Frontotemporal dementia

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease of the frontal and/or temporal lobe generally caused by mutations to proteins in the brain (e.g., Tau, progranulin). Pick disease, formerly used synonymously with FTD, is actually a specific subtype of FTD that can only be diagnosed pathologically; therefore, the two terms are not synonymous. Onset usually occurs in middle-aged individuals (40–60 years). Early symptoms are characterized by inappropriate social behavior (e.g., disinhibition, apathy), but patients typically continue to exhibit normal intelligence and orientation. As the disease progresses, patients may develop motor deficits and akinetic parkinsonism as an end‑stage syndrome. Diagnosis of FTD is based on a combination of factors, including the clinical criteria of dementia and possible frontotemporal brain atrophy on CT or MRI. Further diagnostic procedures may be considered to rule out other possible causes of dementia. No effective causal treatment for FTD exists and symptomatic treatment is limited to associated symptoms (e.g., depression). The disease usually has a fatal outcome within six years.

• Heterogeneous group of syndromes that involve degeneration of the frontal, insular, and/or temporal cortices and manifest with a number of symptoms of dementia.
• FTD is sometimes still referred to as Pick disease, but these terms are not synonymous and should not be confused with one another.
• FTD syndromes are often considered special types of Alzheimer disease (however, initial symptoms are typically not memory‑related).

References:^[1]

• 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

References:^[1]

• Behavioral variant frontotemporal dementia (bvFTD): most frequent subtype (∼ 50% of FTD cases)
• Two variants of primary progressive aphasia (PPA):
  • Progressive nonfluent aphasia (PNFA; also known as nonfluent agrammatic variant primary progressive aphasia)
  • Semantic dementia (SD; fluent type, also known as semantic variant primary progressive aphasia)
• Posterior cortical atrophy (PCA)
• Corticobasal syndrome (CBS)

General features of FTD

• Early changes in personality and behavior → inability to observe social etiquette
  • Apathy
  • Disinhibited behavior
    • A pattern of socially inappropriate and often impulsive behavior that is seen in several neurological disorders
    • Examples include offensive language and inappropriate touching.
  • Exaggerated emotional display
  • Irritability
  • Binge eating (particularly of sweet foods)
• Changes in cognitive functioning
  • Aphasia (but no apraxia)
  • Intelligence, orientation, and memory initially intact
  • Lack of attention
• Motor deficits
  • Parkinsonism (in later stages)
  • Pyramidal signs (e.g., tendon hyperreflexia, Babinski sign)

Patients with FTD display changes of personality and social behavior, but their memory generally remains intact.

Characteristic features FTD syndromes

• Behavioral variant frontotemporal dementia (bvFTD): early changes in personality; apathy
• Progressive Non Fluent Aphasia (PNFA): language impairment (e.g., grammatical errors, apraxia)
• Semantic dementia (SD): language impairment (specifically comprehension)
• Posterior cortical atrophy (PCA): visual disorders (e.g., blurred vision)
• Corticobasal syndrome (CBS): asymmetric kinetic movement disorder

The diagnosis of FTD syndromes is based on a combination of factors:

• Clinical diagnosis of a dementia syndrome (see “Diagnostic criteria for major neurocognitive disorder (previously dementia) in accordance with DSM-5.”)
• Other tests to rule out or confirm specific abnormalities
  • CT/MRI: atrophy of the frontal and/or temporal lobes
  • FDG-PET: shows frontotemporal hypoperfusion/hypometabolism
  • Laboratory tests: to rule out other etiologies of dementia (e.g., infections, hypothyroidism)

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

Macroscopic

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

Microscopic

• Detection of different types of intracellular inclusions in surviving neurons (tau or TDP-43 in approx. 90% of cases)
  • Pick bodies (FTLD-tau); : round cytoplasmic inclusions of aggregated hyperphosphorylated tau proteins ;
    • Associated with Pick disease
    • Found in ∼ 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)

References:^[1]

See “Differential diagnosis of dementia subtypes.”

The differential diagnoses listed here are not exhaustive.

At the moment, no curative treatment is available.

• General measures ^[2]
  • Supportive therapy (e.g., behavioral therapy, speech therapy)
  • Dietary measures
  • Exercise
• Pharmacotherapy ^[2]
  • Dementia: Cholinesterase inhibitors and memantine are usually not effective and may, in some cases, even worsen symptoms.
  • Depression: SSRIs (e.g., citalopram)
  • Agitation, hallucinations, insomnia
    • Atypical antipsychotics (e.g., olanzapine)
    • Trazodone

• Patients with FTD survive an average of six years after symptom onset (progression is usually faster than in Alzheimer disease).
• A common cause of death is intercurrent infection (e.g., pneumonia).

References:^[3]