Cerebral Blood Flow Response to Chronic Hydrocephalus

描述(申请人提供)：慢性成人脑积水是一种 可预防的神经损伤的原因。尽管它的病理生理， 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 最初的机械脑血流(CBF)妥协是后来的 由低氧刺激进化而来的适应性血管生成而暂时性 血管生成因子。我们的第二个普遍假设是大脑脊椎 液体(脑脊液)分流可部分恢复脑血流量和血氧水平，但在此过程中 逆转适应性血管生成。我们已经建立了一种慢性阻塞性肺疾病犬模型。 脑积水，它允许测量脑室大小和压力和 它们与血管、脑血流量和氧输送的关系 大脑。将对实验动物和对照动物进行为期12周的研究 第二阶段，将进行分流。测量包括临床状态、脑室大小、 脑脊液压力、定量区域血管形态(密度、大小、面积)、 免疫组织化学(HIF-1、VEGF、GFAP)、脑血流量 (多微球注射)和氧气水平(微型氧气传感器)。这 这项研究将首次确定慢性低氧的作用和机制 在脑积水中。如果缺氧状态和建议的脑血管反应 演示了基于脑血管操作或 神经保护可作为外科分流和分流的辅助手段。 本身就是最优化的。突发性分流功能障碍引起的继发性损伤可能 被最小化。有更多生理引导的脑脊液引流和辅助装置 以脑血流为主治疗成人慢性阻塞性肺疾病 脑积水将大大加强，其神经系统的发病率将会降低。 最后，从这些研究中获得的见解可能会有更广泛的应用 与其他神经病理有关，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.