Cerebral Blood Flow Response to Chronic Hydrocephalus

描述（由申请人提供）：慢性成人脑积水是一种主要的 可预防的神经损伤的原因尽管其病理生理学， 诊断和治疗知之甚少，很可能是脑缺氧， 通过血管压迫，在这种损伤中起作用。我们首先假设 最初的机械性脑血流量（CBF）受损是在 通过适应性血管生成来延缓， 血管生成因子我们的第二个一般假设是， 液体（CSF）分流部分恢复CBF和氧水平，但在这样做的过程中， 逆转适应性血管生成。我们已经建立了一个慢性 脑积水，允许测量脑室大小和压力， 它们与血管分布、脑血流量和氧气输送的关系， 大脑实验动物和对照动物将研究12周， 第二阶段将被分流。测量包括临床状态，心室大小， CSF压力、定量局部血管形态（密度、大小、面积）， 免疫组化（HIF-1，VEGF，GFAP），脑血流量 （多微球注射）和氧水平（微氧传感器）。这 这项研究将首次确定慢性缺氧的作用和机制， 脑积水如果缺氧状态和脑血管反应 基于脑血管操作或 神经保护可能被建议作为外科分流术和分流术的替代品， 自身优化。突然分流功能障碍导致的继发性损伤可能 最小化。更多的生理引导CSF引流和辅助 治疗基于脑血流量我们的治疗成人慢性 脑积水的发生率将大大提高，其神经系统的发病率将降低。 最后，从这些研究中获得的见解可能有更广泛的应用 其他神经病理学包括逐渐压迫或缺氧。

DESCRIPTION (provided by applicant): Chronic adult hydrocephalus is a leading cause of preventable neurological injury. Although its pathophysiology, diagnosis, and treatment are poorly understood it is likely that brain hypoxia, through vessel compression, plays a role in this injury. We first hypothesize that an initial mechanical cerebral blood flow (CBF) compromise is later temporized by adaptive angiogenesis, which evolves from hypoxia stimulated angiogenic factors. Our second general hypothesis states that cerebral spinal fluid (CSF) shunting partially restores CBF and oxygen level but in so doing reverses the adaptive angiogenesis. We have developed a canine model of chronic hydrocephalus, which allows measurement of ventricular size and pressure and their relationship to vascularity, cerebral blood flow, and oxygen delivery to the brain. Experimental and control animals will be studied for 12 weeks and in phase 2, will be shunted. Measurements include clinical status, ventricle size, CSF pressure, quantitative regional vessel morphology (density, size, area), immunohistochemistry (HIF-1, VEGF, GFAP), cerebral blood flow (multi-microsphere injections), and oxygen level (micro oxygen sensor). This study will be the first to identify the role and mechanism of chronic hypoxia in hydrocephalus. If the hypoxic state and proposed cerebrovascular response are demonstrated, strategies based on cerebrovascular manipulation or neuroprotection may be proposed as adjuncts to surgical shunting and shunting itself optimized. Secondary injury resulting from sudden shunt dysfunction may be minimized. With more physiological guided CSF drainage and adjunct treatments based on cerebral blood flow our treatment of adult chronic hydrocephalus would be greatly enhanced and its neurological morbidity reduced. Finally, the insights gained from these studies may have a broader application to other neuropathologies involving gradual compression or hypoxia.