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.

小血管疾病（SVD）被认为是中枢神经系统中最普遍的疾病之一 并在血管认知障碍和痴呆症（VCID）的综合征中贡献了关键的机械作用。 大脑SVD投资的主要挑战是，小血管完整性无法在体内可视化。 相反，MRI病变，最著名的是白质超强度，目前提供了最广泛接受的 SVD的生物标志物。但是，MRI白质病变代表了SVD的下游效应，进一步是 不针对缺血性脑损伤。能够从机械学检测的非侵入性成像策略 小容器结构或功能的特定变化将改善识别和数量 小血管对认知障碍和痴呆症的贡献，并作为监测的生物标志物 热干预措施在临床试验中的影响。 正如我们在初步数据中所显示的那样，动脉自旋的空间分辨率和灵敏度的最新发展 现在标记（ASL）灌注MRI允许对来自脑血流（CBF）的无创定量 周期性白质（PVWM），由长动脉的末端分布提供的少得多 直径超过100微米。相应的PVWM-CBF代表了小容器的承诺生物标志物 灌注，允许数量的小容器功能完整性，而无需空间解决个体 动脉。随之而来的是，新兴的光学方法，例如光学相干层析造影术 （八八）还允许在人视网膜中快速成像的小血管甚至毛细血管 使用相对便宜且越来越广泛的仪器。两个生物标志物都持有 在小血管结构或功能完整性中检测机械特定变化的潜力 正式建立了大脑病变的发展。但是，虽然视网膜被描述为 大脑的“窗口”，视网膜的八八度与大脑结构和功能之间的关系 还需要进行充分的测试。 该提案的总体目标是验证PVWM CBF和八个衍生的微血管密度为BONA 人类小血管结构的FIDE生物标志物用于临床研究。我们将研究生物学 PVWM CBF和八源微血管密度的技术决定剂 带有脑WML和灌注的视网膜微脉管系统，并先显示其在SVD中的预测价值 将基线测量与健康和临床队列的纵向变化相关。多学科 具有神经影像，视网膜成像，脑血流生理学专业知识的研究人员团队， 脑血管疾病，衰老和痴呆症将合作进行这项工作。