Clinical Manipulation of Testosterone and Its Impact on Dementia and Health

睾酮的临床操作及其对痴呆症和健康的影响

• 批准号: 9934863
• 负责人: RICHARD L HAUGER
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934863
• 关键词: AR gene; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Androgens; Benefits and Risks; Biomedical Research; Brain; CAG repeat; Cardiovascular Diseases; Clinical; Clinical Data; Cognition; Cognitive; DNA Binding Domain; Data; Deltastab; Dementia; Development; Diabetes Mellitus; Disease; Disease Marker; Early Intervention; Effectiveness; Functional disorder; Genetic; Genetic Risk; Health; Healthcare; Healthcare Systems; Hormone replacement therapy; Hypogonadism; Impaired cognition; Individual; Intervention; Knowledge; Length; Ligand Binding; Light; Link; Malignant neoplasm of prostate; Medical; Medical Records; Medicine; Modeling; Motion; Mutation; Nature; Onset of illness; Outcome; Pathway interactions; Patients; Peripheral; Phase; Play; Precipitating Factors; Predisposition; Process; Prostate Cancer therapy; Randomized; Recording of previous events; Recurrence; Relative Risks; Reporting; Research; Resources; Risk; Risk Factors; Role; Sample Size; Symptoms; System; Testing; Testosterone; Treatment Efficacy; Variant; Veterans; age related; androgen deprivation therapy; androgen sensitive; cognitive function; cohort; comorbidity; dementia risk; design; epidemiology study; evidence base; experimental study; hormone sensitivity; improved; innovation; insight; interest; male; men; middle age; mild cognitive impairment; military veteran; novel; older men; pre-clinical; precision medicine; programs; response; success; testosterone replacement therapy; treatment center

The number of veterans with Alzheimer’s disease (AlzD) is dramatically increasing. Testosterone is hypothesized to have an important role in risk, onset, and progression of AlzD in men. Testosterone deficiency prior to AlzD onset can promote AlzD pathophysiology during the preclinical phase when interventions may have the greatest success. Androgen deprivation therapy (ADT) for prostate cancer and testosterone replacement therapy (TRT) for age-related hypogonadism that directly target testosterone levels provide valuable opportunities to examine the impact of this androgen on the risk of developing AlzD, its prodromal condition mild cognitive impairment (MCI), and co-morbid health conditions. In the proposed study, we will utilize genetic and clinical data from the Million Veteran Program (MVP) to determine the impact of low testosterone, ADT, and TRT on the relative risk for MCI and AlzD. We hypothesize that the long-term impact of low testosterone, ADT, and TRT will be regulated by polygenic risk for AlzD and variation in the androgen receptor (AR) gene. These genetic factors represent critical, pre-existing markers of disease vulnerability and hormone sensitivity that have yet to be incorporated into research on protective and beneficial effects of testosterone on cognition and health. In our study, we will first determine if the risks of MCI, AlzD, and co- morbid medical disorders that promote dementia are increased by low testosterone levels in the MVP cohort. Next, we will determine if the clinical manipulation of testosterone levels is associated with differences in risks for MCI and AlzD. We hypothesize that individuals who undergo ADT will be at increased risk for MCI, AlzD and co-morbid health conditions relative to men with a history of prostate cancer but who have not been treated with ADT. We further hypothesize that men who receive TRT will be at decreased risks for these same conditions relative to men with low testosterone who do not receive hormone replacement therapy. We will next test whether pre-existing genetic risk for AlzD modifies the impact of testosterone-centered treatments on MCI and AlzD. We hypothesize that the observed effects of ADT and TRT on the cognitive and health outcomes will be greater in individuals at greater genetic risk for AlzD. Finally, we will determine whether genetically driven changes in androgen sensitivity due to CAG repeat length or ligand and DNA binding domain mutations regulate the long-term risks and benefits of ADT and TRT. We hypothesize that a more sensitive variant of the AR gene will confer greater risk for MCI and AlzD following ADT. Furthermore, we hypothesize that more androgen-sensitive individuals will benefit more from TRT, and will therefore show a reduced risk for MCI and AlzD. With its large sample size, extensive genetic data, and curated medical record data, the MVP represents an ideal resource with which to explore impact of testosterone-centered treatments on dementia risk, and provide a proof-of-principle model of genetically informed precision medicine. By evaluating the long- term risks and benefits of ADT and TRT on cognitive health, in the context of a genetically informative design, the proposed study will provide valuable insights into the role of testosterone as a risk factor for MCI and AlzD, and increase our understanding of a critical AlzD-related pathway that may be responsive to intervention. The present study will also shed light on the long-term risks and benefits associated with ADT and TRT, and clarify whether these treatments, which are efficacious in certain contexts, set in motion or delay pathophysiological processes that result in the emergence of AlzD symptoms in men. Finally, we will determine if our hypothesis driven, genetically informed study investigating underlying genetic risk (i.e., the polygenic risk for AlzD) and genetically determined treatment sensitivity (i.e., variation within the AR gene) can improve treatment efficacy and evidence-based usage of TRT and reduce detrimental outcomes of ADT. We believe our study is ideal for the MVP, and will demonstrate effectiveness of the broader program for biomedical research and the advancement of personalized/precision medicine.

患有阿尔茨海默氏病（ALZD）的退伍军人人数急剧增加。睾丸激素是 假设在男性中ALZD的风险，发作和进展中起重要作用。睾丸激素缺乏 在进行ALZD发作之前，可以在干预措施可能 取得最大的成功。前列腺癌和睾丸激素的雄激素剥夺疗法（ADT） 直接靶向睾丸激素水平的年龄相关性性腺功能减退的替代疗法（TRT）提供 价值机会来检查该雄激素对发展ALZD风险的影响，其前代 条件轻度认知障碍（MCI）和合并健康状况。在拟议的研究中，我们将 利用百万退伍军人计划（MVP）的遗传和临床数据来确定低的影响 MCI和ALZD的相对风险，睾丸激素，ADT和TRT。我们假设长期影响 低睾丸激素，ADT和TRT将受ALZD的多基因风险和雄激素变化的调节 受体（AR）基因。这些遗传因素代表了疾病脆弱性和 尚未将马酮灵敏度纳入对受保护和有益影响的研究 认知和健康的睾丸激素。在我们的研究中，我们将首先确定MCI，ALZD和共同的风险是否存在 MVP队列中睾丸激素水平较低的病态医疗疾病促进痴呆症。 接下来，我们将确定睾丸激素水平的临床操作是否与风险差异有关 对于MCI和ALZD。我们假设接受ADT的个人将面临MCI，ALZD的风险增加 与患有前列腺癌史的男性相对于健康状况的合并健康状况 用ADT处理。我们进一步假设接受TRT的男人的风险将降低 相对于未接受马龙替代疗法的睾丸激素低的男性的条件。我们将 下一个测试是否预先存在ALZD的遗传风险会改变以睾丸激素为中心的治疗对 MCI和ALZD。我们假设观察到的ADT和TRT对认知和健康的影响 ALZD遗传风险更大的个体的结果将更大。最后，我们将确定是否 由于CAG重复长度或配体和DNA结合结构域而导致雄激素灵敏度的基因驱动的变化 突变调节ADT和TRT的长期风险和益处。我们假设一个更敏感的 AR基因的变体将使ADT后MCI和ALZD的风险更大。此外，我们假设 越来越多的雄激素敏感的个体将从TRT中受益更多，因此将显示出降低的风险 MCI和ALZD。 MVP具有较大的样本量，广泛的遗传数据和策划的病历数据 代表了一个理想的资源，可以探索以睾丸激素为中心的治疗对痴呆的影响 风险，并提供一般知情的精确药物的原理证明模型。通过评估长期 在一般有用的设计中，ADT和TRT对认知健康的术语风险和好处， 拟议的研究将为睾丸激素作为MCI和ALZD的危险因素的作用提供宝贵的见解， 并增加我们对可能对干预措施有反应的关键ALZD相关途径的理解。 目前的研究还将阐明与ADT和TRT相关的长期风险和收益，并澄清 这些治疗方法是在某些情况下有效的，是运动还是延迟病理生理 导致男性ALZD症状出现的过程。最后，我们将确定我们的假设是否 驱动的，遗传知情的研究研究了潜在的遗传风险（即ALZD的多基因风险）和 遗传确定的治疗敏感性（即AR基因内的变异）可以提高治疗效率 以及基于证据的TRT使用并减少ADT的确定结果。我们认为我们的研究是理想的选择 MVP，并将展示更广泛的生物医学研究计划的有效性和 个性化/精密医学的进步。