Microbiome Composition and Function Contributes to Cognitive Impairment and Neuroinflammation in Parkinson’s Disease

项目总结/摘要 认知障碍是帕金森病（PD）患者常见的非运动症状。 传统上，认知障碍被认为反映了多巴胺能额叶-纹状体系统的破坏。 然而，目前的概念化并没有彻底解释的异质性概况或轨迹， PD中的认知障碍;表明替代机制可能导致认知障碍。 识别认知障碍的替代机制可能会导致更好的预后预测， 产生新的治疗目标。 肠道被认为是PD早期病理学的一个部位。PD病理学的早期体征（α突触核蛋白和Lewy 身体聚集体）在运动症状显现前数年在胃肠道中检测到。最近 研究提供证据表明，PD患者的肠道细菌组成发生改变（称为生态失调） 相对于对照。迄今为止，生态失调与更严重的运动症状和某些非运动症状有关 （便秘，REM行为睡眠障碍）在PD，但生态失调和认知功能障碍之间的关系， 损伤仍然未知。 动物研究支持微生物群组成在认知障碍中起直接作用的假设。 无菌（GF）小鼠表现出认知缺陷。具体来说，研究结果表明，一个中断的肠道- 微生物环境与升高的应激激素结合可能会造成前 炎性细胞因子与抗炎性细胞因子，其诱导潜在可逆的认知障碍。人 在PD患者中的研究中，神经炎症标志物与认知障碍相关。 然而，生态失调，神经炎症和认知功能之间的关系仍然未知。 该模型具有令人难以置信的临床意义，因为微生物群生态失调可能代表了一种可逆的风险因素， 认知障碍 这项拟议中的研究将检验生态失调导致神经炎症增加的假设， 认知障碍微生物群组成/功能、神经炎症标志物和认知功能将 在100名PD参与者中进行检查。微生物群组成/功能分析将检查丰度 扩增子序列变体（ASV; 16 s）、细菌种/株（宏基因组学）、微生物基因，以及 功能途径。我们假设微生物群的组成/功能与炎症相关， 标志物（例如白细胞介素-6、肿瘤坏死因子-α、c-反应蛋白）和认知障碍。

PROJECT SUMMARY/ABSTRACT Cognitive impairment is a common non-motor symptom among individuals living with Parkinson’s disease (PD). Traditionally, cognitive impairment is thought to reflect disruptions in dopaminergic frontal-striatal systems. However, the current conceptualization does not thoroughly explain the heterogeneous profiles or trajectories of cognitive impairment in PD; suggesting that alternative mechanisms may contribute to cognitive impairments. Identification of alternative mechanisms of cognitive impairment may lead to better prognostic prediction and yield novel treatment targets. The gut is implicated as a site of early pathology in PD. Early signs of PD pathology (alpha synuclein and Lewy body aggregates) are detected in the gastrointestinal tract years before motor symptoms manifest. Recent studies provide evidence that individuals with PD have an altered gut-bacterial composition (termed dysbiosis) relative to controls. To date, dysbiosis is linked to more severe motor symptoms and certain non-motor symptoms (constipation, REM behavioral sleep disorder) in PD, but the relationship between dysbiosis and cognitive impairment remains unknown. Animal studies support the hypothesis that microbiota composition play a direct role in cognitive impairment. Germ free (GF) mice demonstrate deficits in cognition. Specifically, findings suggest that a disrupted gut- microbial environment in conjunction with elevated stress hormones may create an imbalance of pro- inflammatory vs. anti-inflammatory cytokines that induces potentially reversible cognitive impairments. In human studies among individuals with PD, neuroinflammatory markers are associated with cognitive impairment. However, the relationship between dysbiosis, neural inflammation and cognitive functioning remains unknown. This model has incredible clinical implications, as microbiota dysbiosis may represent a reversible risk factor for cognitive impairment. The proposed study will examine the hypothesis that dysbiosis contributes to increased neuroinflammation and cognitive impairment. Microbiota composition/function, neuroinflammatory markers and cognitive functioning will be examined in 100 participants with PD. Analyses of microbiota composition/function will examine abundance of amplicon sequence variants (ASVs; 16s), bacterial species/strains (metagenomics), microbial genes, and functional pathways. We hypothesize that microbiota composition/function will be associated with inflammatory markers (e.g. interleukin-6, tumor necrosis factor-alpha, c-reactive protein) and cognitive impairment.