Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neuropathol Appl Neurobiol. 2018 Dec;44(7):707-721. doi: 10.1111/nan.12485. Epub 2018 May 9.
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).
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.
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.
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.
本研究旨在评估 43kDa 转激活反应 DNA 结合蛋白（TDP-43）病理学在多系统萎缩（MSA）中的临床病理特征及其危险因素。
对 186 例经尸检证实的 MSA 病例的杏仁核和基底前脑的石蜡切片进行免疫组化磷酸化 TDP-43 检测。在存在 TDP-43 病理学的病例中，评估了其他脑区。进行免疫组织化学和免疫荧光双重染色以及免疫金电子显微镜（IEM），以评估 TDP-43 和 α-突触核蛋白的共定位。还分析了 TDP-43 病理学的遗传危险因素。
免疫组化显示 13 例（7％）病例存在多种形态的 TDP-43 病理学，如皮层下星形胶质细胞包涵体、神经元包涵体、营养不良性神经突、血管周围包涵体和神经胶质细胞质包涵体（GCIs）。多变量逻辑回归模型显示，只有高龄，而不是同时存在阿尔茨海默病、嗜银颗粒病或海马硬化，是 MSA 中 TDP-43 病理学的独立危险因素（OR：1.11，95％CI：1.04-1.19，P = 0.002）。TDP-43 病理学在 8 例病例中仅限于杏仁核，在 2 例病例中扩展到海马。其余 3 例病例则广泛存在 TDP-43 病理学。免疫组织化学和免疫荧光双重染色以及 IEM 显示，GCIs 中α-突触核蛋白和 TDP-43 与颗粒包被的细丝共定位。初步的遗传研究未能显示 TMEM106B 或 GRN 的风险变异与 TDP-43 病理学之间存在关联。
TDP-43 病理学在 MSA 中罕见，主要发生在颞叶内侧。高龄是 MSA 中 TDP-43 病理学的危险因素。GCIs 中 TDP-43 和 α-突触核蛋白的共定位提示两种分子之间可能存在直接相互作用。
