Longitudinal MRI biomarkers in Parkinson's disease

帕金森病的纵向 MRI 生物标志物

• 批准号: 8698386
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698386
• 关键词: Affect; Age; Age of Onset; Aging; Anatomy; Area; Attenuated; Autistic Disorder; Bilateral; Biological Markers; Biological Neural Networks; Blood; Brain; Brain region; Cells; Cerebellum; Cerebral cortex; Cerebral hemisphere; Cerebrum; Clinic; Clinical; Clinical Trials; Clinical assessments; Cognition; Cognitive; Corpus striatum structure; Data; Data Analyses; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dopamine; Functional Magnetic Resonance Imaging; Funding; Gilles de la Tourette syndrome; Goals; Handedness; Health; Human; Image; Imaging Techniques; Impaired cognition; Individual Differences; Life; Link; Liquid substance; Magnetic Resonance Imaging; Maps; Measures; Medical center; Metric; Military Personnel; Motor; Movement; Muscle; Nature; Nerve Fibers; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Neurotransmitters; Oxygen; Parkinson Disease; Patient Care; Patients; Physiological; Probability; Procedures; Process; Prospective Studies; Protocols documentation; Recovery; Recruitment Activity; Relative (related person); Research; Research Design; Rest; Role; Sampling; Schizophrenia; Seeds; Services; Severities; Side; Signal Transduction; Signaling Molecule; Staging; Substantia nigra structure; Symptoms; Techniques; Thalamic structure; Time; Tremor; Veterans; Vietnam; Work; agent orange; blood oxygen level dependent; brain cell; career development; cognitive function; cohort; computerized data processing; disorder subtype; executive function; improved; insight; longitudinal design; neuroimaging; neuropsychological; non-motor symptom; pre-clinical; putamen; white matter; white matter change

DESCRIPTION (provided by applicant): 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 decline. The motor symptoms are progressive, and often begin on one side of the body. Motor symptoms become detectable only when a large proportion of cells that manufacture the neurotransmitter dopamine have died. Although we currently have neuroimaging biomarkers for dopamine cells, we do not fully understand how loss of these cells influences brain functional and structural networks to give rise to symptoms. In recent years, magnetic resonance imaging (MRI) techniques have made it possible to begin mapping "the human connectome" - i.e., mapping the structural and functional connections between brain regions that form neural networks. Slow, synchronous fluctuations in blood oxygen dependent signal across the cerebrum can be used to map functional networks (fcMRI), while diffusion tensor imaging (DTI) is used to measure the microstructural health of nerve fibers and to extrapolate "tracks" between neuronal groups. The focus of this proposal will be to use these non-invasive techniques to map functional and structural connectivity changes in the brains of patients with PD, and to relate these changes to clinical symptoms. With prior VA funding through a career development mechanism, the PI gathered pilot MRI data from 15 PD subjects that were compared with control data. Analysis of the fcMRI suggested that two specific networks that link the cerebral cortex with different movement centers interact abnormally in PD. The DTI data suggested that PD also affects the neuronal processes that connect brain regions as nodes in these networks. Our recent work also showed that these DTI changes are related to cognitive function. We plan to extend and validate these findings in a larger sample. Hypotheses: The overall hypotheses are that metrics derived from DTI and fcMRI images will explain the nature and severity of motor and cognitive symptoms of PD. The longitudinal design will identify MRI measures that predict the rate of clinical symptom progression, and the transition from symptoms on one side of the body to both sides of the body. Study Design: This 4-year project will prospectively gather detailed clinical, cognitive, and MRI measures at time points two years apart. Sixty veterans with early PD and twenty healthy, age-matched controls will be recruited through VA clinics and studied as a longitudinal cohort. Study procedures will include brain MRI for network measures, as well as detailed neuropsychological and clinical assessments at two-year intervals. The specific aims are as follows: Aim 1: Measure key functional interactions between two brain networks that have roles in movement and cognition, and determine to what degree these measures reflect the nature and severity of motor and cognitive symptoms in PD. Aim 2: Determine to what degree microstructural and visible changes in the white matter that support these networks are related to clinical symptoms. Aim 3: Identify MRI measures of functional and structural networks that predict the rate and quality of clinical disease progression. The strong preliminary data we present in this application show that our research team has refined the techniques that will be needed to efficiently gather and analyze data for this prospective study. Significance for Veterans: PD currently affects 60,000 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 a first step in identifying new candidate biomarkers to be used in clinical trials.

描述（由申请人提供）： 帕金森病 (PD) 是一种常见的衰老疾病，会导致运动缓慢和震颤等运动症状，以及认知能力下降等非运动症状。运动症状是进行性的，通常从身体的一侧开始。只有当大部分产生神经递质多巴胺的细胞死亡时，运动症状才会被检测到。尽管我们目前拥有多巴胺细胞的神经影像生物标志物，但我们尚未完全了解这些细胞的丢失如何影响大脑功能和结构网络从而引起症状。近年来，磁共振成像（MRI）技术使得绘制“人类连接组”图成为可能，即绘制形成神经网络的大脑区域之间的结构和功能连接。大脑中血氧依赖信号的缓慢、同步波动可用于绘制功能网络 (fcMRI)，而扩散张量成像 (DTI) 用于测量神经纤维的微观结构健康状况并推断神经元组之间的“轨迹”。该提案的重点是使用这些非侵入性技术来绘制帕金森病患者大脑功能和结构连接的变化图，并将这些变化与临床症状联系起来。借助之前 VA 通过职业发展机制提供的资金，PI 收集了 15 名 PD 受试者的试点 MRI 数据，并与对照数据进行了比较。 fcMRI 分析表明，在帕金森病中，连接大脑皮层和不同运动中心的两个特定网络相互作用异常。 DTI 数据表明，PD 还会影响连接大脑区域作为这些网络节点的神经元过程。我们最近的工作还表明，这些 DTI 变化与认知功能有关。我们计划在更大的样本中扩展和验证这些发现。假设：总体假设是，从 DTI 和 fcMRI 图像得出的指标将解释 PD 运动和认知症状的性质和严重程度。纵向设计将确定 MRI 测量值，预测临床症状进展的速度，以及从身体一侧的症状向身体两侧的转变。研究设计：这个为期 4 年的项目将前瞻性地在相隔两年的时间点收集详细的临床、认知和 MRI 测量结果。将通过 VA 诊所招募 60 名患有早期 PD 的退伍军人和 20 名年龄匹配的健康对照者，并作为纵向队列进行研究。研究程序将包括用于网络测量的脑部核磁共振成像，以及每两年进行一次详细的神经心理学和临床评估。具体目标如下： 目标 1：测量在运动和认知中发挥作用的两个大脑网络之间的关键功能相互作用，并确定这些测量在多大程度上反映帕金森病运动和认知症状的性质和严重程度。目标 2：确定支持这些网络的白质微观结构和可见变化与临床症状的相关程度。目标 3：确定功能和结构网络的 MRI 测量值，以预测临床疾病进展的速度和质量。我们在此应用程序中提供的强有力的初步数据表明，我们的研究团队已经改进了有效收集和分析这项前瞻性研究数据所需的技术。对退伍军人的意义：PD 目前影响 60,000 名 VA 患者，随着越战时期服役的退伍军人进入该病发病的高峰年龄，这一数字预计还会增长。该项目将是确定用于临床试验的新候选生物标志物的第一步。