Para-Vascular Basis of Small Vessel Disease

小血管疾病的血管旁基础

• 批准号: 9263196
• 负责人: Maiken Nedergaard
• 金额: $ 78.76万
• 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/9263196
• 关键词: Acute; Address; Adult; Age; Aging; Animals; Antihypertensive Agents; Arteries; Astrocytes; Biological Assay; Biology; Blood Pressure; Blood Vessels; Blood capillaries; Brain; CADASIL; Cerebral Vasculitis; Cerebrospinal Fluid; Cerebrovascular system; Clinical; Cognitive; Collaborations; 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; Pathology; Pathway interactions; Peripheral; Permeability; Physiological; Physiology; Plant Roots; Play; Prevalence; Prevention strategy; Rattus; Refuse Disposal; Research Personnel; Resistance; Rodent; Rodent Model; Role; Shapes; Site; Sleep; Sleeplessness; Stroke; System; Testing; Therapeutic; Tissues; Veins; Venous; Waste Products; White Matter Hyperintensity; abstracting; age related; aquaporin 4; astrogliosis; awake; base; capillary; cognitive function; cognitive performance; diabetic patient; disability; effective therapy; glymphatic system; innovation; insight; loss of function; neuroimaging; neuroinflammation; novel; research study; 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.

抽象的 在成人痴呆症中，很大一部分是由小血管病（SVD）引起或与之相关。 大脑。 SVD 的发生率和患病率可通过老龄化、高血压和糖尿病来预测， 正在上升，并且与痴呆症和与年龄相关的神经功能障碍发病率上升有因果关系。 尽管诊断性 MRI 可以追踪 SVD 的进展，并且有可能 治疗窗口数年至数十年，目前尚无可用的治疗方法。 目前对 SVD 的病理生理学知之甚少。血管周围空间（PVS）扩大 神经影像学白质高信号与 SVD 密切相关。血管周围 SVD 的扩张似乎在结构上与类淋巴系统的血管周围空间相对应，我们的 最近描述的神经胶质介导的类淋巴对流系统，可引导间质液通量 大脑。类淋巴系统类似于周围组织中的淋巴系统，可以清除多余的淋巴液 来自大脑的间质液和废物。类淋巴液运输途径循环脑脊液 与间质液 (ISF) 交换的液体 (CSF)，并依赖于水通道蛋白 4 (AQP4) 定义的水 星形细胞末足中的通道以实现实质进入。星形胶质细胞端足有效地包围 脉管系统，从而在大脑动脉周围形成一个相互连接的甜甜圈形隧道网络， 毛细血管和静脉。星形胶质细胞封闭的血管周围空间的存在被认为是一种独特的 中枢神经系统的解剖学特征，但其功能重要性直到最近才变得明显。既然是一个标志 SVD的特点是血管周围空间的结构重塑，我们在这里提出要问，基于 如果类淋巴液交换的增加在 SVD 病理学。拟议的研究将解决以下问题： 目标 1 将绘制类淋巴活动图 在多种实验性啮齿动物 SVD 模型中，包括 CADASIL、高血压大鼠和小鼠（SHR 和 BPH/2J） 老鼠）。目标 2 将使用 MRI 来评估血压波动、类淋巴流入或流出的作用，以及 SHR 和对照中 BBB 通透性对类淋巴运输和病理性液体积聚的影响。目标3将 检验促进正常类淋巴功能的干预措施将减缓髓鞘质损失的假设 SVD 中的认知障碍。这些实验将直接关联抗高血压治疗的益处， 运动和失眠治疗以及改善类淋巴运输。 据我们所知，该应用程序构成了第一个专注于类淋巴功能和 SVD 中的血管周围空间。拟议的研究将解决我们对 SVD 理解中的关键差距。我们的 希望能够为导致 SVD 髓磷脂缺失的病理事件提供新的机制见解。