383.3 🏥 內科專科考前版

383.3.1 Mechanistic Deep Dive

383.3.1.1 TDP-43 Proteinopathy

  • DNA/RNA-binding protein
  • Mislocalization from nucleus to cytoplasm
  • Aggregation
  • Found in FTD, ALS, AD (LATE)

383.3.1.2 C9orf72 Mechanism

  • GGGGCC hexanucleotide repeat
  • Repeat-associated non-AUG (RAN) translation → dipeptide repeats (toxic)
  • RNA foci
  • Loss of function also possible

383.3.1.3 MAPT Mutations

  • Tau dysfunction
  • Mixed 3R/4R isoforms typically

383.3.1.4 GRN Mutations

  • Haploinsufficiency
  • Decreased progranulin
  • TDP-43 pathology

383.3.2 Recent Trials & Updates

383.3.2.1 Latozinemab (GRN-Directed)

  • Restores progranulin levels
  • Phase 2 for GRN-FTD

383.3.2.2 Tofersen-Like for C9orf72

  • BIIB078 anti-sense
  • Phase 1 trials

383.3.2.3 MAPT Targeting

  • BIIB080 (BMS-986168)

383.3.2.4 Diagnostic Biomarkers

  • CSF neurofilament
  • Plasma NfL
  • TDP-43 (research)

383.3.3 High-Yield Specialist Points

383.3.3.1 bvFTD Phenocopy Syndrome

  • Mimics bvFTD but doesn’t progress
  • May be psychiatric
  • Imaging often normal
  • 6-12 month observation

383.3.3.2 Right Temporal Variant of svPPA

  • Prosopagnosia (face recognition)
  • Loss of person-specific knowledge
  • Behavioral changes
  • Distinct from left svPPA

383.3.3.3 Pick Disease (Historical)

  • 3R tau
  • Pick bodies (round, eosinophilic)
  • Now considered subset of FTD-tau

383.3.3.4 Hyperorality + KlÃŒver-Bucy

  • Hyperorality (sweet tooth, gum, etc.)
  • Hypersexuality
  • Placidity
  • Hyperphagia
  • Visual agnosia
  • Bilateral temporal lobectomy classic (KlÃŒver-Bucy original)
  • Late FTD can show features

383.3.3.5 Psychiatric Misdiagnosis

  • bvFTD often misdiagnosed as:
    • Depression (apathy)
    • Mania (disinhibition)
    • Schizophrenia (especially C9orf72)
    • Bipolar
    • OCD (perseveration)
  • Imaging + course distinguishes

383.3.3.6 Genetic Counseling

  • Family history strong (1st-degree, especially)
  • Refer for genetic counseling
  • Pre-symptomatic testing options
  • Implications for relatives

383.3.3.7 Frontotemporal vs Frontal AD

  • Behavioral first in both possible
  • Imaging + biomarkers help
  • Amyloid PET (positive in AD)

383.3.3.8 Caregiver Education

  • Behavioral focus (not memory like AD)
  • Avoid confrontation
  • Structured environment
  • Distraction techniques
  • Caregiver burnout high

383.3.4 Pearls

  • FTD 2nd most common < 65
  • 3 syndromes: bvFTD + PPA + motor overlap
  • bvFTD: behavior, personality, apathy, disinhibition, hyperorality
  • PPA: svPPA, nfvPPA, lvPPA (AD!)
  • TDP-43, tau, FUS pathologies
  • C9orf72, MAPT, GRN genetics
  • No DMT — SSRIs for behavior
  • Avoid ChEI (worsens)
  • Speech therapy for PPA
  • FTD-ALS overlap (C9orf72)