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: 10683733
• 负责人: JOHN A DETRE
• 金额: $ 74.44万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683733
• 关键词: Adult; Aging; Angiography; Arteries; Biological; Biological Markers; Blood Vessels; Blood capillaries; Brain; Central Nervous System Diseases; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Clinical; Clinical Research; Clinical Trials; Cognitive; Collaborations; Data; Dementia; Development; Diameter; 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; Ventricular; Visualization; White Matter Hyperintensity; Work; arterial spin labeling; arteriole; 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.

小血管疾病（SVD）被认为是中枢神经系统最常见的疾病之一 并在血管性认知障碍和痴呆（VCID）综合征中发挥关键机制作用。 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，最明显的是白色物质高信号，目前提供了最广泛接受的 SVD的生物标志物。然而，MRI白色病变代表SVD的下游效应， 不是缺血性脑损伤的特异性。非侵入性成像策略能够机械地检测- 小血管结构或功能的特异性变化将改善 小血管对认知障碍和痴呆的贡献，并作为监测 临床试验中治疗干预的效果。 正如我们在初步数据中所显示的，动脉自旋的空间分辨率和灵敏度的最新发展 标记（ASL）灌注MRI现在允许无创定量脑血流量（CBF）， 室周白色物质（PVWM），其由长小动脉的终末分布供应， 直径超过100微米。PVWM-CBF因此代表了一种有前途的小血管生物标志物 灌注，允许量化小血管功能完整性，而无需空间分辨个体 动脉同时，新兴的光学方法，如光学相干断层血管造影术， （OCTA）还允许在人类视网膜中快速非侵入性地成像小血管甚至毛细血管 使用相对便宜且日益广泛可用的仪器。这两种生物标志物都保持了 有可能在手术前检测到小血管结构或功能完整性的机械特定变化 脑损伤的发展已正式确立。然而，虽然视网膜被描述为一种 作为大脑的“窗口”，OCTA测量视网膜与大脑结构和功能之间的关系具有重要意义。 尚待充分测试。 本提案的总体目标是验证PVWM CBF和OCTA衍生的微血管密度作为 用于临床研究的人类小血管结构的真正生物标志物。我们将调查 PVWM CBF和OCTA衍生微血管密度的技术决定因素， 视网膜微血管与脑WML和灌注，并初步显示其预测价值SVD 将基线测量与健康和临床队列的纵向变化相关联。一个多学科 一组具有神经成像、视网膜成像、脑血流生理学等专业知识的研究人员， 脑血管疾病，老龄化和痴呆症将合作开展这项工作。