Neurodegeneration

Question 1

What is the neuropathology of AD?

Answer 1

Extracellular plaques: accumulation of protein in brain parenchyma

Neurofibrillary tangles: disruption of neuronal cytoskeleton

Cerebral amyloid angiopathy (CAA)

Neuronal loss (cerebral atrophy)

Question 2

What can be seen here? What are these?

Answer 2

Senile plaques: lumps of protein in brain

Tangles

Question 3

What is this? Where else can this protein be found?

Answer 3

Cerebral amyloid angiopathy

Can be found in blood vessel walls in varying extents in different cases

Question 4

What can be seen here?

Answer 4

Tau immunostaining

Cytoskeleton protein, abnormal Tau is stained brown by antibody

Question 5

Which drug for Alzheimer’s has not yet been approved?

Answer 5

Aducanumab

Question 6

What is this?

Answer 6

Locus classicus

Low pigmented substantia nigra in Parkinson’s

Due to loss of dopaminergic neurones which contain neuromelanin pigment

Question 7

What is this?

Answer 7

Lewy Body

Question 8

What is this?

Answer 8

Lewy Body

Question 9

What is this?

Answer 9

Lewy Body

Question 10

What is the pathology of α-synuclein?

Answer 10

Mutations in α-synuclein gene can result in PD.

Lewy bodies + Lewy neurites are immunoreactive for α-synuclein.

α-synuclein immunostaining is diagnostic gold standard.

Question 11

What are these?

Answer 11

α-synuclein immunostaining

Question 12

What are these? What does this illustrate?

Answer 12

α-Syn deposits in epicardial nerve fascicles (e, f)

Paravertebral sympathetic ganglia (a, b).

Pathology not restricted to CNS- peripheral autonomic ganglia

Also found in the nose

Question 13

What are 7 causes of Parkinsonism?

Answer 13

Idiopathic

Drug-induced Parkinsonism

Multiple system atrophy

Progressive supranuclear palsy

Corticobasal degeneration

Vascular pseudoparkinsonism

Alzheimer’s changes

Fronto-temporal neurodegenerative disorders

20 other disorders

Question 14

What is this? How does this present? Describe the pathology

Answer 14

Multiple System Atrophy (MSA)

A/W falls, can mimic parkinsons

Alpha synucleinopathy: accumulates more in glial support cells rather than neurones

(same protein, different cellular substrate)

Question 15

What is this? What is the pathology?

Answer 15

Corticobasal Degeneration (CBD)

Astrocytic tau plaques

(NOT alpha synucleinopathy)

Question 16

What is this? What problems sometimes characterise this? What is the pathology?

Answer 16

Progressive supranuclear palsy (PSP)

Vertical eye movement problems

Tau-opathy

(NOT alpha synucleinopathy)

Question 17

What is this?

Answer 17

Progressive supranuclear palsy (PSP)

Question 18

What are features of Pick’s Disease?

Answer 18

Fronto-temporal atrophy

Marked gliosis and neuronal loss

Balloon neurons

Tau positive Pick bodies

Question 19

What is this?

Answer 19

Tau positive Pick bodies

Question 20

What is the structure of the TAU protein?

Answer 20

Single gene on 17q21

16 exons

Alternative splicing gives rise to 6 isoforms

3R or 4R-tau (microtubule-binding domains)

2 further inserts with unknown function

Shortest form (3R/0N) foetal

Question 21

How are Prion diseases transmitted?

Answer 21

Transmissible factor: transmission of protein causes disease in recipient

No DNA or RNA involved

PRoteinaceous Infections ONly

Question 22

Name 4 prion diseases seen in humans

Answer 22

Creutzfeldt-Jakob disease

Gerstmann-Straüssler-Sheinker syndrome

Kuru

Fatal familial insomnia

Question 23

Describe prion diseases

Answer 23

Proteinopathies

Prion protein deposits

Spongiform change: holes appear in tissue

Host protein structure is changed by infected protein- causes pathology

Question 24

Describe the aetiology and epidemiology of new variant CJD. Give 2 symptoms of vCJD

Answer 24

Sporadic neuropsychiatric disorder

Linked to BSE: ingestion of infected bovine material

Longer duration than CJD

<45y

Cerebellar ataxia

Dementia

Question 25

What features are present in the right hand image suggestive of Alzheimer's disease?

Answer 25

Cortical atrophy Thinning of cortex Widening of sulci Thinning of gyri Enlargement of ventricles

Question 26

How do plaques form in Alzheimers disease?

Answer 26

Cleavage of amyloid precursor protein Beta amyloid produced Accumulation of beta amyloid intracellularly Expelled beta amyloid forms plaques

Question 27

What are the likely contributors to cell death in Alzheimers disease?

Answer 27

Interruption of cellular processes involved in: Calcium homeostasis Mitochondria + reactive oxygen species Proteosome blockage Intracellular tangle formation

Question 28

What is used for the staging of Tau pathology? What is diagnosis based on?

Answer 28

Braak staging Dx based on amount + site in brain Nearly all \>60s will show some signs of Alzheimers in the brain though not symptomatic

Question 29

Describe the spread of Tau pathology in Alzheimers disease

Answer 29

1. Around hippocampus 2. Posterior hippocampus 3. Temporal cortex 4. Occipital cortex

Question 30

Where do the neurones in the substantial nigra project to?

Answer 30

Neurones project to striatum in basal ganglia where initiation of movement is controlled

Question 31

What are Lewy bodies?

Answer 31

Eosinophilic inclusions in pigmented neurones Composed of aggregates of the protein alpha synuclein