Frontotemporal dementia

Frontotemporal dementia (FTD), frontotemporal degeneration disease,^[1] or frontotemporal neurocognitive disorder^[2] encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes.^[3] FTDs broadly present as behavioral or language disorders with gradual onsets.^[4]

Common signs and symptoms include significant changes in social and personal behavior,

The Pick bodies in behavioral variant FTD are spherical inclusion bodies found in the cytoplasm of affected cells. They consist of tau fibrils as a major component together with a number of other protein products including ubiquitin and tubulin.^[24]

Semantic dementia

Semantic dementia (SD) is characterized by the loss of semantic understanding, resulting in impaired word comprehension. However, speech remains fluent and grammatical.^[22]

Progressive nonfluent aphasia

Progressive nonfluent aphasia (PNFA) is characterized by progressive difficulties in speech production.^[22]

Neuronal intermediate filament inclusion disease

Neuronal intermediate filament inclusion disease (NIFID) is a rare distinct variant. The

Another rare FTD variant, also a FTLD-FUS proteopathy, is basophilic inclusion body disease (BIBD).[27]^[28]

Other characteristics

In later stages of FTD, the clinical phenotypes may overlap.^[22] People with FTD tend to struggle with binge eating and compulsive behaviors.^[29] Binge eating habits are often associated with changes in food preferences (cravings for more sweets, carbohydrates), eating inedible objects and snatching food from others. Recent findings from structural MRI research have indicated that eating changes in FTD are associated with atrophy (wasting) in the right ventral insula, striatum, and orbitofrontal cortex.^[29]

People with FTD show marked deficiencies in

A higher proportion of frontotemporal dementias seem to have a familial component than other neurodegenerative diseases such as Alzheimer's disease. More and more mutations and genetic variants are being identified all the time, needing constant updating of genetic influences.

• Tau-positive
  megabases of each other on chromosome 17.^[34] The only other known autosomal dominant genetic cause of FTLD-tau is a hypomorphic mutation in VCP which is associated with a unique neuropathology called vacuolar tauopathy.^[35]
• FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the
  TDP-43 gene) mutations in a clinically pure FTD (FTD without ALS).^{[citation needed}
  ]
• Several other genes have been linked to this condition. These include
  SQSTM1 and TBK1.^[39]
  These genes have been implicated in the autophagy pathway.
• No genetic causes of
  FUS pathology in FTD have yet been reported.^{[citation needed}
  ]
• Major alleles of TMEM106B SNPs have been found to be associated with risk of FTLD.^[40]

Pathology

There are three main histological subtypes found at post-mortem: FTLD-tau, FTLD-TDP, and FTLD-FUS. In rare cases, patients with clinical FTD were found to have changes consistent with Alzheimer's disease on autopsy.^[41] The most severe brain atrophy appears to be associated with behavioral variant FTD, and corticobasal degeneration.^[42]

With regard to the genetic defects that have been found, repeat expansion in the C9orf72 gene is considered a major contribution to FTLD, although defects in the GRN and MAPT genes are also associated with it.^[43]

DNA damage and the defective repair of such damages have been etiologically linked to various neurodegenerative diseases including FTD.^[44]

Diagnosis

FTD is traditionally difficult to diagnose owing to the diverse nature of the associated symptoms. Signs and symptoms are classified into three groups based on the affected functions of the frontal and temporal lobes:^[12] These are behavioural variant frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia. An overlap between symptoms can occur as the disease progresses and spreads through the brain regions.^[14]

Structural MRI scans often reveal frontal lobe and/or anterior temporal lobe atrophy, but in early cases the scan may seem normal. Atrophy can be either bilateral or asymmetric.

Meta-analyses based on imaging methods have shown that frontotemporal dementia mainly affects a frontomedial network discussed in the context of social cognition or "theory of mind".^[45] This is entirely in keeping with the notion that on the basis of cognitive neuropsychological evidence, the ventromedial prefrontal cortex is a major locus of dysfunction early on in the course of the behavioural variant of frontotemporal degeneration.^[46] The language subtypes of FTLD (semantic dementia and progressive nonfluent aphasia) can be regionally dissociated by imaging approaches in vivo.^[47]

The confusion between Alzheimer's and FTD is justifiable due to the similarities between their initial symptoms. Patients do not have difficulty with movement and other motor tasks.

Recent studies over several years have developed new criteria for the diagnosis of behavioral variant frontotemporal dementia (bvFTD). The confirmatory diagnosis is made by brain biopsy, but other tests can be used to help, such as MRI, EEG, CT, and physical examination and history.[49] As of 2011^[update], six distinct clinical features have been identified as symptoms of bvFTD.^[50]

1. Disinhibition
2. Apathy / Inertia
3. Loss of Sympathy / Empathy
4. Perseverative / Compulsive behaviors
5. Hyperorality
6. Dysexecutive neuropsychological profile

Of the six features, three must be present in a patient to diagnose one with possible bvFTD. Similar to standard FTD, the primary diagnosis stems from clinical trials that identify the associated symptoms, instead of imaging studies.^[50] The above criteria are used to distinguish bvFTD from disorders such as Alzheimer's and other causes of dementia. In addition, the criteria allow for a diagnostic hierarchy distinguished possible, probable, and definite bvFTD based on the number of symptoms present.^[50]

A 2021 study, determined that using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques, tangles, and neurodegeneration, collectively called ATN, can be useful in diagnosing FTD.^[51]

Neuropsychological tests

The progression of the degeneration caused by bvFTD may follow a predictable course. The degeneration begins in the orbitofrontal cortex and medial aspects such as ventromedial prefrontal cortex. In later stages, it gradually expands its area to the dorsolateral prefrontal cortex and the temporal lobe.^[52] Thus, the detection of dysfunction of the orbitofrontal cortex and ventromedial cortex is important in the detection of early stage bvFTD. As stated above, a behavioural change may occur before the appearance of any atrophy in the brain in the course of the disease. Because of that, image scanning such as MRI can be insensitive to the early degeneration and it is difficult to detect early-stage bvFTD.^{[citation needed]}

In neuropsychology, there is an increasing interest in using neuropsychological tests such as the

The other test, the Iowa gambling task, is a psychological test intended to simulate real-life decision making. The underlying concept of this test is the somatic marker hypothesis. This hypothesis argues that when people have to make complex uncertain decisions, they employ both cognitive and emotional processes to assess the values of the choices available to them. Each time a person makes a decision, both physiological signals and evoked emotion (somatic markers) are associated with their outcomes, and this accumulates as experience. People tend to choose the choice which might produce the outcome reinforced with positive stimuli; thus it biases decision-making towards certain behaviors while avoiding others.^[55] It is thought that somatic markers are processed in the orbitofrontal cortex.^{[citation needed]}

The symptoms observed in bvFTD are caused by dysfunction of the orbitofrontal cortex; thus these two neuropsychological tests might be useful in detecting early-stage bvFTD. However, as self-monitoring and somatic marker processes are so complex, it likely involves other brain regions. Therefore, neuropsychological tests are sensitive to the dysfunction of orbitofrontal cortex, yet are not specific to it. The weakness of these tests is that they do not necessarily show dysfunction of the orbitofrontal cortex.^{[citation needed]}

In order to solve this problem, some researchers have combined neuropsychological tests which detect the dysfunction of orbitofrontal cortex into one grouping, so that it increases its specificity to the degeneration of the frontal lobe, in order to detect early-stage bvFTD. They invented the Executive and Social Cognition Battery which comprises five neuropsychological tests:^[53]

• Faux Pas test
• Hotel task
• Iowa gambling task
• Mind in the Eyes
• Multiple Errands task

The result has shown that this combined test is more sensitive in detecting the deficits in early bvFTD.^[53]

Management

Currently, there is no cure for FTD. Treatments are available to manage the behavioral symptoms. Disinhibition and compulsive behaviors can be controlled by

Because FTD often occurs in relatively younger adults (i.e. in their 40s or 50s), it can severely affect families. Patients often still have children living in the home.^[citation needed]

Prognosis

Symptoms of frontotemporal dementia progress at a rapid, steady rate. Patients with the disease can survive for 2–20 years. Eventually patients will need 24-hour care for daily function.^[59]

In 1989, Snowden suggested the term semantic dementia to describe the patient with predominant left temporal atrophy and aphasia that Pick described. The first research criteria for FTD, "Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups", was developed in 1994. The clinical diagnostic criteria were revised in the late 1990s, when the FTD spectrum was divided into a behavioral variant, a nonfluent aphasia variant, and a semantic dementia variant.[20] The most recent revision of the clinical research criteria was by the International Behavioural Variant FTD Criteria Consortium in 2011.^[50]

Notable cases

People who have been diagnosed as having FTD (often referred to as Pick's disease in cases of the behavioral variant) include:

• John Berry (1963–2016), American hardcore punk musician and founding member of the Beastie Boys^[62]
• Clancy Blair (born 1960), American developmental psychologist and professor^{[citation needed]}
• Don Cardwell (1935–2008), Major League Baseball pitcher^[63]
• Charmian Carr (1942–2016), who played Liesl, from the Sound of Music, born Charmian Anne Farnon
• Jerry Corbetta (1947–2016), frontman, organist and keyboardist of American psychedelic rock band Sugarloaf^[64]
• Ted Darling (1935–1996), Buffalo Sabres television announcer
• Robert W. Floyd (1936–2001), computer scientist^[65]
• Lee Holloway (born 1982), computer scientist, co-founder of Cloudflare^[66]
• Colleen Howe (1933–2009), sports agent and ice hockey team manager, known as "Mrs. Hockey"^[67]
• Kazi Nazrul Islam (1899–1976) national poet of Bangladesh^[68]
• Terry Jones (1942–2020), Welsh comedian (Monty Python) and director
• Ralph Klein (1942–2013), former premier of Alberta, Canada
• Kevin Moore (1958–2013), English footballer^[69]
• Ernie Moss (1949–2021), English footballer^[70]
• Nic Potter (1951–2013), British bassist for Van der Graaf Generator^[71]
• Christina Ramberg (1946–1995), American painter associated with the Chicago Imagists^[72]
• David Rumelhart (1942–2011), American cognitive psychologist^{[citation needed]}
• Sir Nicholas Wall (1945–2017), English judge^[73]
• Wendy Williams (born 1964), American broadcaster^[74]
• Bruce Willis (born 1955), American actor ^[75]
• Mark Wirtz (1943–2020), pop musician, composer and producer^[76]

See also

References