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

• Published in: Acta neuropathologica 2011-12, Vol.122 (6), p.703-713
• Main Authors: Davidson, Yvonne S., Raby, Samantha, Foulds, Penelope G., Robinson, Andrew, Thompson, Jennifer C., Sikkink, Stephen, Yusuf, Imran, Amin, Hanan, DuPlessis, Daniel, Troakes, Claire, Al-Sarraj, Safa, Sloan, Carolyn, Esiri, Margaret M., Prasher, Vee P., Allsop, David, Neary, David, Pickering-Brown, Stuart M., Snowden, Julie S., Mann, David M. A.
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Aged, 80 and over; Aging; Aging - metabolism; Aging - pathology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Apolipoproteins E - genetics; Autopsy; Cognition; Cognitive ability; Cohort Studies; Cortex (temporal); Dementia; Demography; Disease; DNA-Binding Proteins - metabolism; Down Syndrome - metabolism; Down Syndrome - pathology; Down's syndrome; Female; flavin-adenine dinucleotide; Genotype; Genotype & phenotype; Geriatrics; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Humans; Male; Medicine; Medicine & Public Health; Mental health; Middle Aged; Neurodegeneration; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Phenotype; Retrospective Studies; Sclerosis; Tau protein; tau Proteins - metabolism; Temporal lobe
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-011-0879-y

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