Mechanisms of Radiation-Induced Cognitive Dysfunction

辐射引起的认知功能障碍的机制

• 批准号: 6970284
• 负责人: WILLIAM ROY BROWN
• 金额: $ 22.67万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-03 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970284
• 关键词: ACE inhibitors; brain circulation; capillary bed; cardiovascular disorder chemotherapy; cardiovascular injury; cerebrovascular imaging /visualization; cognition disorders; laboratory rat; myelinopathy; nonhuman therapy evaluation; radiation therapy dosage; relative biological effectiveness; somatostatin; therapy adverse effect; ACE inhibitors; brain circulation; capillary bed; cardiovascular disorder chemotherapy; cardiovascular injury; cerebrovascular imaging /visualization; cognition disorders; laboratory rat; myelinopathy; nonhuman therapy evaluation; radiation therapy dosage; relative biological effectiveness; somatostatin; therapy adverse effect

DESCRIPTION (provided by applicant): This proposal is focused on studies to elucidate the mechanisms of radiation-induced cognitive dysfunction. This is an important problem because 30-50% of the patients who survive more than 18 months after whole-brain irradiation (WBI) suffer from severe cognitive deficits. We have characterized a rat model of radiation-induced cognitive dysfunction using a fractionated dose of WBI that is biologically equivalent doses typically given to brain tumor patients. During those studies, we made the novel finding that the density of the capillary bed decreased in three areas of the brain, including the hippocampus which is involved in learning and memory. This decrease occurred as early as 10 weeks post-irradiation. There was partial recovery of the capillary bed by 20 weeks, and thereafter a decline in capillary density in the irradiated rats paralleled that observed in the controls, out to one year post-irradiation. The capillary loss occurred much earlier than vascular damage previously reported for high single doses of WBI and much earlier than the appearance of cognitive deficits, which occurred 6-9 months post-irradiation, as measured in a radial-arm maze. These findings suggest that a cascade of events, beginning with capillary loss, leads eventually to cognitive dysfunction. However, the limited numbers of animals (2-6) per group and sampling times, the lack of a quantitative assessment of demyelination and glial cell damage, and the absence of dose-response data leave it uncertain whether there is a causal relationship between the capillary loss and the cognitive deficits. The specific aims of the present grant proposal should strengthen the evidence. If early damage to the blood vessels can be correlated with the late onset of cognitive deficits, it will not only have important mechanistic implications, but it would also provide an early biomarker for testing therapeutic interventions designed to ameliorate radiation-induced brain dysfunction. Such therapeutic intervention studies could potentially be performed in as little as 10 weeks.

描述（由申请人提供）：该提案的重点是阐明辐射引起的认知功能障碍的机制的研究。这是一个重要的问题，因为在全脑辐照（WBI）经过18个月以上的患者中，有30-50％的患者患有严重的认知缺陷。我们已经表征了一种大鼠辐射诱导的认知功能障碍的大鼠模型，该模型使用了一种通常给予脑肿瘤患者的生物学上等效剂量的WBI剂量的WBI。在这些研究中，我们提出了新的发现，即毛细管床的密度在大脑的三个区域，包括与学习和记忆有关的海马。这种减少最早发生在辐射后10周。毛细管床在20周之前部分恢复，此后在对照组中观察到的辐照大鼠的毛细血管密度下降，直到辐照后一年。毛细血管损失比以前报道的高剂量WBI报道的血管损伤要早得多，并且比在辐射臂迷宫中测量的辐射后6-9个月的认知缺陷出现要早得多。这些发现表明，从毛细管损失开始的一系列事件最终导致认知功能障碍。然而，每组动物数量有限和抽样时间，缺乏对脱髓鞘和神经胶质细胞损伤的定量评估，并且缺乏剂量反应数据使毛细血管损失与认知缺陷之间是否存在因果关系。本赠款提案的具体目的应加强证据。如果早期对血管的损害与认知缺陷的晚期发作相关，则它不仅具有重要的机械意义，而且还将提供早期的生物标志物，用于测试旨在减轻放射线诱导脑功能障碍的治疗干预措施。这种治疗性干预研究可能在短短10周内就可以进行。