Frontotemporal dementia

Pathophysiology - The Brain's Bad Build-up

FTD results from progressive neuronal loss and focal atrophy in the frontal and temporal lobes. The underlying cause is the accumulation of one of two main abnormal proteins:

• Tauopathy (~40% of cases)

  • Aggregates of hyperphosphorylated tau protein form neurofibrillary tangles.
  • The classic finding is the Pick body: a spherical, silver-staining intraneuronal inclusion.
  • Associated with mutations in the MAPT gene.

• TDP-43 Proteinopathy (~50% of cases)

  • Cytoplasmic inclusions of TDP-43 protein are the hallmark.

⭐ The C9orf72 gene expansion is the most common genetic cause of both FTD and Amyotrophic Lateral Sclerosis (ALS), creating an FTD-ALS clinical spectrum.

Clinical Presentation - Personality & Language Gone

Presents in two main forms, often before age 65.

• Behavioral Variant (bvFTD): Most common form.

  • Personality/Behavioral Changes: Early, prominent signs.
    • Disinhibition: Socially inappropriate behavior, impulsivity.
    • Apathy: Loss of motivation and interest.
    • Loss of Empathy/Sympathy: Emotional blunting.
  • Stereotyped/Compulsive Behaviors: Repetitive actions, hoarding.
  • Dietary changes: Hyperorality, preference for sweets.

• Primary Progressive Aphasia (PPA): Language function declines first.

  • Semantic Variant (svPPA): "What is a 'fork'?"
    • Loss of word/object meaning (anomia).
    • Fluent, grammatically correct but empty speech.
  • Non-fluent/Agrammatic Variant (nfvPPA): "Fork... eat... food."
    • Effortful, halting speech with grammatical errors (agrammatism).
    • Apraxia of speech often present.

⭐ In early FTD, memory and visuospatial functions are often strikingly preserved, distinguishing it from Alzheimer's disease where memory loss is the initial, dominant feature.

Diagnosis - Finding the Frontal Faults

• Clinical Criteria: Diagnosis relies on international consensus criteria for behavioral variant FTD (bvFTD) or primary progressive aphasia (PPA).
• Neuropsychological Testing: Confirms executive dysfunction (e.g., poor planning, disinhibition) or specific language deficits.
• Neuroimaging: Crucial for diagnosis.
  • MRI: Shows characteristic, often asymmetric, atrophy in the frontal and/or temporal lobes.
  • PET/SPECT: Reveals ↓ frontotemporal hypometabolism or hypoperfusion, helping differentiate from other dementias.

⭐ Exam Favorite: In contrast to Alzheimer's disease, memory and visuospatial skills are typically well-preserved in the early stages of FTD.

Management - Support, Not Cure

• Core Goal: Primarily symptomatic and supportive, as no disease-modifying therapies currently exist. Focus on safety and quality of life.
• Non-Pharmacologic (First-Line):
  • Behavioral redirection, environmental modification.
  • Speech, physical, and occupational therapy.
• Pharmacologic (Symptom-Targeted):
  • Behavioral: SSRIs (e.g., sertraline) for disinhibition, anxiety, and compulsive behaviors.
  • Sleep: Trazodone for insomnia and agitation.

⭐ High-Yield: Unlike Alzheimer's, cholinesterase inhibitors (e.g., donepezil) and memantine are not effective and may worsen agitation in FTD.

High-Yield Points - ⚡ Biggest Takeaways

• Presents at a younger age (<65) than Alzheimer's disease.
• Characterized by early personality and behavior changes (apathy, disinhibition, compulsivity) or language dysfunction.
• Memory and visuospatial skills are relatively preserved in the early stages.
• Two primary variants: behavioral variant (bvFTD) and primary progressive aphasia (PPA).
• Pathology is linked to tau protein (Pick bodies) or TDP-43 proteinopathy.
• Neuroimaging reveals focal atrophy of the frontal and/or temporal lobes.