepwise course of illnessStepwise course of illness

May plateauMay plateau

Course is more variable than the progression of Course is more variable than the progression of ADAD

– Multiple medications and comorbid illnesses Multiple medications and comorbid illnesses associated with the vascular risk factors associated with the vascular risk factors increase vulnerability to delirium (confusion).increase vulnerability to delirium (confusion).

FeaturesFeatures

•Associated with damage to the cerebral blood vessels Associated with damage to the cerebral blood vessels through arteriosclerosisthrough arteriosclerosis•found in middle and later life (age of onset between 50-70)found in middle and later life (age of onset between 50-70)•accumulated effect of multiple cortical and subcortical infarctsaccumulated effect of multiple cortical and subcortical infarctslead to clinical presentationlead to clinical presentation•incidence higher in menincidence higher in men•first sign delirium or small strokefirst sign delirium or small stroke

Dementia: Vascular DementiaDementia: Vascular Dementia

Vascular DementiaVascular Dementia

MRI Imaging:Periventricular hyperintensitiesVentricular capping“Small vessel ischemia”

Clinical PresentationClinical Presentation

•Abrupt onsetAbrupt onset•step-wise deteriorationstep-wise deterioration•somatic complaintssomatic complaints•emotional incontinenceemotional incontinence•history of hypertensionhistory of hypertension•history of cebrovascular accidentshistory of cebrovascular accidents•focal neurological symptomsfocal neurological symptoms•focal neurological signsfocal neurological signs

Dementia: Vascular DementiaDementia: Vascular Dementia

Management of vascular dementiaManagement of vascular dementia

Risk assessment Risk assessment

– Age, hypertension, smoking, diabetes, history of Age, hypertension, smoking, diabetes, history of stroke/TIAstroke/TIA

Reduction of risk of further damageReduction of risk of further damage

– Management of stroke and risk factorsManagement of stroke and risk factors

Treatment of secondary conditionsTreatment of secondary conditions11

– Depression, anxiety, agitationDepression, anxiety, agitation

Treatment of dementia symptomsTreatment of dementia symptoms

– Cognition, global function, activities of daily livingCognition, global function, activities of daily living1Gupta A, et al. Int J Clin Pract. 2002;56:531-537.

•Patient Auguste D. had dementia Patient Auguste D. had dementia symptomssymptoms•Brain studies after her death revealed Brain studies after her death revealed microscopic changes microscopic changes

Alois Alzheimer (1864-1915)Alois Alzheimer (1864-1915)

•Symptoms due to neuronal changesSymptoms due to neuronal changes

Dementia:Dementia:Alzheimer’s Disease HistoryAlzheimer’s Disease History

•DementiaDementia•Significant cognitive deficienciesSignificant cognitive deficiencies•Progressive deteriorationProgressive deterioration•No loss of consciousnessNo loss of consciousness•40-90 years of age40-90 years of age•No other diseasesNo other diseases

Criteria for probable Alzheimer’s diagnosis=Criteria for probable Alzheimer’s diagnosis=

Also includesAlso includes

•Medical testsMedical tests•Family historyFamily history•Brain scansBrain scans•Other symptomsOther symptoms

Dementia and Related Neurological Dementia and Related Neurological Disorders: Disorders: Alzheimer’s DiseaseAlzheimer’s Disease

EarlyEarly

MiddleMiddle

LateLate

Memory loss for familiar Memory loss for familiar objects and eventsobjects and events

Personality changesPersonality changesBehavior changesBehavior changes

Loss of ability to perform simple Loss of ability to perform simple everyday functionseveryday functions

Regular progressionof loss

Alzheimer’s Disease: “Stages” of ProgressionAlzheimer’s Disease: “Stages” of Progression

Psychological SymptomsPsychological Symptoms

People do not die of Alzheimer’s per se.People do not die of Alzheimer’s per se.

Clinical PresentationClinical Presentation::

•Memory lossMemory loss•AphasiaAphasia•ApraxiaApraxia•AgnosiaAgnosia•Disturbance in executive functioningDisturbance in executive functioning

Diagnosisdone byexclusion

Diagnosisdone byexclusion

Autopsy is onlyAutopsy is onlyreliable methodreliable method

Pathologic Hallmarks of ADPathologic Hallmarks of AD

Neurofibrillary Tangles (NFT)Neurofibrillary Tangles (NFT)– Cytoskeletal proteinCytoskeletal protein– Hyperphosphorylated Tau proteinHyperphosphorylated Tau protein

Neuritic PlaquesNeuritic Plaques– Extracellular compacted insoluble amyloid Extracellular compacted insoluble amyloid

proteinprotein– AAßß4242 peptide – abnormal secretase cleavage peptide – abnormal secretase cleavage– Neurotoxic propertiesNeurotoxic properties

CSF Amyloid and TauCSF Amyloid and TauCSFCSF– AAßß4242 levels (not total Aß) are levels (not total Aß) are reducedreduced in CSF in AD in CSF in AD

compared to other dementias or control subjects.compared to other dementias or control subjects.Reduction due to insolubility of Aß42 in plaquesReduction due to insolubility of Aß42 in plaques

CSF Tau CSF Tau – ElevatedElevated in AD relative to controls in AD relative to controls– BUT also elevated in patients with other neurologic diseasesBUT also elevated in patients with other neurologic diseases

Current ConsenusCurrent Consenus– Combination of ACombination of Aß and Tau better than either aloneß and Tau better than either alone

Knopman D, Arch. Neurol, 58; 2001.Knopman D, Arch. Neurol, 58; 2001.

AD Etiology – microscopic

Neuritic PlaquesNeurofibrillary Tangles

Amyloid

Beta-amyloid deposits

Secretase

Tau microtubules hyperphosphorylation & collapse

MAP protein

Amyloid PlaquesAmyloid Plaques

•Collection of waste Collection of waste products of dead neurons products of dead neurons around a core of around a core of amyloid.amyloid.•Formation occurs long Formation occurs long before symptoms are before symptoms are evidentevident

•Amyloid-42 most common form found in plaquesAmyloid-42 most common form found in plaques

Alzheimer’s DiseaseAlzheimer’s Disease

Amyloid plaqueAmyloid plaque

Tangles and Plaques

http://www.ahaf.org/alzdis/about/AmyloidPlaques.htm

Neurofibrillary TanglesNeurofibrillary Tangles

•Made up of tau proteinMade up of tau protein•Tau maintains microtubules Tau maintains microtubules within axonswithin axons•Tangles form when tau Tangles form when tau changes chemically and can changes chemically and can no longer support the no longer support the microtubulesmicrotubules•Leads to collapse of Leads to collapse of transport system within transport system within neuronneuron

Neurofibrillarytangle

Neurofibrillarytangle


http://www.alzheimers.org/tangle.html

Neurofibrillary TanglesNeurofibrillary Tangles


EnvironmentalEnvironmental

Life styleLife style Head injury Head injury •Twin dataTwin data•Japanese men who moved Japanese men who moved to Hawaiito Hawaii•Nun Study on mental Nun Study on mental activityactivity

•Severe injuries Severe injuries involving loss of involving loss of consciousnessconsciousness•Causes damage to Causes damage to neuronsneurons


Causes of Alzheimer’s DiseaseCauses of Alzheimer’s Disease

Genetic theoryGenetic theoryGenetic theoryGenetic theoryFamilial Familial Alzheimer’s Alzheimer’s DiseaseDisease

Familial Familial Alzheimer’s Alzheimer’s DiseaseDisease

ApoE gene 19

APP gene 21

PresenilinPresenilin 11 1414

Presenilin 2 1

GeneGene ChromosomeChromosome

•Early onsetEarly onset•Late onsetLate onset

supports


Causes of Alzheimer’s DiseaseCauses of Alzheimer’s Disease

Majority of early-onset cases

Majority of early-onset cases

Genes and Alzheimer’s disease(60% - 80 % of causation)

(all known genes relate to amyloid)

Familial AD (onset < 60 y/o) (<5%)– Presenilin I, II (ch 14, 1)– APP (ch 21)

Non-familial (late onset)– APOE

Clinical studies suggest 40 – 50% due to 4If is considered, may be 95% of causation

Population studies suggest 10 – 20% cause

Evolution over last 300,000 to 200,000 years

– At least 20 other genes

Risk Factors

Advanced age

4-allele of apolipoprotein E-Gene (ApoE)

Female gender?

Focal neurodegenerative dementias: Focal neurodegenerative dementias: Frontotemporal Lobar Degeneration (FTLDFrontotemporal Lobar Degeneration (FTLD))

Focal neurodegenerative diseases, Focal neurodegenerative diseases, affecting primarily temporal and frontal affecting primarily temporal and frontal lobes:lobes:

1. Fronto-temporal dementia1. Fronto-temporal dementia

2. Primary progressive aphasia2. Primary progressive aphasia

3. Semantic dementia3. Semantic dementia

Pick’s Disease -1892 Arnold Pick

Frontotemporal dementia– Frontal lobar atrophy– Pick’s bodies – tau

protein– Chr 17 abnormality

FTLD - General FeaturesFTLD - General Features

1. Pre-senile dementias (<65 years of age)1. Pre-senile dementias (<65 years of age)

2. SPECT Scan: Anterior (frontotemporal 2. SPECT Scan: Anterior (frontotemporal defects)defects)

3. Normal EEG3. Normal EEG

4. Memory and visuospatial functions are 4. Memory and visuospatial functions are normal until the disease is advancednormal until the disease is advanced

Pick’s diseasePick’s disease

Non-specific frontal degenerationNon-specific frontal degeneration

Frontal degeneration with anterior spinal Frontal degeneration with anterior spinal neuron lossneuron loss

FTD: Pathological TypesFTD: Pathological Types

FTD: Clinical Features (I)FTD: Clinical Features (I)

Behavioral abnormalities. Behavioral abnormalities.

Inertia, loss of volition, decreased initiative.Inertia, loss of volition, decreased initiative.

Social disinhibition, loss of insight.Social disinhibition, loss of insight.

Impulsivity, overactivity.Impulsivity, overactivity.

Emotional blunting.Emotional blunting.

Stereotyped and perseverative behavior.Stereotyped and perseverative behavior.

FTD: Clinical Features (II)FTD: Clinical Features (II)

Mean age of presentation: 53 yearsMean age of presentation: 53 years

Predominantly malesPredominantly males

High familial aggregationHigh familial aggregation

Cognitive impairment mostly in areas of executive function (planning, Cognitive impairment mostly in areas of executive function (planning, judgement, problem-solving) and attentionjudgement, problem-solving) and attention

Memory, visuospatial and calculation might be relatively preserved at the Memory, visuospatial and calculation might be relatively preserved at the beginningbeginning

Speech might be either economical leading to mutism, or increased / Speech might be either economical leading to mutism, or increased / pressed in disinhibited patientspressed in disinhibited patients

The brain of a person with frontotemporal dementia shows a shrunken and sometimes asymmetric frontal lobe and a normal parietal lobe.

Frontotemporal Dementia

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May appear similar to Alzheimer’s…..Early treatment may reverse cognitive changes before they become permanentTriad of symptoms: gait instability, urinary incontinence and dementia – Wide-based, shuffling gait with poor coordination– Incontinence follows gait change, includes urgency– Slow thinking/response, decreased spontaneity

Enlarged ventricles on MRI– But no evidence of atrophy: Alzheimer’s shows large

ventricles due to brain atrophy

Normal-Pressure HydrocephalusNormal-Pressure Hydrocephalus

MRI: Hydrocephalus

Dementia with Lewy BodiesDementia with Lewy Bodies

Cortical Lewy Bodies on pathCortical Lewy Bodies on pathOverlap with AD and PDOverlap with AD and PDFluctuations in mental status (may appear Fluctuations in mental status (may appear delirious)delirious)Early delusions and hallucinationsEarly delusions and hallucinationsMild extrapyramidal signsMild extrapyramidal signsNeuroleptic hypersensitivity!!!Neuroleptic hypersensitivity!!!Unexplained falls or transient changes in Unexplained falls or transient changes in consciousnessconsciousness

Dementia with Lewy Bodies (DLB)

Etiology– Lewy bodies – protein deposits containing

damaged neurons

Symptoms: decline in– memory – language – Judgment & reasoning

Lewy Bodies

AIDS dementia complexAIDS dementia complex

Approximately two-thirds of persons with AIDS develop dementia, mostly due to AIDS dementia complex.In some patients HIV is found in the CNS at postmortem. In others an immune mechanism or an unidentified pathogen is blamed.Dementia is initially of a "subcortical " type.CT - atrophy; MRI - increased T2 signal from white matter.Treatment with Zidovudine (AZT) halts and partially revers neuropsychological deficit.

Differential DiagnosisDifferential DiagnosisDelirium DementiaDelirium Dementia

Rapid onsetRapid onset

marked attentional marked attentional disturbancedisturbance

confusion confusion prominent/clouding of prominent/clouding of consciousnessconsciousness

fluctuating clinical coursefluctuating clinical course

agitation and behavioral agitation and behavioral symptomssymptoms

potentially reversiblepotentially reversible

Usually insidious onsetUsually insidious onset

memory systems impairedmemory systems impaired

consciousness intactconsciousness intact

slower, progressive courseslower, progressive course

subtle behavioral symptomssubtle behavioral symptoms

can be irreversiblecan be irreversible

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MANAGEMENTMANAGEMENT.……….………

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SYMPTOM MANAGEMENTSYMPTOM MANAGEMENT

Psychoses (delusions, hallucinations)

Sleep disturbances

Aggression, agitation

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NONPHARMACOLOGICNONPHARMACOLOGIC

Cognitive enhancement

Individual and group therapy

Regular appointments

Communication with family, caregivers

Environmental modification

Attention to safety

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PHARMACOLOGICPHARMACOLOGICCholinesterase inhibitors:

Inhibit cholinesterase at the synaptic cleft

Offer a small improvement : cognition and activities of daily

living

Examples: donepezil, rivastigmine, galantamine

Memantine: (Namenda): N-Methyl-D-Aspartate Antagonist: A receptor activated by glutamate: decr nmda

excessive nmda: excitotoxicity and neurotransmittter damage

Memantine is neuroprotective & disease modifying;

for moderate to severe dementia

alone or in combination

Other cognitive enhancers: estrogen, NSAIDs, ginkgo, vit. E

CategoryCategory

Labazimide

AnticholinesteraseAnticholinesterase

GlutamateGlutamate

enhancersenhancers

ActionAction NameName

Nerve growthNerve growth

factorsfactors

Stimulate

neuron growth

Increases

available

acetylcholine

Tacrine

No trade name

AntioxidantsAntioxidants

Anti-inflammatoryAnti-inflammatory Not known Advil

HRTHRT Not known Estrogen

Facilitate

glutamate

SeligilineStop free radicals

Treatment: Alzheimer’s DiseaseTreatment: Alzheimer’s Disease

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TREATING PSYCHOSIS IN TREATING PSYCHOSIS IN DEMENTIADEMENTIA

Antipsychotic medications (side effects):Higher potency: haloperidol (extrapyramidal symptoms)

Lower potency: thioridazine (anticholinergic effects, sedation, hypotension, constipation, urine retention)

Atypical antipsychotics: clozapine, risperidone, olanzapine Beware new prescribing information on some of the atypical

antipsychotics!

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MANAGING SLEEP MANAGING SLEEP DISTURBANCESDISTURBANCES

Improve sleep hygiene (e.g, consistent bedtime, comfortable setting)

Provide daytime activity, prevent daytime sleeping

Use bright-light therapy

Treat associated depression, delusions

If the above do not succeed, consider:trazodone 25-150 mgnefazodone 100-500 mgzolpidem 5-10 mg

Avoid benzodiazepines or antihistamines

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MANAGING AGITATIONMANAGING AGITATIONBehavioral interventions: distraction, supervision, routine, structure

Behavior modification using rewards

Pharmacologic interventions: antipsychotics, antidepressants, mood stabilizers, buspirone, -blockers

Avoid physical restraints

Dementia – diagnostic approachDementia – diagnostic approach

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DEMENTIA Prof. Abdulkader Daif Consultant Neurologist 2011