Neural Predictors and RAS Modulation of Radiation-induced Cognitive Impairment

描述（由申请人提供）：每年有多达20万患者接受全脑照射（WBI）。这些患者中的大多数不是治疗原发性脑瘤，而是治疗黑色素瘤、乳腺癌或肺癌的脑转移，这些疾病在中年时增加。随着WBI后患者生存率的增加，20-50%的长期幸存者会发生辐射性脑损伤，包括认知障碍。辐射引起的认知损伤发生在没有总体结构病理的情况下，这表明这种现象可能在髓鞘或构成认知功能基础的神经元之间的突触连接发生细微变化之前。然而，目前还没有关于辐射诱导髓磷脂和突触变化的定量研究，没有发表的辐射诱导认知损伤与临床相关的分级放射过程的研究，也没有尝试改善或预防中年动物这种辐射诱导的结构或认知损伤。本奖助金的总体目标是回答以下问题。中年大鼠给予临床相关剂量的分离性脑损伤后髓磷脂和突触发生了什么变化？髓磷脂和突触的细微变化是否预示着随后的辐射引起的认知障碍？脑内肾素-血管紧张素系统（RAS）的调节是否能改善或预防这种辐射引起的脑损伤，包括认知损伤？因此，需要验证的假设是：1)髓磷脂和突触的改变是辐射引起的脑损伤与认知障碍相关的早期预测因子；2)脑损伤引起的结构改变和认知障碍都可以通过调节脑内RAS来改善或预防。为了验证这些假设，我们将：i]量化12月龄F344XBN大鼠接受临床相关的WBI治疗后髓鞘、突触和认知的变化，ii]确定ACE抑制剂或Ang ii型1受体拮抗剂对脑内RAS的抑制是否会调节F344XBN大鼠接受分级WBI治疗后的结构和/或认知损伤。这些研究应该提供可能导致治疗的信息，以改善辐射引起的脑损伤，包括认知障碍；因此，解决了NCI公共卫生重点的新领域之一。

DESCRIPTION (provided by applicant): Every year as many as 200,000 patients receive whole brain irradiation (WBI). Most of these patients are treated not for primary brain tumors, but for brain metastases from melanomas, breast cancer or lung cancer that increase in middle age. As patient survival after WBI has increased, 20-50% of the long term survivors develop radiation-induced brain injury, including cognitive impairment. Radiation-induced cognitive impairment occurs in the absence of gross structural pathology, suggesting that this phenomenon is likely preceded by subtle changes in the myelin or the synaptic connections among neurons that underlie cognitive function. However, there have been, i] no quantitative studies of radiation-induced changes in myelin and synapses, ii] no published studies of radiation-induced cognitive impairment with a clinically relevant fractionated course of radiation, and iii] no attempts to ameliorate or prevent this radiation-induced structural or cognitive damage in middle-aged animals. The overall goal of the present grant is to answer the following questions. What changes in myelin and synapses occur when middle-aged rats are given a clinically relevant dose of fractionated WBI? Are the subtle changes in myelin and synapses early predictors of the ensuing radiation-induced cognitive impairment? Will modulation of the intrinsic brain renin-angiotensin system (RAS) ameliorate or prevent this radiation-induced brain injury, including cognitive impairment? Accordingly, the hypotheses to be tested are that, 1) modifications in myelin and synapses are early predictors of radiation-induced brain injury associated with cognitive impairment, and 2) both the structural modifications and the cognitive impairment induced by WBI can be ameliorated or prevented by modulating the intrinsic brain RAS. To test these hypotheses, we will, i] quantify the changes in myelin, synapses and cognition after treating 12 month old F344XBN rats with a clinically relevant course of WBI, and ii] determine if inhibition of the intrinsic brain RAS by administration of ACE inhibitors or Ang II type 1 receptor antagonists will modulate the structural and/or cognitive damage after 12 month old F344XBN rats are treated with fractionated WBI. These studies should provide information that is likely to lead to treatments that ameliorate radiation-induced brain injury, including cognitive impairment; thereby, addressing one of NCI's new areas of public health emphasis.