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1. Behavioral Variant FTD (bvFTD) â Most Common
- Mean onset 50-65
- Personality + behavior changes (often noticed by family first)
- Apathy (loss of motivation)
- Disinhibition (impulsive, social transgressions, gambling)
- Loss of empathy + insight
- Perseveration (stereotyped, repetitive behavior)
- Hyperorality / dietary changes (sweet tooth, overeating, pica)
- Executive dysfunction
- Relatively preserved memory + visuospatial early
- Disease progression: 6-10 years
2. Primary Progressive Aphasia (PPA)
Semantic Variant (svPPA, semantic dementia):
- Loss of semantic knowledge
- Word-finding difficulty (anomic)
- Loss of word meaning (semantic paraphasias)
- Surface dyslexia (irregular words)
- Object recognition impaired
- Behavioral changes can develop
- Asymmetric anterior temporal atrophy
Nonfluent/Agrammatic Variant (nfvPPA):
- Agrammatism (omission of function words)
- Apraxia of speech (effortful, distorted)
- Comprehension of complex syntax impaired
- Word meaning + object knowledge preserved
- Left frontal/insular atrophy
- May progress to mutism
Logopenic Variant (lvPPA):
- Anomia (word-finding)
- Sentence repetition impaired
- Phonological errors
- Often AD pathology (not FTD)
- Posterior parietal/temporoparietal atrophy
3. FTD-Motor Overlap
- FTD-ALS (~ 15% of FTD; ~ 50% of ALS develop FTD features; C9orf72 common)
- FTD-PSP
- FTD-CBS
Categories
FTD-TDP (~ 50%):
- TDP-43 inclusions
- Types A, B, C, D
- Type A: GRN mutations, sporadic
- Type B: C9orf72, FTD-ALS
- Type C: svPPA
- Type D: rare, VCP
FTD-tau (~ 40%):
- Pick disease (3R tau, Pick bodies)
- PSP, CBD (4R tau)
- MAPT mutations (mixed 3R/4R)
FTD-FUS (~ 5-10%):
- FUS inclusions
- Young onset often
Genetics
- ~ 30-50% familial
- C9orf72 hexanucleotide repeat expansion (most common, AD)
- Also causes ALS
- Repeat > 30 typically pathogenic
- MAPT (microtubule-associated protein tau) â AD
- GRN (progranulin) â AD, FTLD-TDP
- TBK1, VCP, CHMP2B, FUS (rarer)
Clinical Diagnosis (Rascovsky bvFTD Criteria 2011)
- Possible bvFTD: 3 of 6 behavioral/cognitive features
- Probable: + functional decline + characteristic imaging
- Definite: pathological confirmation or known mutation
Imaging
- MRI: frontal/temporal atrophy
- Symmetric in bvFTD
- Asymmetric L in PPA
- FDG-PET: frontotemporal hypometabolism
- Amyloid PET: usually negative (helps distinguish from lvPPA = AD)
Diagnosis
- Clinical + imaging
- Genetic testing if familial
- CSF biomarkers helpful to exclude AD
- Plasma neurofilament light (NfL) often elevated
No Disease-Modifying
- Multiple trials (latrepirdine, etc. â failed)
- GRN-targeted (PR006, latozinemab) in trials
- C9orf72 antisense oligonucleotides (BIIB078) â phase 1
Symptomatic + Supportive
Behavioral:
- SSRIs (sertraline, citalopram) for disinhibition + compulsive behaviors
- Trazodone for agitation
- Atypical antipsychotics (judicious â sensitivity to EPS)
- AVOID cholinesterase inhibitors (may worsen)
Aphasia (PPA):
- Speech-language therapy
- Communication strategies
- Aids
Motor (FTD-ALS, PSP, CBS):
- See respective chapters
Caregiver:
- Education (different from AD)
- Behavioral management
- Safety planning
- Support groups
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- FTD = 2nd most common dementia < 65
- 3 syndromes: bvFTD + PPA (svPPA, nfvPPA, lvPPA) + FTD-motor
- bvFTD: behavior/personality + apathy + disinhibition + hyperorality
- svPPA: loss of semantic knowledge + surface dyslexia
- nfvPPA: agrammatism + apraxia of speech
- lvPPA: AD pathology often
- Pathology: TDP-43 (C9orf72) > tau > FUS
- Genetic ~ 30-50%: C9orf72, MAPT, GRN
- No disease-modifying
- SSRIs for behavior; avoid cholinesterase inhibitors