Frontotemporal dementia pathology

FTD pathology organized by clinical syndrome (Ljubenkov and Miller, 2016)

• Behavioral variant frontotemporal dementia:
  • Tau (3R > 4R) ≈ TDP-43 (type A ≥ type B > type D) > (Alzheimer’s pathology) > FUS
• Semantic variant primary progressive aphasia
  • TDP-43 type C > 3R tau
• Nonfluent / agrammatic variant primary progressive aphasia
  • 4R tau (CBD and PSP) > 3R tau and TDP-43 type A
• Frontotemporal dementia-motor neuron disease
  • TDP-43 type B > TDP-43 type A > FUS
• Corticobasal syndrome / corticobasal degeneration
  • 4R tau (CBD) > (Alzheimer’s pathology) > PSP, TDP-43 > 3R tau
• Progressive supranuclear palsy (Steele-Richardson-Olszewski)
  • 4R tau (PSP > CBD)

FTD organized by underlying pathology (Ljubenkov and Miller, 2016

• FTLD-tau: (MAPT)
  • 3R tau (Pick’s disease)
    • bvFTD > nfvPPA, svPPA, CBS
  • 4R tau, CBD
    • Motor dysexecutive (including CBS) > PSP-S, nfvPPA, bvFTD
  • 4R tau, PSP
    • PSP-S > CBS, nfvPPA, bvFTD
• FTLD-TDP
  • TDP type A (GRN)
    • bvFTD > CBS, nfsvPPA > FTD-MND
  • TDP type B (C9ORF72)
    • bvFTD, FTD-MND, ALS
  • TDP type C
    • svPPA
  • TDP type D (always VCP mutation)
    • bvFTD, ALS, Paget’s disease of the bone, inclusion body myositis
• FTLD-FUS (FUS gene)
  • atypical FTLD with ubiquitin inclusions, basophilic inclusion body disease; neuronal intermediate filament inclusion disease
    • bvFTD if sporadic (w/ early age of onset (22-46 years) versus ALS if genetic

References

Ljubenkov, P. A. & Miller, B. L. A Clinical Guide to Frontotemporal Dementias. FOCUS 14, 448–464 (2016). https://pubmed.ncbi.nlm.nih.gov/31975825/