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
• 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)

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 (bovine spongiform encephalopathy - mad cow disease)
• Clinical features include cerebellar ataxia and dementia

Question 6

List and describe the main neuropathological features of Alzheimer’s disease.

Answer 6

• Extracellular plaques - extracellular accumulations of amyloid beta
• Neurofibrilliary tangles - intra-neuronal pathology caused by disruption of the cytoskeleton of neurones
• Cerebral amyloid angiopathy - deposits of protein in blood vessel walls which impairs normal vascular function
• Cerebral atrophy - supporting feature

Question 7

Which part of the brain is often affected by cortical atrophy in Alzheimer’s disease?

Answer 7

• Inferior horn of the lateral ventricles where the hippocampus is found (this is responsible for loss of short term memory)

Question 8

Describe how amyloid precursor protein processing leads to the formation of beta-amyloid plaques.

Answer 8

• Non-amyloidogenic processing: involves cleavage of the A-beta sequence
• Amyloidogenic: cleavage occurs at the amino-terminus of A-beta and a second cleavage leads to the production of A-beta

NOTE: the toxicity of A-beta is likely to be intracellular (extracellular plaques are unlikely to cause many issues themselves)

Question 9

What is tau protein?

Answer 9

• Micro-tubule associated protein that is important for maintaining the stability of the cytoskeleton
• When it becomes hyperphosphorylated it accumulates inside cells and causes cell death

Question 10

Describe the Braak stages of Alzheimer’s disease.

Answer 10

• Stage 1: tau pathology in the transentorhinal cortex
• Stage 2: posterior hippocampus
• Stage 3: immunostaining is visible by eye, affects substantia nigra
• Stage 4: superior temporal gyrus
• Stage 5: peristriate cortex
• Stage 6: striate cortex

NOTE: clinically, symptoms tend to arise in stage 3 or 4

Question 11

Describe the results of effort made to remove A-beta from the brains of humans.

Answer 11

• Associated with encephalitis
• Did not affect disease progression

Question 12

What type of disease is chronic traumatic encephalopathy?

Answer 12

Tauopathy

Question 13

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

Answer 13

Neuromelanin - this is a by-product of dopamine metabolism

Question 14

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

Answer 14

• Death of dopaminergic cells of the substantia nigra
• Cells from the substantia nigra usually project to the basal ganglie (which is important for the initiation of the movement)

Question 15

Outline the main histological features of Parkinson’s disease.

Answer 15

• Characterised by the presence of Lewy bodies which are intracellular accumulations of alpha-synuclein
• Parkinson’s disease is caused by abhorrent metabolism of alpha-synuclein

NOTE: this was discovered because mutations in the alpha-synuclein gene are associated with rare familial forms of Parkinson’s disease

Question 16

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

Answer 16

Alpha-synuclein immunostaining

Question 17

Where is alpha-synuclein pathology in Parkinson’s disease thought to arise from?

Answer 17

• Starts in the brainstem (medulla) and rises up the pons and midbrain
• NOTE: nigral pathology is about stage III. It eventually moves to the basal forebrain and cortices
• NOTE: alpha-synuclein pathology is also seen in peripheral ganglie, in the gut and in the nose

Question 18

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

Answer 18

• Sleep disorders
• Depression
• Anosmia

Question 19

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 19

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

Question 20

What are three important differentials to consider in a patient with Parkinson’s disease?

Answer 20

• Multiple system atrophy (MSA)
• Corticobasal degeneration (CBD)
• Progressive supranuclear palsy (PSP)

Question 21

What is multisystem atrophy?

Answer 21

• alpha-synucleinopathy like PD
• accumulates in glial cells rather than neurones
• presents similarly to PD
• It mainly affects the cerebellum so the patients are more likely to present with falls

Question 22

What type of diseases are PSP and CBD?

Answer 22

Tauopathies

Question 23

What is Pick’s disease?

Answer 23

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

Question 24

What are the main histological features of Pick’s disease?

Answer 24

• Marked gliosis and neuronal loss
• Balloon neurones
• Tau-positive Pick bodies

NOTE: mutations in tau are associated with a fronto-temporal dementia phenotype often associated with Parkinson’s disease

NOTE: there are 17 autosomal dominant syndromes resulting from mutations in tau

Question 25

Which gene encodes tau?

Answer 25

17q21

Question 26

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

Answer 26

• 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 27

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

Answer 27

• 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 28

Mutations in which genes can cause fronto-temporal dementia?

Answer 28

Tau

Progranulin

Question 29

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

Answer 29

Atrophy tends to be unilateral

Question 30

Which other protein (aside from tau and progranulin) is thought to be implicated in some types of fronto-temporal dementia?

Answer 30

TDP-43 (trafficking protein)

Question 31

What is dementia lacking distinctive histology (DLDH)?

Answer 31

There is no obvious change in brain structure that would explain the pathology