Neurovascular Determinants of Cognitive Function in Adults with Sickle Cell Disease

 描述(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，导致严重的功能障碍，其发病机制、危险因素和自然病史尚不清楚。因此，阐明CI具有很高的公共卫生意义，因为它将有助于制定预防和治疗策略。在第一个RO1应用中，Novelli博士建立在他在SCD血管生物学方面的PRIR工作的基础上，提出CI是由特定的、可量化的脑微血管疾病引起的，而后者又是由病理性活性氧(ROS)引起的炎症和氧化损伤引起的。他特别提出，炎性蛋白TSP1促进ROS的产生，从而导致脑血管疾病，最终导致脑梗塞。这一新途径从未在SCD中被测试过，因为缺乏对CI危险因素的全面纵向评估，以及缺乏足够的MRI方法来成像脑微血管。这项建议通过在一组具有良好特征的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记物来解决这些障碍。该项目有望在脑梗塞的病理生理学及其危险因素方面产生关键的新知识，作为早期预防、筛查和干预的目标。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博士正在进行的这一队列研究的基础上，得到了机构资金的支持、强大的临床研究基础设施以及与研究人员在神经流行病学、生物统计学、神经成像、精神病学、神经心理学和微血管疾病方面的专家的现有合作努力。这些合作已经导致了支持这一应用程序的强有力的、已公布的初步结果。该项目还具有很高的创新性，因为它使用最先进的技术测试了SCD中与微血管功能障碍相关的CI的新范式。我们的科学问题被表述为两个目标，目标1，横截面，目标2，纵向。在目标1中，我们首先计划在更大的队列(n=160名患者和70名对照组)中扩展和确认我们的初步结果，即与对照组(H1)相比，患者的7T MRI微血管异常的认知功能和负担更差。在患者体内，我们将检验这样的假设，即较差的7T MRI异常与较差的认知功能(H2)有关，而高TSP1水平与较差的7T MRI异常和认知功能(H3)都相关。最后，我们检验了ROS调节TSP1和这些结果之间的联系的假设(H4)。在目标2中，这些假设将以纵向设计进行验证，在3年重复磁共振，在3年和5年重复血液和认知测量。

 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.