Cognitive impairment associated with androgen deprivation therapy for prostate cancer

前列腺癌雄激素剥夺疗法相关的认知障碍

• 批准号: 10287767
• 负责人: David A Morilak
• 金额: $ 30.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287767
• 关键词: Address; Administrative Supplement; Adverse effects; Age; Age of Onset; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anti-Inflammatory Agents; Apolipoprotein E; Attention; Brain; CD44 gene; CX3CL1 gene; Cell Respiration; Cognition; Coupled; Data; Development; Diagnosis; Down-Regulation; Ensure; Family; Fractalkine; Functional disorder; Future; Gene Expression; Genes; Grant; Hippocampus (Brain); IL6 gene; Impaired cognition; Impairment; Implant; Inflammatory; JAK2 gene; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medial; Mediating; Metabolic; Microglia; Nerve Degeneration; Parents; Pathology; Prefrontal Cortex; Prostate Cancer therapy; Quality of life; Rat Strains; Rattus; Risk; Role; Signal Transduction; Site; Sprague-Dawley Rats; Survival Rate; Synaptic plasticity; TREM2 gene; Testing; Time; Visuospatial; aging brain; androgen deprivation therapy; cancer therapy; cognitive function; cytokine; experimental study; improved; indexing; male; men; middle age; neuroinflammation; neuropathology; novel; novel therapeutic intervention; older men; prostate cancer cell; prostate cancer survivors; receptor; reconstitution; response; subcutaneous; success; tau Proteins; tau phosphorylation; tau-1; tumor; Address; Administrative Supplement; Adverse effects; Age; Age of Onset; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anti-Inflammatory Agents; Apolipoprotein E; Attention; Brain; CD44 gene; CX3CL1 gene; Cell Respiration; Cognition; Coupled; Data; Development; Diagnosis; Down-Regulation; Ensure; Family; Fractalkine; Functional disorder; Future; Gene Expression; Genes; Grant; Hippocampus (Brain); IL6 gene; Impaired cognition; Impairment; Implant; Inflammatory; JAK2 gene; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medial; Mediating; Metabolic; Microglia; Nerve Degeneration; Parents; Pathology; Prefrontal Cortex; Prostate Cancer therapy; Quality of life; Rat Strains; Rattus; Risk; Role; Signal Transduction; Site; Sprague-Dawley Rats; Survival Rate; Synaptic plasticity; TREM2 gene; Testing; Time; Visuospatial; aging brain; androgen deprivation therapy; cancer therapy; cognitive function; cytokine; experimental study; improved; indexing; male; men; middle age; neuroinflammation; neuropathology; novel; novel therapeutic intervention; older men; prostate cancer cell; prostate cancer survivors; receptor; reconstitution; response; subcutaneous; success; tau Proteins; tau phosphorylation; tau-1; tumor

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.

雄激素剥夺疗法（ADT）是前列腺癌的主要治疗方法。 ADT大大增加了 前列腺癌男性的存活率，诊断后5年的存活率超过98％。那，确保 前列腺癌存活的强大生活质量已成为成功治疗的重要组成部分。 毫无疑问，在癌症治疗方面是成功的故事，但ADT是通过不利影响完成的，但 包括严重的认知障碍，对前列腺的生活质量提出了严重的挑战 癌症存活及其家人。此外，与ADT相关的认知障碍会损害依从性， 并增加了随后诊断阿尔茨海默氏病（AD）和相关痴呆症的风险。最后 观察尤其重要，因为前列腺癌通常会影响老年男性，典型的发病年龄 60年代中期，这是与年龄相关的认知障碍的时候，通常只是出现。目的 与此行政补充相关的父母R01赠款是为了解决该机制 ADT会损害大脑功能和认知，并测试旨在改善的新型治疗干预措施 ADT之后的认知。该行政补充的目的，响应于Not-AG-20-034， 是开始测试生产中癌症病理生理学和ADT的相互作用有害影响 认知障碍特别在衰老的大脑中，并确定可能增加的潜在因素 发展阿尔茨海默氏病和相关痴呆症的可能性，包括与 神经变性，以及阿尔茨海默氏症相关的神经病理学的指标 与年龄相关的认知障碍的年龄刚刚开始出现。在AIM 1中，我们将测试决心 ADT对在神经变性中实施的认知，炎症信号的影响以及阿尔茨海默氏症的指标 12-mo老雄性Sprague-Dawley大鼠的大脑中相关的神经病理学，我们在此中使用的菌株 迄今为止的项目，以及我们将在以后的研究中使用的新哥本哈根老鼠压力 前列腺癌。措施将在注意力集中测试中包括认知功能，并在 介质前额叶皮层（MPFC）和新颖对象位置测试的视觉认知功能，介导 在海马（Hipp）中； MPFC和 嬉皮士；和脑氧化代谢状态，通过测量MPFC和HIPP中的NAD+评估。在AIM 2中，我们将 检验前列腺癌病理生理学放大器或素数的假设 认知，神经退行性中隐含的炎症信号传导以及与阿尔茨海默氏症相关的神经病理学。我们 将测试阿德顿（Adton 通过在侧面皮下皮下植入合成性Dunning R-3327-G大鼠前列腺癌细胞引起的诱导。这 此补充中提出的实验结果应提供初步数据 未来的赠款旨在进一步研究前列腺癌及其在AD和痴呆症中的治疗作用。