Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease

BBB 水交换减少作为小血管疾病的临床前生物标志物

• 批准号: 10369462
• 负责人: BRIAN Timothy GOLD
• 金额: $ 195.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369462
• 关键词: Affect; Amino Acids; Amyloid beta-Protein; Biological; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebrospinal Fluid; Clinical Trials; Cognitive; Data; Development; Diffusion Magnetic Resonance Imaging; Disease Progression; Early Diagnosis; Early identification; Elderly; Extravasation; Functional disorder; Glucose; Goals; Growth; Image; Impaired cognition; Individual; Isoprostanes; MRI Scans; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Modeling; Monitor; Neurocognitive Deficit; Neuropsychology; Outcome Study; Oxidative Stress; Participant; Plasma; Predisposition; Public Health; Regression Analysis; Research; Research Priority; Risk; Risk Factors; Sampling; Serum Albumin; System; Testing; Therapeutic Intervention; Water; White Matter Hyperintensity; arterial spin labeling; blood-brain barrier function; cerebral microbleeds; cerebrovascular; cognitive performance; dementia risk; diffusion weighted; early detection biomarkers; executive function; follow-up; high risk; improved; indexing; inflammatory marker; innovation; neuroimaging; neuroimaging marker; novel; novel marker; pre-clinical; response; tau Proteins; tau-1; tool; vascular cognitive impairment and dementia; vascular risk factor; white matter

Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease Vascular cognitive impairment and dementia (VCID) is common in older adults and is a major public health risk. VCID affects the network of small blood vessels that supply all parts of the brain, resulting in cognitive decline. Clinical trials have been hampered by the lack of non- invasive tools to detect early stages of VCID. Consequently, innovative tools for the identification of early-stage VCID have become a major research priority. The blood-brain barrier (BBB) may be a key system affected early in the course of VCID. Recent advances in the development of a novel diffusion-weighted ASL (DW-ASL) sequence and post-processing analyses have made it possible to quantify water exchange rate across the BBB, a metric of BBB functioning. Our preliminary results using this novel sequence suggest that low water exchange across the BBB (low kw) is associated with high concentrations of plasma vascular inflammatory markers and poor cognitive performance, suggesting that it may represent an early marker of VCID. Longitudinal research is required to test this possibility. This proposal seeks to assess the accuracy of low kw as a predictor of subsequent neurocognitive declines. We will also test the possibility that low kw is associated with oxidative stress, assessed via cerebrospinal fluid (CSF) isoprostane levels. We propose to study 140 healthy older adults at baseline using DW-ASL, plasma inflammatory markers and CSF measures of isoprostanes, Aβ, p-tau and t-tau. In addition, structural neuroimaging measures will be obtained and quantified, including regional volumes, white matter hyperintensity (WMH) volumes, diffusion tensor imaging for quantification of regionally distributed white matter abnormalities and susceptibility weighted imaging for quantification of cerebral microbleeds. A subset of participants will complete the same neuroimaging and biofluid measures approximately 3 years later. We aim to identify the relationship between baseline BBB water exchange and subsequent WMH growth (Aim 1); cognitive declines (Aim 2) and biofluid indices of oxidative stress (Aim 3). The overall hypothesis we will test is that that low water exchange rate assessed with a novel DW-ASL sequence represents an early marker BBB dysfunction associated with later WMH growth, cognitive declines and oxidative stress.

BBB水交换减少作为小血管疾病的临床前生物标志物 血管性认知障碍和痴呆（VCID）在老年人中很常见，是一种主要的 公共健康风险。VCID会影响供应血管所有部分的小血管网络。 大脑，导致认知能力下降。临床试验由于缺乏非- 侵入性工具来检测VCID的早期阶段。因此， 早期VCID识别已成为主要的研究优先事项。血脑 血脑屏障（BBB）可能是VCID早期受影响的关键系统。的最新进展 新型扩散加权ASL（DW-ASL）序列和后处理的开发 分析使量化BBB的水交换率成为可能，这是一个衡量 BBB功能正常。我们使用这种新序列的初步结果表明， 通过BBB的交换（低kw）与高浓度的血浆血管内皮细胞相关。 炎症标志物和认知能力差，这表明它可能代表了一种 VCID的早期标志物。需要进行纵向研究来检验这种可能性。这项建议 试图评估低kw作为随后神经认知下降的预测因子的准确性。 我们还将测试低kw与氧化应激相关的可能性，通过 脑脊液（CSF）异前列腺素水平。我们建议研究140名健康的老年人， 基线使用DW-ASL、血浆炎症标志物和CSF测量的异前列腺素、Aβ， p-tau和t-tau。此外，将获得并量化结构神经成像测量， 包括区域体积、白色高信号（WMH）体积、扩散张量 用于定量区域分布的白色物质异常和易感性的成像 用于定量脑微出血的加权成像。一部分参与者将 大约3年后完成相同的神经成像和生物流体测量。我们的目标是 确定基线BBB水交换与随后WMH增长之间的关系 (Aim 1）;认知能力下降（目标2）和氧化应激的生物流体指数（目标3）。整体 我们将检验假设是，用新型DW-ASL评估的最低水交换率 序列代表与后期WMH生长相关的早期标记BBB功能障碍， 认知能力下降和氧化应激。