Novel Biomarkers of Small Vessel Contributions to Vascular Cognitive Impairment and Dementia (VCID)

小血管对血管认知障碍和痴呆 (VCID) 贡献的新型生物标志物

• 批准号: 10436194
• 负责人: JOHN A DETRE
• 金额: $ 75.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436194
• 关键词: Adult; Aging; Angiography; Arteries; Biological; Biological Markers; Blood Vessels; Blood capillaries; Brain; Caliber; Central Nervous System Diseases; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Clinical; Clinical Research; Clinical Trials; Cognitive; Data; Dementia; Development; Disease; Disease Progression; Functional disorder; Goals; Human; Impaired cognition; Individual; Investigation; Ischemic Brain Injury; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Microvascular Dysfunction; Monitor; Optical Coherence Tomography; Optical Methods; Organ; Patients; Perfusion; Persons; Physiology; Predictive Value; Research; Research Personnel; Resolution; Retina; Role; Site; Structure; Syndrome; Technology; Testing; Therapeutic Effect; Therapeutic Intervention; Vascular Cognitive Impairment; Vascular Diseases; Vascular blood supply; White Matter Hyperintensity; Work; arterial spin labeling; arteriole; base; brain magnetic resonance imaging; cohort; density; gray matter; imaging modality; improved; in vivo; instrumentation; interest; middle age; millimeter; multidisciplinary; neuroimaging; non-invasive imaging; novel; novel marker; predictive marker; recruit; retinal imaging; specific biomarkers; vascular cognitive impairment and dementia; white matter

Small vessel disease (SVD) is thought to be among the most prevalent disorders of the central nervous system and contributes a key mechanistic role in the syndrome of vascular cognitive impairment and dementia (VCID). A major challenge in the investigation of cerebral SVD is that small vessel integrity cannot be visualized in vivo. Instead, MRI lesions, most notably white matter hyperintensities, currently provide the most widely accepted biomarker of SVD. However, MRI white matter lesions represent downstream effects of SVD and further are not specific to ischemic brain injury. Noninvasive imaging strategies capable of detecting mechanistically- specific changes in small vessel structure or function would improve the identification and quantification of small vessel contributions to cognitive impairment and dementia and serve as biomarkers for monitoring the effects of therapeutic interventions in clinical trials. As we show in preliminary data, recent developments in the spatial resolution and sensitivity of arterial spin labeled (ASL) perfusion MRI now allow noninvasive quantification of cerebral blood flow (CBF) from the periventricular white matter (PVWM), which is supplied by the terminal distributions of long arterioles much less than 100 microns in diameter. PVWM-CBF accordingly represents a promising biomarker of small vessel perfusion, allowing quantification of small vessel functional integrity without spatially resolving individual arteries. Concomitantly, emerging optical methods such as optical coherence tomographic angiography (OCTA) also allow small vessels and even capillaries to be rapidly noninvasively imaged in the human retina using relatively inexpensive and increasingly widely available instrumentation. Both biomarkers hold the potential to detect mechanistically specific changes in small vessel structural or functional integrity prior to the development of brain lesions been formally established. However, while retina has been described as a “window” to the brain, the relationship between OCTA measures of retina and brain structure and function has yet to be adequately tested. The overall goal of this proposal is to validate PVWM CBF and OCTA-derived microvascular density as bona fide biomarkers of human small vessel structure for use in clinical research. We will investigate the biological and technical determinants of PVWM CBF and OCTA-derived microvascular density, associate changes in retinal microvasculature with brain WML and perfusion, and preliminarily show their predictive value in SVD by correlating baseline measures with longitudinal changes in healthy and clinical cohorts. A multidisciplinary team of investigators with expertise in neuroimaging, retinal imaging, cerebral blood flow physiology, cerebrovascular disorders, aging, and dementia will collaborate to carry out this work.

小血管病 (SVD) 被认为是最常见的中枢神经系统疾病之一 并在血管性认知障碍和痴呆综合征（VCID）中发挥关键的机制作用。 脑 SVD 研究的一个主要挑战是小血管完整性无法在体内可视化。 相反，MRI 病变，尤其是白质高信号，目前提供了最广泛接受的 SVD 的生物标志物。然而，MRI 白质病变代表了 SVD 的下游影响，并且进一步表明 并非针对缺血性脑损伤。能够机械检测的非侵入性成像策略 小血管结构或功能的具体变化将改善对小血管结构或功能的识别和量化 小血管对认知障碍和痴呆症有贡献，并可作为监测 临床试验中治疗干预的效果。 正如我们在初步数据中所示，动脉旋转的空间分辨率和敏感性的最新发展 标记 (ASL) 灌注 MRI 现在可以对脑血流 (CBF) 进行无创定量 室周白质（PVWM），由长小动脉的末端分布提供 直径大于100微米。因此，PVWM-CBF 代表了一种有前途的小血管生物标志物 灌注，无需空间分辨个体即可量化小血管功能完整性 动脉。与此同时，新兴的光学方法，例如光学相干断层扫描血管造影 (OCTA) 还可以在人类视网膜中对小血管甚至毛细血管进行快速无创成像 使用相对便宜且日益广泛使用的仪器。两种生物标志物均具有 在小血管结构或功能完整性之前检测机械特定变化的潜力 脑部病变的发展已正式确立。然而，虽然视网膜被描述为 大脑的“窗口”，视网膜的OCTA测量与大脑结构和功能之间的关系 尚待充分测试。 该提案的总体目标是验证 PVWM CBF 和 OCTA 衍生的微血管密度是否合理 用于临床研究的人体小血管结构的真实生物标志物。我们将研究生物 PVWM CBF 和 OCTA 衍生的微血管密度的技术决定因素，相关变化 视网膜微血管与脑 WML 和灌注，并初步显示其对 SVD 的预测价值 将基线测量与健康和临床队列的纵向变化相关联。多学科 拥有神经影像学、视网膜成像、脑血流生理学专业知识的研究团队， 脑血管疾病、衰老和痴呆症将合作开展这项工作。