Frontotemporal Dementia (FTD)

Frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), or less commonly, Pick's disease, is the most common causes of dementia in adults younger than 60 years. It is characterized by uninhibited behavior, hyperorality, lack of empathy, impaired executive function, and lack of sympathy. Loss of insight is one of the core features of the frontal/behavioural variant frontotemporal dementia (FTD).

Epidemiology

Approximately 2-10 per 100,000 people. The peak age of onset is between ages 45-70, and has a “presenile” onset compared to other dementias. Approximately 20%-25% of cases of frontotemporal NCD occur in individuals older than 65 years. Frontotemporal NCD accounts for approximately 5% of all cases of dementia. Overall, more males are affected than females. The behavioural variants and semantic language variant are higher in males, and and non-fluent language variant are higher among females. FTD is the 3rd most common dementia, after Alzheimer's and Lewy body dementia.

Prognosis

The disease is gradually progressive, with a median survival of 5-10 years after symptom onset and 4 years after diagnosis.

Comorbidity
Risk Factors
Criterion A

The criteria are met for major or mild neurocognitive disorder.

Criterion B

The disturbance has insidious onset and gradual progression.

Criterion C

Either (1) or (2);

  1. Behavioural variant
    • a. 3 or more of the following behavioural symptoms:
      • Behavioural disinhibition
      • Apathy or inertia
      • Loss of sympathy or empathy
      • Perseverative, stereotyped or compulsive/ritualistic behaviour
      • Hyperorality and dietary changes
    • b. Prominent decline in social cognition and/or executive abilities
  2. Language variant
    • a. Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension.
Criterion D

Relative sparing of learning and memory and perceptual-motor function.

Criterion E

The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder.

Probable frontotemporal neurocognitive disorder is diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed:

  1. Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from either family history or genetic testing.
  2. Evidence of disproportionate frontal and/or temporal lobe involvement from neuroimaging.

Possible frontotemporal neurocognitive disorder is diagnosed if there is no evidence of a genetic mutation, and neuroimaging has not been performed.

Individuals with behavioral-variant frontotemporal dementia may present with apathy or disinhibition. Patients typically lose interest in socialization, self care, and personal responsibilities, or display socially inappropriate behaviours, such as sexual disinhibition. Insight is usually impaired as well. Cognitive impairment is much less prominent during the early stages, and few deficits are found on cognitive testing.

The International Behavioural Variant FTD Criteria Consortium (FTDC) developed revised guidelines for the diagnosis of bvFTD in 2011 that are more comprehensive than the DSM-5.[1]

I. Neurodegenerative disease

The following symptom must be present to meet criteria for bvFTD:

  • A. Shows progressive deterioration of behaviour and/or cognition by observation or history (as provided by a knowledgeable informant).
II. Possible bvFTD

3 of the following behavioural/cognitive symptoms (A–F) must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events.

  • A. Early* behavioural disinhibition [1 of the following symptoms (A1–A3) must be present]:
    • A1. Socially inappropriate behaviour
    • A2. Loss of manners or decorum
    • A3. Impulsive, rash or careless actions
  • B. Early apathy or inertia [1 of the following symptoms (B1–B2) must be present]:
    • B1. Apathy
    • B2. Inertia
  • C. Early loss of sympathy or empathy [1 of the following symptoms (C1–C2) must be present]:
    • C1. Diminished response to other people’s needs and feelings
    • C2. Diminished social interest, interrelatedness or personal warmth
  • D. Early perseverative, stereotyped or compulsive/ritualistic behaviour [1 of the following symptoms (D1–D3) must be present]:
    • D1. Simple repetitive movements
    • D2. Complex, compulsive or ritualistic behaviours
    • D3. Stereotypy of speech
  • E. Hyperorality and dietary changes [1 of the following symptoms (E1–E3) must be present]:
    • E1. Altered food preferences
    • E2. Binge eating, increased consumption of alcohol or cigarettes
    • E3. Oral exploration or consumption of inedible objects
  • F. Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions [all of the following symptoms (F1–F3) must be present]:
    • F1. Deficits in executive tasks
    • F2. Relative sparing of episodic memory
    • F3. Relative sparing of visuospatial skills
III. Probable bvFTD

All of the following symptoms (A–C) must be present to meet criteria.

  • A. Meets criteria for possible bvFTD
  • B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores)
  • C. Imaging results consistent with bvFTD [1 of the following (C1–C2) must be present]:
    • C1. Frontal and/or anterior temporal atrophy on MRI or CT
    • C2. Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or SPECT
IV. Behavioural variant FTD with definite FTLD Pathology

Criterion A and either criterion B or C must be present to meet criteria.

  • A. Meets criteria for possible or probable bvFTD
  • B. Histopathological evidence of FTLD on biopsy or at post-mortem
  • C. Presence of a known pathogenic mutation
V. Exclusionary criteria for bvFTD

Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD.

  • A. Pattern of deficits is better accounted for by other non-degenerative nervous system or medical disorders
  • B. Behavioural disturbance is better accounted for by a psychiatric diagnosis
  • C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process
* = As a general guideline ‘early’ refers to symptom presentation within the first 3 years

Frontotemporal dementia can be classified into different clinical variants or subtypes:[2]

  1. Behavioral (or frontal) Variant (bvFTD) - there is relative preservation of recall, and behaviour is usually the first change
  2. Semantic variant primary progressive aphasia (svPPA, or PPA-S), patients have difficulty naming objects, difficulty with single-word comprehension, but speech production is spared along with repetition
  3. Non-fluent (agrammatic) variant primary progressive aphasia (nfvPPA or PPA-G), patients are often stumbling for words and grammar is very poor
  4. Logopenic variant primary progressive aphasia (lvPPA or PPA-L), usually rare in FTD, and more commonly seen in Alzheimer's. Patients have impaired naming and repetition, but grammar and single-word comprehension is preserved
  5. Additionally, there is FTD overlaps with other tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD).

ALS (Amyotrophic Lateral Sclerosis) and FTD have a considerable clinical and pathological overlap. A pathogenic hexanucleotide repeat expansion within the C9ORF72 gene is thought to be a major cause of both disorders.[3] Indeed, a proportion of patients with FTD also develop ALS.[4]

Genetic mutations associated with FTD include the encoding of microtubule-associated protein tau (MAPT) and granulin (GRN), C90RF72,[5] transactive response DNA-binding protein of 43 kDa (TDP-43, or TARDBP), valosin-containing protein (VCP), chromatin modifying protein 2B (CHMP2B), and fused in sarcoma protein (PUS). The majority of FTD cases remain sporadic.

A CT head or MRI head can show patterns of atrophy of the frontal lobes that can aid in the clinical diagnosis. Neuroimaging is also helpful to exclude other differential diagnoses such as mass lesions and hydrocephalus.

Neuroimaging Findings

Variant Neuroimaging Findings
Behavioral variant Both frontal lobes (in particular the medial frontal lobes) and anterior temporal lobes have atrophy
Semantic variant Middle, inferior, and anterior temporal lobes are atrophic bilaterally but asymmetrically, with the left side usually being more affected
Logopenic variant Associated with predominantly left posterior perisylvian or parietal atrophy
Nonfluent variant Associated with predominantly left posterior frontal-insular atrophy

The Frontal Assessment Battery (FAB) is commonly used as a screening test. The Montreal Cognitive Assessment (MoCA) can also be used to screen for early mild cognitive changes. Since the Mini-Mental Status Exam (MMSE) does not include an assessment for impaired executive function, it may not detect changes indicative of FTD.

There are no approved treatments for FTD. All current treatments are thus off-label and used to manage symptoms of the disease.[6] Antidepressants as a class have been shown to lead to some behavioural improvement.[7]

Behavioural Symptoms

For behavioural symptoms (such as disinhibition, impulsivity, repetitive behaviors and eating disorders), SSRIs may be effective, including: citalopram, fluoxetine, and sertraline. Trazodone similarly has evidence for the treatment of behavioural symptoms related to FTD[8] Antipsychotics and anti-epileptics have also been shown to be effective in the management of behavioural symptoms, but are limited in use due to their side effect profile. Like with managing all forms of behavioural symptoms of dementia it is very important to rule out potential triggers for behavioural disturbances such as infections, electrolyte changes, medical issues, and environmental stressors prior to initiating psychotropic medications.

Do not use acetylcholinesterase inhibitors in FTD or frontal-variant AD

Evidence suggests cholinesterase inhibitors may actually exacerbate behavioural symptoms. This is because unlike in Alzheimer's dementia, cholinergic neurons are relatively preserved in FTD.[9]

Dementia Guidelines

Guideline Location Year PDF Website
Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) Canada 2020 - Link
National Institute for Health and Care Excellence (NICE) UK 2018 - Link
American Psychiatric Association (APA) USA 2007, 2014 - Guideline (2007)
Guideline Watch (2014)
Quick Reference

Behavioural and Psychological Symptoms of Dementia (BPSD) Guidelines

Guideline Location Year PDF Website
Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) Canada 2012 - Link
Canadian Coalition for Seniors' Mental Health (CCSMH) Assessment and Treatment of Mental Health Issues in Long-Term Care Canada 2006, 2014 2006 Guideline
2014 Update
Link
National Institute for Health and Care Excellence (NICE) UK 2018 - Link
Treatment of Inappropriate
Sexual Behavior in Dementia
UK 2016 - Link
American Psychiatric Association (APA) USA 2016 - Link
Articles
Clinical Cases