Investigating Enlarged Perivascular Spaces as a Neuroimaging Biomarker of Cerebral Small Vessel Disease

摘要 脑部小血管疾病(Csvd)是一个重要的危险因素，可能在血管发病前数年出现。 认知障碍和痴呆症(VCID)的贡献。CSVD的特征是活体神经成像 生物标志物包括血管周围间隙扩大(EPVS)。PVS是间质之间的互换部位 液体和脑脊液，据信在清除大脑废物方面发挥作用。减少的间隙 可能导致PVS增大并随后积累具有以下特征的有毒溶质 神经退行性变。鉴于它们存在于支持认知的大脑区域，我们假设 认知正常老年人的定量横断面ePVS计数可作为早期生物标志物 是VCID的。具体地说，我们预计ePVS将预测认知功能障碍和脑白质损害增加。 三年后的负担。我们将在121名认知正常的老年人中测试这一假设 基线年龄从60岁到86岁。参与者接受3T西门子Prisma磁共振成像扫描 带有通道磁头线圈的扫描仪。EPV由经验丰富的评分员手动计数，对参与者视而不见 遵循使用T1 MPRAGE、T2 FLAIR和定量易感性的共识指南的人口统计数据 映射图像。所有的ePVs被计算在一个单一的轴向切片中，包括四个具有高ePVS负荷的脑区 包括半卵圆中心(CS EPVS)、基底节(BG EPVS)、海马体和中脑。目标1将 检验CS ePVS预测执行功能纵向变化的假设，执行功能是特定的认知领域 受VCID影响。我们使用相同队列的初步数据包括CS ePVS之间的负相关 以及基线蒙特利尔认知评估(MoCA)评分，这是全球认知的标准化筛选工具。 目标2将验证基线CS ePVS负荷预测深层白质高信号增加的假设 (WMH)三年后半卵圆中心的体积。这是对CS ePVS的初步发现的扩展 与全脑WMH量呈正相关，全脑WMH量是进展期cSVD的标志。在目标3中，区域 脑血管反应性(CVR)，一种衡量微血管功能障碍的指标，将使用一种新的BOLD- FMRI测试范式，作为ePVS的潜在机制贡献者。它们之间的横截面关系 我们将分析BG、ePVS和基底节CVR，以利用我们的初步数据，这些数据显示 BG ePVS与全球CVR的关系我们将进一步测试另一种假设，即 脑脊液淀粉样蛋白-β42/40比值，淀粉样蛋白负荷的生物标志物，与 EPVS优于CVR。这些实验将在肯塔基大学的磁共振和 成像中心和桑德斯-布朗老龄化中心，在科学家和 临床医生导师。这个F30博士前奖学金将提供必要的经验、培训和知识 帮助学员过渡到他职业生涯的下一步，成为一名科学家-神经放射科医生，在 使用基础神经成像技术和平移神经成像技术测量相似终点的衰老神经科学。

ABSTRACT Cerebral small vessel disease (cSVD) is an important risk factor that may arise years before the onset of vascular contributions to cognitive impairment and dementia (VCID). cSVD is characterized by in-vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are the site of interchange between interstitial fluid and cerebrospinal fluid which is believed to play a role in the removal of brain waste. Reduced clearance may lead to enlargement of the PVS and subsequent accumulation of toxic solutes characteristic of neurodegeneration. Given their presence in brain regions that support cognition, we hypothesize that quantitative, cross-sectional ePVS counts in cognitively normal older adults could serve as an early biomarker of VCID. Specifically, we anticipate ePVS will predict cognitive dysfunction and increased white matter lesion burden after three years. We will test this hypothesis in a cohort of 121 cognitively normal older adults ranging in age from 60-86 at baseline. Participants are scanned on a 3T Siemens Prisma magnetic resonance imaging scanner with a 64-channel head coil. ePVS are manually counted by an experienced rater blinded to participant demographics following consensus guidelines using T1 MPRAGE, T2 FLAIR, and Quantitative Susceptibility Mapping images. All ePVS are counted in a single, axial slice of four brain regions with high ePVS burden including the centrum semiovale (CS ePVS), basal ganglia (BG ePVS), hippocampus, and midbrain. Aim 1 will test the hypothesis that CS ePVS predict longitudinal changes in executive function, a specific cognitive domain affected in VCID. Our preliminary data using the same cohort include a negative relationship between CS ePVS and baseline Montreal Cognitive Assessment (MoCA) score, a standardized screening tool of global cognition. Aim 2 will test the hypothesis that baseline CS ePVS burden predicts increased deep white matter hyperintensity (WMH) volume in the centrum semiovale after three years. This expands on preliminary findings that CS ePVS are positively related to whole brain WMH volume, a marker of advanced cSVD. In Aim 3, regional cerebrovascular reactivity (CVR), a measure of microvascular dysfunction, will be analyzed using a novel BOLD- fMRI testing paradigm, as a potential mechanistic contributor of ePVS. The cross-sectional relationship between BG ePVS and basal ganglia CVR will be analyzed to capitalize on our preliminary data which show a negative relationship between BG ePVS and global CVR. We will further test an alternative hypothesis that the cerebrospinal fluid amyloid-beta 42/40 ratio, a biomarker of amyloid burden, is more closely associated with ePVS than CVR. These experiments will be carried out at the University of Kentucky Magnetic Resonance and Imaging Center and the Sanders-Brown Center on Aging, under the direction of an expert team of scientist and clinician mentors. This F30 predoctoral fellowship will provide the requisite experience, training, and knowledge to aid the trainee’s transition into the next step of his career as a scientist-neuroradiologist in the field of neuroscience of aging measuring similar endpoints using basic and translational neuroimaging techniques.