Histo: Neurodegeneration

Question 1

What are prion diseases?

Answer 1

Proteinaceous infections only

They are transmissible diseases that have no DNA or RNA

Question 2

List some examples of prion diseases.

Answer 2

• Creutzfeldt-Jakob disease (variant linked to bovine spongiform encephalopathy i.e. mad cow disease)
• Gerstmann-Straussler-Sheinker syndrome
• Kuru
• Fatal familial insomnia

Question 3

Describe the histological appearance of brains affectd by prion diseases.

Answer 3

The tissue is full of vacuoles (spongiform encephalopathies/changes and prion protein deposits)

Question 4

Outline the pathophysiology of prion diseases.

Answer 4

• The normal PrP^Sc protein will unfold and refold into a beta-pleated sheet form which is more susceptible to aggregation
• Once a little bit forms, it can propagate
• The accumulation of insoluble protein in the parenchyma leads to cell death

Question 5

What are the key features of new variant CJD?

Answer 5

• Sporadic neuropsychiatric disorder occurring in mainly younger patients (<45 years) associated with BSE
• Clinical features include cerebellar ataxia and dementia

Question 6

Pathophysiology of alzheimer’s?

Answer 6

Accumulation of beta-amyloid deposits outside neurons which interferes with neuronal communication

Hyperphosphorylation of Tau protein means that neurons turn into neurofibrillary tangles which causes cerebral atrophy

Question 7

Radiology signs in alzheimer’s?

Answer 7

General brain atrophy

Widened sulci, narrowed gyri and enlarged ventricles

Most marked in temporal and frontal lobes and hippocampal degneration (loss of short term memory)

Question 8

What type of disease is chronic traumatic encephalopathy?

Answer 8

Tauopathy

Question 9

What is responsible for the dark colour of the substantia nigra?

Answer 9

Neuromelanin - this is a by-product of dopamine metabolism

Question 10

On a cellular level, what causes Parkinson’s disease?

Answer 10

• Death of dopaminergic cells of the substantia nigra in basal ganglia

this leads to widespread motor deficits

Question 11

Explain the pathophysiology of parkinson’s disease

Answer 11

• Characterised by the presence of Lewy bodies in affected neurons (which are intracellular accumulations of alpha-synuclein)

this leads to death of dopaminergic cells of the substantia nigra in basal ganglia

and so widespread motor deficits

Question 12

What is the diagnostic gold standard for Parkinson’s disease?

Answer 12

Alpha-synuclein immunostaining

Question 13

What are the cardinal signs of parkinson’s?

Answer 13

TRAP

Tremor
Rigidity
Akinesia
Postural instability

+/- psychiatric issues later

Question 14

What are some non-extrapyramidal symptoms of Parkinson’s disease?

Answer 14

• Sleep disorders
• Depression
• Anosmia

Question 15

It is hypothesised that environmental agents may have a part to play in the onset of Parkinson’s disease. Describe two routes by which these agents can enter the brain from the environment.

Answer 15

• Retrograde from the gut to the medulla via the vagus nerve
• Through the nose

Question 16

What is multisystem atrophy?

Answer 16

• It is an alpha-synucleinopathy like Parkinson’s disease which targets glial cells
• It presents similarly to Parkinson’s disease
• It mainly affects the cerebellum so the patients are more likely to present with falls

Question 17

What type of diseases are PSP and CBD?

Answer 17

Tauopathies

Question 18

What is Pick’s disease?

Answer 18

Characterised by fronto-temporal atrophy which presents with frontal lobe pathology (e.g. dysexecutive syndrome)

= frontotemporal dementia

Question 19

What age group does pick’s disease affect and

what are the main histiological/radiological features?

and symptoms?

Answer 19

Younger people (40-60)

Only affects the frontal and temporal lobes –> atrophy

On histology, pick bodes = hyperphosphorylated tau

Personality change, disinhibition, overeating, emotional blunting

Question 20

Which gene encodes tau?

Answer 20

17q21

Question 21

How many isoforms of tau are there and how are they classified?

Answer 21

• There are 16 exons and alternative splicing can produce 6 isoforms that are either 3R or 4R tau depending on the number of microtubule-binding domains
• NOTE: there are two further inserts with unknown function

Question 22

Describe how the types of tau present in Alzheimer’s disease is different from CBD, PSP and Pick’s diease.

Answer 22

• Alzheimer’s - when the tau is put through a Western blot, it will form 3 dense bands. If this is dephosphorylated it will show all 6 isoforms of tau
• CBD and PSP - produces 2 dense bands which, when dephosphorylated, are shown to be made up of only 4R tau (i.e. it is a 4R tauopathy)
• Pick’s disease - it is a 3R tauopathy

Question 23

Mutations in which genes can cause fronto-temporal dementia?

Answer 23

Tau

Progranulin

Question 24

What is a characteristic feature of frontotemporal dementia associated with progranulin mutations?

Answer 24

Atrophy tends to be unilateral

Question 25

Which other protein is thought to be implicated in some types of fronto-temporal dementia?

Answer 25

TDP-43 (trafficking protein)

Question 26

buzzword for acquired prion disease Kuru?

Answer 26

cannibalism

Question 27

buzzword for creutzfeld-jakob disease

Answer 27

rapid decline <1y

Question 28

rank the different dementias in terms of incidence

Answer 28

alzheimer’s > vascular > lewy body > frontotemporal

Question 29

commonest cause of dementa?

Answer 29

alzheimer’s

Question 30

Explain the symptoms and pathology of lewy body dementia

Answer 30

Psychological disturbances

Visual hallucinations (little people/animals running about)

Pathologically indistinguishable from parkinson’s (lewy bodys and alpha synuclein)