Frontotemporal Dementia Flashcards
What is the second most common young onset degenerative dementia?
Frontotemporal dementia
What is the prevalence and incidence of FTD?
Prevalence
– 10-20 per 100,000 (ages 45-64)
Incidence
– 3-4 per 100,000 (ages 45-64)
FTD is a ________ disease
Heterogeneous
What are the 2 variants of FTD?
Behavioral (bvFTD) and language (non fluent variiant nfvPPA, semantic variant svPPA)
What do the language variants lead to?
Primary progressive aphasia (PPA)
What other conditions does FTD overlap with?
Atypical parkinsonian syndromes:
– Progressive supranuclear palsy (bvFTD, nfvPPA)
– Corticobasal (degeneration) syndrome (bvFTD, nfvPPA)
- Motor neurone disease/amyotrophic lateral sclerosis
(bvFTD»_space; nfvPPA and rare descriptions of svPPA)
What are the consensus criteria for FTD?
*Lund-Manchester criteria 1994
*Neary criteria 1998
* McKhann criteria 2001
* Mesulam PPA criteria 1998/2001
New criteria:
*Rascovsky
International bvFTD
Consortium criteria
for bvFTD
(Brain, 2011)
What are the features of the behavioral variant of FTD?
- Disinhibition
– Socially inappropriate behaviour
– Loss of manners or decorum
– Impulsive, rash or careless actions - Apathy/inertia
- Loss of sympathy/empathy
- Perseverative, stereotyped and compulsive behaviour
– Simple repetitive movements
– Complex, compulsive or ritualistic behaviours - Hyperorality/dietary changes
– Altered food preference – sweet tooth, binge eating - Executive dysfunction
What are the other symptoms not in bvFTD criteria?
- Loss of insight
- Impaired social cognition
- Altered sensitivity to pain and/or temperature
- Delusions and/or hallucinations (usually visual)
What are the subtypes of PPA?
3 (rather than 2)
subtypes:
– svPPA
– nfvPPA
– lvPPA
= logopenic
aphasia (first
described 2004)
What are the features of svPPA? (semantic)
- Multimodal loss of semantic knowledge: verbal initially
then… visual, auditory, olfactory, gustatory - Fluent speech with semantic errors
- Anomia
- Single word comprehension problems
- Surface dyslexia
- Later, nonverbal impairment e.g. visual agnosia
What is the problem with nonfluent aphasia nfvPPA?
Problem: nfvPPA very mixed
– Agrammatism
– Apraxia of speech
– Anomia
– Word-finding pauses
* New classification splits “nonfluent” patients into nfvPPA
and lvPPA
What are the features of nfvPPA?
- ‘Motor’ speech impairment
- Can be v slow and
misdiagnosed as
functional - Agrammatism
- May develop CBS/PSP
- More anterior (left inferior
frontal and insula) atrophy - Underlying pathology is
FTLD: tau»_space; TDP-43
What are the features of ivPPA?
- Hard to characterise as
‘fluent’ vs ‘nonfluent’ - Word-finding difficulties
- Motor speech/grammar
normal - More posterior atrophy
- Underlying pathology AD
What are the pathological subtypes of frontotemporal lobar degeneration?
Tau positive (commonest) or ubiquitin positive tau negative (FTLD-U)
What are the genetics of FTD?
- Up to 50% of patients with FTD describe a family history of
a dementia - But… a smaller number have an autosomal dominant
inheritance (~a third) - And variable across clinical syndromes
What are the main genetic findings?
2011 – Chromosome 9 open reading frame 72 (C9ORF72)
2006 – Progranulin (GRN)
1998 – Microtubule-associated protein tau (MAPT)
In our series: C9ORF72 9%, MAPT 10%, GRN 7%…
but variable across the world
What to test?
On family history
– Autosomal dominant family history commonly present… but
not always
* On clinical syndrome:
– bvFTD/FTD-MND > nfvPPA > CBS»_space; PSP»_space; svPPA
– bvFTD: any of the genes (C9orf72 if delusions)
– FTD-MND: C9orf72
– nfvPPA: GRN»_space;C9orf72
– CBS: MAPT > GRN mutations
– PSP syndrome: rare cases of MAPT mutations
What allows us to test all the genes at the same time?
next generation sequencing
but multiple variants in same person? whats pathogenic? some people carry double mutations
Imaging of bvFTD involves which lobes
variable
not just frontal and temporal lobes but
also insula and anterior cingulate; usually asymmetrical
* Whitwell et al, 2009, Brain suggest 4 subtypes:
– Frontal predominant
– Temporal predominant
– Frontal = temporal
– Temporofrontoparieta
What is the problem?
we cannot diagnose underlying pathology in life
What are the FTD biomarkers?
- Tau pathology
– PSP syndrome (highly likely)
– MAPT mutations
– Tau PET ligand
– Tau isoforms in CSF - TDP pathology
– FTD-MND syndrome/svPPA syndrome (highly likely)
– GRN mutations or serum GRN level
– TDP-43 levels in serum or CSF - FUS pathology
– Very young onset
Management directed to
controlling symptoms and helping patients and caregivers cope with impact of their illness
What are the non pharmacological managements?
– Simple interventions (puzzles, music, controlled access to food/drink) may help govern troublesome behaviours and contribute to a stable routine
– Speech and language therapy can provide communication aids, plus
assessment of swallowing and advice on dietary modification
– Programmed respite, counselling, and psychological support for
caregivers
– Genetic counselling of at-risk family members
Clinical trial evidence of FTD includes
- Phase 3:
– LMTM (TauRx) FAILED - Phase 2:
– HDAC inhibitor (FORUM) – GRN mutation carriers FAILED - Phase 1:
– ASOs (Ionis) – C9orf72 mutation carriers/MAPT mutation
carriers
– ASO (Wave) – C9orf72 mutation carriers
– Sortilin antibody (Alector) – GRN mutation carriers
What are the pharmacological management options for FTD?
No clear symptomatic benefit
for cholinesterase inhibitors or memantine; these agents may aggravate behavioural
disturbance
– Small, double blind, controlled trials have provided some evidence for modest improvement of behavioural symptoms with selective serotonin reuptake inhibitors
