Frontotemporal Dementia

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders caused by degeneration of the frontal and temporal lobes. It is a leading cause of dementia in people under 65 and presents either as progressive changes in behaviour and personality or as progressive loss of language, depending on which regions are most affected.

Definition

Frontotemporal dementia denotes a group of neurodegenerative syndromes arising from frontotemporal lobar degeneration, characterised clinically by progressive deterioration of behaviour and personality (behavioural variant) or of language (primary progressive aphasia), and pathologically by aggregation of tau or TDP-43 (and, less commonly, FUS) proteins.

Scope

This entry covers the principal clinical syndromes grouped under frontotemporal dementia (the behavioural variant and the primary progressive aphasias), the underlying frontotemporal lobar degeneration pathologies (notably tau and TDP-43 proteinopathies), the genetics, and the relationship to amyotrophic lateral sclerosis. It is a reference overview, not clinical guidance for any individual.

Core questions

• How do behavioural and language presentations map onto regional degeneration?
• How do distinct molecular pathologies (tau versus TDP-43) relate to clinical syndromes?
• What links frontotemporal dementia genetically and pathologically to amyotrophic lateral sclerosis?
• How can the syndromes be distinguished from Alzheimer disease and psychiatric disorders?

Key concepts

• Behavioural-variant frontotemporal dementia
• Primary progressive aphasia (nonfluent/agrammatic, semantic, and logopenic variants)
• Frontotemporal lobar degeneration (FTLD)
• Tau and TDP-43 proteinopathies
• MAPT, GRN, and C9orf72 genetics
• Frontotemporal dementia-amyotrophic lateral sclerosis overlap
• Young-onset dementia

Key theories

TDP-43 proteinopathy

The discovery that ubiquitinated TDP-43 is the major aggregated protein in a large proportion of frontotemporal lobar degeneration cases, and in amyotrophic lateral sclerosis, established a molecular link between the two disorders and reframed much of frontotemporal dementia as a TDP-43 proteinopathy.

Genetic and clinicopathological heterogeneity

Frontotemporal dementia is unusually heterogeneous: distinct genes (including those encoding tau and progranulin, and the C9orf72 repeat expansion) and distinct molecular pathologies underlie overlapping clinical syndromes, so clinical presentation predicts the underlying pathology only imperfectly.

Mechanisms

Frontotemporal dementia results from progressive degeneration of the frontal and anterior temporal lobes, with the clinical picture determined by the regions most affected: predominantly frontal and anterior temporal involvement produces behavioural and personality change, while left-lateralised perisylvian or temporal degeneration produces progressive aphasia. At the molecular level most cases are classified as frontotemporal lobar degeneration with tau pathology or with TDP-43 pathology; the identification of TDP-43 and of progranulin mutations clarified these subtypes and tied a substantial share of cases to amyotrophic lateral sclerosis through shared genetics and pathology (Bang et al., 2015; Neumann et al., 2006; Baker et al., 2006; Dugger & Dickson, 2017).

Clinical relevance

Frontotemporal dementia is an important and frequently under-recognised cause of dementia, especially before age 65, and its behavioural presentations can be mistaken for primary psychiatric illness. Classification systems for the behavioural variant and for primary progressive aphasia structure how the syndromes are recognised. This entry describes how the disorder is understood and classified; it is not a basis for individual diagnostic or treatment decisions.

Epidemiology

Frontotemporal dementia is one of the more common causes of young-onset dementia and, in that age group, approaches the frequency of Alzheimer disease. Onset is most often between the fifth and seventh decades, and a substantial minority of patients have a family history, reflecting the disorder's strong genetic component (Bang et al., 2015).

History

Arnold Pick described focal frontal and temporal atrophy with language and behavioural disturbance in the 1890s, and the associated argyrophilic inclusions later became known as Pick bodies. The modern concept of frontotemporal lobar degeneration consolidated these and related disorders, and consensus criteria for primary progressive aphasia variants (Gorno-Tempini et al., 2011) refined the language syndromes. The identification of TDP-43 (Neumann et al., 2006) and of progranulin mutations (Baker et al., 2006) in the 2000s transformed understanding of the underlying molecular pathology.

Debates

How should frontotemporal dementia be classified?

Because clinical syndromes, molecular pathologies, and causative genes intersect imperfectly, there is ongoing discussion about whether to classify cases primarily by clinical syndrome, by underlying proteinopathy, or by genetics, with consequences for diagnosis and trial design.

Key figures

• Arnold Pick
• Bruce L. Miller
• Marsel Mesulam
• Maria Luisa Gorno-Tempini
• Manuela Neumann

Seminal works

• bang-2015
• neumann-2006
• gorno-tempini-2011

Frequently asked questions

How does frontotemporal dementia differ from Alzheimer disease?

Frontotemporal dementia typically begins with changes in behaviour, personality, or language rather than the prominent early memory loss characteristic of Alzheimer disease, tends to start at a younger age, and arises from degeneration concentrated in the frontal and temporal lobes with tau or TDP-43 (rather than amyloid and tau) pathology.

What is the connection between frontotemporal dementia and amyotrophic lateral sclerosis?

The two disorders share molecular pathology (notably TDP-43 aggregation) and genetics (such as the C9orf72 repeat expansion), and some patients develop features of both, so they are increasingly viewed as parts of a single disease spectrum.