Frontotemporal dementia (FTD), also known as frontotemporal degeneration, and historically as Pick's disease, is a family of neurodegenerative disorders, caused by frontotemporal lobar degeneration that affects the frontal and temporal lobes. The FTD family includes behavioral variant FTD (bvFTD), primary progressive aphasia (PPA) and its semantic and nonfluent/agrammatic variants (svPPA and nfvPPA) progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Symptoms of FTD will typically match a specific disorder at first, though symptoms of other disorders will inevitably begin to show as the disease progresses to different areas of the brain. FTD disorders are a common young-onset dementia occurring under the age of 60.

Approximately 60% of people diagnosed with FTD have no known cause and no family history of FTD or related conditions; this is known as sporadic FTD. While environmental causes and unidentified gene variants are suspected causes of sporadic FTD, research in this area is still ongoing. When people have a family history of FTD, other dementias, or conditions like depression and anxiety, it is referred to as familial FTD, and roughly 20% have an underlying genetic basis. Variants in three genes are responsible for most genetic FTD. Notably, in about 10% of people with seemingly sporadic FTD, a genetic variant is identified.

FTD diagnosis currently relies on clinical examination based on the signs and symptoms experienced and imaging of the brain through MRI or FTDG-PET. FTD disorders have heterogeneous symptoms and pathological features, which contribute to a lengthy differential diagnostic process and high rates of misdiagnosis. A neuropathological examination after death usually provides a definitive diagnosis by identifying the specific features of FTD subtypes. Death is usually the result of complications of FTD, such as pneumonia or fall-related injuries. The average life expectancy after symptoms start is 7 to 13 years.

The clinical features of FTD were first described by Czech-German psychiatrist Arnold Pick between 1892 and 1906. Pick's observations were followed by Alois Alzheimer's first description of tau aggregations in neurons (called "Pick bodies") in 1911. The disorder described by Pick, now known as bvFTD, was named "Pick's disease" in 1922. The first research criteria were created in 1994, and the publication was the first to use the term "frontotemporal dementia".

Signs and symptoms

Frontotemporal dementia (FTD) is an early onset disorder that mostly occurs between the ages of 45 and 65, but can begin earlier, and in 20–25% of cases onset is later. Men and women appear to be equally affected. It is the most common early presenting dementia. FTD is the second most prevalent type of early onset dementia after Alzheimer's disease.

The International Classification of Diseases recognizes the disease as causative to disorders affecting mental and behavioral aspects. Dissociation from family, compulsive buying disorder (oniomania), vulgar speech characteristics, screaming, and inability to control emotions, behavior, personality, or temperament are characteristic social display patterns. The gradual onset and progression of subtle changes in behavior or language deficits commonly leads to a long delay between the onset of symptoms and time of presentation to a neurologist. – as well as FTD associated with amyotrophic lateral sclerosis (FTD–ALS or FTD-MND). About 12–13% of people with bvFTD develop motor neuron disease.

The Pick bodies which are present 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.

Semantic dementia

Semantic dementia (SD) is characterized by the loss of semantic understanding, resulting in impaired word comprehension. However, speech remains fluent and grammatical. Imaging commonly shows atrophy in the frontotemporal region, and in part of the striatum in the basal ganglia. Post-mortem studies show a marked reduction in the caudate nucleus of the striatum; frontotemporal gyri are narrowed, with widened intervening sulci, and the lateral ventricles are enlarged.

Other characteristics

In later stages of FTD, the clinical phenotypes may overlap. 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. Most become unable to perform skills that require complex planning or sequencing. In addition to the characteristic cognitive dysfunction, a number of primitive reflexes known as frontal release signs are often able to be elicited. Usually the first of these frontal release signs to appear is the palmomental reflex which appears relatively early in the disease course whereas the palmar grasp reflex and rooting reflex appear late in the disease course. Importantly, the presence of primitive reflexes in FTD is not highly sensitive or specific for the disease process, but their presence is helpful when considered within a broader neurological assessment, particularly with other suggestive features like behavioral and personality changes, disinhibition, executive dysfunction, and memory impairment.

In rare cases, FTD can occur in people with amyotrophic lateral sclerosis (ALS), a motor neuron disease. , the prognosis for people with ALS was worse when combined with FTD, shortening survival by about a year. Up to 50% of patients with ALS go on to develop cognitive and behavioral symptoms, with around 10–15% meeting criteria for FTD, most commonly the behavioral variant. Some FTD patients conversely also go on to develop features of motor neuron disease similar to those of ALS. The two disease entities are thought to have interrelated clinical and genetic factors and are considered part of a disease spectrum rather than two completely separate processes. This is due to a spontaneous intracranial hypertension which may present with neuropsychiatric symptoms that mimic FTD, particularly the behavioral type. Treatment of the leak results in partial or complete resolution of symptoms in the majority of cases, in contrast with neurodegenerative FTD, which is a primary and mostly irreversible process. It has been determined that there is a direct relationship between the type of tau mutation and the neuropathology of gene mutations. The mutations at the splice junction of exon 10 of tau lead to the selective deposition of the repetitive tau in neurons and glia. The pathological phenotype associated with mutations elsewhere in tau is less predictable, with both typical neurofibrillary tangles (consisting of both 3-repeat and 4-repeat tau) and Pick bodies (consisting of 3-repeat tau) having been described. The presence of tau deposits within glia is also variable in families with mutations outside of exon 10. This disease is now informally designated FTDP-17T. FTD shows a linkage to the region of the tau locus on chromosome 17, but it is believed that there are two loci leading to FTD within megabases of each other on chromosome 17. 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.

  • FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the GRN gene, also located on chromosome 17. Others are caused by hypomorphic VCP mutations, although these patients present with a complex picture of multisystem proteinopathy that can include amyotrophic lateral sclerosis, inclusion body myopathy, Paget's disease of bone, and FTD. The most recent addition to the list () was a hexanucleotide repeat expansion in intron 1 of C9ORF72. Only one or two cases have been reported describing TARDBP (the TDP-43 gene) mutations in a clinically pure FTD (FTD without ALS).
  • Several other genes have been linked to this condition. These include CYLD, OPTN, SQSTM1 and TBK1. These genes have been implicated in the autophagy pathway.
  • No genetic causes of FUS pathology in FTD have yet been reported.
  • Major alleles of TMEM106B SNPs have been found to be associated with risk of FTLD.

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. The most severe brain atrophy appears to be associated with behavioral variant FTD, and corticobasal degeneration.

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.

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

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: These are behavioral 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. 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 behavioral variant of frontotemporal degeneration. The language subtypes of FTLD (semantic dementia and progressive nonfluent aphasia) can be regionally dissociated by imaging approaches in vivo.

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. As FTD symptoms appear, it is difficult to differentiate between a diagnosis of Alzheimer's disease and FTD. There are distinct differences in the behavioral and emotional symptoms of the two dementias, notably, the blunting of affect seen in FTD patients.

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. , six distinct clinical features have been identified as symptoms of bvFTD.

  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.

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. 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 behavioral 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.

In neuropsychology, there is an increasing interest in using neuropsychological tests such as the Iowa gambling task or Faux Pas Recognition test as an alternative to imaging for the diagnosis of bvFTD. Both the Iowa gambling task and the Faux Pas test are known to be sensitive to dysfunction of the orbitofrontal cortex.

The Faux Pas Recognition test is intended to measure one's ability to detect faux pas types of social blunders (accidentally making a statement or an action that offends others). It is suggested that people with orbitofrontal cortex dysfunction show a tendency to make social blunders due to a deficit in self-monitoring. Self-monitoring is the ability of individuals to evaluate their own behavior to make sure that their behavior is appropriate in particular situations. The impairment in self-monitoring leads to a lack of social emotion signals. The social emotions such as embarrassment are important in the way that they alert the individual to adapt social behavior in an appropriate manner to maintain relationships with others. Though patients with damage to the OFC retain intact knowledge of social norms, they fail to apply it to actual behavior, because they fail to generate social emotions that promote adaptive social behavior. It is thought that somatic markers are processed in the orbitofrontal cortex.

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.

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: Pharmacologic therapy is primarily aimed towards managing neuropsychiatric symptoms associated with FTD. Disinhibition, hyperorality, and compulsive behaviors can be controlled by selective serotonin reuptake inhibitors (SSRIs). Agitation or aggression can be controlled with small doses of atypical antipsychotics. Although Alzheimer's and FTD share certain symptoms, they cannot be treated with the same pharmacological agents because the cholinergic systems are not affected in FTD.

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.

History

Features of FTD were first described by the Czech psychiatrist Arnold Pick between 1892 and 1906. The name Pick's disease was coined in 1922. This term is now reserved only for behavioral variant FTD which shows the presence of the characteristic Pick bodies and Pick cells, A nonprofit organization, the Association for Frontotemporal Degeneration (AFTD) was founded in 2002 and convenes a number of scientific conferences, a global FTD registry, and provides investment in research to slow and potentially treat the disease.

The most recent revision of the clinical research criteria was by the International Behavioural Variant FTD Criteria Consortium in 2011.

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See also

  • Alcoholic dementia
  • Lewy body dementia
  • Logopenic progressive aphasia
  • Mini-SEA
  • Proteopathy
  • Transportin 1
  • Vascular dementia

References

Further reading

  • Patient group