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.

抽象的 在成年痴呆症中，很大一部分是由于小血管疾病（SVD）的原因 大脑。 SVD的发病率和患病率可能会通过衰老，高血压和糖尿病预期 正在上升，并与痴呆症和与年龄有关的神经疾病的发生率上升。 尽管诊断性MRI可以在premifest时期跟踪SVD的进展，并且潜在 几十年来的治疗窗口，尚无治疗。 SVD的病理生理学目前知之甚少。血管周空间（PVS）的扩大 神经影像学上的白质超强度与SVD密切相关。血管周围 SVD中的膨胀似乎与Glymphatic System的血管周空间结构对应，我们 最近描述了神经胶质介导的淋巴样流动流，该系统导致间质性流体通量 大脑。淋巴系统类似于周围组织中的淋巴系统，这清除了多余的 大脑的间质液和废物产物。胶囊流体传输途径循环脑脊 液体（CSF）与间质流体（ISF）交换，并依靠Aquaporin-4（AQP4）定义的水 星形胶质细胞终端中的通道以实质进入实质。星形胶质细胞端面有效地包围 脉管系统，从而在大脑的动脉周围建立了一个互连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周围空间的存在被认为是独特的 中枢神经系统的解剖学特征，但其功能重要性直到最近才显而易见。自一个标志以来 SVD的特征是血管周间空间的结构重塑，我们在这里建议您根据一个 引人入胜的初步观察集，如果增加糖液交换在 SVD病理生物学。拟议的研究将解决以下问题：AIM 1将绘制胶囊活动 在几种实验性啮齿动物SVD模型中，包括卡达西，高血压大鼠和小鼠（SHR和BPH/2J 小鼠）。 AIM 2将使用MRI评估血压波动的作用，Glymphatic Imprux或外排，以及 BBB渗透性对SHR和对照中的肾小球运输和病理流体的积累。目标3意志 检验以下假设，即促进正常糖瘤功能的干预措施将减缓髓磷脂损失和 SVD中的认知障碍。实验将直接将抗高血压治疗的益处与 运动和失眠治疗，并改善糖型运输。 据我们所知，该应用程序构成了第一个正式研究，该研究侧重于肾小球功能和 SVD中的血管周空间。拟议的研究将解决我们对SVD的理解中的关键差距。我们的 希望是对导致SVD中髓磷脂损失的病理事件的新型机械洞察力。