John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Acta Neuropathol Commun. 2020 Dec 3;8(1):211. doi: 10.1186/s40478-020-01083-5.
Parkinson's disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer's disease-type pathology. Whilst immune activation is well-described in Parkinson's disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4 T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4 T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.
帕金森病痴呆在神经病理学上的特征是大脑边缘和新皮质区域中α-突触核蛋白（路易体）的聚集，并且还伴有阿尔茨海默病型病理学的额外参与。虽然帕金森病（PD）中的免疫激活已有很好的描述，但它与蛋白聚集的关系及其在 PD 痴呆中的作用尚未得到探索。我们假设神经炎症过程是 PDD 病理学的一个关键贡献者。为了验证这一假设，我们检查了 17 名无痴呆的帕金森病患者（PDND）、11 名帕金森病痴呆患者（PDD）和 14 名年龄和性别匹配的神经健康对照者的 17 个脑区的尸检组织。免疫组化染色后的数字定量显示，与 PDND 病例相比，PDD 患者的海马体、内嗅皮层和枕颞叶皮层的α-突触核蛋白病理严重程度显著增加。相比之下，在任何检查区域，各组之间的 tau 或淀粉样蛋白-β 病理学均无差异。重要的是，我们发现与对照组相比，痴呆 PD 大脑的杏仁核中激活的小胶质细胞增加，并且与该区域中α-突触核蛋白病理学的程度显著相关。与对照组相比，PDND 和 PDD 病例的黑质和杏仁核中常见 CD4 T 淋巴细胞浸润到脑实质中。在 PDND/PDD 病例中，杏仁核中的 CD4 T 细胞计数与激活的小胶质细胞、α-突触核蛋白和 tau 病理学相关。与对照组相比，促炎细胞因子白细胞介素 1β在黑质和额叶皮层中的表达也上调，并且这些区域以及杏仁核中的 Toll 样受体 4（TLR4）也上调。本研究提供的证据表明，边缘和皮质脑区的免疫反应增强，包括小胶质细胞激活、T 淋巴细胞浸润、促炎细胞因子和 TLR 基因表达上调，这在以前的 PDD 尸检大脑中尚未报道过。
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