Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease

It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of alpha-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether alpha-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11-14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, alpha-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe alpha-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with alpha-synuclein or tau. Given these findings, we suggest that alpha-synuclein pathology is associated with TDP-43 accumulation in LBD cases.