Frontotemporal dementia

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that affects the frontal, insular, and/or temporal cortices and is associated with pathological protein accumulations (e.g., tau, TDP-43). Historically, the term Pick disease was often used synonymously with FTD; however, it specifically refers to a pathological subtype. Onset is typically between 40 and 60 years of age. Early symptoms include behavioral changes (e.g., disinhibition, apathy), while intelligence, memory, and orientation are initially preserved. As the disease progresses, motor deficits (such as parkinsonism) and more widespread cognitive decline may develop. Diagnosis is primarily clinical and is supported by neuroimaging findings, with additional investigations used to exclude alternative causes of symptoms. There is currently no disease-modifying treatment, and management focuses on supportive care and symptomatic relief.

• Age of onset: : usually between 40 and 60 years (typically younger than in Alzheimer disease)
• Prevalence: 3–4/100,000 in patients ≤ 65 years

Epidemiological data refers to the US, unless otherwise specified.

• Generally associated with pathological intracellular inclusion bodies (Pick bodies) that are caused by mutations in tau (main protein component of Pick bodies) or progranulin (precursor of granulin, which regulates cell growth) proteins
• Also associated with ubiquitin inclusion bodies hypothesized to be caused by dysfunction of the ubiquitin proteasome system
• Familial predisposition (autosomal dominant): ∼ 10–25% of FTD cases

Frontotemporal dementia can be classified based on the following. ^[2]

• Clinical presentation
  • Determined by initial predominant clinical features (e.g., behavioral variant frontotemporal dementia)
  • See “Clinical subtypes of FTD” for details.
• Frontotemporal lobar degeneration (FTLD) pathology
  • Characterized by the type of intracellular inclusion bodies in brain tissue (e.g., FTLD-tauopathies like Pick disease, progressive supranuclear palsy, and corticobasal degeneration)
  • See “Pathology” for details.

The occurrence, timing, and prominence of features depend on the subtype of FTD.

• Personality and behavioral changes ; ^[3]
  • Disinhibited behavior
    • Inability to observe social etiquette (e.g., offensive language, not respecting personal boundaries, lack of embarrassment)
    • Impulsivity (e.g., reckless spending) ^[4]
  • Overeating, change in dietary preferences (e.g., new preference for sweet foods)
  • Hyperorality
  • Emotional symptoms
    • Apathy
    • Loss of empathy
    • Exaggerated emotional display
    • Irritability
  • Stereotypies
  • Compulsive behaviors
• Speech and language impairment ^[3]
  • Aphasia
    • Anomic aphasia
    • Agrammatism
  • Verbal apraxia
• Late symptoms ^[3]
  • Motor symptoms (e.g., parkinsonism, dysphagia)
  • Global cognitive decline

Global memory, intelligence, and orientation are usually initially preserved.

Clinical subtypes of FTD ^[3]

• Behavioral variant frontotemporal dementia
  • Most common subtype (50–70% of cases) ^[3]
  • Early personality and behavioral changes (e.g., apathy, disinhibition)
• Primary progressive aphasia (PPA)
  • Nonfluent variant PPA
    • Agrammatism
    • Verbal apraxia
    • Phonological errors
    • Impaired comprehension of complex sentences
  • Semantic variant PPA
    • Anomic aphasia
    • Impaired word comprehension

FTD-related disorders ^[4]

Disorders with similar pathological characteristics (e.g., tau protein deposition) include:

• Progressive supranuclear palsy
• Corticobasal degeneration
• FTD-motor neuron disease

General principles ^[3][5]

• FTD is a primarily clinical diagnosis.
  • Perform a comprehensive clinical evaluation, including cognitive testing.
  • Interview family members, as information obtained from patients may be unreliable.
  • Diagnostic criteria may be used by specialists to confirm FTD subtypes.
• Neuroimaging is required to exclude other causes and can also help identify the FTD subtype.
• Consider further testing as needed.
  • Laboratory tests are used to rule out alternative causes of cognitive decline (see “Initial evaluation of major neurocognitive disorder”).
  • Advanced testing may be done in consultation with neurology (e.g., testing for genetic factors).
• Definitive diagnosis requires postmortem neurohistopathological confirmation (not usually performed).

Neuroimaging ^[3][5]

• MRI brain
  • Evaluation for characteristic structural changes
  • Exclusion of other reversible or nondegenerative causes of cognitive decline
  • Supportive findings: atrophy of the frontal and/or temporal lobes
  • Common patterns and localizations of subtypes differ.
• FDG-PET/CT
  • May help distinguish between FTD and Alzheimer disease, as well as between different FTD subtypes
  • Findings: frontotemporal hypometabolism

Pathological changes in FTD are commonly referred to as frontotemporal lobar degeneration (FTLD).

Macroscopic ^[6]

• Atrophy of the temporal and/or frontal lobes
• Often beginning on one side and subsequently affecting both hemispheres

Microscopic ^[6]

• Detection of different types of intracellular inclusions in surviving neurons (tau or TDP-43 occur in approx. 90%)
  • Pick bodies (FTLD-tau); : round cytoplasmic inclusions of aggregated hyperphosphorylated tau proteins ;
    • Associated with Pick disease
    • Found in approx. 40% of patients with FTLD
    • Also found in other neurodegenerative diseases (e.g., progressive supranuclear palsy, corticobasal degeneration)
    • Silver stain: classic Pick bodies stain positive, but many patients with tau inclusions stain negative
  • FTLD‑TDP: inclusions with ubiquitinated TDP‑43
  • FTLD‑ALS/DPR
  • FTLD‑FUS
• Nonspecific gliosis
• Formation of microvacuoles
• Loss of neuronal tissue
• Swollen neurons (Pick cells)

Historically, FTD was referred to as Pick disease; however, Pick disease is a pathological subtype of FTD.

See “Differential diagnosis of dementia subtypes.”

The differential diagnoses listed here are not exhaustive.

General principles ^[7]

• There is currently no disease-modifying therapy for FTD. ^[2]
• SSRIs may be effective for the management of some behavioral symptoms (e.g., disinhibition and hyperorality).
• Speech therapy may be effective for verbal apraxia.

Supportive management ^[7]

• Supportive care for dementia, e.g.:
  • Lifestyle modifications
  • Cognitive training
  • Referral for swallowing assessment and occupational therapy as needed
• Management of neuropsychiatric symptoms of dementia, e.g.:
  • Low-dose SSRIs for depression
  • Low-dose atypical antipsychotics may be considered for agitation or psychosis under specialist guidance.
• Management of conditions in advanced dementia

Cholinesterase inhibitors and memantine are usually not effective and may even worsen symptoms in patients with FTD. ^[7]

Atypical antipsychotic use in dementia is associated with increased mortality and should be used with caution. ^[8]

• Mean survival: 6.6–9 years after symptom onset ^[9]
• Infection (e.g., pneumonia) is a common cause of death.