Neurovascular Determinants of Cognitive Function in Adults with Sickle Cell Disease

 描述（由申请人提供）：镰状细胞病（SCD）的特征是炎症和氧化损伤引起的微血管疾病。许多成年SCD患者患有认知障碍（CI），这是一种严重的并发症，可导致严重的功能限制，其发病机制、风险因素和自然史尚不清楚。因此，阐明CI具有很高的公共卫生意义，因为它将允许预防和治疗策略的发展。在第一个RO1应用中，Novelli博士基于他对SCD血管生物学的初步研究，提出CI是由特定的、可量化的脑微血管疾病引起的，而这些疾病又是由炎症和病理性活性氧（ROS）的氧化损伤引起的。他特别提出，炎症蛋白TSP1促进ROS的产生，导致脑血管疾病，最终CI。由于缺乏对CI危险因素的全面纵向评估和对脑微血管成像的适当MRI方法，这种新途径从未在SCD中进行过测试。该提案通过在充分表征的SCD成人队列中应用7T MRI神经成像，结合神经认知测试和炎症和氧化损伤的血液生物标志物来解决这些障碍。该项目预计将产生关键的新知识的病理生理学CI及其危险因素的目标，早期预防，筛查和干预。这项研究利用了Novelli博士在SCD血管生物学方面的专业知识和目前的工作，并建立在Novelli博士在该队列中正在进行的研究的基础上，由机构基金，强大的临床研究基础设施以及与神经流行病学，生物统计学，神经影像学，精神病学，神经心理学和微血管疾病研究专家的现有合作努力支持。这些合作已经产生了强有力的、已发表的初步结果，支持这一应用。该项目也具有高度创新性，因为它采用最先进的技术测试了SCD中微血管功能障碍相关CI的新范式。我们的科学问题分为两个目标，目标1，横截面和目标2，纵向。在目标1中，我们首先计划在更大的队列（n=160例患者和70例对照）中扩展和确认我们的初步结果，该结果显示与对照组相比，患者的认知功能和7T MRI微血管异常负担更差（H1）。在患者中，我们将检验以下假设：更差的7T MRI异常与更差的认知功能相关（H2），高TSP 1水平与更差的7T MRI异常和认知功能相关（H3）。最后，我们检验了ROS介导TSP 1与这些结果之间的关联的假设（H4）。在目标2中，将在纵向设计中对这些假设进行检验，在3年时重复进行MRI，在3年和5年时重复进行血液和认知测量。

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is characterized by microvascular disease from inflammation and oxidative damage. Many adult patients with SCD suffer from cognitive impairment (CI), a serious complication responsible for severe functional limitations, and whose pathogenesis, risk factors, and natural history are unknown. Thus, elucidating CI holds high public health significance because it will allow the development of preventive and therapeutic strategies. In this first RO1 application, Dr. Novelli builds on his prir work on the vascular biology of SCD and proposes that CI is caused by specific, quantifiable, cerebral microvascular disease, in turn caused by inflammation and oxidative damage from pathologic reactive oxygen species (ROS). He specifically proposes that the inflammatory protein TSP1 promotes ROS generation that leads to cerebrovascular disease and ultimately CI. This novel pathway has never been tested in SCD because of the lack of comprehensive longitudinal assessments of risk factors of CI and adequate MRI methods to image the cerebral microvasculature. This proposal addresses these barriers via the application of 7T MRI neuroimaging in a well- characterized cohort of adults with SCD in combination with neurocognitive testing and blood biomarkers of inflammation and oxidative damage. This project is expected to generate critical new knowledge on the pathophysiology of CI and its risk factors as targets for early prevention, screening and intervention. This study leverages Dr. Novelli's expertise and current work in the vascular biology of SCD, and builds on Dr. Novelli's ongoing study in this cohort, supported by institutional funds, a strong clinical research infrastructure ad existing collaborative efforts with investigators expert in Neuroepidemiology, Biostatistics, Neuroimaging, Psychiatry, Neuropsychology, and microvascular disease. These collaborations have already led to strong, published, preliminary results that support this application. This project is also highly innovative because it tests a new paradigm of microvascular dysfunction-related CI in SCD with state-of-the-art technology. Our scientific questions are articulated into two aims, Aim1, cross-sectional and Aim 2, longitudinal. In Aim 1 we first plan to extend and confirm in a larger cohort (n=160 patients and 70 controls) our preliminary results showing worse cognitive function and burden of 7T MRI microvascular abnormalities in patients as compared to controls (H1). Within patients, we will then test the hypothesis that worse 7T MRI abnormalities are linked to worse cognitive function (H2) and that high TSP1 levels are associated with both worse 7T MRI abnormalities and cognitive function (H3). Finally, we test the hypothesis that ROS mediates the association between TSP1 and these outcomes (H4). In Aim 2, these hypotheses will be tested in a longitudinal design with repeated MRI at 3 years and repeated blood and cognitive measures at 3 and 5 years.