Neuropathology 2: Demyelination and Dementia Flashcards

Question

What are shadow plaques?

Answer 1

Describes inactive plaques that appear LESS WELL-DEFINED LESION, due to either: • A degree of peripheral remyelination OR • Progressively thinned-out myelin sheaths

Answer 2

Association with latitude and vitamin D deficiency Hypothesised that there may be a viral trigger, e.g: EBV

Answer 3

1st degree relative affected - 15x increased risk Affected monozygotic twin - 150x increased risk There is a genetic link with HLA DRB1 NOTE - there is a definite genetic contribution

Answer 4

Lymphocytic infiltration in histology Oligoclonal IgG bands in CSF sample Genetic linkage to HLA DRB1

Answer 5

TH1 cells (these are INFγ activating macrophages) TH17 cells (responsible for recruiting and activating damaging leukocytes) NOTE - transferring these TH1 and TH17 cells into unimmunised animals triggers the same demyelinating disease

Answer 6

Oligoclonal IgG bands on CSF NOTE - anti B-cell therapies reduce relapses and frequency of myelinating lesions

Answer 7

Alzheimer's disease Pick Disease CJD

Answer 8

Parkinson's disease Progressive supranuclear palsy Multi-system atrophy Huntington's disease

Answer 9

Spinocerebellar ataxias (Friedrich ataxia)

Answer 10

Motor Neurone Disease (MND)

Answer 11

SIMPLE NEURONAL ATROPHY and subsequent GLIOSIS

Answer 12

An acquired and persistent generalised disturbance of higher mental functions, in an otherwise fully alert person DEMENTIA IS NOT PART OF THE NORMAL AGEING PROCESS but risk, e.g: of Alzheimer's disease, does increase with age; it is ALWAYS PATHOLOGICAL

Answer 13

Progressive loss of neurones, typically affecting functionally related neuronal groups

Answer 14

``` Primary dementia: • Alzheimer's disease • Lewy body dementia • Pick's disease (AKA fronto-temporal dementia) • Huntington's disease ``` ``` Secondary dementias, i.e: arise from another underlying disorder: • Multi-infarct (VASCULAR) dementia (most common secondary dementia) • Infection (HIV, syphilis) • Trauma • Metabolic • Drugs and toxins (alcohol) • Vitamin deficiencies (vitamin B1) • Paraneoplastic syndromes • Intracranial SOLs • Chronic hydrocephalus ```

Answer 15

Most common cause of dementia in the elderly; it is more common in females There is an increased incidence in trisomy 21 (due to extra amyloid precursor protein); in cases like this, disease is typically early onset

Answer 16

Amyloid precursor protein (APP) - cleavage of APP produces Aß (a central element of neuritis plaques in Alzheimer's) ``` Familial Alzheimer's disease: • Point mutations in APP are cause • Presenilin 1 (chromosome 14) • Presenilin 2 (chromosome 1 ) Most common familial cause of Alzheimer's is ApoE E (allele e14) ```

Answer 17

INSIDIOUS impairment of higher intellectual function with alterations in mood and behaviour; there is steady progression Later, there are signs of severe cortical dysfunction • Progressive disorientation • Memory loss • Aphasia NOTE - Alzheimer's disease and wandering go hand-in-hand

Answer 18

Profound disability Muteness Immobility Death usually occurs due to a secondary cause, bronchopneumonia

Answer 19

Decreased size and weight of brain, due to cortical atrophy mainly occurring at the frontal, temporal and parietal lobes SPARING OF OCCIPITAL LOBE, BRAINSTEM AND CEREBRUM Widening of sulci and narrowing of gyri Secondary hydrocephalus ex vacuo (compensatory dilatation of ventricles)

Answer 20

There are functionally OR | anatomically related neurones that are affected, while others are spared, e.g: occipital lobe

Answer 21

Extensive neuronal loss (simple neuronal atrophy) with assoc. astrocyte proliferation (gliosis) NEUROFIBRILLARY TANGLES - bundles of insoluble microtubules in the cytoplasm of neurones (intra-cytoplasmic) NEURITIC PLAQUES (AKA Aß amyloid plaques) - focal collections of dilated, tortuous neurona processes that surround a central amyloid core; often surrounded by astrocytes and microglia Amyloid angiopathy occur

Answer 22

Hippocampus and temporal lobe

Answer 23

Tau protein (dysregulated in Alzheimer's disease)

Answer 24

1. Abnormal production of Aß results in oligomerisation, leading to amyloid fibril formation and, from this, plaques 2. Aß oligomers are than main toxic lesion; they enter the synaptic space and cause excitotoxicity (Ca2+ influx, mitochondrial dysregulation and cell death) 3. Oligomers also cause Tau hyper-phosphorylation and mislocalisation of Tau, which enhances the excitotoxicity effect of Aß oligomers

Answer 25

Another lesion that occurs in Alzheimer's disease; in this situation, the amyloid that accumulates, in the walls of arterioles, is Aß Leads to stiffening and thickening of vessel walls

Answer 26

Extracellular eosinophilic accumulation Polymerised beta-pleated sheets are formed by Aß

Answer 27

Disrupts BBB, leading to: • Local oedema and hypoxia • Exacerbation of oxidative stress, excitotoxicity and neuronal injury

Answer 28

A progressive dementia that occurs alongside VISUAL HALLUCINATIONS and fluctuating levels of attention / cognition It is common

Answer 29

There is some overlap with Alzheimer's but memory is affected later in Lewy body

Answer 30

Fluctuating cognitive dysfunction, inc. attention; i.e: the severity of the condition fluctuates on a day-to-day basis Features of PARKINSONISM at onset, or they emerge shortly after

Answer 31

Loss of facial expression Stooping and shuffling gait Slow initiation of movement Stiffness Pill-rolling tremor

Answer 32

Seen in conditions which affect the substantia nigra dopaminergic pathways Most cases are idiopathic and called Parkinson's disease

Answer 33

All those with Lewy body dementia get features of Parkinsonism Only a small proportion of those with Parkinson's disease go on to get Lewy body dementia

Answer 34

Degeneration of the substantia nigra (as seen in Parkinson's disease)

Answer 35

Pallor in the substantia nigra, where the pigmented dopaminergic neurones run

Answer 36

Loss of pigmented neurones; remaining neurones may show Lewy bodies Reactive gliosis and microglial accumulation

Answer 37

Single / multiple intra-cytoplasmic inclusion; it has a dense core and pale surrounding halo There are aggregates of α-synuclein and ubiquitin

Answer 38

Relentlessly progressive neuropsychiatric disorder Onset most commonly at 35-50 years of age but can occur any time

Answer 39

Triad of emotional, cognitive and motor disturbance

Answer 40

Chorea (dance-like movements) Myoclonus Clumsiness Slurred speech Depression Irritability and apathy Dementia develops later

Answer 41

Autosomal dominant; the Huntingtin gene is on chromosome 4 Mutation of the healthy gene creates a mutant with additional CAG repeats, i.e: it is one of the trinucleotide repeat diseases

Answer 42

Atrophy of basal ganglia, affecting mainly the CAUDATE NUCLEUS and PUTAMEN Cortical atrophy occurs later

Answer 43

Simple neuronal atrophy of striatal neurones of the basal ganglia, mainly in the caudate nucleus and putamen There is pronounced astrocytis gliosis

Answer 44

AKA Pick's disease Progressive dementia, commencing in MIDDLE AGE (50-60 years) and characterised by progressive changes in character and social deterioration; this leads to impaired intellect, memory and language

Answer 45

``` Related to damage of frontal and temporal lobes: • Personality and behavioural change • Speech and communication problems • Changes in eating habits • Reduced attention span ```

Answer 46

Rapidly progressive; it may last 2-10 years

Answer 47

Extreme atrophy of cerebral cortex in frontal and, later, in the temporal lobes; the weight of the brain drops to <1 kg

Answer 48

Neuronal loss and gliosis Pick's cells (swollen neurones) Pick bodies - intra-cytoplasmic filamentous inclusions, which are enriched with Tau protein

Answer 49

Disorder inv. deterioration in mental function, due to cumulative damage to the brain via hypoxia or anoxia Occurs due to multiple blood clots within the blood vessels supplying the brain

Answer 50

Successive, multiple cerebral infarctions cause increasingly larger areas of cell death When a sufficient area of the brain is damaged, dementia results

Answer 51

More common in men Usually occurs >60 years but can be seen in middle-aged hypertensives

Answer 52

Sufferers are aware of the mental deficits and are prone to depression and anxiety

Answer 53

ABRUPT onset and has a STEP-WISE PROGRESSION (due to to episodic vascular induced brain infarction)

Answer 54

Often have clues like a previous stroke, Hx of hypertension and evidence of previous stroke on CT / MRI scan

Answer 55

Large vessel infarcts (more common) - occurs due ot atheroma of large cerebral arteries provoking thromboembolism Small vessel (lacunar) infarcts) are rare; mainly in those with long-standing hypertension and arteriosclerosis of small vessels

Answer 56

Large vessel infarcts - scattered throughout hemispheres Small vessel infarcts - central, sub-cortical distribution