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.
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