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大幅增加 男性前列腺癌患者存活率，确诊后5年存活率超过98%。因此，确保 前列腺癌幸存者的高质量生活已成为成功治疗的重要组成部分。 虽然ADT在癌症治疗方面无疑是一个成功的故事，但它也伴随着不良反应， 包括严重的认知障碍，对前列腺的生活质量构成严重挑战 癌症幸存者和他们的家人。此外，与ADT相关的认知障碍会损害遵从性， 并增加随后诊断为阿尔茨海默病(AD)和相关痴呆症的风险。这是最后一个 观察尤其重要，因为前列腺癌通常困扰老年男性，典型的发病年龄为 60年代中后期的S，这一时期与年龄相关的认知障碍往往才刚刚出现。该计划的目的是 与本行政补充协议相关的家长R01拨款旨在解决以下机制 ADT损害大脑功能和认知，并测试一种旨在改善 ADT后的认知功能。根据NOT-AG-20-034号文件提交的本行政补编的目的是： 是开始测试癌症病理生理学和ADT在生产过程中相互作用的有害影响 认知损害，特别是在老化的大脑，并确定可能增加 发生阿尔茨海默病和相关痴呆的可能性，包括与以下相关的炎症信号 12个月龄大鼠的神经变性和阿尔茨海默氏症相关神经病理指标，也是一种 与年龄相关的认知障碍刚刚开始出现的年龄。在目标1中，我们将测试有害的 ADT对认知、参与神经变性的炎症信号以及阿尔茨海默氏症指数的影响 12个月龄雄性Spraogue-Dawley大鼠大脑中的相关神经病理学，我们在本实验中使用的品系 项目到目前为止，以及我们将在未来的研究中使用的新重组的哥本哈根大鼠品系 前列腺癌。措施将包括注意定势转移测试的认知功能，在 内侧前额叶皮质(MPFC)和视觉空间认知功能在新物体定位测验中的中介作用 在海马区(HIPP)；测定mPFC和AD相关的神经炎性信号和神经病理学。 和大脑氧化代谢状态，通过测量mPFC和HIPP中的NAD+来评估。在目标2中，我们将 检验前列腺癌病理生理学放大或启动ADT的有害影响的假设 认知、与神经退化有关的炎症信号，以及阿尔茨海默氏症相关的神经病理学。我们 将在携带前列腺癌肿瘤的12个月大的哥本哈根大鼠身上测试ADT对相同指标的影响， 将同基因大鼠前列腺癌细胞Dunning R-3327-G皮下移植于大鼠前列腺癌模型。这个 本附录中提出的实验结果应该为开发提供初步数据 一项旨在进一步研究前列腺癌及其治疗在AD和痴呆症中的作用的未来拨款。

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.