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.

项目摘要/摘要 Lewy身体痴呆症的认知能力下降[帕金森氏病痴呆症（PDD）和痴呆症与Lewy 身体（DLB）;阿尔茨海默氏病和相关痴呆症（ADRD）的类别导致了重要的功能 损害，对现有治疗的反应不佳。也许是发展的最大挑战 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理解。 越来越多的证据表明，由硫酸盐还原的开花驱动的肌肉微生物组（营养不良） 细菌和肠道通透性增加可能是驱动疾病发病机理的关键机制 身体疾病。有必要评估这些因素是否存在于疾病过程中的早期，并且 与已知疾病过程有关，例如中脑变性和临床结果。特发性 REM睡眠行为障碍（IRBD）是Lewy身体的最早，最特定的前驱指标之一 在14年的随访中，疾病中高达96.6％的IRBD患者将发展为α-核酸疾病。这 因此，人口提供了一个机会，可以对盛开的存在进行新颖的评估 SRB/营养不良和疾病早期肠道通透性的增加以及这些机制是否为 与已知疾病过程有关（α-突触核蛋白，中脑变性和临床的增加 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。 H2S浓度升高的乳糖呼吸测试异常（作为营养不良的标志和SRB的花朵 在肠道中存在于疾病的前驱阶段，与增加的标记增加有关 脂多糖的肠渗透性和微生物易位（总细菌16S rRNA基因和 脂多糖结合蛋白； LBP），已知疾病过程（血浆浓度的α-突触核蛋白，MRI SNC和LC的完整性生物标志物以及临床结果。我们将招募前令（IRBD），有症状 Lewy身体疾病患者（PD和DLB）和HC评估我们的假设。与几个一致 PAR-22-211中概述的目标，拟议项目的完成将提高我们的机制 了解繁荣在SRB/营养不良中的影响，有可能识别疾病修饰的靶标 治疗。我们的结果是否应确定肠道SRB Bloom/营养不良在病理生理学中的重要作用 在路易的身体疾病中，可以将这些测量结果纳入常规临床实践中，以筛选 新兴的致病过程。值得注意的是，许多针对微生物组的潜在治疗很容易 可用和随后的临床试验可以评估针对SRB/营养不良的开花的干预措施是否 可以在开发明显的电动机和认知符号之前用于干预。