Frontotemporal lobar degeneration (
FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century,
FTLD has only recently been appreciated as a leading cause of
dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of
FTLD have been described: (i) behavioural-variant
frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii)
semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii)
progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical
atrophy. The majority of pathologies associated with
FTLD clinical syndromes include either tau-positive (
FTLD-TAU) or TAR
DNA-binding protein 43 (TDP-43)-positive (
FTLD-TDP) inclusion bodies.
FTLD overlaps clinically and pathologically with the atypical
parkinsonian disorders corticobasal degeneration and
progressive supranuclear palsy, and with
amyotrophic lateral sclerosis. The majority of familial
FTLD cases are caused by mutations in the genes encoding
microtubule-associated protein tau (leading to
FTLD-TAU) or
progranulin (leading to
FTLD-TDP). The clinical and pathological heterogeneity of
FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging
biological markers. Current
pharmacotherapy for
FTLD focuses on manipulating serotonergic or dopaminergic
neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in
FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific
therapies for
FTLD seem closer than ever.