Cardiovascular Risk Factors and Rapid Disease Progression in Parkinson Disease

 描述(由申请人提供)： 多巴胺神经元的缺失导致帕金森病(PD)的许多临床特征，但不能解释关键的轴运动特征的进展，包括姿势不稳定和步态障碍，这些往往对多巴胺能药物无效，并在残疾中发挥重要作用。我们最近发表了将心血管危险因素与帕金森病患者轴运动功能发生率联系起来的横断面研究结果。这种影响的部分原因是慢性微血管病变的严重性，以脑部MRI上所见的白质高信号(WMH)来衡量。如果微血管脑部病变是导致帕金森病药物难治性运动障碍的罪魁祸首，那么使用有针对性的心血管风险因子减少干预措施及早识别和治疗高危受试者有可能成为一种疾病改善策略，影响许多患有帕金森病的退伍军人的医疗保健，在这些退伍军人中，心血管合并症更常见。然而，为了设计有效的临床试验，以降低因脑微血管病变而引起的并发症，更详细地了解心血管危险因素与临床有意义的预后之间的机制联系是至关重要的。我建议在一项为期两年的早期帕金森病患者纵向队列研究中，研究心血管危险因素和微血管脑病理对轴向运动特征的影响。目的1将验证从我们的初步横断面数据中得出的纵向假设：在2年的随访中，基线心血管危险因素负荷较大的PD患者发展更快的轴运动特征进展和更大的WMH负荷。目的2将使用动脉自旋标记(ASL)MRI来识别早期PD患者的脑血流量(CBF)和脑血管储备能力(CVRC)的局部损害，以防止进展为不可逆转的微血管损伤。这些研究不仅将作为一种新的自然 除了对帕金森病微血管改变的历史研究外，这些研究还将有助于确定帕金森病患者并发微血管改变的最高风险，从而允许设计一项未来的干预试验，重点是有针对性的早期心血管危险因素减少。这一潜在疾病调整策略的目标将是减缓患有帕金森病的退伍军人的轴向运动功能的药物难治率。如果成功，这种方法也将对其他神经退行性疾病产生影响。这个项目的实践经验，以及CDA-2提案中包括的神经影像、流行病学和临床试验方法学的正式培训计划，将有助于我的职业生涯成长为一名优秀的临床医生兼研究员，旨在将新的治疗策略引入PD临床试验领域。

 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.