Frontotemporal Dementia

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders that selectively affect the frontal and temporal lobes, producing progressive changes in behaviour, personality, and language rather than the early memory loss typical of Alzheimer disease. It is a leading cause of dementia in people under 65.

Definition

Frontotemporal dementia is a group of neurodegenerative syndromes caused by frontotemporal lobar degeneration, characterised clinically by progressive deterioration in behaviour, executive function, or language with relative early sparing of memory, and pathologically by the accumulation of misfolded tau or TDP-43 (and, less often, FUS) proteins.

Scope

This topic covers frontotemporal dementia as an umbrella of related syndromes: the behavioural variant and the primary progressive aphasias, the underlying frontotemporal lobar degeneration pathologies (chiefly tau and TDP-43 proteinopathies), the genetic forms, and the overlap with amyotrophic lateral sclerosis. It is a reference overview and does not provide diagnostic protocols or treatment guidance.

Core questions

• How do behavioural and language variants relate to the same disease family?
• Which molecular pathologies underlie the clinical syndromes?
• How does frontotemporal dementia overlap with motor-neuron disease?
• What is the role of genetic mutations in causing the disease?

Key concepts

• Behavioural-variant FTD
• Primary progressive aphasia (semantic, nonfluent, logopenic variants)
• Frontotemporal lobar degeneration (FTLD)
• Tau and TDP-43 pathology
• Genetic forms (C9orf72, GRN, MAPT)
• FTD-ALS overlap
• Young-onset dementia

Key theories

FTLD as tau and TDP-43 proteinopathy

Frontotemporal lobar degeneration is divided pathologically according to the protein that aggregates, principally tau (FTLD-tau) or TDP-43 (FTLD-TDP), with a smaller FUS-associated group; the identification of TDP-43 unified a large share of cases and linked them mechanistically to amyotrophic lateral sclerosis.

Clinical-anatomical syndromes

The clinical phenotypes map onto regional atrophy: behavioural-variant FTD reflects predominantly frontal and anterior temporal involvement, while the primary progressive aphasias reflect more focal language-network degeneration, formalised in consensus classifications of their variants.

Mechanisms

Frontotemporal dementia results from frontotemporal lobar degeneration, in which misfolded proteins accumulate and drive neuronal loss concentrated in the frontal and temporal lobes. Most cases are associated with aggregates of either tau or TDP-43, with a smaller FUS-related group; the discovery of ubiquitinated TDP-43 as the major pathological protein in many cases connected frontotemporal dementia mechanistically with amyotrophic lateral sclerosis. The regional pattern of degeneration determines the clinical syndrome, so frontal-predominant atrophy produces behavioural and executive change while language-network degeneration produces the primary progressive aphasias (Neumann et al., 2006; Bang et al., 2015; Gorno-Tempini et al., 2011).

Clinical relevance

Frontotemporal dementia is an important cause of young-onset dementia, and understanding its behavioural and language syndromes and their molecular and genetic underpinnings informs how it is recognised and distinguished from Alzheimer disease and primary psychiatric disorders. This entry describes how the disease is defined and studied; it is not a basis for individual diagnosis or treatment decisions.

Epidemiology

Frontotemporal dementia is among the most common causes of dementia in people younger than 65, with onset frequently in the sixth decade, and affects men and women similarly. A substantial minority of cases are familial, often associated with mutations in C9orf72, GRN, or MAPT (Bang et al., 2015).

History

Arnold Pick described focal frontotemporal atrophy with language and behavioural change in the 1890s, and the eponymous Pick bodies were later identified as tau pathology. The modern concept of frontotemporal lobar degeneration emerged from the recognition of a spectrum of clinical syndromes and pathologies, consolidated by the discovery of TDP-43 as a major aggregating protein in 2006 and by consensus classifications of the behavioural and language variants (Bang et al., 2015; Neumann et al., 2006; Gorno-Tempini et al., 2011).

Debates

How should the FTD-ALS spectrum be conceptualised?

Shared TDP-43 pathology and shared genetic causes such as C9orf72 expansions place frontotemporal dementia and amyotrophic lateral sclerosis on a continuum, raising questions about whether they are distinct diseases or poles of one spectrum.

Key figures

• Arnold Pick
• Bruce 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 and tends to affect younger people, whereas Alzheimer disease usually begins with prominent memory loss; they also differ in their underlying brain pathology.

Is frontotemporal dementia related to motor-neuron disease?

Yes. Frontotemporal dementia and amyotrophic lateral sclerosis share TDP-43 pathology and genetic causes such as C9orf72 expansions, and some people develop features of both, placing them on a common disease spectrum.