Effects of Radiation on Brain Microvasculature and Cognition

描述(申请人提供)：全脑照射(WBI)导致大约20%-50%的脑肿瘤患者进展性痴呆，这些患者在治疗后长期存活。目前，放射性脑损伤还没有成功的治疗方法，也没有已知的有效的预防策略。我们和其他人提出，随着年龄的增加，WBI后认知功能的下降会加剧，导致这些损害的部分机制是血管密度、内皮细胞和血脑屏障功能的下降。我们假设，分割的WBI通过加剧与年龄相关的脑血管稀疏导致脑血流量下降和葡萄糖代谢障碍而导致认知障碍；这些改变(连同血管内皮生长因子分泌障碍)是认知功能下降的一个促成因素，并可通过抑制大脑肾素血管紧张素系统(RAS)来调节。提出了以下目标：1.评估照射后与学习和记忆相关的脑区的脑微血管稀疏和相应的局部脑血流量(LCBF)下降。2.确定受辐射动物的海马微环境中，由血管系统和神经胶质细胞产生的营养因子(如血管内皮生长因子及其受体)是否减少，这些营养因子被发现是海马依赖的学习和记忆过程所必需的。3.评估照射是否导致微血管内皮细胞功能障碍和血脑屏障完整性的破坏，以及抑制RAS系统是否能改善照射的效果。4.确定给予血管紧张素转换酶抑制剂(雷米普利)或AT1受体拮抗剂(氯沙坦)(已被证明可防止辐射引起的损害)是否能改善辐射引起的血管密度、LCBF和葡萄糖代谢的下降，并与改善认知状态有关/这一应用的意义/创新在于，将使用临床相关的分次WBI的效果，将在认知状态已知的动物中评估依赖变量，并将在中年动物中进行研究。这些程序将使我们能够对WBI引起的认知损害的病因做出更准确的结论，并评估减少辐射后认知损害的干预措施的有效性。

DESCRIPTION (provided by applicant): Whole brain irradiation (WBI) leads to a progressive dementia in approximately 20-50% of brain tumor patients who are long-term survivors after treatment. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. We, and others, have proposed that the decline in cognitive function after WBI is exacerbated by increasing age and part of the mechanisms contributing to these impairments is a decrease in vascular density, and function of endothelial cells and the blood brain barrier. We hypothesize that fractionated WBI results in cognitive impairment by exacerbating age-related cerebrovascular rarefaction resulting in a decline in cerebral blood flow and impairments in glucose metabolism; these alterations (together with impairments in VEGF secretion) are a contributing factor in the decline in cognitive function and can be modulated by inhibition of the brain renin angiotensin system (RAS). The following aims are proposed: 1. Assess rarefaction of brain microvasculature and the corresponding decline in local cerebral blood flow (LCBF) after irradiation in brain regions specifically associated with learning and memory. 2. Determine whether trophic factors (e.g. VEGF and its receptors) produced by the vasculature and glia and found to be necessary for hippocampally- dependent processes of learning and memory are reduced in the hippocampal microenvironment of irradiated animals. 3. Assess whether irradiation results in microvascular endothelial dysfunction and disruptions in blood brain barrier integrity and whether the effects of irradiation are ameliorated by inhibition of the RAS system. 4. Determine whether administration of an ACE inhibitor (ramipril) or an AT1 receptor antagonist (losartan) (that have been shown to prevent radiation induced damage) ameliorate the radiation- induced decline in vascular density, LCBF, glucose metabolism and associated with improved cognitive status/The significance/innovation of this application is that the effects of a clinically relevant fractionated dose of WBI will be used, dependent variables will be assessed in animals of known cognitive status and studies will be conducted in middle-aged animals. These procedures will allow us to make more precise conclusions related to the etiology of cognitive impairment that occurs in response to WBI and assess the efficacy of interventions to reduce cognitive impairment after radiation.