• Clinical science

Frontotemporal dementia (Pick's disease…)

Abstract

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's 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.

Definition

  • FTD is a 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's disease, but this term should be avoided.
  • FTD syndromes are often considered special types of Alzheimer's disease (however, initial symptoms are typically not memory‑related).

References:[1][2]

Epidemiology

References:[2]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Generally associated with pathological intracellular inclusion bodies; (Pick bodies) that are caused by mutations in tau or progranulin 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
    • Various genes have been associated with inherited forms of FTD (particularly C9ORF72, MAPT, and GRN).

References:[1][2]

Classification

  • Behavioral variant frontotemporal dementia (bvFTD) → most frequent subtype (∼ 50% of FTD cases)
  • Progressive nonfluent aphasia (PNFA)
  • Semantic dementia (SD)
  • Posterior cortical atrophy (PCA)
  • Corticobasal syndrome (CBS)

Clinical features

General features of FTD

  • Early changes in personality and behavior → failure to observe social etiquette
    • Apathy
    • Disinhibition (e.g., hypersexual behavior)
    • Exaggerated emotional display
    • Irritability
    • Binge eating (particularly of sweet foods)
  • Changes in cognitive functioning
    • Intelligence, orientation, and memory initially intact
    • Aphasia (but no apraxia)
    • Lack of attention
  • Motor deficits

Characteristic features of each FTD syndrome

  • bvFTD → early changes in personality, apathy
  • PNFA → language impairment (e.g., grammatical errors, apraxia)
  • SD → language impairment (specifically comprehension)
  • PCA → visual disorders (e.g., blurred vision)
  • CBS → asymmetric kinetic movement disorder

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

References:[3][4]

Diagnostics

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

  1. Clinical diagnosis of a dementia syndrome → see diagnostic criteria for major neurocognitive disorder (previously dementia) in accordance with DSM-5
  2. Other tests to rule out or confirm specific abnormalities
    • CT/MRI: atrophy of the frontal and/or temporal lobes
    • Laboratory tests: to rule out other etiologies of dementia (e.g., infections, hypothyroidism)

References:[3]

Pathology

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
  • Histological
    • Nonspecific gliosis ; formation of microvacuoles and loss of neuronal tissue
    • Swollen neurons (= pick cells)
    • Detection of different types of intracellular inclusions in surviving neurons (tau or TDP-43 in approx. 90% of cases)

References:[1][2][3][4]

Differential diagnoses

See differential diagnosis of dementia subtypes.

The differential diagnoses listed here are not exhaustive.

Treatment

No curative treatment exists → symptomatic treatment

References:[4][5][6]

Prognosis

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

References:[4][7]