TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions

Aims: This study aimed to assess clinicopathologic features of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and its risk factors in multiple system atrophy (MSA). Methods: Paraffin-embedded sections of the amygdala and basal forebrain from 186 autopsy-confirmed MSA cases were screened with immunohistochemistry for phospho-TDP-43. In cases having TDP-43 pathology, additional brain regions were assessed. Immunohistochemical and immunofluorescence double-staining and immunogold electron microscopy (IEM) were performed to evaluate colocalization of TDP-43 and α-synuclein. Genetic risk factors for TDP-43 pathology were also analysed. Results: Immunohistochemistry showed various morphologies of TDP-43 pathology in 13 cases (7%), such as subpial astrocytic inclusions, neuronal inclusions, dystrophic neurites, perivascular inclusions and glial cytoplasmic inclusions (GCIs). Multivariable logistic regression models revealed that only advanced age, but not concurrent Alzheimer's disease, argyrophilic grain disease or hippocampal sclerosis, was an independent risk factor for TDP-43 pathology in MSA (OR: 1.11, 95% CI: 1.04–1.19, P = 0.002). TDP-43 pathology was restricted to the amygdala in eight cases and extended to the hippocampus in two cases. The remaining three cases had widespread TDP-43 pathology. Immunohistochemical and immunofluorescence double-staining and IEM revealed colocalization of α-synuclein and TDP-43 in GCIs with granule-coated filaments. Pilot genetic studies failed to show associations between risk variants of TMEM106B or GRN and TDP-43 pathology. Conclusions: TDP-43 pathology is rare in MSA and occurs mainly in the medial temporal lobe. Advanced age is a risk factor for TDP-43 pathology in MSA. Colocalization of TDP-43 and α-synuclein in GCIs suggests possible direct interaction between the two molecules.