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    Research Grants Awarded

    A Longitudinal Study of Alterations in Cognitive Function and Brain Metabolites among Women Receiving Chemotherapy for Primary Breast Cancer.

    Study Section:
    Psychosocial and Complementary Treatment Approache

    Scientific Abstract:
    Cancer patients treated with chemotherapy frequently complain of cognitive deficits during treatment and often for some years thereafter. It is not known if these cognitive changes are lasting and, if not, what factors influence recovery. Few investigators have assessed cognitive changes longitudinally, and the underlying pathophysiological mechanisms have not been systematically examined. Many cytotoxic drugs commonly used in chemotherapy result in cognitive deficits via direct neurotoxicity to the cerebral parenchyma, neuronal axons, microglia, and/or oligodendrocytes. This chemotherapy-induced neurotoxicity may lead to changes in the levels of the various brain metabolites. Previous studies using Magnetic Resonance Spectroscopy (MRS) suggest that cognitive impairment is accompanied by changes in specific brain metabolites such as N-acetyl aspartate (NAA), creatine, choline, and myo-inositol. This project will begin to elucidate the mechanisms by which chemotherapy adversely affects cognition. Because metabolic changes are likely to precede clinically detectable cognitive dysfunction, MRS may allow early identification of patients who will develop cognitive dysfunction associated with cancer treatments. We hypothesize that individual neuropsychological test scores and brain metabolite concentrations (detected by MRS) will decrease over time in breast cancer patients receiving chemotherapy. Furthermore, we hypothesize that the decline of metabolite concentrations will correlate with neuropsychological test scores. The specific aims of the proposed pilot study are as follows: (1) To evaluate cognitive function using neuropsychological testing, before and after chemotherapy treatments. (2) To collect MRS data from left thalamus, hippocampus, and frontal and parietal lobes regions of these patients before and after chemotherapy to determine whether selected metabolites (e.g. N-acetyl aspartate, creatine, and myo-inositol) represent a useful marker of cognitive changes in this population. (3) To characterize the temporal relationship between brain metabolite concentrations and cognitive functioning. This study will enroll 33 breast cancer patients. Neuropsychological tests will be scored by standard procedures with adjustments and converted to Z-scores. Results will provide estimates of treatment-induced cognitive decline and importantly demonstrate feasibility for a larger study of chemotherapy-induced cognitive change. Additionally, an estimate of the degree to which the decline correlates with selected metabolite levels in the brain will also be obtained. The results of this study will be used to support a R01 proposal to identify neurochemical factors that may play a role in cognitive problems associated with chemotherapy. Identification of these factors could lead to greater understanding of chemotherapy-induced cognitive impairment and improved prevention/treatment strategies in this population of cancer survivors.

    Lay Abstract:
    Chemotherapy has improved overall cancer survival, but many breast cancer patients complain of troubling changes in cognitive function ("chemo-brain") that negatively affect quality of life. There are very few prospective studies of cognitive changes in this population and the underlying pathophysiological mechanisms have not been systematically examined. Brain imaging could help to identify these mechanisms, yet there are no prospective, well-controlled studies. Because metabolic changes are likely to precede cognitive dysfunction detected by conventional neuropsychological testing, Magnetic Resonance Spectroscopy (MRS) may allow early identification of patients who will develop cognitive dysfunction associated with cancer treatments. We hypothesize that individual neuropsychological test scores and brain metabolite concentrations (detected by MRS) will decrease over time in breast cancer patients receiving chemotherapy. Furthermore, we hypothesize that the decline of metabolite concentrations will correlate with neuropsychological test scores. We will use neuropsychological tests to examine changes in cognitive function (aim 1), and brain imaging with magnetic resonance spectroscopy (MRS) to identify specific changes in brain structure and function (aim 2). We will then relate the neuropsychological test scores and the MRS data to identify useful markers of cognitive change (aim 3). This study will enroll 33 breast cancer patients who will receive adjuvant chemotherapy. Each patient will be tested before and after receiving chemotherapy. Cognitive function will be evaluated by neuropsychological tests and by MRS before the start of treatment (pre-chemotherapy) and between 4-8 weeks after completion (post-chemotherapy). Neuropsychological tests will be scored with standard procedures, and concentrations of brain chemicals will be calculated for both time points by standard methods. This investigation will help identify factors that may play an important role in susceptibility to cognitive changes due to treatment side effects. Identification of these factors could lead to greater understanding of chemotherapy-induced cognitive impairment and improved prevention/treatment strategies in this population of cancer survivors.