Microbiome-gut-brain dysfunction in prodromal and symptomatic Lewy body diseases

项目摘要/摘要 路易体痴呆[帕金森氏病痴呆(PDD)和路易氏痴呆 躯体(DLB)；阿尔茨海默病和相关痴呆(ADRD)的一类]，导致显著的功能性 损伤，对现有的治疗方法反应不佳。也许开发的最大挑战是 有效的治疗方法是缺乏对驱动病理生理学的关键事件的机械性了解。 越来越多的证据表明，由硫酸盐还原中的水华驱动的肠道微生物群(微生物失调) 细菌和肠道通透性增加可能是导致路易斯病发病的关键机制 身体疾病。有必要评估这些因素是否出现在病程的早期和 与已知的疾病过程有关，如中脑变性和临床结果。特发性 快速眼动睡眠行为障碍(IRBD)是路易体最早、最特异的前驱指标之一 高达96.6%的iRBD患者在14年的随访中将进展为阿尔法-突触核病。这 因此，种群提供了一个机会，可以对水华的存在进行新的评估 疾病早期的SRB/生物失调和肠道通透性增加，以及这些机制是否 与已知疾病过程有关(α-突触核蛋白增加、中脑变性和临床 结果)。拟议的项目将进行一项前瞻性的横断面研究，以检验以下假设 乳果糖呼气试验异常，硫化氢浓度升高(作为生物失调和SRB开花的标志) 在肠道中)出现在疾病的前驱阶段，并与升高的标志物增加有关 细菌总16S rRNA基因和细菌内毒素的肠道通透性和微生物易位 脂多糖结合蛋白)，已知的疾病过程(血浆α-突触核蛋白浓度，磁共振 SNC和LC的完整性的生物标志物)和临床结果。我们将招募前驱(IRBD)，有症状的 路易体病患者(PD和DLB)和HC来评估我们的假设。与几个 在PAR-22-211中概述的目标，拟议项目的完成将推动我们的机械化 了解SRB/生物失调热潮的影响，潜在地确定疾病修改的目标 治疗。我们的结果是否应该确定肠道SRB大量繁殖/生物失调在病理生理学中的重要作用 对于路易身体疾病，这些测量可以结合到常规临床实践中进行筛查 新出现的致病过程。值得注意的是，许多针对微生物组的潜在治疗方法很容易 现有的和后续的临床试验可以评估针对SRB水华/生物失调的干预措施 可用于在明显的运动和认知症状发展之前进行干预。

PROJECT SUMMARY/ABSTRACT Cognitive decline in Lewy body dementias [Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB); a category of Alzheimer’s disease and related dementias (ADRD)], causes significant functional impairment and does not respond well to existing treatments. Perhaps the greatest challenge for developing effective treatments is the lack of a mechanistic understanding of the key events driving pathophysiology. Increasing evidence suggests that a perturbed gut microbiome (dysbiosis) driven by a bloom in sulfate reducing bacteria and increased intestinal permeability may be key mechanisms driving disease pathogenesis in Lewy body diseases. There is a need to evaluate whether these factors are present early in the disease course and associated with known disease processes, such as midbrain degeneration and clinical outcomes. Idiopathic REM Sleep behavior disorder (iRBD), is one of the earliest and most specific prodromal indicators of Lewy body diseases as up to 96.6% of iRBD patients will progress to an alpha-synucleinopathy at 14 years follow up. This population therefore provides an opportunity to conduct a novel evaluation of the presence of a bloom in SRB/dysbiosis and increased intestinal permeability early in the disease and whether these mechanisms are associated with known disease processes (increases in α-synuclein, midbrain degeneration and clinical outcomes). The proposed project will conduct a prospective, cross-sectional study to test the hypothesis that abnormal lactulose breath tests with elevated H2S concentration (as a marker of dysbiosis and a bloom of SRB in the gut) are present at prodromal stages of the disease and associated with increases in markers of increased intestinal permeability and microbial translocation of lipopolysaccharide (total bacterial 16S rRNA gene and lipopolysaccharide binding protein; LBP), known disease processes (plasma concentration of α-synuclein, MRI biomarkers of integrity of SNc and LC) and clinical outcomes. We will recruit prodromal (iRBD), symptomatic Lewy body disease patients (PD and DLB) and HC to evaluate our hypotheses. Consistent with several objectives outlined in PAR-22-211, the completion of the proposed project will advance our mechanistic understanding of the effects of a boom in SRB/dysbiosis, potentially identifying targets for disease modifying treatments. Should our results determine an important role of gut SRB bloom/dysbiosis in the pathophysiology of Lewy body diseases, these measurements could be incorporated into routine clinical practice to screen for emerging pathogenic processes. Notably, many potential treatments targeting the microbiome are readily available and subsequent clinical trials can evaluate whether interventions targeting a bloom in SRB/dysbiosis could be used to intervene before overt motor and cognitive symptoms develop.