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

血脑屏障水交换减少可作为小血管疾病的临床前生物标志物 血管性认知损害和痴呆(VCID)在老年人中很常见，是一种主要的 公共健康风险。VCID影响供应血管各部分的小血管网络 大脑，导致认知能力下降。临床试验因缺乏非药物而受到阻碍。 用于检测VCID早期阶段的侵入性工具。因此，创新的工具 VCID的早期识别已成为一项重要的研究重点。血脑 屏障(BBB)可能是VCID早期受累的关键系统。的最新进展 一种新的扩散加权ASL(DW-ASL)序列及其后处理 分析已经使量化整个BBB的水交换率成为可能，这是 血脑屏障功能正常。我们使用这一新序列的初步结果表明，低水位 跨血脑屏障的交换(低千瓦)与高浓度的血浆血管有关 炎性标志物和认知能力差，这表明它可能代表着 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 旨在评估低kw作为随后神经认知衰退的预测指标的准确性。 我们还将测试低千瓦时与氧化应激有关的可能性，通过 脑脊液(CSF)中异前列腺素水平。我们计划对140名健康的老年人进行研究， 基线使用DW-ASL、血浆炎性标志物和脑脊液测定异前列腺素、Aβ、 P-tau和t-tau。此外，还将获得并量化结构性神经成像措施， 包括区域体积、白质高强度(WMH)体积、扩散张量 脑白质区域分布异常和敏感性的成像研究 加权成像用于脑微出血的定量。参与者的子集将 大约3年后完成相同的神经成像和生物体液测量。我们的目标是 确定基线血脑屏障水交换和随后的WMH增长之间的关系 (目标1)；认知下降(目标2)和氧化应激的生物流体指数(目标3)。整体而言 我们要检验的假设是，用一种新的DW-ASL评估较低的水交换率 序列代表了与后期WMH生长相关的早期标志物BBB功能障碍， 认知能力下降和氧化应激。

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.