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

项目摘要/摘要 认知障碍是帕金森氏病(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-纹状体系统的中断。 然而，目前的概念化并不能完全解释 帕金森病中的认知损害；提示替代机制可能对认知损害起作用。 识别认知障碍的替代机制可能会导致更好的预后预测和 产生新的治疗靶点。 肠道被认为是帕金森病的早期病理部位。帕金森病的早期病理征象(阿尔法突触核蛋白和路易 在运动症状出现前几年，在胃肠道中检测到身体聚集体)。近期 研究提供的证据表明，帕金森病患者的肠道细菌组成发生了变化(称为生物失调)。 相对于控件。迄今为止，生物失调与更严重的运动症状和某些非运动症状有关。 (便秘，快速眼动行为睡眠障碍)在帕金森病中，但生态失调与认知之间的关系 损伤仍未可知。 动物研究支持微生物区系组成在认知障碍中起直接作用的假说。 无菌(GF)小鼠表现出认知缺陷。具体地说，研究结果表明，肠道受损- 微生物环境与压力荷尔蒙的升高可能会造成促前-内分泌失衡。 炎症性细胞因子与抗炎性细胞因子导致潜在的可逆性认知损害。在人类中 在帕金森病患者中的研究表明，神经炎性标志物与认知障碍有关。 然而，生物失调、神经炎症和认知功能之间的关系仍不清楚。 这个模型具有令人难以置信的临床意义，因为微生物区系失调可能代表着一种可逆的风险因素 认知障碍。 这项拟议的研究将检验这样一种假设，即生物失调导致神经炎症增加，并 认知障碍。微生物区系组成/功能、神经炎性标志物和认知功能 对100名帕金森病患者进行检查。对微生物群组成/功能的分析将检查丰度 扩增子序列变异(ASV；16S)、细菌物种/菌株(元基因组学)、微生物基因和 功能通路。我们假设微生物区系的组成/功能将与炎症有关 标记物(如白介素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.