New variant CJD (vCJD): - typical presentation? - Linked to...? - of cases in last 5 years?

New variant CJD (vCJD): - typical presentation = young patient (\<45), cerebellar ataxia, dementia, longer duration than CJD - Linked to BSE - of cases in last 5 years = 0!!

W23 - Neurodegeneration Flashcards by ghazal n

A patient with a clinical history consistent with dementia and movement disorder, who dies within 1 year = what should you think of?

CJD/Prion disease

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Prion disease - what is involved?

proteinaceous infectious only = prion

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Kuru - what is it and what causes it?

One of the first forms of transmissible spongiform encephalopathies (TSE), also known as prion diseases, arising from cannabalism

kuru = to shake

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Name 4 types of Prion diseases that affect humans

•Creutzfeldt-Jakob disease (sporadic or genetic)

•Gerstmann-Straüssler-Sheinker syndrome

Kuru (cannibalism)
Fatal familial insomnia (found in some families in Italy and North America)

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What does this H&E stain on brain tissue show?

Spongiform changes

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Prion protein:

What protein form is it normally in?
What protein form can it turn into?
What is the abnormal protein?

Prion protein:

What protein form is it normally in = typically alpha helical format
What protein form can it turn into = unfolded form, beta-sheet form
What is the abnormal protein = aggregates of beta sheet form

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Which form of prion protein does it appear we could spread?

beta sheet

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Left = normal elderly brain

What do you see in right scan and specimen? Diagnosis?

Right = massive ventricles, cerebral atrophy (large spaces, large lateral fissure), severe atrophy of the hippocampus bilaterally

specimen = frontal atrophy, widening of sulci, thinning of gyri

DIAGNOSIS = AD!

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What are these in a brain tissue staining?

Senile plaques, aka Amyloid plaques /Aβ plaques -

extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain.

*look like lump of protein, halo, more diffuse protein around it*

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This is a staining of vessels in brain tissue. What does it show?

build up of amyloid in blood vessels = cerebral amyloid angiopathy (seen in AD)

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New variant CJD (vCJD):

typical presentation?
Linked to…?
# of cases in last 5 years?

New variant CJD (vCJD):

typical presentation = young patient (<45), cerebellar ataxia, dementia, longer duration than CJD
Linked to BSE
# of cases in last 5 years = 0!!

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What 5 effects could buildup of intracellular AB oligomers cause?

Calcium dysfunction
Synaptic dysfunction
Proteosome blockage
Mitochondrial block => buildup of ROS
Hyperphosphorylated tau => tau tangles

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Describe 4 pathologies seen in brain of those with AD

Extracellular plaques
Neurofibrillary tangles (intraneuronal)
Cerebral amyloid angiopathy (due to extracellular plaques)
Cerebral loss/neuronal loss (due to protein buildup)

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Amyloid protein precursor - explain the 2 processing pathways

1. Non amyloidogenic pathway (does not produce AB peptide)

2. Amyloidogenic pathway = produces AB peptide = when this increases, it can accumulate + aggregate

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Tau is an intra/extra cellular pathology

Tau is a _____________ protein

Tau is an intracellular pathology

Tau is a cytoskeletal protein

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What is the phosphorylation status of tau in AD?

hyperphosphorylated

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Staging of Tau in AD - What is Braak stage I?

changes in medial temporal lobe (MTL), transentorhinal regions

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Staging of Tau in AD - What is Braak stage II?

spread to posterior parts of temporal lobe + hippocampus, entorhinal region

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These are post-mortem dissections of midbrain. Explain the 2 samples

Left = normal brain, , you see the substansia nigra

Right = Parkinson’s Disease brain, lack of substantia nigra

Staging of Tau in AD - What is Braak stage III?

temporo-occipital gyrus involvement

Staging of Tau in AD - What is Braak stage IV?

temporal cortex involvement

What do these stains of the midbrain show?

Pigmented neurons in substantia nigra being disrupted by the lewy bodies

lewy bodies are the circular clumps of protein

Staging of Tau in AD - What is Braak stage V?

Peristriatal cortex involvement

Staging of Tau in AD - What is Braak stage VI?

Striatal cortex involvement

This is brain immunostaining for alpha synuclein - what does it show?

Lewy body on left neuronal axons (sperm-looking thing) = changes in PD

Which of the following is not a prion disease? A) Creutzfeldt-Jakob B) Huntington's C) Fatal Familial Insomnia D) Kuru

B) Huntington's

Tau immunostaining in the peristriate but not the striate cortx is consistent with this Braak grading?

What is the importance of substansia nigra in midbrain?

descending motor fibres and the susbtantia nigra (the black substance) – **its important in the initiation of movement**

Multiple System Atrophy (MSA) - where does the protein acccumulate in MSA? - what pathology is MSA associated with?

**glial cells (oligodendrocytes)** NB: comma shaped inclusions in oligodendrocytes Pathology = **alpha-synuclein**

PD results from loss of ____________ neurons in the ________ \_\_\_\_\_\_\_\_\_\_\_

PD results from loss of **_dopaminergic_** neurons in the **_substantia_** **_nigra_**

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ immunostaining is considered as the diagnostic gold standard for PD

**α-synuclein**

Mutations in which gene can result in PD? What entities are immunoreactive to staining for this?

Mutations in which gene can result in PD? **α-synuclein** **Lewy bodies** and **lewy neurites** are immunoreactive to α-synuclein gene

Braak PD stages 1 to 6 - where does spread start from and where does it spread to in the most severe form?

spread from the **dorsal motor (Braak 1)** nucleus of the vagus nerve in medulla all the way up to the **frontal cortex (Braak 6)**

Tau isoforms and diff pathologies: Insoluble 68 kDa, 64 kDa, 60 kDa bands = if we dephosphorylate them, we get all 6 isoform bands back = what disease is this?

Tau isoforms and diff pathologies: Insoluble 68 kDa, 64 kDa bands = if we dephosphorylate them, we get back only 4R bands = what disease is this? Insoluble 64 kDa, 60 kDa bands = if we dephosphorylate them, we get back only 3R bands = what disease is this?

4R bands = CBD or PSP 3R bands = Pick's Disease

At what PD Braak Stage do people usually become symptomatic

Braak Stage 3

PD is a disease typically arising from both environmental and genetic factors. The obvious access points of environment to brain are from the gut and nose. What do people with early PD present with?

Anosmia, and we've already identified olfactory bulb damage

Parkinsonism - name 5 causes

1. Idiopathic PD 2. Drug-induced Parkinsonism 3. Multiple system atrophy (MSA) 4. Progressive supranuclear palsy (PSP) 5. Corticobasal degeneration

* Progressive supranuclear palsy (PSP) * Corticobasal degeneration (CBD) which protein pathology are they associated with?

Tau protein

Exluding PD, which other disorder, often presenting with parkinsonism, is associated with alpha synuclein pathology?

Multiple System Atrophy (MSA)

**Pick's Disease** - Where is the pathology? - Clinical presentation? - Cellular changes?

**Pick's Disease** - Where is the pathology = **frontotemporal atrophy** - Clinical presentation = **aggressive, personality changes, executive issues** - Cellular changes = **gliosis, neuronal loss, balloon neurons, tau + pick bodies**

Tau protein - alternative splicing gives rise to ____ isoforms.

6 isoforms 3R or 4R-tau (depending on # of microtubule-binding domains) + 2 further inserts (N) with unknown function

The shortest isoform of tau is...

3R/0N

List the tau isoforms

4R/0N 4R/1N 4R/2N 3R/0N 3R/1N 3R/2N

Frontotemporal lobar degeneration (unilateral changes) in this familial disease =\> what gene is mutated?

**progranulin** (a gene very near tau in chr 17)

Which of the following proteins is not associated with frontotemporal dementia? A) APP B) Tau C) TDP D) FUS

A) APP Tau is Pick's TDP-43 and FUS are the ones that have emerged in recent years

In recent years, mutations in certain genes have been identified to cause frontotemporal dementia - name 4

1. Progranulin 2. TDP-43 3. FUS 4. C9ORF72 \*Tau from Pick's disease is the classical protein\*