title: Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.
abstract: Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
authors: Dementia Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors: Jonathan D
authors: JD
authors: Rohrer
authors: Tammaryn
authors: T
authors: Lashley
authors: Jonathan M
authors: JM
authors: Schott
authors: Jane E
authors: JE
authors: Warren
authors: Simon
authors: S
authors: Mead
authors: Adrian M
authors: AM
authors: Isaacs
authors: Jonathan
authors: J
authors: Beck
authors: John
authors: J
authors: Hardy
authors: Rohan
authors: R
authors: de Silva
authors: Elizabeth
authors: E
authors: Warrington
authors: Claire
authors: C
authors: Troakes
authors: Safa
authors: S
authors: Al-Sarraj
authors: Andrew
authors: A
authors: King
authors: Barbara
authors: B
authors: Borroni
authors: Matthew J
authors: MJ
authors: Clarkson
authors: Sebastien
authors: S
authors: Ourselin
authors: Janice L
authors: JL
authors: Holton
authors: Nick C
authors: NC
authors: Fox
authors: Tamas
authors: T
authors: Revesz
authors: Martin N
authors: MN
authors: Rossor
authors: Jason D
authors: JD
authors: Warren
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016000:Cluster Analysis; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020774:Pick Disease of the Brain / Q000473:pathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D034702:RNA-Binding Protein FUS; D016875:tau Proteins