CNS DEGENERATION

FM Brett MD., FRCPath

At the end of this lecture you should be able to:

1.Understand the definition of dementia

2.Be able to list the common causes of dementia

3.Understand Parkinson’s Disease

4.Understand what is meant by Multiple Sclerosis.

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

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 basisDestruction of brain areas involved in memory, intellect

Frontal & Temporal cortices

Sub-cortical association areas

Common causes of dementia

Neurodegenerative – common – AD DLBD

CVS - multi-infarct dementiaHydrocephalusToxic and metabolic Drugs

AlcoholMitochondrial encephalopathyDemyelinating diseaseHead injuryPrion diseasesInfective – HIV, neurosyphylisNeoplasia – paraneoplastic syndromes

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

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,

Parkinson’s Disease

Clinical diagnosis REQUIRE 2 of the 3 cardinal features

BradykinesiaResting tremor

Rigidity

Associated features:

Autonomic dysfunctionCognitive 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

DLBDDLBDProgressive cognitive decline

+ two of the following • Fluctating cognition• Recurrent visual hallucinations• Spontaneous motor features of Parkinsonism

Supportive featuresSupportive features – Repeated fallsSyncopeNeuroleptic sensitivitySystematised delusionsHallucinations

DLBDDLBD

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

Disease Kuru GSS FFI

Clinical Ataxia, tremor, and later dementia

Loss of co-ordination, followed by dementia

Sleep disturbances, dysautonomia and dementia

Aetiology Infection PrP mutation PrP mutation

Geographical

distribution

Fore tribe of New Guinea

Selected families

Selected families

Pathology Cerebellar Cerebellar

(predominantly)

Thalamic

Disease duration

3mo-1 year 2-6 years Less than 1 year

Spongiform encephalopathies

Disease sCJD nvCJD

Age/onset 55-75yrs 19-39

Features Dementia, myoclonus Behavioural changes, ataxia, dysesthesia

Course Rapidly progressive Insidious onset/prolonged course

Pathology Spongiform change Characteristic PrP amyloid plaques

EEG Characteristic complexes in 70%

Not present

14-3-3 Present but not specific

Not helpful

Tonsil b/x Negative Positive in pts with clinical course

Sporadic versus nvCJD

Classification of demyelinating disorders of the CNS

1. Primary demyelinating diseases – MS, ADEM, AHL

2. Secondary demyelinating diseases CPM, PML, SADC,

3. Leukodystrophies and metabolic disorders e.g sudanophilic leucodystrophy, metachromatic leucodystrophy, adrenoleucodystrophy, Krabbes leucodystrophy, Canavans disease

4. Toxic demyelination - Hexachlorophane, cyanide, carbon monoxide, chronic solvent vapour abuse.

MS

• Chronic, progressive immune-mediated CNS disease

• Characterized by demyelination and axonal loss neurologic impairment and disability

• Axonal damage and brain atrophy occur earlyand may be irreversible

~ 85 % RRMS i.e sporadic attacks followed by complete, partialor no improvement

~ Within 10 years half of these pts develop secondary-progressive disease (essentially unrelenting clinical progression with possible superimposed acute attacks and minor remissions)

~ Remainder primary-relapsing disease – characterised either byprogression from onset with acute relapses

ORPrimary progressive disease progression without relapse or remission

Epediomology of MS• ~350,000 affected in US

– ~8,500–10,000 new cases yearly

• Most cases strike between ages 15 and 45– Women outnumber men 2:1

• 85% present with RRMS– Within 10 years, 50% of these patients develop

secondary-progressive MS associated with significant disability

Presenting features of MS

Limb weakness 50%

Optic neuritis 20%

Diplopia 10%

Parasthesia 10%

Bladder Parasthesia 10%

Vertigo and nystagmus 5%

Diagnosis of MS

Dissemination of lesionsin time

Dissemination of lesions in space

Clinical history

Paraclinical testsVER, MRI

Less commonly acute mass lesion difficult to distinguish clinically and pathologically from a neoplasm

MS Characteristics1. Immune-mediated CNS

disease2. Characterized by demyelination and axonal loss neurologic impairment and disability

3. Dissemination of lesions in space

Normal white matter

Active demyelination

Inactive plaque

Normal white matter

Active demyelination

Inactive plaque

Biopsy

F21 wheelchair bound

F23Ambulant14 yrs later

F 36 Died 56 dys after admission

Normal white matter

Active demyelination

Inactive plaque

Pathological features of acute demyelination

Hypercellularity – macrophages +++++

Areas of complete myelin loss

Relative axonal preservation

Perivascular lymphocytic cuffing

Annesley-Williams et al., JNEN 2000;59:477-89

ADEM vs MS

Clinical CSF Radiology Pathology

ADEM monophasic

Cells ++

OB+

Abn

Symmetric

Cerebrum

Cerebellum

Basal ganglia

Inflam +++

Demyel +

MS monosymptomatic

Cells +

OB +

Multiple lesions Inflam +

Demyel ++++

Diagnosis of MS

Dissemination of lesionsin time

Dissemination of lesions in space

Clinical history

Paraclinical testsVER, MRI

Less commonly acute mass lesion difficult to distinguish clinically and pathologically from a neoplasm

Central Pontine Myelinolysis

~ Middle aged or elderly patients who are malnourished or chronically debilitated

~ Associated with fluid-electrolyte imbalance particularly wherehyponatremia has been treated rapidly with hypo-osmolar saline~ Mechanism of demyelination is unknown but may relate to

impaired vascular perfusion during the episode of rapid electrolyte shift

~ Myelin loss usually occurs in the central pons

Progressive Multifocal leucoencephalopathy

~ Lytic infection of oligodendrocytes by JC virus~ Usually debilitated or immunosupressed patients~ well recognised complication of Aids

CONCLUSION:

• Dementia is…

• Commonest cause worldwide is Alzheimer’s Disease

• Commonest cause of PD is idiopathic

• Incidence of CJD is 1 per million worldwide per year.

• Diagnosis of MS is based on dissemination of lesions in time (clinical history) and space (based on appropriate paraclinical tests)