Neuroinflammation, NMDA receptors and cognitive function in chemobrain

神经炎症、NMDA 受体和化学脑中的认知功能

• 批准号: 8756317
• 负责人: ANAT BIEGON
• 金额: $ 23.01万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756317
• 关键词: Affect; Animal Model; Animals; Brain; Brain Injuries; Brain region; Cancer Survivor; Cognitive; Cognitive deficits; Cycloserine; Development; Evaluation; Glutamate Receptor; Hippocampus (Brain); Human; Impaired cognition; Lead; Life; Measures; Memory; Minocycline; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Performance; Play; Positron-Emission Tomography; Prevention; Quality of life; Receptor Activation; Role; Scanning; Syndrome; Therapeutic; Tracer; Woman; base; breast cancer diagnosis; cancer therapy; chemobrain; chemotherapy; cognitive function; human disease; improved; instrument; malignant breast neoplasm; neuroinflammation; neuropsychological; novel; novel diagnostics; novel therapeutics; public health relevance; radiotracer; statistics; tool; uptake

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.

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“化疗脑”或化疗引起的认知障碍（CICI）。迄今为止，这些缺陷背后的机制尚未阐明。对多种人类疾病和动物模型的研究表明，认知大脑区域和 NMDA 谷氨酸受体（已知在记忆形成中发挥重要作用）相对容易受到神经炎症的影响。使用放射性示踪剂 [11C]PK11195 可以观察活人大脑中的神经炎症。我们最近开发了一种 PET 放射性示踪剂 ([11C]CNS5161)，适用于测量大脑中 NMDA 受体的激活。使用这 2 种示踪剂与经过验证的神经心理学仪器相结合来评估认知能力，我们计划检验“化学脑”与认知大脑区域的神经炎症和 NMDA 受体丧失相关的假设，为这种衰弱综合征提出新的治疗或预防目标。具体来说，我们将检查 乳腺癌女性化疗前后 [11C]PK11195 和 [11C]CNS5161 的区域分布。 12 名确诊患有乳腺癌、即将开始化疗的女性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进行。使用受试者内的配对t统计，我们将检验以下假设：化疗后皮质和海马区域会发现[11C]PK11195增加和[11C]CNS5161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，这可能会导致新的诊断工具以及治疗工具的开发，例如已经批准用于人类使用的米诺环素和 d-环丝氨酸，以解决化疗影响生活质量的这一令人不安的后果。大量女性。