Para-Vascular Basis of Small Vessel Disease

小血管疾病的血管旁基础

• 批准号: 9756479
• 负责人: Maiken Nedergaard
• 金额: $ 75.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756479
• 关键词: Acute; Address; Adult; Age; Aging; Anatomy; Animals; Antihypertensive Agents; Arteries; Astrocytes; Biological Assay; Biology; Blood Pressure; Blood Vessels; Blood capillaries; Brain; Brain Diseases; CADASIL; Cerebral Vasculitis; Cerebrospinal Fluid; Clinical; Cognitive; Collaborations; Convection; Dementia; Development; Diabetes Mellitus; Diagnostic; Diffusion; Disease; Disease Progression; Disease model; Edema; Elderly; Epidemic; Event; Exercise; Functional disorder; Goals; Homeostasis; Human; Hypertension; Image; Impaired cognition; Incidence; Inflammation; Intercellular Fluid; Intervention; Label; Link; Liquid substance; Lymphatic; Lymphatic System; Magnetic Resonance Imaging; Maps; Mediating; Microvascular Dysfunction; Multiple Sclerosis; Mus; Myelin; Neurobiology; Neurologic; Neurology; Outcome Measure; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Permeability; Physiological; Physiology; Plant Roots; Play; Prevalence; Prevention strategy; Rattus; Refuse Disposal; Research Personnel; Resistance; Rodent; Rodent Model; Role; Site; Sleep; Sleeplessness; Stroke; Structure; System; Testing; Therapeutic; Tissues; Veins; Venous; Waste Products; White Matter Hyperintensity; age related; aquaporin 4; awake; base; cognitive function; cognitive performance; diabetic patient; disability; effective therapy; experimental study; glymphatic system; innovation; insight; loss of function; neuroimaging; neuroinflammation; novel; uptake; water channel; white matter

Abstract Among adult dementias, a large proportion are either due to or associated with small vessel disease (SVD) of the brain. The incidence and prevalence of SVD, which may be anticipated by aging, hypertension and diabetes, is on the rise, and causally linked to the rising incidence of dementia and age-related neurological disability. Despite the fact that diagnostic MRI can track SVD progression during a premanifest period and potential therapeutic window of years to decades, no treatments are yet available. The pathophysiology of SVD is presently poorly understood. A widening of perivascular spaces (PVS) and white matter hyperintensities on neuroimaging are strongly associated with SVD. The perivascular expansion in SVD appears to correspond structurally with the perivascular spaces of the glymphatic system, our recently described system of glial-mediated lymphatic-like convective flow that directs interstitial fluid fluxes in the brain. The glymphatic system is analogous to the lymphatic system in peripheral tissues, which clears excess interstitial fluid and waste products from the brain. Glymphatic fluid transport pathways circulate cerebrospinal fluid (CSF) which exchanges with interstitial fluid (ISF), and relies on the aquaporin-4 (AQP4)-defined water channels in astrocytic endfeet to achieve parenchymal entry. Astrocytic endfeet effectively enclose the vasculature and thereby create a network of interconnected donut-shaped tunnels around the brain's arteries, capillaries, and veins. The existence of an astrocyte-enclosed perivascular space is recognized as a unique anatomical feature of the CNS, but its functional importance has only recently become apparent. Since a hallmark feature of SVD is the structural remodeling of the perivascular space, we here propose to ask, based on a compelling set of preliminary observations, if an increase of glymphatic fluid exchange plays an essential role in SVD pathobiology. The proposed studies will address the following questions: Aim 1 will map glymphatic activity in several experimental rodent SVD models, including CADASIL, hypertensive rats and mice (SHR and BPH/2J mice). Aim 2 will use MRI to assess the roles of blood pressure fluctuations, glymphatic influx or efflux, and BBB permeability on glymphatic transport and pathological fluid accumulation in SHR and controls. Aim 3 will test the hypothesis that interventions which promote normal glymphatic function will slow myelin loss and the cognitive impairment in SVD. The experiments will directly correlate the benefits of anti-hypertensive treatment, exercise, and insomnia treatment with improvements in glymphatic transport. To our knowledge, this application constitutes the first formal study focused on glymphatic functions and the perivascular space in SVD. The proposed studies will address key gaps in our understanding of SVD. Our hope is to provide novel mechanistic insight into the pathological events that leads to myelin loss in SVD.

摘要 在成人痴呆症中，很大一部分是由于或与小血管疾病（SVD）有关， 大脑SVD的发病率和患病率可能与衰老、高血压和糖尿病有关， 这与痴呆症和与年龄有关的神经系统残疾的发病率上升有因果关系。 尽管诊断性MRI可以在表现前期跟踪SVD进展， 治疗窗口期为数年至数十年，目前尚无可用的治疗方法。 SVD的病理生理学目前知之甚少。血管周围间隙增宽（PVS） 神经影像学上的白色高信号与SVD密切相关。血管周围 SVD的扩张似乎在结构上与胶质淋巴系统的血管周围空间相对应， 最近描述的神经胶质介导的神经胶质样对流系统，其引导组织间液通量， 大脑胶质淋巴系统类似于外周组织中的淋巴系统， 间质液和大脑的废物淋巴液转运途径循环脑脊髓 与间质液（ISF）交换的脑脊液（CSF），并依赖于水通道蛋白-4（AQP 4）定义的水 星形胶质细胞终足中的通道以实现实质进入。星形胶质细胞终足有效地包围了 从而在脑动脉周围形成一个相互连接的环形隧道网络， 毛细血管和静脉星形胶质细胞包围的血管周围空间的存在被认为是一种独特的 CNS的解剖特征，但其功能的重要性只是最近才变得明显。自从一个标志性的 SVD的特征是血管周围空间的结构重塑，我们在这里提出，基于一个 令人信服的初步观察结果，如果胶质淋巴液交换的增加在 SVD病理生物学拟议的研究将解决以下问题：目标1将绘制胶质淋巴活动图 在几种实验性啮齿动物SVD模型中，包括CADASIL、高血压大鼠和小鼠（SHR和BPH/2 J 小鼠）。目标2将使用MRI评估血压波动、胶质淋巴流入或流出的作用， BBB通透性对SHR和对照组胶质淋巴转运和病理性液体蓄积的影响目标3将 测试促进正常胶质淋巴功能的干预措施将减缓髓鞘丢失和神经胶质细胞损伤的假设。 SVD的认知障碍这些实验将直接关联抗高血压治疗的益处， 运动和改善胶质淋巴运输的失眠治疗。 据我们所知，该应用构成了第一个专注于胶质淋巴功能的正式研究， SVD的血管周围间隙。拟议的研究将解决我们对SVD理解的关键差距。我们 希望能为SVD中导致髓鞘丢失的病理事件提供新的机制见解。