Neuroinflammation, NMDA receptors and cognitive function in chemobrain

描述（由申请人提供）：接受乳腺癌化疗的女性通常会出现一系列认知缺陷，有时称为“化疗障碍”或化疗诱导的认知障碍（CICI）。这些缺陷的机制至今尚未阐明。对几种人类疾病和动物模型的研究表明，认知脑区和NMDA谷氨酸受体（已知在记忆形成中起重要作用）相对容易受到神经炎症的影响。使用放射性示踪剂[11 C] PK 11195可以在活体人脑中观察到神经炎症。我们最近开发了一种PET放射性示踪剂（[11 C] CNS 5161），适用于测量大脑中NMDA受体的激活。使用这2种示踪剂结合经验证的神经心理学仪器用于评估认知能力，我们计划检查“chemobrain”与认知脑区域的神经炎症和NMDA受体丢失相关的假设，为这种衰弱综合征提出新的治疗或预防目标。具体来说，我们将研究 [11 C] PK 11195和[11 C] CNS 5161在乳腺癌患者化疗前后的区域分布。12名确诊为乳腺癌即将开始化疗的妇女将在同一天接受神经心理学评估和2次PET扫描。这些将在女性完成一个疗程的化疗后重复。使用受试者内的配对t统计，我们将检验以下假设：化疗后在皮质和海马区发现[11 C] PK 11195摄取增加和[11 C] CNS 5161摄取减少，这与认知能力下降相关。如果这一假设得到实验结果的支持，这可能会导致开发新的诊断工具以及治疗工具，如米诺环素和d-环丝氨酸，已经批准用于人类使用，这一令人不安的后果化疗影响生活质量的大量妇女。

DESCRIPTION (provided by applicant): Women receiving chemotherapy for breast cancer often develop a range of cognitive deficits sometimes called "chemobrain" or chemotherapy-induced cognitive impairment (CICI). The mechanism underlying these deficits has not been elucidated to date. Studies in several human diseases and animal models suggest that cognitive brain regions and NMDA glutamate receptors (known to play an important role in memory formation) are relatively vulnerable to neuroinflammation. Neuroinflammation can be visualized in the living human brain using the radiotracer [11C]PK11195. We have recently developed a PET radiotracer ([11C]CNS5161) suitable for measuring NMDA receptor activation in the brain. Using these 2 tracers in combination with validated neuropsychological instruments for the assessment of cognitive abilities, we plan to examine the hypothesis that "chemobrain" is related to neuroinflammation and NMDA receptor loss in cognitive brain regions, suggesting novel treatment or prevention targets for this debilitating syndrome. Specifically, we will examine the regional distribution of [11C]PK11195 and [11C]CNS5161 in women with breast cancer before and after a course of chemotherapy. Twelve women with a confirmed diagnosis of breast cancer about to commence chemotherapy will undergo neuropsychological evaluation and 2 PET scans on the same day. These will be repeated after the women complete a course of chemotherapy. Using paired-t statistics within subjects, we will examine the hypothesis that increased [11C]PK11195 and decreased [11C]CNS5161 uptake will be found in cortical and hippocampal regions following chemotherapy which will correlate with decreased cognitive performance. If this hypothesis is supported by experimental findings, this may lead to the development of new diagnostic tools as well as therapeutic tools such as minocycline and d-cycloserine, already approved for human use, for this troubling consequence of chemotherapy affecting quality of life in a large number of women.