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Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population

Lookup NU author(s): Dr Tuomo Polvikoski, Dr Thais Minett, Professor Fiona MatthewsORCiD, Professor Carol Brayne



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Hippocampal neuron loss is a common neuropathological feature in old age with various underlying aetiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43kDa (TDP-43) aggregations. Its aetiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n=642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study.HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher’s exact, p=0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher’s exact, p<0.001) and high Braak stage (Fisher’s exact, p=0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP-43.We conclude that hippocampal neuron loss patterns are associated with different aetiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than “end-stage” HS-Aging only.

Publication metadata

Author(s): Hokkanen SRK, Hunter S, Polvikoski TM, Keage HAD, Minett T, Matthews FE, Brayne C

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2018

Volume: 28

Issue: 4

Pages: 548-559

Print publication date: 01/07/2018

Online publication date: 25/09/2017

Acceptance date: 10/08/2017

Date deposited: 26/09/2017

ISSN (print): 1015-6305

ISSN (electronic): 1750-3639

Publisher: Wiley-Blackwell Publishing, Inc.


DOI: 10.1111/bpa.12556


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Funder referenceFunder name
ART PG2006/6
G9901400Medical Research Council (MRC)