Longitudinal MRI in Preclinical Parkinson Disease

临床前帕金森病的纵向 MRI

• 批准号: 10426281
• 负责人: Catherine L. Gallagher
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426281
• 关键词: Affect; Age; Age of Onset; Aging; Allium cepa; Anisotropy; Anosmia; Area; Biological Markers; Brain; Brain Stem; Cells; Cerebrum; Clinical; Clinical Trials; Cognition; Cognitive; Constipation; Control Groups; Data; Development; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dreams; Education; Equilibrium; Exposure to; Fiber; Funding; Future; Gait; Gender; Goals; Human; Image; Imaging Techniques; Impaired cognition; Laboratories; Learning; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Measures; Medical center; Methods; Military Personnel; Modeling; Motor; Movement; Myelin; Myelin Sheath; Nature; Nervous System Trauma; Neurites; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Outcome Measure; Parkinson Disease; Participant; Patient Care; Patients; Peripheral Nervous System; Persons; Physiologic pulse; Physiological; Population; Procedures; Process; Questionnaires; REM Sleep Behavior Disorder; Radial; Registries; Research; Risk; Sampling; Sensory; Services; Sleep; Smell Perception; Speed; Standardization; Symptoms; Techniques; Testing; Thick; Tremor; Veterans; Vietnam; Walking; Water; Water Movements; White Matter Hyperintensity; Work; age related; agent orange; brain magnetic resonance imaging; clinical development; cohort; density; disorder risk; experience; gait examination; high risk; high risk population; hyposmia; in vivo; indexing; interest; magnetic resonance imaging biomarker; motor impairment; motor symptom; muscle stiffness; non-motor symptom; novel therapeutics; pre-clinical; predictive marker; primary outcome; programs; prospective; rate of change; recruit; secondary outcome; smell test; white matter

Work Accomplished/Background: Parkinson's disease (PD) is a common disease of aging that causes motor symptoms such as slow movement and tremor, as well as non-motor symptoms, such as cognitive difficulties and constipation. Non-motor symptoms can precede the development of motor symptoms by years—this observation has led to the hypothesis that PD has a long “preclinical” period during which cells in the brain and peripheral nervous system are damaged, but the damage has not exceeded a threshold for motor symptom expression. We do not have validated methods to detect this “preclinical” disease stage. Due to the long timecourse of PD, such biomarkers will be critical to evaluate the effects of new therapies as they become available. Using sophisticated magnetic resonance imaging (MRI) techniques that are sensitive to changes in the brain microstructure, we have shown differences between the brains of PD subjects and age-matched healthy controls. One such technique, diffusion tensor imaging (DTI), estimates the direction and magnitude of water movement inside and around nerve cells in the brain. Another technique, multicomponent relaxometry, is able to quantify the amount of water trapped inside the layers of the onion-like myelin sheaths that insulate nerve cells. In the past four years of our VA-funded research program, we have shown both diffusion and myelin measures to differ in PD patients in comparison to healthy controls. We hypothesize that these microstructural differences may be detectable in preclinical disease, and may predict “conversion” from preclinical to clinical PD. For this proposal we plan to study two populations at higher than background risk for PD: Veterans who have been exposed to Agent Orange (AO) during service in Vietnam and have reduced sense of smell (hyposmia), and persons with rapid eye movement sleep behavior disorder (RBD), a condition that causes sleepers to act out their dreams. Objectives: (1) To evaluate the regional distribution and degree of microstructural difference in the brains of Veterans with high, medium, and low risk for the development of PD; (2) compare the rate of change in MRI microstructural measures between these groups; (3) determine to what degree microstructural measures predict the emergence of additional symptoms of PD (such as subtle motor impairment), or conversion to PD. Methods: This 4-year project will prospectively recruit a cohort of 135 Veterans with RBD, AO exposure with hyposmia, and AO exposure with normal olfactory function. Veterans will be recruited through the busy local VA sleep laboratory, while Veterans with AO exposure will be contacted through the National AO Examination Registry. AO-exposed Veterans will be mailed a standardized test of smell acuity as well as a sleep questionnaire, which will be used to select persons to join the study. Study procedures will include a brain MRI as well as detailed analyses of cognition and learning, movement speed, and walking ability (gait analysis). We will use these specific measures to divide our participant group into persons with low, medium, and high risk for the development of PD. Brain MRI microstructural measures and longitudinal changes within these measures will then be compared between groups. Significance for Veterans: PD currently affects 80,000 VA patients, and this number is expected to grow as Veterans who served in the Vietnam era enter peak ages for onset of the disease. This project will be the next step in understanding how PD progresses through the brain in vivo and in developing new MRI biomarkers to be used in clinical trials.

工作完成/背景：帕金森病（PD）是一种常见的衰老疾病，会导致运动能力下降 运动缓慢和震颤等症状，以及认知困难等非运动症状 非运动症状可能会先于运动症状出现数年——这就是。 观察得出这样的假设：帕金森病有一个很长的“临床前”时期，在此期间，大脑和细胞中的细胞 周围神经系统受损，但损害尚未超过运动症状阈值 由于漫长的时间，我们没有有效的方法来检测这种“临床前”疾病阶段。 随着 PD 的时间进程，此类生物标志物对于评估新疗法的效果至关重要。 可用的。 使用对环境变化敏感的复杂磁共振成像 (MRI) 技术 通过大脑微观结构，我们显示了帕金森病受试者的大脑与年龄匹配的健康人的大脑之间的差异 其中一种技术是扩散张量成像 (DTI)，它可以估计水的方向和大小。 另一种技术，即多成分松弛测量法，能够实现大脑神经细胞内部和周围的运动。 量化隔离神经的洋葱状髓鞘层内的水量 在我们 VA 资助的研究项目的过去四年中，我们已经展示了扩散和髓磷脂。 与健康对照相比，PD 患者的测量有所不同。 在临床前疾病中可以检测到差异，并可以预测从临床前到临床的“转变” PD。 对于这项提案，我们计划研究两个 PD 风险高于背景风险的人群：退伍军人 在越南服役期间接触过橙剂（AO）并导致嗅觉下降的人 （嗅觉减退），以及患有快速动眼睡眠行为障碍（RBD）的人，这种情况会导致 睡觉的人去实现他们的梦想。 目的：（1）评价大脑微结构的区域分布和差异程度。 患有PD高、中、低风险的退伍军人（2）比较MRI的变化率； (3) 确定微观结构措施的程度 预测帕金森病其他症状的出现（例如轻微的运动障碍）或转变为帕金森病。 方法：这个为期 4 年的项目将前瞻性地招募 135 名患有 RBD、AO 暴露的退伍军人 嗅觉减退和AO暴露的嗅觉功能正常的退伍军人将通过繁忙的地方招募。 VA 睡眠实验室，而患有 AO 暴露的退伍军人将通过国家 AO 检查进行联系 登记处将向接触过 AO 的退伍军人邮寄一份标准化嗅觉敏锐度测试和睡眠测试。 调查问卷将用于选择参加研究的人员。研究程序将包括脑部 MRI 扫描。 以及认知和学习、运动速度和行走能力（步态分析）的详细分析。 将使用这些具体措施将我们的参与者群体分为低、中、高风险人群 脑 MRI 微观结构测量的发展以及这些测量中的纵向变化。 然后将在组之间进行比较。 对退伍军人的意义：PD 目前影响 80,000 名退伍军人患者，预计这一数字将继续增长 越战时期服役的退伍军人进入了疾病发病的高峰年龄，该项目将是下一个项目。 进一步了解 PD 在体内如何在大脑中进展，并开发新的 MRI 生物标志物 用于临床试验。