Frontotemporal dementia (FTD) is a collective name for three neurodegenerative syndromes. Behavioural variant frontotemporal dementia (bvFTD) is one of these. First clinicians thought it to be rare, but now they know that it is equally as common as Alzheimer’s Disease (AD) in individuals under the age of 65 and it is also the third most common dementia after Alzheimer’s disease and dementia with Lewy bodies (DBL). The estimates of the prevalence of FTD vary and studies from the United States and United Kingdom estimate an occurrence at around 3.3-3.5/100000 in individuals between 45 and 65 years of age. Age of onset is often before the senior years, but onset ranges from the 30s to 90s. usually, the duration of FTD ranges from 8 to 11 years. FTD is expressed as three main variants. BvFTD is characterized by early changes in personality and behaviour. This is the most common phenotype of the disease and accounts for approximately 70% of the clinical expression of the disease. Therefore, bvFTD is the subject of this article. The other two are primary progressive aphasic syndromes. The first one is the semantic variant (svPPA) and it is associated with the loss of word knowledge and the second one is the nonfluent variant (nfPPA) and is characterized by early disturbances in motor speech output and the loss of grammatical structures of language. Many studies find a male bias in bvFTD and svPPA and a female bias in nfPPA.

Signs and criteria of bvFTD

The earliest signs of disease in bvFTD are subtle personality and behavioural changes that become more pronounced as time goes on. Some of these are apathy, reduced emotional response, changes in belief and personality, impaired in personal awareness and poor judgment. The changes are often dramatic and they result in the dissolution of the individual’s former self and relatives and partners no longer recognize their loved one. Some patients may begin to make impulsive decisions or actions, like shoplifting, assaulting others or driving recklessly. They might become cold and self-centered and don’t respond to the needs of others anymore.

The diagnosis of bvFTD has most often been made using certain criteria, but advancements in our understanding of the disease has led to the development of new criteria. Now, diagnosis of possible bvFTD is based solely on clinical presentation. Patients must meet at least three of the six criteria: early apathy, early behavioural disinhibition, early stereotyped or compulsive behaviours, early loss of sympathy, hyperorality or dietary changes and a neuropsychological profile suggesting deficits on tasks of executive function, while relatively sparing the memory and visuospatial function. To meet criteria for probable bvFTD, one must meet the criteria for possible bvFTD, exhibit functional decline and show evidence of temporal and/or frontal atrophy.

Neuroanatomy and pathology

A recent study suggests that initial degeneration occurs in paralimbic structures, like the anterior cingulate cortex, dorsal anterior insula, frontoinsular region and lateral orbitofrontal cortex. These structures have been implicated in human social function and awareness of the self and they are part of a neural network thought to play a role in the decoding of emotional salience of a stimulus, in order to facilitate appropriate action. When the disease progresses, neurodegeneration occurs in many areas of the frontal and temporal lobes. BvFTD is caused by abnormal aggregation of protein in the brain, this is called frontotemporal lobar degeneration (FTLD). The two most common pathologies associated with bvFTD are FTLD with tau-positive inclusions (FTLD-tau) and FTLD with TDP-43 positive inclusion (FTLD-TDP). Under normal conditions, TDP-43 and tau play important roles in neuronal cells structure and function. However, under pathological conditions, these proteins aggregate and they are associated with cell death. New findings of the past ten years have demonstrated links with diseases not historically believed to be associated with changes in behaviour and cognition. FTLD-tau is associated with frontotemporal dementia, parkinsonism and progressive supranuclear palsy (PSP).

Genetics

Approximately 30-40% of bvFTD cases are genetic in nature. At this time, we know on which three chromosomes genetic mutations that cause familial FTD can be found (three, nine, seventeen). The greatest proportion of familial cases comes from people who have mutations on two independent, but extremely close locations on chromosome 17. One is caused by mutations in the microtubule-associated protein (MAPT) gene. The MAPT codes for the protein tau is a major pathological subtype of bvFTD. Also, the growth factor progranulin is associated with bvFTD. All three variants of FTD may occur in familial forms of the disease, but some variants are more likely to be expressed than others. For example, PGRN mutation carriers develop symptoms characteristic of bvFTD.

Differential diagnosis

Diagnosis of bvFTD remains challenging. BvFTD is sometimes misdiagnosed as early onset AD. This is not weird, because AD is the most prevalent dementia syndrome. Many symptoms of these two diseases overlap, like executive function. People with neurodegenerative motor syndromes may also show symptoms consistent with a diagnosis of bvFTD. Huntington’s disease also mimics many of the psychiatric and behavioural disturbances seen in bvFTD. People with bvFTD may also be misdiagnosed with a late-onset psychiatric disturbance. The symptoms of euphoria, poor judgments and disinhibition can mimic the symptoms of mania and apathy and eating disturbance might be seen as depression. In one study, of the patients with bvFTD, 51% of patients had received a prior diagnosis of a psychiatric disorder (schizophrenia, major depression), compared to 23% of patients with Alzheimer’s disease. This suggests that the symptoms of bvFTD are misunderstood by mental-health-care providers. Accurate differential diagnosis is important, because treatments must match the appropriate diagnosis. Scientists are busy developing specific, disease-modifying therapies for FTLD and they focus on the major proteins that are involved in the pathogenesis of the disease. Researchers are trying to manipulate tau and they are also trying to modify PGRN and TDP-43 levels. Researchers must test the efficacy of these medications by using homogeneous samples in clinical trials. There are no methods for determining pathology prior to autopsy, so predicting pathology antemortem remains a key challenge.

Neuropsychological literature

A number of significant issues contributes to discrepancies in research data (the lack of a universal diagnostic criteria, small sample sizes, lumping the three clinical variants together). These issues can also arise due to test selection and interpretation issues. For example, the impaired performance on tests can be due to factors that are beyond what the test is meant to measure. The behavioural manifestations of the disease itself, like poor motivation, can contribute to variability in cognitive performance scores. Our understanding of the neuropsychology of bvFTD lies within the context of research seeking to improve differential diagnosis between neurodegenerative diseases. Mostly, patients with bvFTD are compared to patients with AD.

Patients with AD exhibit severe verbal and visuospatial episodic memory deficits, while patients with bvFTD show a relative preservation in their episodic memory. One study found that serial-order recall was more common in people with bvFTD than in those with AD. The most salient difference between patients with bvFTD and those with AD is that bvFTD patients tend to retain information over delays, while patients with AD forget more rapidly. Visual memory is also relatively spared in patients with bvFTD. However, these patterns of memory performance are not specific to bvFTD. Parkinson’s disease and PSP may also show similar patterns. People with bvFTD have reductions in spontaneous speech and this decreased verbal output can progress to complete mutism. Other speech disorders can also occur, like verbal stereotypes and automatic speech. There have been not so many studies that have examined differential language patterns between bvFTD and other diseases.

One study did find that people with AD scores lower on semantic fluency (category fluency) than phonemic fluency (letter fluency), while people with FTD performed poorly on both types of fluency. Some studies have found that patients with bvFTD have visuo-constructional deficits on par with AD when the figure is complex, but most studies have indicated that visuo-construction and visual perceptual skills are better preserved in patients with bvFTD than in patients with AD. Difficulties for patients with bvFTD can arise when the task relies much on top-down control of spatial processing. There is much discrepancy in the research on attention and executive functions in bvFTD. Some studies find impairments in these domains, while others do not. Some researchers expect to see executive deficits manifested later in the disease. Some even say that certain subtypes are less likely to show executive function deficits. One reason for the inconsistent findings is the fact that executive functions are a poorly defined construct. So some studies have broader conceptions of executive functions than others. Many studies did find that people with bvFTD perform faster on measures of executive function (like the Stroop Inhibition task) than patients with AD, but they make also more errors. This means that they have an inbalance in their ability to accurately make speed/error trade-offs. The dorsolateral prefrontal cortex degenerates both in AD and bvFTD. This may occur at different stages in disease course. Because of this, people with bvFTD may show flat affect, more perseveration and reduced initiative than patients with other neurodegenerative disease. Other studies have found poor social judgment in people with bvFTD. Researchers have also found that people with bvFTD have less self-awareness regarding their current personality and behavioural deficits, compared to patients with AD. This may be due to the emotion-processing deficits that people with bvFTD have. Basic emotion processing remains intact, but more complex forms of emotion (embarrassment, recognizing emotions in others) show deficits.

Clinical assessment

An evaluation of bvFTD should include a clinical interview, assessment of social and emotional function, neuropsychological assessment and informant based measures. Cognition can be relatively preserved in the early stages of the disease, so the informant report, history and observable behaviour seen throughout assessment will be very helpful information. A well-constructed clinical interview with a good informant is critical. The patients often lack insight into the emotional, social or behavioural issues that are seen by their informants and they also deny problems. Sometimes, the informant doesn’t feel comfortable to speak freely when the patients is around, so a clinician should consider conducting a separate interview. During the interview, a couple of subjects need to be covered. One of these is the onset and progression of the disease. BvFTD is an insidious disease that may begin many years before changes become obvious. Also, because the age of onset of bvFTD is in the late 50s, some people might interpret the personality changes as mid-life troubles. Abrupt onset changes in personality and behaviour are less likely to be bvFTD. During the interview, one must also look at the nature of change. There are six things a clinician needs to figure out:

• Early behaviour disinhibition: does the person show socially unacceptable behaviour? Has the person become socially, cognitively or behaviourally disinhibited?

• Early loss of empathy/sympathy: does the person make insensitive comments?

• Early apathy: does the patient show a loss of interest, drive or initiation of behaviour?

• Compulsive/stereotypes behaviour: people with bvFTD can manifest complex compulsions, like checking rituals or hoarding.

• Neuropsychological profile: does the patient seem to have trouble doing two things at once or completing complex tasks?

• Hyperorality or dietary changes: does the patient consume certain foods/drinks in more quantities than before? Does the patient take up another diet? Weight gain is common in bvFTD.

During the interview, the clinician also needs to find out more about the potential family history of the disease. 30 to 40% of all people with bvFTD have a strong family history of the disease. However, it is often difficult to elicit clear family histories. Some may have a vague recollection that one of their grandparents was senile. However, if the family history reveals that a family member exhibited changes in social behaviour and personality after the fifth decade of life or who had symptoms of motor disorder, these are clues that the individual may have a genetic form of the disease. It will also be helpful if the patient has had neuroimaging. A report of the scan can best be used with other information from the interview, to come up with a diagnosis.

Cognitive assessment and behaviour observation

The writers of this text find that a short battery (1 to 1.5 hours) that examines all major cognitive domains is a quick and useful way to help aid differential diagnosis without overtaxing the patient. The neuropsychological profile of a person with bvFTD is one of spared visuospatial and language function and relatively better performance than people with AD on tests of semantic and episodic memory. The writers recommend executive function tests that elicit and quantify performance errors. In the centre of the writers, after the neuropsychological evaluation, the examiners of the centre complete a brief behaviour-rating scale where patients are rated on a scale ranging from none to severe on a couple of behaviour. Some of these behaviours are agitation, lack of social engagement, impulsivity, fluctuation levels of attention, motor stereotypies and inappropriate behaviour. inappropriate behaviour and lack of social engagement discriminate between patients with bvFTD and AD. The inclusion of informant-based measures will give more (sometimes more reliable) information. According to the writers, it is a good idea to include a neuropsychiatric inventory which the informant needs to fill in about the patient. Scales of emotional responses, measures of social function, measures of emotional recognition and social norms questionnaires should be included, so the level of emotional and social functioning of the patient can be assessed.