Parkinson Disease Neural Circuitry and Gastrointestinal Pathobiology

帕金森病神经回路和胃肠道病理学

• 批准号: 10740119
• 负责人: MICHAEL L. CAMILLERI
• 金额: $ 58.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740119
• 关键词: Acceleration; Address; Age; Aging; Animal Model; Attention; Autonomic Dysfunction; Autonomic Pathways; Biochemical; Braak' s hypothesis; Brain; Brain Stem; Cell Nucleus; Central Nervous System; Cerebral cortex; Clinic; Clinical; Clinical Trials; Cognitive; Colon; Constipation; Control Groups; Corpus striatum structure; Deglutition Disorders; Dopamine; Dopamine Receptor; Duodenum; Educational workshop; Elderly; Enteral; Enteric Nervous System; Enteroendocrine Cell; Functional disorder; Future; Gastric Emptying; Gastroenterology; Gastrointestinal Transit; Gastrointestinal tract structure; Gut Mucosa; Human; Image; Impaired cognition; Individual; Infectious Agent; Inflammation; Intervention; Intestinal permeability; Intestines; Investigation; Literature; Molecular; Motor; Mucous Membrane; Nausea; Nerve; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathway interactions; Patients; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Poison; Prevention; Process; Prospective cohort; Proteins; Quality of life; Questionnaires; Research Design; Role; Short-Term Memory; Sigmoid colon; Small Intestines; Specificity; Squalamine; Stomach; Submucosa; Symptoms; Tight Junctions; Time; Tissues; Travel; United States National Institutes of Health; Vagus nerve structure; absorption; alpha synuclein; basal forebrain; cell motility; cognitive impairment in Parkinson' s; density; design; dopamine transporter; dopaminergic neuron; dorsal motor nucleus; fecal microbiome; gastrointestinal; gastrointestinal function; gastrointestinal symptom; gut microbiota; gut-brain axis; improved; in vivo; intestinal epithelium; microbiome; motility disorder; motor disorder; motor symptom; multidisciplinary; neural; neural circuit; neurotoxic; occludin; preclinical study; prospective; protein misfolding; receptor density; receptor expression; single photon emission computed tomography; synucleinopathy; transcriptome

Gastrointestinal (GI) symptoms are significant non-motor manifestations of Parkinson disease (PD) that can precede PD motor symptoms by years; cognitive dysfunction is an important late, non-motor manifestation. Braak’s hypothesis proposes that α-synuclein (αS) aggregates propagate along vagal or olfactory afferents to the central nervous system (CNS), leading to motor and non-motor features of PD. However, αS aggregates are also identified in enteric neurons in elderly people without PD. Squalamine prevention of αS aggregates improved constipation in PD. Density of nigrostriatal dopamine transporters (as assessed by 123I-FP-CIT SPECT) are relevant to cognitive processing in PD. αS oligomers in CSF is a marker of early synucleinopathies and αS protein misfolding in PD implies propagation from the gut to brainstem via the vagus nerve. The relationship between density of nigrostriatal dopamine or aS misfolding in gastrointestinal mucosa and the GI pathophysiology in human PD is unknown. To date, prior studies have typically addressed one pathological mechanism and one GI manifestation. Our multidisciplinary characterization of GI and neural phenotype in PD is key for this first study in 3 groups of humans of the mechanistic roles of the central neural circuitry, central dopamine receptors’ density, autonomic pathways, as well as αS expression in the gastrointestinal and colonic mucosa and microbiome in gut pathophysiology in human PD. Our overall hypothesis is that reduced nigrostriatal dopamine transmitter, autonomic dysfunction and increased αS expression or misfolding in the gastric, duodenal or sigmoid mucosa are associated with abnormal GI motor and barrier functions and with submucosal neuronal dopamine and αS expression in patients with PD with GI symptoms. We propose a prospective cohort design study with two aims in 3 groups, that is, PD patients with Hoehn and Yahr motor stages 1-3 with/without GI symptoms, and age-matched controls with n=24 per group: Aim 1: To compare GI motor functions (gastric emptying and accommodation, colonic transit, defecatory function), small bowel permeability, duodenal and stool microbiome and putative mechanisms (GI and sigmoid mucosal transcriptome, including αS misfolding, tight junction protein, and dopamine receptor expression). Aim 2: To quantitate nigrostriatal dopamine transporter expression, autonomic symptoms, and vagal and sympathetic functions using validated 123I-FP-CIT SPECT, COMPASS-31 questionnaires, and CASS scores, respectively and compare the central dopamine transporter expression and autonomic functions In sub-aims, we compare central and autonomic functions, GI transit and permeability, and mucosal αS mucosal expression or mis-folding in the 3 groups. The significance of the proposal lies in identification of mechanisms, and potential targets for future interventions directed to vagal and autonomic dysfunction, aggregation or misfolding of αS in gut mucosa, as well as dopamine expression to treat GI manifestations of PD.

胃肠道（GI）症状是帕金森氏病（PD）的重要非运动表现，可以在PD运动症状之前多年；认知功能障碍是重要的晚期，非运动表现。 Braak提出的假设α-突触核蛋白（αs）聚集了沿迷走神经或嗅觉传播到中枢神经系统（CNS）的传播，从而导致PD的运动和非运动特征。但是，在没有PD的老年人的Enter神经元中也发现了αS聚集体。挑胺预防αs聚集体改善了PD的便秘。黑质纹状体多巴胺转运蛋白的密度（通过123i-fp-CIT SPECT评估）与PD中的认知处理有关。 CSF中的αS低聚物是早期突触核酸的标志物，PD中的αs蛋白折叠折叠倍不形成，这意味着通过迷走神经从肠道传播到脑干。人类PD中胃肠道多巴胺的密度与胃肠道粘膜中的错误折叠与GI病理生理学之间的关系是未知的。迄今为止，先前的研究通常已经解决了一种病理机制和一种胃肠道表现。在PD中，我们对GI和神经表型的多学科表征是第一个研究的关键，这是三组人类中心神经回路，中央多巴胺受体的密度，自主神经途径的机理作用的关键，以及在胃肠道和结肠粘膜和微生物组中的αS表达。我们的总体假设是，在胃，十二指肠或sigmoid Mucosa中降低了鼻骨多巴胺发射机，自主功能障碍以及增加的αs表达或αS表达或错误折叠与与粘膜下神经元的多巴胺和αs表达相关的异常gi gi运动和障碍物与与pD的表达有关。我们提出了一项前瞻性队列设计研究，在3组中有两个目标，即Hoehn和Yahr电动机阶段1-3的PD患者，带有/不使用GI符号，以及每组n = 24的年龄匹配的对照： 目的1：比较GI运动功能（胃排空和住宿，结肠传输，缺乏功能），小肠渗透率，十二指肠和粪便微生物组以及推定的机制（GI和Sigmoid粘膜转运素组，包括αS错误折叠，紧密连接蛋白和多巴胺受体表达）。 目的2：使用经过验证的123i-fp-CIT SPECT，Compass-31问卷和CASS得分，并比较中央多巴胺的表达和自动函数，以量化黑质纹状体多巴胺转运蛋白转运蛋白转运蛋白表达，自主症状以及迷走神经和交感神经功能 在子-IAM中，我们比较了三组中的中心和自主功能，胃肠道传输和渗透性以及粘膜αs粘膜表达或错误折叠。该提案的意义在于鉴定机制，以及针对肠粘膜中αs的迷走神经和自主功能障碍，αs的聚集或折叠的潜在靶标，以及多巴胺表达以治疗PD的GI表现。