Frontotemporal Dementia (FTD)

Frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), or less commonly, Pick's disease, is one of the most common causes of dementia in adults younger than 60 years. FTD is actually an umbrella clinical term that encompasses a group of neurodegenerative diseases (behavioural-variant frontotemporal dementia, non-fluent variant primary progressive aphasia, and semantic-variant primary progressive aphasia). Individuals with behavioural variant may have disinhibited 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). Those with primary progressive aphasia will have progressive deficits in speech, grammar, word output, semantic knowledge, or naming.

• FTD is the second or third most common dementia in most meta-analytic studies, after Alzheimer's and dementia with Lewy bodies.
  • Affects approximately 2-10 per 100,000 people.
  • Frontotemporal dementias accounts for approximately 5% of all cases of dementia.
• The peak age of onset is between ages 45-70, and has a “presenile” onset compared to other dementias.
  • Approximately 10% of cases have onset before age 45 years.
  • Approximately 60% of cases have onset between 45-64 years, and about 30% of cases occur in individuals older than 65 years.^[1]
• Overall, more males are affected than females.
  • The behavioural variants and semantic language variant are higher in males, while and non-fluent language variant are higher among females.

• The disease is gradually progressive, with a median survival of 5-10 years after symptom onset and 4 years after diagnosis.^[2]

• A high rate of late-onset psychosis is a characteristic feature of inherited frontotemporal dementia associated with C9ORF72 mutations, the most common genetic form of the disorder.
  • C9ORF72 mutations are also associated with schizophrenia and bipolar disorder.^[3]
• There is a substantial overlap of symptoms between Alzheimer’s disease and frontotemporal dementia.

• Genetics is an important risk factor for frontotemporal dementia.
  • A family history of dementia is reported in up to 40% of cases of frontotemporal lobar degeneration, although a clear autosomal dominant history accounts for only 10% of cases

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.^[4]

Frontotemporal dementia can be classified into different clinical variants or subtypes:^[5]

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.^[6] Indeed, a proportion of patients with FTD also develop ALS.^[7]

• The majority of FTD cases remain sporadic.
• Genetic mutations associated with FTD include the encoding of microtubule-associated protein tau (MAPT), TANK-binding kinase 1 (TBK-1),^[8], granulin (GRN), C9orf72,^[9] 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 orbitofrontal cortex (OFC) is the first area of the brain that shows atrophy and volume loss when FTD develops.^[10] The OFC is the anatomical region associated with normal social and emotional behaviour, stimulus-reward reversal learning, response inhibition, and appropriate behaviours in social contexts.^[11]

• Primary psychiatric disorders
  • Late-life depression
  • Late-onset psychosis or schizophrenia
  • Late-onset bipolar disorder
• Neurodegenerative disorders
  • Phenocopy syndrome of behavioural variant frontotemporal dementia^[12]
    • The absence of atrophy in bvFTD is very unusual (as you usually should see atrophy), so one might consider bvFTD phenotype syndrome if there are neuropsychiatric symptoms mimicking bvFTD, but lacking the classic frontotemporal atrophy/hypometabolism on neuroimaging and also not evolving to dementia during follow-up.
  • Alzheimer's Disease (AD)
  • About 10%-30% of patients presenting symptoms suggestive of FTD are found at autopsy to have Alzheimer's disease pathology.
  • Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)
    • FTD overlaps with on brain pathology with both PSP and CBD.
  • Creutzfeldt-Jakob Disease (CJD)
    • Usually has a much more progressive onset, compared to FTD, which is slowly progressive.

• Blood work includes comprehensive metabolic panels, liver and kidney function tests, complete blood count, vitamin B12 concentration, and thyroid hormone levels.
• Cerebrospinal fluid assessment should be done in atypical cases.
• Toxic (heavy metals, illicit drugs), inflammatory (autoimmune, paraneoplastic), or infectious (syphilis, HIV) causes should be considered in certain cases.^[13]

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.

• 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 cannot detect changes indicative of FTD.
• Individuals with FTD have similar impairments in both semantic (i.e. - naming animals) and letter fluency tasks (i.e. - naming as many words as they can that start with the letter 'F') , due to frontal lobe retrieval deficits.^[14]
  • On the other hand, patients with Alzheimer's disease are more impaired in semantic than the letter fluency tasks (consistent with impaired access to semantic information due to involvement of the temporal lobes instead)

• There are no approved treatments for FTD. All current treatments are thus off-label and used to manage symptoms of the disease, primarily behavioural symptoms.^[15]
• Antidepressants as a class have been shown to lead to some behavioural improvement.^[16]

• For behavioural symptoms (such as disinhibition, impulsivity, repetitive behaviors and eating disorders) may respond to antidepressant class medications (response is thought to be due to loss of serotonergic neurons in FTD^[17]), this includes:
  • Trazodone has very good evidence for the treatment of behavioural symptoms related to FTD.^[18][19]
  • Selective serotonin reuptake inhibitors such has citalopram, fluoxetine, and sertraline.
• 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.
• Memantine is not effective.^[20]

• WIRED: The Devastating Decline of a Brilliant Young Coder

• Kelley, R. E., & El-Khoury, R. (2016). Frontotemporal dementia. Neurologic clinics, 34(1), 171-181.