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显著增加 男性前列腺癌患者的生存率，诊断后5年生存率超过98%。因此，确保 前列腺癌幸存者良好的生活质量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，这对前列腺患者的生活质量提出了严重的挑战。 癌症幸存者及其家人此外，与ADT相关的认知障碍损害了依从性， 并增加了随后诊断为阿尔茨海默病（AD）和相关痴呆的风险。这最后一 观察是特别重要的，因为前列腺癌通常折磨老年男性，典型的发病年龄是15岁。 60年代中后期，与年龄相关的认知障碍往往刚刚出现。的目的 与本行政补助金相关的父R01补助金旨在解决以下机制： ADT损害脑功能和认知，并测试一种旨在改善 ADT后的认知本行政补充文件的目的是响应NOT-AG-20 - 034， 是开始测试癌症病理生理学和ADT在产生 认知障碍，特别是在老龄化的大脑，并确定潜在的因素，可能会增加 发展阿尔茨海默病和相关痴呆症的可能性，包括与 神经退行性变和阿尔茨海默氏症相关的神经病理学指标在12个月大的大鼠，也是一个 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 ADT对认知、神经退行性变中的炎症信号传导和阿尔茨海默氏症指数的影响- 12月龄雄性Sprague-Dawley大鼠脑中的相关神经病理学，我们在本研究中使用的品系 项目迄今为止，和新重建的哥本哈根大鼠品系，我们将在未来的研究中使用，介绍 前列腺癌测量将包括注意力转移测试的认知功能，以 内侧前额叶皮层（mPFC）和视觉空间认知功能的新的物体定位测试，介导 在海马（Hipp）中;在mPFC和 和脑氧化代谢状态，通过测量mPFC和Hipp中的NAD+进行评估。在目标2中，我们将 检验前列腺癌病理生理学放大或引发ADT对前列腺癌的不利影响的假设。 认知、神经变性中的炎症信号传导和阿尔茨海默病相关的神经病理学。我们 将在12个月大的携带前列腺癌肿瘤的哥本哈根大鼠中测试ADT对相同测量的影响， 通过在侧腹皮下植入同系Dunning R-3327-G大鼠前列腺癌细胞诱导。的 在本附录中提出的实验结果，应该为发展这种技术提供初步的数据 未来的拨款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。

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.