Cardiovascular Risk Factors and Rapid Disease Progression in Parkinson Disease

帕金森病的心血管危险因素和疾病快速进展

• 批准号: 9022671
• 负责人: Vikas Kotagal
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022671
• 关键词: Accounting; Acetazolamide; Affect; Aging; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Cardiovascular system; Cerebrovascular Circulation; Chronic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Comorbidity; Data; Dementia; Disease; Disease Progression; Dopamine; Early identification; Early treatment; Epidemiology; Equilibrium; Exhibits; Functional disorder; Funding; Future; Gait; Goals; Growth; Health system; Healthcare; Impaired cognition; Impairment; Individual; Injury; Intervention; Intervention Trial; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Metabolic stress; Methodology; Methods; Modification; Motor; Natural History; Nerve Degeneration; Neurodegenerative Disorders; Odds Ratio; Outcome; Parkinson Disease; Pathogenesis; Patients; Pharmaceutical Preparations; Platelet Factor 4; Play; Process; Prospective Studies; Publishing; Quality of life; Refractory; Research; Research Personnel; Resistance; Risk; Risk Factors; Role; Severities; Spin Labels; Staging; Symptoms; Techniques; Testing; Training; Veterans; Walking; White Matter Hyperintensity; cardiovascular risk factor; career; career development; cerebrovascular; conventional therapy; design; disability; dopaminergic neuron; effective intervention; effective therapy; experience; falls; follow-up; high risk; improved; microvascular pathology; mortality; motor impairment; neuroimaging; neurovascular unit; novel; novel therapeutics; prevent; prospective; public health relevance; treatment strategy; white matter damage; white matter injury

 DESCRIPTION (provided by applicant): Loss of dopamine neurons leads to many of the clinical features of Parkinson disease (PD) but does not account for the progression of critical axial motor features, including postural instabiliy and gait impairments that tend to be refractory to dopaminergic medications and play a large role in disability. We recently published cross-sectional findings linking cardiovascular risk factors with the rate of axial motor feature accrual in PD. This effect was partially explained by the severity of chronic microvascular pathology, measured as white matter hyperintensities (WMHs) seen on brain MRI. If microvascular brain pathologies are responsible for causing medication-refractory motor impairments in PD, the early identification and treatment of high-risk subjects using targeted cardiovascular risk factor reduction interventions has the potential to serve as a disease modifying strategy impacting the health care of many Veterans with PD, in whom cardiovascular comorbidities are seen more commonly. In order to design effective clinical trials aimed at lowering complications due to comorbid microvascular brain pathology, however, a more detailed understanding of the mechanistic link between cardiovascular risk factors and clinically meaningful outcomes is essential. I propose to study the impact of cardiovascular risk factors and microvascular brain pathology on axial motor features in a 2-year longitudinal cohort study of individuals with early Parkinson disease. Aim 1 will test a longitudinal hypothesis drawn from our preliminary cross-sectional data: PD patients with greater baseline cardiovascular risk factor burden develop more rapid progression of axial motor features and greater WMH burden at 2 year follow-up. Aim 2 will use arterial spin labeling (ASL) MRI to identify regional impairments in cerebral blood flow (CBF) and cerebrovascular reserve capacity (CvRC) in early PD subjects with cardiovascular risk factors before the progression to irreversible microvascular injury takes place. These studies will not only serve as a novel natural history study of microvascular changes in PD, they will also facilitate the identification of PD subjects at highest risk for comorbid microvascular changes, permitting the design of a future intervention trial focused on targeted, early cardiovascular risk factor reduction. The goal of thi potential disease modifying strategy would be to slow the rate of medically refractory axial motor feature accrual in Veterans with PD. If successful, this approach would have implications for other neurodegenerative conditions as well. The practical experience of this project along with the formal training plan in neuroimaging, epidemiology, and clinical trials methodology included in this CDA-2 proposal will facilitate my career growth into a MERIT-funded clinician-investigator who aims to usher novel therapeutic strategies into the realm of PD clinical trials.

 描述（由申请人提供）： 多巴胺神经元的丧失导致帕金森病（PD）的许多临床特征，但不能解释关键轴向运动特征的进展，包括姿势不稳和步态障碍，这些往往是多巴胺能药物难治性的，并在残疾中发挥重要作用。我们最近发表了横断面研究结果，将心血管危险因素与PD患者轴向运动功能增加率联系起来。这种效应部分由慢性微血管病理学的严重程度解释，测量为脑MRI上观察到的白色高信号（WMH）。如果微血管脑病变是导致PD中药物难治性运动障碍的原因，则使用靶向心血管风险因素降低干预措施早期识别和治疗高风险受试者有可能作为影响许多患有PD的退伍军人的医疗保健的疾病改善策略，其中心血管合并症更常见。然而，为了设计有效的临床试验，旨在降低并发症，由于共病微血管脑病理，心血管危险因素和临床有意义的结果之间的机制联系的更详细的了解是必不可少的。我建议在一项对早期帕金森病患者的2年纵向队列研究中，研究心血管危险因素和微血管脑病理学对轴向运动功能的影响。目标1将检验从我们的初步横断面数据中得出的纵向假设：基线心血管风险因素负荷较大的PD患者在2年随访时轴向运动功能进展更快，WMH负荷更大。目的2将使用动脉自旋标记（ASL）MRI来识别具有心血管风险因素的早期PD受试者在进展为不可逆微血管损伤之前的脑血流量（CBF）和脑血管储备能力（CvRC）的局部损伤。这些研究将不仅作为一个新的自然 通过对PD中微血管变化的历史研究，它们还将有助于识别具有最高共病微血管变化风险的PD受试者，从而允许设计未来的干预试验，重点关注靶向的早期心血管风险因素降低。这种潜在疾病改善策略的目标是减缓PD退伍军人的医学难治性轴向运动功能累积的速率。如果成功，这种方法也将对其他神经退行性疾病产生影响。该项目的实践经验沿着正式的培训计划，包括神经影像学，流行病学和临床试验方法，包括在这个CDA-2的建议将促进我的职业生涯成长为MERIT资助的临床研究者，旨在引进新的治疗策略进入PD临床试验领域。