title: TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype.
abstract: TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.
authors.affiliation: Mental Health and Neurodegeneration Research Group, Salford Royal Foundation Trust, University of Manchester, Salford M6 8HD, UK.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Davidson
authors.forename: Samantha
authors.initials: S
authors.lastname: Raby
authors.forename: Penelope G
authors.initials: PG
authors.lastname: Foulds
authors.forename: Andrew
authors.initials: A
authors.lastname: Robinson
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Thompson
authors.forename: Stephen
authors.initials: S
authors.lastname: Sikkink
authors.forename: Imran
authors.initials: I
authors.lastname: Yusuf
authors.forename: Hanan
authors.initials: H
authors.lastname: Amin
authors.forename: Daniel
authors.initials: D
authors.lastname: DuPlessis
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sloan
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
authors.forename: Vee P
authors.initials: VP
authors.lastname: Prasher
authors.forename: David
authors.initials: D
authors.lastname: Allsop
authors.forename: David
authors.initials: D
authors.lastname: Neary
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.forename: Julie S
authors.initials: JS
authors.lastname: Snowden
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001344:Autopsy; D003071:Cognition; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies; D012598:Sclerosis; D016875:tau Proteins / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D016875:tau Proteins