Histo: Neurodegeneration Flashcards
What are prion diseases?
Proteinaceous infections only
They are transmissible diseases that have no DNA or RNA
List some examples of prion diseases.
- Creutzfeldt-Jakob disease
- Gerstmann-Straussler-Sheinker syndrome
- Kuru
- Fatal familial insomnia
Describe the histological appearance of brains affectd by prion diseases.
The tissue is full of vacuoles (spongiform encephalopathies)
Outline the pathophysiology of prion diseases.
- The normal PrPSc 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
What are the key features of new variant CJD?
- Sporadic neuropsychiatric disorder occurring in mainly younger patients (<45 years) associated with BSE
- Clinical features include cerebellar ataxia and dementia
List and describe the main neuropathological features of Alzheimer’s disease.
- 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
Which part of the brain is often affected by cortical atrophy in Alzheimer’s disease?
- Inferior horn of the lateral ventricles where the hippocampus is found (this is responsible for loss of short term memory)
Describe how amyloid precursor protein processing leads to the formation of beta-amyloid plaques.
- 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)
What is tau protein?
- 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
Describe the Braak stages of Alzheimer’s disease.
- 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
Describe the results of effort made to remove A-beta from the brains of humans.
- Associated with encephalitis
- Did not affect disease progression
What type of disease is chronic traumatic encephalopathy?
Tauopathy
What is responsible for the dark colour of the substantia nigra?
Neuromelanin - this is a by-product of dopamine metabolism
On a cellular level, what causes Parkinson’s disease?
- 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)
Outline the main histological features of Parkinson’s disease.
- 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
What is the diagnostic gold standard for Parkinson’s disease?
Alpha-synuclein immunostaining
Where is alpha-synuclein pathology in Parkinson’s disease thought to arise from?
- 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
What are some non-extrapyramidal symptoms of Parkinson’s disease?
- Sleep disorders
- Depression
- Anosmia
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.
- Retrograde from the gut to the medulla via the vagus nerve
- Through the nose
What are three important differentials to consider in a patient with Parkinson’s disease?
- Multiple system atrophy
- Corticobasal degeneration
- Progressive supranuclear palsy
What is multisystem atrophy?
- 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
What type of diseases are PSP and CBD?
Tauopathies
What is Pick’s disease?
Characterised by fronto-temporal atrophy which presents with frontal lobe pathology (e.g. dysexecutive syndrome)
What are the main histological features of Pick’s disease?
- 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
Which gene encodes tau?
17q21
How many isoforms of tau are there and how are they classified?
- 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
Describe how the types of tau present in Alzheimer’s disease is different from CBD, PSP and Pick’s diease.
- 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
Mutations in which genes can cause fronto-temporal dementia?
Tau
Progranulin
What is a characteristic feature of frontotemporal dementia associated with progranulin mutations?
Atrophy tends to be unilateral
Which other protein is thought to be implicated in some types of fronto-temporal dementia?
TDP-43 (trafficking protein)
What is dementia lacking distinctive histology (DLDH)?
There is no obvious change in brain structure that would explain the pathology
