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

研究扩大的血管周围空间作为脑小血管疾病的神经影像生物标志物

• 批准号: 10674098
• 负责人: TJ Libecap
• 金额: $ 4.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-10 至 2025-11-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674098
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-42; Amyloid beta-Protein; Basal Ganglia; Biological Markers; Blinded; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Disorders; Characteristics; Clinical; Cognition; Cognitive; Consensus; Data; Data Analyses; Dementia; Development; Disease; Early Diagnosis; Elderly; Excision; Experimental Designs; Fellowship; Flushing; Foundations; Functional Magnetic Resonance Imaging; Gases; Gold; Growth; Guidelines; Head; Hematological Disease; Hippocampus; Image; Impaired cognition; Intercellular Fluid; Kentucky; Knowledge; Laboratories; Lesion; Liquid substance; MRI Scans; Magnetic Resonance; Magnetic Resonance Imaging; Manuals; Maps; Measures; Mentors; Methods; Microvascular Dysfunction; Midbrain structure; Nerve Degeneration; Neuropsychological Tests; Neurosciences; Participant; Patients; Persons; Predisposition; Protocols documentation; Psyche structure; Regression Analysis; Risk; Risk Factors; Scanning; Scientist; Screening procedure; Site; Slice; Standardization; Techniques; Testing; Therapeutic; Time; Training; Universities; White Matter Hyperintensity; biomarker development; blood oxygen level dependent; burden of illness; career; cerebrovascular; cognitive function; cognitive testing; cohort; constriction; demographics; early detection biomarkers; environmental change; executive function; experience; experimental study; follow-up; imaging facilities; improved; in vivo; indexing; innovation; interest; longitudinal design; modifiable risk; neuroimaging; neuroimaging marker; neurovascular coupling; novel; pre-doctoral; predictive marker; prisma; response; solute; tool; vascular cognitive impairment and dementia; wasting; white matter; β-amyloid burden

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.

摘要 脑小血管病（cSVD）是一种重要的危险因素，可能在血管性脑卒中发作前数年出现。 认知障碍和痴呆（VCID）。cSVD的特征在于体内神经成像 生物标志物包括扩大的血管周围空间（ePVS）。PVS是间质细胞之间的交换部位， 脑脊液和脑脊髓液被认为在清除脑废物中起作用。清除率降低 可能导致PVS扩大和随后的毒性溶质特征的积累， 神经变性鉴于它们存在于支持认知的大脑区域，我们假设， 在认知正常的老年人中，定量的横断面ePVS计数可以作为早期生物标志物 的VCID。具体来说，我们预计ePVS将预测认知功能障碍和白色病变增加 三年后的负担。我们将在一组121名认知正常的老年人中测试这一假设， 基线时年龄为60-86岁。参与者在3 T Siemens Prisma磁共振成像仪上进行扫描 带64通道头部线圈的扫描仪ePVS由对参与者设盲的经验丰富的评估者手动计数 人口统计学遵循共识指南，使用T1 MPT、T2 FLAIR和定量敏感性 映射图像。所有ePVS均在具有高ePVS负荷的四个脑区的单个轴向切片中计数 包括半卵圆中心（CS ePVS）、基底神经节（BG ePVS）、海马和中脑。目标1将 测试CS ePVS预测执行功能（一个特定的认知领域）纵向变化的假设 受VCID影响。我们使用同一队列的初步数据包括CS ePVS与 和蒙特利尔认知评估（莫卡）评分（一种标准化的整体认知筛查工具）。 目标2将检验基线CS ePVS负荷预测深部白色高信号增加的假设 (WMH)三年后半卵圆中心的体积。这扩展了CS ePVS 与全脑WMH体积（晚期cSVD的标志物）呈正相关。在目标3中， 脑血管反应性（CVR）是微血管功能障碍的一种指标，将使用一种新的BOLD- fMRI测试范式，作为一个潜在的机制贡献者ePVS。之间的横截面关系 将分析BG ePVS和基底神经节CVR，以利用我们的初步数据，这些数据显示阴性 BG ePVS与总体CVR之间的关系。我们将进一步检验另一种假设， 脑脊液淀粉样蛋白-β 42/40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州大学磁共振实验室进行， 成像中心和桑德斯-布朗老龄化中心，在科学家和 临床医师导师。这个F30博士前奖学金将提供必要的经验，培训和知识 帮助受训者过渡到他的职业生涯的下一步，作为一个科学家，神经放射科医生在该领域的 使用基本和转化神经成像技术测量类似终点的衰老神经科学。