WK10 - FTD

Question 1

What is frontotemporal dementia (FTD)?

Answer 1

Degen of n. in frontal &/or temporal lobes
* Earlier onset (45-65y)
* Annual incidence and prevalence may be innacurate due to misdiagnosis
* Disease course variable (2-20y survival)

Question 2

First symptoms of FTD depend on…

Answer 2

Which part of brain is first affected:
* Frontal - planning, attention, empathy → bvFTD
* Temporal - language → PPA
* Basal ganglia - movement → atypical PDs

Question 3

Frontotemporal lobar degeneration (FTLD)
types

Answer 3

1. FTLD-tau ~40-45%
2. FTLD-TDP-43 ~50%
3. FTLD-FUS ~5-10%

Question 4

FTLD-tau

Answer 4

Neurons AND glia affected
* Astrocytes prominently affected in mFTD

Question 5

FTLD-TDP-43

Answer 5

Lives in nucleus > shunted out to cytoplasm in pathological subtypes
* Then aggregates
* Mostly in n., but also in oligodendrocytes

Question 6

FTLD-FUS

Answer 6

Much rarer
* similar pathology process to TDP-43

Question 7

Misdiagnosis of bvFTD and mFTD

Answer 7

• bvFTD - late onset psychiatric illness
• mFTD - PD

Question 8

Can clinical subtype predict neuropathology?

Answer 8

No
* Share many pathologies
* Diagnosis not certain until postmortem

Question 9

Risk factors of FTD

Answer 9

1. Age
2. European ancestry
3. Family history (20-40% of FTD have 1+ affected relative(s)

Question 10

Mutations in FTD

Answer 10

40-60% of fFTD + 5-10% of “sporadic” FTD accounted by mutations in:
* MAPT
* GRN
* C9orf72

Question 11

MAPT

Answer 11

Microtubule-associated protein Tau
* ~5-20% fFTD
* Missense→ alter protein structure
* Mutations at/near exon, intron, splice-site → alter 3R/4R ratio
* → changes in microtubule assembly/axonal transport, propensity of tau aggregation

Question 12

GRN

Answer 12

(Pro)granulin
* ~5-20% fFTD
* Mostly nonsense or frameshift mutations
* Nonsense-mediated decay of mRNA → ↓ protein expression
* Can’t be compensated by remaining copy of gene (‘haploinsufficiency’)

Question 13

What is progranulin needed for?

Answer 13

• Expressed in all brain cell types (highest in microglia)
• Secreted + in lysosome
• Involved in neurite outgrowth, microglial response & inflammation

Question 14

C9orf72

Answer 14

Chromosome 9, open reading frame 72
* 20-30% fFTD, ~5% sFTD
* Hexanucleotide repeat expansion
* 2-8 copies – fine
* »30-1000s – pathogenic
* 20-30 - ??risk factor??

Question 15

How does C9orf72 expansion cause disease?

Answer 15

1. Dipeptide repeat protein toxicity (GoF)
2. RNA toxicity (GoF)
3. Haploinsufficiency (LoF)

Question 16

Overlap between FTD and MND/ALS

Answer 16

~15% bvFTD cases meet clinical criteria for MND (vice versa)
* TDP-43 mislocalization, aggregation in >95% ALS, ~50% FTD
* C9orf72 most common genetic cause of FTD AND ALS

Question 17

Progress on treatment

Answer 17

Limited due to limited understanding of underlying biological causes
* biology greatly informed by gene discovery

Question 18

Susceptibility genes of “sporadic” FTD

Answer 18

TMEM106B & UNC13A

Question 19

TMEM106B

Answer 19

Transmembrane protein
* Regulates lysosome fxn & transport

Question 20

UNC13A

Answer 20

Presynaptic protein
* Controls release of neurotransmitter in vesicles

Question 21

Loss of nuclear TDP-43

Answer 21

STMN2 mis-splicing (cryptic exon included) → truncated transcript

Question 22

Risk variants in UNC13A…

Answer 22

Increases misplicing - may basis of disease?

Question 23

How can we use CSF/blood to distinguish AD from FTD

Answer 23

High tau, low Aβ42 in AD

Question 24

Gene-specific biomarkers

Answer 24

↓ progranulin > highly specific for GRN mutation carriers
↑ poly(GP) protein > highly specific for C9orf72 expansion carriers

Question 25

Developing biomarkers for FTLD Proteinopathies

Answer 25

TDP-43 target ***cryptic*** exons (**STMN2, UNC13A**) or cryptic proteins highly *specific* – promising area for biomarker development