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.

摘要 在成人痴呆症中，很大比例是由于或与小血管疾病(SVD)有关 大脑。可通过老龄化、高血压和糖尿病预测的SVD的发生率和流行率， 正在上升，并与痴呆症和与年龄相关的神经残疾的发生率上升有因果关系。 尽管诊断性MRI可以跟踪SVD在显性前期和潜伏期的进展 在数年到数十年的治疗窗口，目前还没有可用的治疗方法。 SVD的病理生理学目前知之甚少。血管周围间隙(PVS)增宽 神经影像上的白质高信号与SVD密切相关。血管周围 SVD的扩张在结构上似乎与淋巴系统的血管周围间隙相对应，我们的 最近描述的神经胶质细胞介导的类淋巴管对流系统，引导间质液体在 大脑。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。 脑部的间质液体和废物。淋巴液体转运途径在脑脊液循环中的作用 与间质液体(ISF)交换的液体(CSF)，依赖水通道蛋白-4(AQP4)定义的水 在星形细胞末端的通道，以实现实质进入。星形细胞的末端脚有效地包围了 血管系统，从而在大脑动脉周围形成一个相互连接的甜甜圈状隧道网络， 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 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。因为这是一个标志 SVD的特征是血管周围间隙的结构性重构，我们在这里建议询问，基于 一组令人信服的初步观察，如果淋巴液体交换的增加在 SVD病理生物学。拟议的研究将解决以下问题：目标1将绘制淋巴活动图 在几种实验性的啮齿动物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、淋巴流入或流出的作用，以及 自发性高血压大鼠和对照组血脑屏障通透性对淋巴转运和病理性积液的影响。目标3将 检验这样一种假设，即促进正常淋巴功能的干预措施将减缓髓鞘丢失和 SVD中的认知损害。这些实验将与降压治疗的益处直接相关， 运动，通过改善淋巴运输来治疗失眠。 据我们所知，这一应用构成了第一个专注于淋巴功能和 SVD的血管周围间隙。拟议的研究将解决我们对奇异值问题认识上的主要差距。我们的 希望为SVD中导致髓鞘丢失的病理事件提供新的机制洞察力。