SeriesFrontotemporal dementia
Introduction
Frontotemporal dementia is an insidious neurodegenerative clinical syndrome characterised by progressive deficits in behaviour, executive function, and language. The disorder is the third most common form of dementia across all age groups, after Alzheimer's disease and dementia with Lewy bodies, and is a leading type of early-onset dementia.1 The first description of a patient with frontotemporal dementia was made by Arnold Pick in 1892;2 the patient had aphasia, lobar atrophy, and presenile dementia. In 1911, Alois Alzheimer recognised the characteristic association with Pick bodies and named the clinicopathological entity Pick's disease,3 which led to the use of Pick's disease as a synonym for frontotemporal dementia. In 1982, Mesulam described a language subtype of the disorder, later defined as primary progressive aphasia.4 Revised diagnostic criteria have recently been issued.5, 6
Because of the close similarity of behavioural changes in patients with frontotemporal dementia to those seen in patients with psychiatric disorders, diagnosis is challenging. Here we review the clinical and laboratory features, epidemiology, genetics, and neuropathology of frontotemporal dementia to provide a comprehensive insight into this disorder and help differentiate it from psychiatric disorders and other neurodegenerative diseases. We also discuss therapeutic strategies for symptom management, and the most promising areas of therapeutic development.
Section snippets
Epidemiology
WHO estimates that dementia rates will double every 20 years, reaching 115·4 million in 2050.7 In a meta-analysis of 73 articles of early-onset dementia (patient age <65 years), frontotemporal dementia was the second or third most prevalent dementia subtype in most studies, with a prevalence ranging from 3% to 26%.1 Table 1 summarises the epidemiology of frontotemporal dementia.8, 9, 10 Because the disorder is still missed and misdiagnosed, most numbers probably underestimate its true
Clinical features
Frontotemporal dementia is classified into three clinical variants: behavioural-variant frontotemporal dementia, which is associated with early behavioural and executive deficits; non-fluent variant primary progressive aphasia, with progressive deficits in speech, grammar, and word output; and semantic-variant primary progressive aphasia, which is a progressive disorder of semantic knowledge and naming. The diagnostic criteria outline features, (ie, clinical, imaging-supported, and genetically
Differential diagnosis
Differential diagnosis of frontotemporal dementia needs a careful history that examines the progression of behavioural changes, family history, behaviour in face-to-face interviews, performance on neuropsychological testing, laboratory studies, and neuroimaging. Blood work should include a comprehensive metabolic panel including liver and kidney function tests, complete blood count, vitamin B12 concentration, and thyroid studies. Cerebrospinal fluid assessment should be done in atypical cases.
Adult-onset psychiatric disorders
Psychiatric disorders can mimic frontotemporal dementia. The repetitive and compulsive behaviours noted in patients with behavioural-variant frontotemporal dementia might lead to a misdiagnosis of obsessive-compulsive disorder. Similarly, apathy and emotional withdrawal might lead to a misdiagnosis of depression, although patients with frontotemporal dementia do not usually have other symptoms typical of depression and often deny sadness. Frontotemporal dementia can cause delusions and
Alzheimer's disease and other neurodegenerative diseases
There is a substantial overlap of symptoms between Alzheimer's disease and frontotemporal dementia. Alzheimer's pathology could be suggested by predominance of memory and visuospatial deficits, social appropriateness, normal neurological examination, and evidence of generalised brain atrophy on imaging. A form of progressive aphasia with prominent anomia, acalculia, and word-finding pauses (logopenic-variant primary progressive aphasia) is usually caused by Alzheimer's neuropathology.6
The
Imaging
With continuing advances in imaging techniques, several methods can be used to help in the diagnosis of frontotemporal dementia. Structural MRI and CT show patterns of atrophy: frontotemporal dementia is characterised by predominant frontal or temporal atrophy, and atrophy in the frontoinsular region is especially indicative of frontotemporal dementia.27 Fluorodeoxyglucose PET, functional MRI, and single-photon-emission CT likewise show disproportionate hypoperfusion and hypometabolism in these
Neuropathology
Frontotemporal lobar degeneration is characterised by neuronal loss, gliosis, and microvacuolar changes of frontal lobes, anterior temporal lobes, anterior cingulate cortex, and insular cortex. Subtypes are associated with characteristic patterns of abnormal protein deposition.33 Initial changes occur in the anterior cingulate cortex, fronto-insular cortex, orbitofrontal cortex, and cingulate-frontal transitional zones.34 These regions have von Economo neurons and fork cells in layer 5 of the
Genetics
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.47 Mutations in C9orf72, MAPT, and GRN genes account for about 60% of all cases of inherited frontotemporal lobar degeneration.48 Genetic testing should be considered in patients with frontotemporal dementia with a strong family history of autosomal dominant neurological disorders including frontotemporal dementia,
Treatment
No approved disease-modifying drugs are available for the treatment of frontotemporal dementia. Treatment is focused on management of behavioural symptoms. Severity of compulsion, agitation, aggressiveness, impulsivity, and aberrant eating behaviour can improve with the use of selective serotonin reuptake inhibitors.72 Behavioural abnormalities can be managed with low doses of atypical antipsychotics.73 Caution should be used when treating elderly patients with dementia with atypical
Conclusion and future directions
Frontotemporal dementia is a common dementia, particularly in individuals younger than 65 years. The clinical presentation of behavioural-variant frontotemporal dementia is characterised by the predominance of behavioural symptoms. Differentiation of the initial changes of this devastating neurodegenerative disease from common psychiatric disorders, particularly schizophrenia, depression, bipolar disorder, delusional disorders, obsessive-compulsive behaviour, and borderline, schizoidal, and
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These authors contributed equally