DEMENTIAFM Brett MD., FRCPath

DEMENTIAAcquired global impairment of intellect memory and personality Impairment of intellectual function in the presence of normal consciousness affectingLanguageVisuospatial skillsEmotion or personalityCognition

DementiaDistinguished from mental retardation on the basis of having attained an appropriate degree of occupational and social functioning

Presence of multiple cortical defects implies involvement of multiple cortical areas

Prevalence at least 2% at age 65-70

20 % at age 80

Exclude

Temporary confusion

Primary memory loss

Pathological basis

Destruction of brain areas involved in memory, intellectFrontal & Temporal corticesSub-cortical association areas

Two main clinical patterns of Dementia

Temporoparietal dementias- begin with impairment of memory and dysfunction of the temporal lobes. Patients later develop parietal lobe dysfunction dysphasias and dyspraxiasFrontotemporal dementias behavioural disturbances of frontal lobe type. Patients later develop temporal lobe dysfunction. Typically parietal lobe function is preserved

Common causes of dementiaNeurodegenerative common AD DLBDCVS - multi-infarct dementiaHydrocephalusToxic and metabolic DrugsAlcoholMitochondrial encephalopathyDemyelinating diseaseHead injuryPrion diseasesInfective HIV, neurosyphylisNeoplasia paraneoplastic syndromes

Specific cell systems

Neurone Transmitter loss depletion

Alzheimers Disease

~ Commonest cause of dementia~ 50-75% of all cases of dementia~ 5 groups

~ Sporadic late onset (commonest)~ Familial late onset (uncommon)~ Familial early onset (rare)~ Associated with Downs syndrome~ Associated other degenerative disease

ATROPHY PARTICULARLYTEMPORAL LOBES

Pathological features of AD

~ Deposition of amyloid in the brain as plaques

~ Intraneuronal filamentous inclusions NFT~ Dystrophic neurites~ Loss of synapses and later neurones

Associated pathologic changes include:

Amyloid angiopathyGranulovacuolar degenerationHirano bodiesIncreased lipofuscin in neuronesCorpora amylacea

TRANSMEMBRANE RECEPTOR

AMYLOID PRECURSOR PROTEINAbnormal proteolytic clevage

Amyloidogenic fragments released

Plaques

DIFFUSE PRIMITIVE CLASSICAL BURNT-OUT? progression

SENILE PLAQUES

PHF Amyloid fibrilsDegenerate neuritesGlial cell processes

PAIRED HELICAL FILAMENTS

NOT

DERIVED FROM NEURONE CYTOSKELETON

Antigenic similarity with a protein in normal neurones

? PHF ALTERED NEURAL PROTEIN

TAU

Microtubular associated protein

ControlsMICROTUBULE FORMATION

NERVE CELL SKELETON

TANGLE

ACCUMULATION NEURONE OF PHF DEATH

Molecular pathology of ADAD1 mutations in the APP on Ch21AD2 ass with the APOE4 allele on Ch 19

AD3 associated with the presenilin 1 gene on Ch 14AD4 mutation in the presenilin 2 gene on Ch 1

CAUSES OF PARKINSONISM COMMON PD

LESS COMMON Drug induced, MSA, PSP, vascular

RARE - CBD, AD, MSD, hydrocephalus, FTD, HC, Dementia pugilistica, toxins, WD

Parkinsons Disease

Clinical diagnosis REQUIRE 2 of the 3 cardinal features

BradykinesiaResting tremorRigidity

Associated features:

Autonomic dysfunctionCognitive disturbanceDysphagia

Manifestations of PD largely attributable to reduced dopaminergic input into the striatum due to degeneration of neurones in the pars compacta of the SN

Genetic

Free radical damage

Environmental agents

DLBD

Progressive cognitive decline+ two of the following Fluctating cognition Recurrent visual hallucinationsSpontaneous motor features of Parkinsonism

Supportive features Repeated fallsSyncopeNeuroleptic sensitivitySystematised delusionsHallucinations

DLBD

Frontotemporal dementia

Patients presenting with progressive frontal lobe dysfunction (that may later be followed by evidence of temporal lobe dysfunction)

Accounts for 10% of all cases of dementia

Vascular Dementia

~ Cumulative cognitive decline caused by effects of multiple episodes of cerebral ischaemia

~ Excludes cases caused by diffuse cerebral cortical damage due to a single episode of severe hypoxia or global cerebral hypoperfusion

Vascular Dementia

~ arteriolosclerosis

~ Small vessel disease causing granular cortical atrophy

~ Large regional infarct

~ Critically sited infarcts e.g hippocampal region may cause hippocampal sclerosis

Spongiform encephalopathies

DiseaseKuruGSSFFIClinical Ataxia, tremor, and later dementiaLoss of co-ordination, followed by dementiaSleep disturbances, dysautonomia and dementiaAetiologyInfectionPrP mutationPrP mutation

GeographicaldistributionFore tribe of New GuineaSelected familiesSelected familiesPathologyCerebellar Cerebellar (predominantly)ThalamicDisease duration3mo-1 year2-6 yearsLess than 1 year

CJD historical aspects1920-21 Jacob and Creutzfeldt fatal brain disease1950 - Kuru New Guinea1958 Gajdusek arrives New Guinea1959 - Wm Hadlow- Uk to study scrapie1976 - Gadjusek nobel prize for CJD research

CJD historical aspects1982 - Pruisner prion disease

1985 BSE- cows, Pt dies CJD post GH

1987 CJD post dura mater graft

1996 nvCJD

1998 Pruisner Nobel prize

CJD classification

Definite sporadicProbable sporadicIatrogenicFamilialGSS

Epidemiology of CJD

Annual worldwide incidence of 1-2 cases per million

Higher rates in Libyan Jews, Slovakia, Hungary and eastern England (families with mutations)

M=F; Onset 55-75 (peak 7th decade)

10% FAMILIAL

Clinical

Age onset 58 (32-78)

Duration of illness 21.5 weeksAge at death 58

Presentation 100% dementia73% myoclonus

sCJDPATHOLOGY

MACROSCOPIC normal or mild atrophy

MICROSCOPIC Neuronal lossSpongiform changeAstrocytosisSynaptic lossAccumulation of PrPc

Atrophy may or may not be present

Polymorphism at codon 129 (coding for methionine or Valine) acts as susceptibility factorFrequency in caucasian populations

VV 12%MM 37%VM 51%

Frequency in Japanese

VV 0%MM 92%VM 8%

sCJD are homozygous for either M or V at codon 129nvCJD ALL homozygous for M

vCJD and the Pulvinar sign (Zeidler et al: Lancet, 2000, 35, 1412-18)Hyperintensity of the pulvinar (posterior nucleus) of the thalamus relative to other basal ganglia (or cortical grey matter if basal ganglia abnormal also)Sensitivity 79%, Specificity >95% in appropriate populationPD-weighted and T2-weighted images

Normal thalamus: hypointense to putamen and other grey matterDr. Don Collie, UK CJD Surveillance Unit

vCJD:Pulvinar signT2-weighted imageDr. Don Collie, UK CJD Surveillance Unit

Sporadic versus nvCJD

DiseasesCJDnvCJDAge/onset55-75yrs19-39FeaturesDementia, myoclonusBehavioural changes, ataxia, dysesthesiaCourseRapidly progressiveInsidious onset/prolonged coursePathologySpongiform changeCharacteristic PrP amyloid plaquesEEGCharacteristic complexes in 70%Not present 14-3-3Present but not specific Not helpfulTonsil b/xNegativePositive in pts with clinical course