Acta Neuropathologica

, Volume 122, Issue 6, pp 703–713

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

  • Yvonne S. Davidson
  • Samantha Raby
  • Penelope G. Foulds
  • Andrew Robinson
  • Jennifer C. Thompson
  • Stephen Sikkink
  • Imran Yusuf
  • Hanan Amin
  • Daniel DuPlessis
  • Claire Troakes
  • Safa Al-Sarraj
  • Carolyn Sloan
  • Margaret M. Esiri
  • Vee P. Prasher
  • David Allsop
  • David Neary
  • Stuart M. Pickering-Brown
  • Julie S. Snowden
  • David M. A. Mann
Original Paper

DOI: 10.1007/s00401-011-0879-y

Cite this article as:
Davidson, Y.S., Raby, S., Foulds, P.G. et al. Acta Neuropathol (2011) 122: 703. doi:10.1007/s00401-011-0879-y

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.

Keywords

Alzheimer’s disease Down’s syndrome TDP-43 Hippocampal sclerosis 

Supplementary material

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Supplementary material 1 (TIFF 3076 kb)
401_2011_879_MOESM2_ESM.doc (804 kb)
Supplementary material 2 (DOC 803 kb)
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Supplementary material 3 (TIFF 3076 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Yvonne S. Davidson
    • 1
  • Samantha Raby
    • 2
  • Penelope G. Foulds
    • 2
  • Andrew Robinson
    • 1
  • Jennifer C. Thompson
    • 1
    • 8
  • Stephen Sikkink
    • 3
  • Imran Yusuf
    • 1
  • Hanan Amin
    • 1
  • Daniel DuPlessis
    • 1
  • Claire Troakes
    • 4
  • Safa Al-Sarraj
    • 4
  • Carolyn Sloan
    • 5
  • Margaret M. Esiri
    • 5
  • Vee P. Prasher
    • 6
    • 7
  • David Allsop
    • 2
  • David Neary
    • 8
  • Stuart M. Pickering-Brown
    • 3
  • Julie S. Snowden
    • 8
  • David M. A. Mann
    • 1
  1. 1.Mental Health and Neurodegeneration Research Group, Faculty of Medical and Human Sciences, Salford Royal Foundation TrustUniversity of ManchesterSalfordUK
  2. 2.Division of Biomedical and Life Sciences, School of Health and MedicineUniversity of LancasterLancasterUK
  3. 3.Mental Health and Neurodegeneration Research Group, Faculty of Medical and Human SciencesUniversity of ManchesterManchesterUK
  4. 4.London Neurodegenerative Diseases Brain Bank, Department of Clinical Neuroscience, Institute of PsychiatryKing’s College LondonLondonUK
  5. 5.Neuropathology Department, John Radcliffe InfirmaryUniversity of OxfordOxfordUK
  6. 6.South Birmingham Community NHS TrustBirminghamUK
  7. 7.Liverpool John Moores UniversityLiverpoolUK
  8. 8.Cerebral Function Unit, Greater Manchester Neuroscience CentreSalford Royal Foundation Trust, Hope HospitalSalfordUK

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