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. 2017 Jul;27(4):472-479.
doi: 10.1111/bpa.12424. Epub 2016 Aug 24.

TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing

Kirsty E McAleese  1 , Lauren Walker  1 , Daniel Erskine  1 , Alan J Thomas  1 , Ian G McKeith  1 , Johannes Attems  1
Affiliations

TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing

Kirsty E McAleese et al. Brain Pathol. 2017 Jul.

Abstract

Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration.

Keywords: Alzheimer's disease; Lewy body diseases; TDP-43; ageing; dementia with Lewy bodies; hippocampal sclerosis; mixed Alzheimer's disease and dementia with Lewy bodies.

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Conflict of interest statement

The authors declare they have no conflict of interest.

Figures

Figure 1
Figure 1
Photomicrograph illustrating types of TDP‐43 pathology observed in the study, taken from a mixed AD/DLB case. A. Highlights a neuronal intranuclear inclusion (NII)—blue arrow, seen in the dentate gyrus of the hippocampus (stage III). B. Demonstrates a neuronal cytoplasmic inclusion (NCI)—black arrow, and dystrophic neurite (DN)—black arrowhead seen in the amygdala (stage I). Scale bar in (A) represents 50 μm and is valid for (B).
Figure 2
Figure 2
Age of onset of cognitive decline, rate of cognitive decline per year and final MMSE score in cases with and without TDP‐43 pathology. A. No significant differences were seen in age of onset between cases with and without TDP‐43 pathology in AD, DLB and Mx AD/DLB. B. No significant difference were seen in rate of cognitive decline per year between cases with and without TDP‐43 pathology in AD, DLB and Mx AD/DLB. C. Final MMSE score was significantly lower in AD cases with TDP‐43 pathology compared to AD cases without TDP‐43 pathology. No significant difference was seen in DLB, Mx AD/DLB or controls. AD, Alzheimer's disease, DLB, dementia with Lewy bodies; Mx AD/DLB, mixed AD/DLB; *, P < 0.05.
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