title: Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis.
abstract: Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a 'continuum' without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the 'stage' of the disease, and (3) within the FTLD-TDP 'continuum' cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.
authors.affiliation: Vision Sciences, Aston University, Birmingham B4 7ET, UK. R.A.Armstrong@aston.ac.uk
authors.forename: Richard A
authors.initials: RA
authors.lastname: Armstrong
authors.forename: William
authors.initials: W
authors.lastname: Ellis
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: John
authors.initials: J
authors.lastname: Hedreen
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Thomas
authors.initials: T
authors.lastname: Montine
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D025341:Principal Component Analysis; D000077153:Progranulins; D012598:Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins