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

前驱期和症状性路易体病中的微生物组-肠-脑功能障碍

• 批准号: 10720677
• 负责人: Sephira Ryman
• 金额: $ 81.59万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720677
• 关键词: Accounting; Age; Aging; Alzheimer' s disease related dementia; Area; Automobile Driving; Bacterial Translocation; Blood specimen; Breath Tests; Categories; Cell Nucleus; Central Nervous System; Clinic; Clinical; Clinical Trials; Cross-Sectional Studies; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Evaluation; Event; Exhibits; Exposure to; Functional disorder; Future; Health Sciences; Hydrogen Sulfide; Impaired cognition; Intervention; Intestinal permeability; Knowledge; Lactulose; Leaky Gut; Lewy Body Dementia; Lewy Body Disease; Lipopolysaccharides; Measurement; Memory; Midbrain structure; Movement Disorders; Nerve Degeneration; Neurobehavioral Manifestations; New Mexico; Outcome; Parkinson Disease; Parkinson' s Dementia; Participant; Pathogenesis; Pathogenicity; Pathologic; Patients; Plasma; Population; Prevalence; Process; REM Sleep Behavior Disorder; Ribosomal RNA; Role; Signal Transduction; Sleep; Substantia nigra structure; Symptoms; Testing; Universities; Vagus nerve structure; alpha synuclein; brain dysfunction; clinical practice; dysbiosis; effective therapy; follow-up; functional disability; gut bacteria; gut microbiome; lipopolysaccharide-binding protein; locus ceruleus structure; magnetic resonance imaging biomarker; microbial; microbiome; motor symptom; neuron loss; novel; pars compacta; prion-like; prospective; rRNA Genes; recruit; sex; sulfate reducing bacteria; synucleinopathy

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.

项目概要/摘要 路易体痴呆的认知能力下降[帕金森病痴呆 (PDD) 和路易体痴呆 身体（DLB）；一类阿尔茨海默病和相关痴呆症（ADRD）]，导致显着的功能障碍 损伤并且对现有治疗反应不佳也许是开发的最大挑战。 有效的治疗缺乏对驱动病理生理学的关键事件的机械理解。 越来越多的证据表明，硫酸盐还原酶的大量繁殖导致肠道微生物群受到干扰（生态失调） 细菌和肠道通透性增加可能是路易疾病发病机制的关键机制 需要评估这些因素是否在病程早期就存在。 与已知的疾病过程相关，例如中脑变性和特发性临床结果。 快速眼动睡眠行为障碍（iRBD）是路易体最早、最具体的前驱指标之一 高达 96.6% 的 iRBD 患者将在 14 年随访时进展为 α-突触核蛋白病。 因此，人口提供了一个机会，可以对水华的存在进行新颖的评估。 疾病早期SRB/生态失调和肠道通透性增加是否以及这些机制是否 与已知的疾病过程相关（α-突触核蛋白增加、中脑变性和临床 拟议的项目将进行一项前瞻性、横断面研究来检验以下假设： 乳果糖呼气试验异常且 H2S 浓度升高（作为生态失调和 SRB 大量繁殖的标志） 在肠道中）存在于疾病的前驱阶段，并且与增加的标记物的增加相关 肠道通透性和脂多糖的微生物易位（总细菌 16S rRNA 基因和 脂多糖结合蛋白；LBP），已知的疾病过程（α-突触核蛋白的血浆浓度，MRI SNc 和 LC 完整性的生物标志物）和临床结果我们将招募前驱期 (iRBD)、有症状的患者。 路易体病患者（PD 和 DLB）和 HC 来评估我们的几个假设。 PAR-22-211 中概述的目标，拟议项目的完成将推进我们的机制 了解SRB/生态失调激增的影响，可能确定疾病改变的目标 我们的结果是否应该确定肠道 SRB 繁殖/生态失调在病理生理学中的重要作用。 对于路易体疾病，这些测量可以纳入常规临床实践中以筛查 值得注意的是，许多针对微生物组的潜在治疗方法很容易实现。 现有的和后续的临床试验可以评估是否针对SRB/生态失调的水华的干预措施 可用于在明显的运动和认知症状出现之前进行干预。