Frontotemporal Dementia

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative conditions. They are characterised by progressive, focal atrophy predominantly affecting the frontal and temporal lobes.

They produce a range of clinical syndromes with early, prominent behavioural or language change, in contrast to the early, prominent episodic memory impairment more typical of Alzheimer disease. They are the second commonest cause of younger onset dementia (generally defined as onset before age sixty five), after younger onset Alzheimer disease.

The underlying pathology and clinical presentation vary considerably. Pathology involves tau, TDP-43 and, less commonly, FUS protein deposits, together grouped under the term frontotemporal lobar degeneration.

A substantial proportion of cases show a genetic, familial basis. Consider genetic testing and family counselling in appropriately selected cases.

Classification and pathophysiology

• Behavioural variant frontotemporal dementia is the commonest clinical subtype. It is characterised by early, progressive change in personality, behaviour and social conduct. This reflects predominant frontal lobe involvement and its extensive connections relevant to executive function, social cognition and behavioural regulation.
• Primary progressive aphasia is a further important presentation. It reflects predominant early involvement of language networks within the dominant, typically left, hemisphere. It has three variants, listed below.

• Semantic variant: progressive loss of word and object meaning.
• Non-fluent/agrammatic variant: effortful, agrammatic speech production.
• Logopenic variant: word finding difficulty and impaired sentence repetition. This variant is more frequently associated with underlying Alzheimer pathology than with frontotemporal lobar degeneration, which has some relevance to prognosis and, potentially, eligibility for emerging disease specific treatments.

• A substantial proportion of frontotemporal dementia, particularly the behavioural variant, shows a genetic, familial basis. Mutations in the MAPT (microtubule associated protein tau), GRN (progranulin) and C9orf72 genes are the commonest identified causes.
• The C9orf72 hexanucleotide repeat expansion is an important shared genetic cause linking frontotemporal dementia to amyotrophic lateral sclerosis. The two conditions show significant clinical and pathological overlap. Some patients have overlapping features of both, or develop one following initial presentation with the other.

• Behavioural variant frontotemporal dementia presents with early, progressive change in personality and behaviour. Features include disinhibition (socially inappropriate behaviour or comments), apathy or loss of motivation, loss of empathy and interpersonal warmth, and perseverative, stereotyped or compulsive behaviour.
• Dietary preference changes, frequently including hyperphagia or a new preference for sweet foods, and impaired executive function also occur.
• Episodic memory and visuospatial function are relatively preserved, at least in the earlier stages. This distinguishes the condition from typical Alzheimer disease.
• Family members are frequently the first to recognise the behavioural changes, and may describe a fundamental change in the person's personality. The changes are commonly misattributed initially to a primary psychiatric condition (particularly depression or a late onset personality change) or to relationship or occupational stress.
• This contributes to frequent, substantial diagnostic delay, particularly given the characteristic, often profound lack of insight into their own behavioural change.
• Primary progressive aphasia presents with progressive language impairment as the predominant, isolated or clearly dominant initial feature. The pattern reflects the underlying variant and the pattern of language network involvement: word and object meaning loss in the semantic variant, effortful, agrammatic speech in the non-fluent variant, or word finding difficulty and repetition impairment in the logopenic variant.
• As the disease progresses, features from the different clinical syndromes frequently converge. Initially behavioural presentations develop increasing language impairment, and vice versa.
• In a proportion of patients, motor features develop that overlap with corticobasal degeneration, progressive supranuclear palsy or, given the shared genetic basis, amyotrophic lateral sclerosis. Frontotemporal dementia sits within this broader spectrum of related, overlapping neurodegenerative conditions.

• Full clinical assessment is the essential foundation of diagnosis. It includes a detailed history, with particular emphasis on collateral history from family members about behavioural and personality change, given the characteristic, profound lack of insight.
• Formal neuropsychological assessment characterises the pattern of executive, behavioural and language domain involvement relative to the generally preserved memory and visuospatial function, at least in earlier disease.
• Structural neuroimaging characteristically shows focal frontal and/or temporal lobe atrophy. The pattern and laterality of atrophy vary with the clinical subtype.
• Functional imaging (single photon emission computed tomography or positron emission tomography) may show corresponding focal hypoperfusion or hypometabolism. This provides additional supportive evidence, particularly valuable in earlier disease before structural atrophy is clearly apparent.
• Screen carefully for and exclude an underlying primary psychiatric condition, given the frequent, substantial overlap and diagnostic confusion with depression or other psychiatric presentations. Assess for any coexisting or emerging motor neurone disease features.
• Genetic testing, guided by a relevant family history or by suggestive clinical features, with structured genetic counselling, is appropriate in a meaningful proportion of cases given the substantial genetic contribution.
• A positive result has important implications for the individual patient's prognosis and for at risk family members. Similar principles apply as detailed under Huntington disease regarding predictive testing in asymptomatic relatives.

• There is no currently available disease modifying treatment for frontotemporal dementia. Management is entirely symptomatic and supportive, addressing the behavioural, language and, where present, motor manifestations.
• Standard cholinesterase inhibitor and memantine treatment, used in Alzheimer disease, has not demonstrated consistent benefit in frontotemporal dementia and is generally not recommended. The underlying neurotransmitter pathology differs fundamentally from Alzheimer disease, which is relevant to targeted pharmacological decisions.
• Management of significant behavioural disturbance follows general principles similar to those detailed under major neurocognitive disorder. Non-pharmacological, behavioural and environmental strategies are the preferred first line approach.
• Selective serotonin reuptake inhibitor antidepressants are a reasonable pharmacological option for significant behavioural symptoms (including disinhibition and compulsive behaviour). There is some supportive evidence, and safety is generally more favourable than with antipsychotic medication in this population.
• Speech and language therapy is a central component of management for primary progressive aphasia. It addresses direct communication strategies and, as the disease progresses, augmentative and alternative communication approaches to support communication as verbal language function declines.
• Full, structured psychosocial support for the patient is essential. Support for the family and carers is of particular importance, given the substantial burden characteristic of this condition.
• Many family members and carers find significant behavioural and personality change particularly distressing and difficult to adapt to. The fundamental alteration to the person's core character and their relationship with the affected individual is in some ways distinct from the challenges of the more purely cognitive impairment of Alzheimer disease.
• Practical safety and care planning is needed given the frequently significant behavioural disturbance. Given the younger age of onset, the impact on employment, family roles and financial circumstances is substantial.
• Offer genetic counselling for the family where a genetic cause is confirmed or strongly suspected. Connect families to relevant specialist services and patient support organisations.
• Ongoing, structured multidisciplinary follow up throughout the progressive disease course follows broader principles shared with major neurocognitive disorder, while incorporating the considerations specific to this condition's younger age of onset and behavioural presentation.