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）：接受乳腺癌化学疗法的妇女通常会出现一系列认知缺陷，有时称为“化学邻磷脂”或化学疗法引起的认知障碍（CICI）。迄今为止，这些缺陷的基础机制尚未阐明。在几种人类疾病和动物模型中的研究表明，认知大脑区域和NMDA谷氨酸受体（已知在记忆形成中起重要作用）相对容易受到神经炎症的影响。神经炎症可以使用radiotracer [11C] PK11195在活的人脑中可视化。我们最近开发了一种适用于测量大脑中NMDA受体激活的PET radiotracer（[11C] CNS5161）。使用这2个示踪剂与经过验证的神经心理学工具进行评估认知能力，我们计划研究以下假设：“ Chemobrain”与认知大脑区域中的神经炎症和NMDA受体丧失有关，这表明这种衰弱综合症的新型治疗或预防目标。具体来说，我们将检查 在化疗前后，乳腺癌女性的[11C] PK11195和[11C] CNS5161的区域分布。有十二名对乳腺癌诊断为开始化疗的女性将接受神经心理学评估，并在同一天进行2次PET扫描。在妇女完成化疗过程后，这些将重复。使用受试者中的配对-T统计数据，我们将研究以下假设：在化学疗法后，在皮质和海马区域中会发现[11C] PK11195并减少[11C] CNS5161摄取，这将与认知能力降低相关。如果实验发现支持了这一假设，这可能导致开发新的诊断工具以及已经批准用于人类使用的米诺环素和D-胞糖氨酸等治疗工具，这是由于化学疗法影响大量女性生活质量的令人不安的结果。