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: 10201780
• 负责人: JOHN A DETRE
• 金额: $ 73.53万
• 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/10201780
• 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; Spin Labels; Structure; Syndrome; Technology; Testing; Therapeutic Effect; Therapeutic Intervention; Vascular Cognitive Impairment; Vascular Diseases; Vascular blood supply; White Matter Hyperintensity; Work; arteriole; base; 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)被认为是最常见的中枢神经系统疾病之一 在血管性认知障碍和痴呆(VCID)综合征中起着关键的机制作用。 脑SVD研究中的一个主要挑战是无法在活体内观察到小血管的完整性。 相反，MRI损伤，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脑白质损害代表SVD的下游效应，并进一步 不是缺血性脑损伤所特有。非侵入性成像策略能够机械地检测- 小血管结构或功能的具体变化将有助于识别和量化 小血管对认知障碍和痴呆症的贡献，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，动脉脊柱的空间分辨率和敏感性的最新发展 标记(ASL)灌注MRI现在可以从脑血流(CBF)无创定量 脑室周围白质(PVWM)，由长小动脉终末分布供应的要少得多 直径超过100微米。PVWM-CBF是一种很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。与此同时，新兴的光学方法，如光学相干断层血管成像 (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。这两个生物标志物都持有 检测小血管结构或功能完整性在机械上的具体变化的可能性 脑部病变的发展正式确立。然而，尽管视网膜被描述为一种 大脑的窗口，视网膜的OCTA测量与大脑结构和功能的关系 还没有得到充分的测试。 该提案的总体目标是验证PVWM、CBF和OCTA来源的微血管密度是否为骨密度 临床研究中使用的人体小血管结构的真实生物标志物。我们将调查生物 和PVWM CBF和OCTA来源的微血管密度的技术决定因素，相关变化 视网膜微血管构筑与脑WML及血流灌注的关系，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中的纵向变化相关联。一个多学科的 一支在神经成像、视网膜成像、脑血流生理学方面有专长的调查团队， 脑血管疾病、衰老和痴呆症将合作开展这项工作。