Lecture 8 Flashcards
(42 cards)
Why is frontotemporal dementia (FTD) difficult to diagnose?
Clinically, pathologically and genetically a heterogeneous disease
Which disease does FTD overlap with?
ALS - having mainly similar mutations
What is the umbrella term for the pathology?
Frontotemporal lobar degeneration
When does it arise?
Predominately a pre-senile dementia (second most common) but also seen in over 65’s (fourth most common)
What are the frontotemporal lobes associated with?
Social interaction and language
How quickly does it kill?
Within 5-10 years of onset
What are the three grouping for the disease?
What other diseases are similar?
- Behavioural variant dementia; lethargy and loss of social inhibition
- Progressive non-fluent aphasia: Loss of speech fluency but preservation of listening comprehension
- Semantic dementia; aphasia loss of comprehension also loss of social inhibition
Picks disease, progressive supranuclear palsy, corticobasal dementia
What test was developed for FTD?
Cambridge test
What causes the clinical heterogeneity?
The brain region in which the dementia started
What causes the pathological heterogeneity?
Different neuronal inclsuions; 45% of cases have tau (FTLD-Tau), 43% have TDP43 (FTLD-TDP), 9% have FUS (FTLD-FUS) and 1% are triple-negative (FTLD-U)
What percentage of cases have familial association what type of inheritance is seen?
50% have familial association
10-20% of cases are autosomal dominant inheritance
Where are genetic mutations are seen?
Tau and progranulin (50% cases), TARDP, valosin containing protein (VCP), fused in sarcoma (FUS), chromatin modifying protein 2B and C9ORF72
What is tau?
Where else is it seen?
Microtubule binding protein
Seen in PD (Lewy bodies) and ALS
What are the five clinical presentations?
- Behavioural Variant
- Progressive non-fluent aphasia
- Semantic dementia
- Corticobasal Syndrome
- Progressive supranuclear palsy syndrome
Why is the actual classification difficult?
Requires brain tissue from site to see what is causing the disease; so commonly only properly diagnosed after death
Where is tau gene found?
Where do its mutations cluster?
Found on chromosome 17
Mutations cluster in exons 9-13; region that controls the number of microtubule binding domains (either 3 or 4)
What do the mutations cause?
- Damages MT stabilisation
- Aberrant phosphorylation of tau
- Affects alternative splicing; usually increasing number of four binding domain isoforms
What causes the aggregate formation of tau?
Hyperphosphorylation of soluble tau; now thought that it is this hyperphosphorylation that is toxic
How are the mutations that cause Pick’s disease different?
Due to formation of the 3 binding domain isoforms
What is GWAS?
Genome-wide association study; allows association with heterozygous mutations in genome with onset of disease
What affect do the tau aggregates have?
Defects in cytoskeletal transport due to loss of interaction between tau and microtubule and aggregates blocking transport. Neuron dies, (due to caspases and loss of trophic factor transport) and cognitive decline occurs
What type of mutations are seen in progranulin?
non-sense, mis-sense and frame shifts
What commonly happens to the RNA of progranulin mutations?
What is the outcome
nonsense mediated decay
Haploinsufficiency, only one copy of the gene being transcribed; and this is not enough when you reach a certain age
What happens to functional progranule transcript?
What role does it play?
Translated in neurons and then pro-protein is cleaved into a granulin by enzymes from microglia and astrocytes and secreted
Function not totally known; widely expressed by microglia (growth factor, immune factor, supressing microglia activation?)
