Language impairment in frontotemporal lobar degeneration

The term frontotemporal lobar degeneration (FTLD) describes a heterogeneous group of neurodegenerative disorders associated with frontal and temporal lobe atrophy. Within this spectrum, two progressive aphasia syndromes, progressive nonfluent aphasia (PNFA) and semantic dementia (SD), are well described. FTLD is commonly a genetic disorder and mutations in two genes, microtubule-associated protein tau (MAPT) and progranulin (GRN) account for a large proportion of familial cases. A retrospective imaging study using cortical thickness measures shows involvement of the anteroinferior temporal lobes in SD and the left inferior frontal lobe/insula in PNFA. Studies of disease severity and of longitudinal imaging reveal spread through the left hemisphere and into the right hemisphere in both groups. A genetics and heritability study shows that PNFA can be familial, although much less than the behavioural variant of FTLD, and that this is often due to mutations in GRN. Differing patterns of atrophy are shown between different genetic mutations and also between different pathologies with the same clinical syndrome. Evidence from the neurological, neuropsychological, neuroanatomical, genetic and pathological features of the nonfluent aphasias suggests that there are at least three nonfluent aphasia syndromes: a disorder with motor speech impairment with or without agrammatism, a disorder with agrammatism but no apraxia of speech (found in patients with progranulin mutations) and a disorder without agrammatism or apraxia of speech but with word-finding pauses (consistent with descriptions of logopenic/phonological aphasia and pathologically associated with Alzheimer’s disease). Studies of specific deficits (single word processing, prosody, neologistic jargon, apraxia and behavioural symptoms) in the progressive aphasias provide further insight into the disease. This thesis therefore provides neurological, neuropsychological and imaging data with related genetic and pathological information that can provide greater insights into the natural history and classification, and therefore pathophysiological basis of the neurodegenerative disorders that cause primary progressive language impairment.