Cognitive impairment associated with androgen deprivation therapy for prostate cancer

雄激素剥夺疗法（ADT）是前列腺癌的主要治疗方法。ADT急剧增加

Androgen deprivation therapy (ADT) is a mainstay treatment for prostate cancer. ADT has dramatically increased survival of men with prostate cancer, with a 5-year post-diagnosis survival rate exceeding 98%. Thus, ensuring a strong quality of life for prostate cancer survivors has become an essential component of successful treatment. While undoubtedly a success story in terms of cancer treatment, ADT is accompanied by adverse effects, including significant cognitive impairment that presents a serious challenge to the quality of life for prostate cancer survivors and their families. Further, cognitive impairment associated with ADT compromises compliance, and increases the risk of a subsequent diagnosis of Alzheimer’s Disease (AD) and related dementia. This last observation is especially important, as prostate cancer typically afflicts older men, with a typical age of onset in the mid-to-late 60’s, a time at which age-related cognitive impairment is often just emerging. The purpose of the parent R01 grant with which this administrative supplement is associated is to address the mechanism by which ADT impairs brain function and cognition, and to test a novel therapeutic intervention aimed at improving cognition after ADT. The purpose of this administrative supplement, submitted in response to NOT-AG-20-034, is to begin testing the interacting detrimental influences of cancer pathophysiology and ADT in producing cognitive impairment specifically in the aging brain, and to identify potential factors that may increase the likelihood of developing Alzheimer’s disease and related dementias, including inflammatory signaling related to neurodegeneration, and indices of Alzheimer’s-related neuropathology in the brains of 12-mo old rats, also an age at which age-related cognitive impairment is just starting to emerge. In aim 1, we will test the detrimental effects of ADT on cognition, inflammatory signaling implicated in neurodegeneration, and indices of Alzheimer’s- related neuropathology in the brains of 12-mo old male Sprague-Dawley rats, the strain we have used in this project to date, and the newly reconstituted Copenhagen rat strain that we will use in future studies to introduce prostate cancer. Measures will include cognitive function on the attentional set-shifting test, mediated in the medial prefrontal cortex (mPFC), and visuospatial cognitive function on the novel object location test, mediated in hippocampus (Hipp); measures of neuroinflammatory signaling and AD-related neuropathology in mPFC and Hipp; and brain oxidative metabolic status, assessed by measuring NAD+ in mPFC and Hipp. In aim 2, we will test the hypothesis that prostate cancer pathophysiology amplifies or primes the detrimental effects of ADT on cognition, inflammatory signaling implicated in neurodegeneration, and Alzheimer’s-related neuropathology. We will test the effects of ADTon the same measures in 12-mo old Copenhagen rats bearing prostate cancer tumors, induced by implanting syngeneic Dunning R-3327-G rat prostate cancer cells subcutaneously in the flank. The results of the experiments proposed in this supplement should provide preliminary data toward the development of a future grant aimed at investigating further the role of prostate cancer and its treatment in AD and dementia.