A link between sleep-wake disturbances and enlarged perivascular spaces in youth with traumatic brain injury

患有创伤性脑损伤的青少年睡眠-觉醒障碍与血管周围间隙扩大之间的联系

• 批准号: 10368063
• 负责人: Juan Andres Piantino
• 金额: $ 16.54万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368063
• 关键词: 18 year old; Accident and Emergency department; Accounting; Active Learning; Acute; Address; Affect; Age; Alzheimer' s Disease; Animal Model; Animals; Anxiety; Appearance; Award; Biological; Biometry; Brain; Brain Concussion; Caring; Cerebrum; Child; Childhood; Clinical; Confusion; Contrast Media; Control Groups; Data; Data Analyses; Development; Devices; Emergency research; Enrollment; Equipment and supply inventories; Excision; Experimental Models; Fatigue; Fellowship; Foundations; Functional disorder; Future; Goals; Headache; Health Sciences; Human; Image; Impaired cognition; Impairment; Injury; Intervention; Intrathecal Injections; K-Series Research Career Programs; Knowledge; Link; Long-Term Effects; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Memory impairment; Mental Depression; Mentors; Methods; Minor; Modeling; Moods; Morbidity - disease rate; Mycobacterium tuberculosis; Normal Pressure Hydrocephalus; Oregon; Orthopedics; Outcome; Outcome Study; Pathology; Patients; Pediatric Neurology; Play; Population; Positioning Attribute; Post-Concussion Syndrome; Procedures; Publishing; Recording of previous events; Recovery; Reporting; Research; Research Personnel; Research Training; Residencies; Rodent Model; Role; Sleep; Sleep Disorders; Sleep disturbances; Symptoms; Techniques; Testing; Therapeutic Intervention; Training; Training Programs; Traumatic Brain Injury; United States; Universities; Vascular Dementia; Work; Youth; actigraphy; age group; base; brain magnetic resonance imaging; career; cohort; design; follow-up; glymphatic dysfunction; glymphatic function; glymphatic system; image processing; insight; interstitial; longitudinal analysis; meetings; mild traumatic brain injury; neurophysiology; new technology; novel; prevent; professor; risk stratification; skills; sleep pattern; sleep quality; solute; tool; wasting

Project Summary: I propose a 5-year mentored research training program to become a leader in the field of pediatric sleep research. I am residency-trained in Child Neurology, and dual fellowship-trained in Pediatric Neurocritical Care, and Clinical Neurophysiology. I am currently Assistant Professor of Child Neurology at Oregon Health and Science University. This proposal focuses specifically on understanding the role of sleep as a mediator of recovery in youth with mild TBI (mTBI), and the biological mechanisms underlying this mediator effect. My career plan will provide me advanced quantitative skills in biostatistical modeling and longitudinal analysis, use of actigraphy in sleep research, and advanced imaging processing. The training will come through formal coursework, mentored research, experiential learning, and scientific meetings. The overall objective of this proposal is to establish the mechanisms linking sleep-wake disturbances (SWD), glymphatic pathway disturbances, and persistent post-concussive symptoms in youth with mTBI. Every year, millions of youth are affected by mTBI. Post-concussive symptoms include headaches, fatigue, irritability, confusion, forgetfulness, and mood problems. Sleep problems are also a common complaint in this population. Patients with mTBI and subjective sleep problems report more prolonged post-concussive symptoms. However, despite this knowledge, several questions remain: 1) In youth with acute mTBI, to what extent do sleep disturbances play a mediating role in the persistence of post-concussive symptoms? 2) What are the biological mechanisms underlying this mediator effect? In order to answer these questions, I have decided to study the glymphatic pathway, a network of perivascular spaces that supports the clearance of interstitial solutes and wastes from the brain during sleep. Recently, the presence of enlarged perivascular spaces (ePVS) seen on brain MRI has been proposed as a noninvasive marker of glymphatic pathway dysfunction. Our preliminary data and findings from other investigators suggest that enlarged ePVS are seen in patients with mTBI, particularly in those with sleep disturbances. We will take advantage of novel technology developed at OHSU to measure ePVS in a cohort of youth with mTBI. The central hypothesis of this proposal is that glymphatic pathway dysfunction resulting from SWD drives the development and persistence of post-concussive symptoms. To test this hypothesis we will 1) Define the role of SWD as a mediator of persistent post-concussive symptoms in youth with mTBI; 2) Determine the combined effect of mTBI and SWD on ePVS burden in youth and the relationship between ePVS burden and persistent post- concussive symptoms. This research will help understand how sleep affects recovery after mTBI, and the mechanisms underlying this mediator effect. Data generated through this work will allow the design of larger longitudinal studies aimed at defining the long-term effects of SWD on outcomes after mTBI. It will also encourage the exploration of novel mechanisms affecting recovery in animal models of TBI.

项目概要： 我提出了一个为期 5 年的指导研究培训计划，以成为儿科睡眠领域的领导者 研究。我接受过儿童神经病学住院医师培训，并接受过儿科神经重症监护双重专科培训， 和临床神经生理学。我目前是俄勒冈健康中心儿童神经病学助理教授 理科大学。该提案特别侧重于了解睡眠作为调节因素的作用 患有轻度 TBI (mTBI) 的青少年的康复，以及这种中介效应背后的生物学机制。我的 职业规划将为我提供生物统计建模和纵向分析方面的高级定量技能，使用 睡眠研究中的体动记录仪和先进的成像处理。培训将通过正式的方式进行 课程作业、指导研究、体验式学习和科学会议。 该提案的总体目标是建立联系睡眠-觉醒障碍的机制 (SWD)、类淋巴通路紊乱和青少年持续性脑震荡后症状 mTBI。每年，数以百万计的青少年受到 mTBI 的影响。脑震荡后症状包括头痛、 疲劳、烦躁、混乱、健忘和情绪问题。睡眠问题也是常见的抱怨 在这个人群中。患有 mTBI 和主观睡眠问题的患者报告脑震荡后的时间更长 症状。然而，尽管有了这些知识，仍然存在几个问题：1）对于患有急性 mTBI 的青少年，应该采取什么措施？ 睡眠障碍在多大程度上对脑震荡后症状的持续存在起到中介作用？ 2) 什么 这种中介效应背后的生物学机制是什么？为了回答这些问题，我有 决定研究类淋巴通路，这是一种血管周围空间的网络，支持清除 睡眠期间大脑中的间质溶质和废物。最近发现血管周围肥大 脑 MRI 上看到的间隙 (ePVS) 已被提议作为类淋巴通路的无创标记物 功能障碍。我们的初步数据和其他研究人员的发现表明，扩大的 ePVS 见于 患有 mTBI 的患者，尤其是有睡眠障碍的患者。我们将利用新技术 OHSU 开发用于测量患有 mTBI 的年轻人队列中的 ePVS。本研究的中心假设 提议认为，SWD 导致的类淋巴通路功能障碍会驱动发育和 脑震荡后症状持续存在。为了验证这一假设，我们将 1) 将社署的角色定义为 患有 mTBI 的青少年中持续性脑震荡后症状的中介因素； 2) 确定综合效应 mTBI 和 SWD 对青少年 ePVS 负担的影响以及 ePVS 负担与持续性后遗症之间的关系 脑震荡症状。这项研究将有助于了解睡眠如何影响 mTBI 后的恢复，以及 这种中介效应的机制。通过这项工作生成的数据将允许设计更大的 纵向研究旨在确定 SWD 对 mTBI 后结局的长期影响。它还将 鼓励探索影响 TBI 动物模型恢复的新机制。