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，有时被称为“化疗脑”或化疗诱导的认知障碍（CICI）。迄今为止，这些缺陷背后的机制尚未阐明。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。使用放射性示踪剂[11C]PK11195可以在活体人脑中可视化神经炎症。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。使用这两种示踪剂结合经过验证的神经心理学工具来评估认知能力，我们计划检验“化学脑”与认知脑区域的神经炎症和NMDA受体丢失有关的假设，为这种衰弱综合征提供新的治疗或预防靶点。具体来说，我们将检查