DEMENTIA FM Brett MD., FRCPath

DEMENTIA Acquired global impairment of intellect memory and personality Impairment of intellectual function in the presence of normal consciousness affecting Language Visuospatial skills Emotion or personality Cognition

Dementia Distinguished 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 % at age 80

Exclude Temporary confusion Primary memory loss

Pathological basis Destruction of brain areas involved in memory, intellect Frontal & Temporal cortices Sub-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 dyspraxias Frontotemporal dementias – behavioural disturbances of frontal lobe type. Patients later develop temporal lobe dysfunction. Typically parietal lobe function is preserved

Common causes of dementia Neurodegenerative – common – AD DLBD CVS - multi-infarct dementia Hydrocephalus Toxic and metabolic Drugs Alcohol Mitochondrial encephalopathy Demyelinating disease Head injury Prion diseases Infective – HIV, neurosyphylis Neoplasia – paraneoplastic syndromes

Specific cell systems Neurone Transmitter loss depletion

Alzheimer’s 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 Down’s syndrome ~ Associated other degenerative disease

ATROPHY PARTICULARLY TEMPORAL 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 angiopathy Granulovacuolar degeneration Hirano bodies Increased lipofuscin in neurones Corpora amylacea

TRANSMEMBRANE RECEPTOR AMYLOID PRECURSOR PROTEIN Abnormal proteolytic clevage Amyloidogenic fragments released

Plaques DIFFUSE PRIMITIVE CLASSICAL BURNT-OUT ? progression

SENILE PLAQUES PHF Amyloid fibrils Degenerate neurites Glial 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 Controls MICROTUBULE FORMATION NERVE CELL SKELETON

TANGLE ACCUMULATION NEURONE OF PHF DEATH

Molecular pathology of AD AD1 mutations in the APP on Ch21 AD2 ass with the APOE4 allele on Ch 19 AD3 associated with the presenilin 1 gene on Ch 14 AD4 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

Parkinson’s Disease Clinical diagnosis REQUIRE 2 of the 3 cardinal features Bradykinesia Resting tremor Rigidity Associated features: Autonomic dysfunction Cognitive disturbance Dysphagia

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 hallucinations Spontaneous motor features of Parkinsonism

Supportive features Supportive features – Repeated falls Syncope Neuroleptic sensitivity Systematised delusions Hallucinations 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

DiseaseKuruGSSFFI Clinical Ataxia, tremor, and later dementia Loss of co- ordination, followed by dementia Sleep disturbances, dysautonomia and dementia Aetiology InfectionPrP mutation Geographical distribution Fore tribe of New Guinea Selected families Pathology Cerebellar (predominantly) Thalamic Disease duration 3mo-1 year2-6 yearsLess than 1 year Spongiform encephalopathies

CJD historical aspects Jacob and Creutzfeldt – fatal brain disease Kuru – New Guinea 1958 – Gajdusek – arrives New Guinea Wm Hadlow- Uk to study scrapie Gadjusek nobel prize for CJD research

CJD historical aspects 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 sporadic Probable sporadic Iatrogenic Familial GSS

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 (peak 7 th decade) 10% FAMILIAL

Clinical Age onset 58 (32-78) Duration of illness 21.5 weeks Age at death 58 Presentation 100% dementia 73% myoclonus

sCJD PATHOLOGY MACROSCOPIC – normal or mild atrophy MICROSCOPIC –Neuronal loss Spongiform change Astrocytosis Synaptic loss Accumulation of PrPc

Atrophy may or may not be present

Polymorphism at codon 129 (coding for methionine or Valine) acts as susceptibility factor Frequency 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 129 nvCJD ALL homozygous for M

vCJD and the Pulvinar sign (Zeidler et al: Lancet, 2000, 35, ) 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 population PD-weighted and T2-weighted images

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

vCJD: Pulvinar sign T2-weighted image Dr. Don Collie, UK CJD Surveillance Unit

DiseasesCJDnvCJD Age/onset 55-75yrs19-39 Features Dementia, myoclonusBehavioural changes, ataxia, dysesthesia Course Rapidly progressiveInsidious onset/prolonged course Pathology Spongiform changeCharacteristic PrP amyloid plaques EEG Characteristic complexes in 70% Not present Present but not specificNot helpful Tonsil b/x NegativePositive in pts with clinical course Sporadic versus nvCJD