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) 症状是帕金森病 (PD) 的重要非运动表现，可能早于帕金森病运动症状数年；认知功能障碍是一种重要的晚期非运动表现。 Braak 的假设提出，α-突触核蛋白 (αS) 聚集体沿着迷走神经或嗅觉传入神经传播到中枢神经系统 (CNS)，导致 PD 的运动和非运动特征。然而，在没有帕金森病的老年人的肠神经元中也发现了 αS 聚集体。角鲨胺预防 αS 聚集体可改善 PD 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 的认知处理相关。脑脊液中的 αS 寡聚体是早期突触核蛋白病的标志，PD 中的 αS 蛋白错误折叠意味着通过迷走神经从肠道传播到脑干。黑质纹状体多巴胺密度或胃肠粘膜中 aS 错误折叠与人类 PD 胃肠道病理生理学之间的关系尚不清楚。迄今为止，先前的研究通常涉及一种病理机制和一种胃肠道表现。我们对帕金森病胃肠道和神经表型的多学科表征是这项首次研究的关键，该研究对 3 组人类进行了中枢神经回路、中枢多巴胺受体密度、自主神经通路以及胃肠道和结肠粘膜中的 αS 表达以及微生物组在人类帕金森病肠道病理生理学中的机制作用。我们的总体假设是，黑质纹状体多巴胺递质减少、自主神经功能障碍以及胃、十二指肠或乙状结肠粘膜中αS表达增加或错误折叠与胃肠道运动和屏障功能异常以及具有胃肠道症状的PD患者的粘膜下神经元多巴胺和αS表达相关。我们提出一项前瞻性队列设计研究，将两个目标分为 3 组，即 Hoehn 和 Yahr 运动阶段 1-3 且有/无胃肠道症状的 PD 患者，以及每组 n=24 的年龄匹配对照： 目标 1：比较胃肠道运动功能（胃排空和调节、结肠转运、排便功能）、小肠通透性、十二指肠和粪便微生物组和假定机制（胃肠道和乙状结肠粘膜转录组，包括 αS 错误折叠、紧密连接蛋白和多巴胺受体表达）。 目标 2：分别使用经过验证的 123I-FP-CIT SPECT、COMPASS-31 问卷和 CASS 评分定量黑质纹状体多巴胺转运蛋白表达、自主神经症状以及迷走神经和交感神经功能，并比较中枢多巴胺转运蛋白表达和自主神经功能 在子目标中，我们比较了 3 组的中枢和自主功能、胃肠道转运和通透性以及粘膜 αS 粘膜表达或错误折叠。该提案的意义在于确定机制，以及未来针对迷走神经和自主神经功能障碍、肠粘膜中 αS 聚集或错误折叠以及多巴胺表达治疗 PD 胃肠道表现的干预措施的潜在目标。