Longitudinal MRI in Preclinical Parkinson Disease

临床前帕金森病的纵向 MRI

• 批准号: 10357728
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357728
• 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; 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.

工作成就/背景：帕金森氏病（PD）是导致运动的常见疾病 诸如运动缓慢和震颤以及非运动症状之类的症状，例如认知困难 和便秘。非运动症状可以在数年以前的运动症状发展之前 观察结果导致了以下假设：PD具有较长的“临床前”时期，在此期间，大脑中的细胞和 周围神经系统受损，但损害尚未超过运动症状的阈值 表达。我们没有验证的方法来检测这种“临床前”疾病阶段。由于很长 PD的时间，这种生物标志物对于评估新疗法的影响至关重要 可用的。 使用对变化敏感的复杂磁共振成像（MRI）技术 大脑微观结构，我们已经显示出PD受试者的大脑与年龄匹配的健康之间的差异 控件。一种这样的技术，即扩散张量成像（DTI），估计水的方向和幅度 在大脑中的神经细胞内部和周围运动。另一种技术是多组分放松，能够 量化被困在洋葱状髓鞘鞘层内的水量，使神经隔离 细胞。在我们VA资助的研究计划的过去四年中，我们展示了扩散和髓磷脂 与健康对照相比，PD患者的措施不同。我们假设这些微观结构 在临床前疾病中可能可以检测到差异，并且可以预测从临床前的“转化” PD。 对于此提案，我们计划研究两个人口，高于PD的背景风险：退伍军人 在越南服务期间，他们暴露于特工橙（AO），并减少了嗅觉 （低质量），患有快速眼动睡眠行为障碍（RBD）的人，这种疾病导致 卧铺以实现自己的梦想。 目标：（1）评估大脑中的区域分布和微观结构差异程度 PD发展风险高，中和低风险的退伍军人； （2）比较MRI的变化率 这些群体之间的微观结构措施； （3）确定微观结构的程度 预测PD的其他症状的出现（例如微妙的运动障碍）或转换为PD。 方法：这个为期4年的项目将前瞻性地招募135名退伍军人与RBD，AO​​暴露与 低质量和具有正常嗅觉功能的AO暴露。退伍军人将通过繁忙的当地人招募 VA睡眠实验室，而将通过国家AO考试与具有AO暴露的退伍军人联系 注册表。 AO暴露的退伍军人将被邮寄标准化的气味敏锐度和睡眠测试 问卷，将用于选择人员加入研究。研究程序将包括大脑MRI 以及对认知和学习，运动速度和步行能力的详细分析（步态分析）。我们 将使用这些特定措施将我们的参与者组分为低，中和高风险的人 PD的发展。大脑MRI微观结构测量和这些测量中的纵向变化 然后将在组之间比较。 对退伍军人的重要性：PD目前影响80,000名VA患者，预计该数字将增长为 在越南时代服役的退伍军人进入了疾病的峰值年龄。这个项目将是下一个 了解PD在体内如何通过大脑以及开发新的MRI生物标志物的一步 用于临床试验。