Neurodegeneration

Question 1

what is the New Variant CJD (vCJD)? epidemiology? presentation?

Answer 1

Sporadic neuropsychiatric disorder

Patients <45 yrs old
Cerebellar ataxia
Dementia
Longer duration than CJD
Linked to BSE - bovine spongiform encephalopathy
Diagnosed at autopsy since 1990

Question 2

what is required to diagnose alzheimers?

Answer 2

Extracellular plaques
Neurofibrillary tangles

+ symptoms are needed for diagnosis

other features:
Cerebral amyloid angiopathy (CAA)
Neuronal loss (cerebral atrophy)

Question 3

spongiform changes in the brain are seen in which condition?

which other findings will be seen? why?

Answer 3

Prion

will also see prion protein deposits - prion protein is usually in a structure, it unfolds and forms B structure. this process keeps happening. no1 knows what causes it.

Question 4

what is the common mechanism of these neurodegenerative disorders?

Answer 4

prion type spread - where protein changes it shape

Question 5

most common neurodegenerative disorder?

Answer 5

alzheimers

Question 6

list some imaging findings for Alzheimers?

Answer 6

Cortical atrophy - especially temporal lobe

Senile plaques - (a beta- AB proteins forming tangles or amyloid plaques stained brown) on silver stain

Cerebral amyloid angiopathy

Tau proteins?

Question 7

AB - A beta proteins are formed via what process?

Answer 7

APP processing - amyloid precursor proteins

Question 8

what is Tau? relevance in alzheimers?

Answer 8

cytoskeletal protein

becomes hyperphosphorylated in AD

Alzheimers - 3R + 4R tauopathy

Question 9

where is the earliest appearance of tau pathology? where does its course go? how do we characterise this?

Answer 9

anterior hippocampus

the spread to posterior h. then into temporal lobe. then occipital.

this is called the Braak staging - thee further the spread, the higher the stage

Question 10

what is the aetiology behind CTE - chronic traumatic encephalopathy?

Answer 10

tau pathology

is similar to alzheimers but not the same.

caused by repetitive trauma to the head

Question 11

what is the definitive lesion in Parkinson’s?

Answer 11

lewy body in substantia nigra

Question 12

what is the most common lewy body disease?

Answer 12

parkinsons

Question 13

what is the locus of pathology in parkinsons?

Answer 13

substantia nigra

loss of dopaminergic cells* = loss of pigment / pale

which usually project from SN to basal ganglia

Question 14

what is the diagnostic gold standard in parkinsons?

Answer 14

α-synuclein immunostaining is considered as the diagnostic gold standard

as they react with lewy bodies and lewy neurite

Question 15

braak can also be used to stage?

Answer 15

parkinsons

Question 16

the following conditions present with Parkinsonism, what proteins are they associated with;

Multiple system atrophy
Progressive supranuclear palsy
Corticobasal degeneration

Answer 16

Multiple system atrophy – a synuclein (affects glial cells)
Progressive supranuclear palsy - tau*
Corticobasal degeneration - tau

ALPHA SYNUCLEINism - idiopathic Parkinsons!!!

*4R tauopathy

Question 17

briefly how can you tell the difference between alzhiermers and Frontotemporal dementia’s?

Answer 17

alzhiemers - more a temporal/ memory disorder

FTD - mood and behaviour disorder

Question 18

what is Pick’s disease? presentation?

what protein is present?

characteristic findings?

Answer 18

Fronto-temporal atrophy
is a type of frontotemporal dementia

Marked gliosis and neuronal loss
Balloon neurons

Tau positive Pick bodies - 3R Tauopathy

Presentation: Mood change, aggression, disinhibition

Question 19

what are the genetics in FTDP-17 (frontotemporal dementia) syndromes?

Answer 19

Autosomal dominant
Abundant TAU pathology

> 20 pathogenic mutations identified
Missense and splicing mutations

Question 20

what is the structure of tau?

Answer 20

Single gene on 17q21
16 exons
Alternative splicing gives rise to 6 isoforms
3R or 4R-tau (microtubule-binding domains)
Two further inserts with unknown function
Shortest form (3R/0N) foetal

Question 21

what can lead to tau negative frontotemporal dementia?

Answer 21

Progranulin gene mutation

on chromosome 17

Some FTPD not tau positive but are progranulin positive

Question 22

what is the pathological classifciation of frontotemporal dementias?

Answer 22

Tauopathies:
3R Tau - Picks disease
4R Tau - PSP (progressive supranu…)
3R + 4R Tau - Alzheimers

Tau negative FTLD:
TDP-43 +- ones
FUS associated ones