Effects of Androgen Deprivation Therapy on Preclinical Symptoms of Alzheimer's Disease

项目摘要 老年男性睾丸激素水平低与老年痴呆症风险增加有关 疾病（AlzD）。睾丸激素的下降开始早在30多岁，并在中年后期 许多与男性衰老有关的生理和心理问题。这些的时机 这些变化与AlzD的临床前阶段重叠，这一时期被定为治疗过程中的最佳时间。 哪种疾病的干预措施效果最好。睾丸激素下降的程度 影响AlzD的临床前标志物-认知，β-淀粉样蛋白（Aβ）和tau -代表了一个显著的 知识差距还有待充分研究。在这项研究中，我们将从认知的角度来考察 正常男性接受雄激素剥夺治疗（ADT）的非转移性前列腺癌，以及 非ADT前列腺癌阳性对照组，目的是阐明睾酮耗竭的影响 阿尔茨海默病的临床前标志物ADT是前列腺癌的常用治疗方法， 通过该方案来研究急剧的睾酮耗竭对临床前标志物的影响， 阿兹海默症虽然ADT是一种有效的癌症治疗方法，但它与各种各样的副作用有关， 包括患老年痴呆症的风险增加在目标1中，我们将描述ADT对认知功能的影响。 我们将评估一系列认知测试，并利用一个有效的认知努力，任务诱发的措施， 瞳孔扩张，以评估ADT引起的认知变化。我们假设ADT会对认知能力征税， 资源，导致工作和绩效的变化。在目标2中，我们将测试多基因风险是否 AlzD改变ADT对认知的影响。我们假设阿尔茨海默病敏感认知能力的变化 在AD遗传风险更高的个体中会更大。目标3将决定 Aβ和tau的测量值受ADT的影响。我们将采用基于金标准CSF的措施， 来自血浆的神经元来源的外泌体以获得Aβ40、Aβ42、总tau和磷酸化tau的水平。 我们假设在ADT过程中，我们将观察到Aβ和tau水平的显著变化， 这些变化在那些有更大遗传风险的人中会更明显。此外，我们假设 Aβ和tau蛋白的变化与认知能力和认知努力的相关性更强， 那些有更大遗传风险的人。将在治疗前进行评估，然后在6和 12个月随访（共3次评估）。这项对独特临床人群的自然主义研究提供了一个 这是一个宝贵的机会，可以检查单个AlzD风险因素（睾酮水平）变化的影响。在 与睾丸激素临床显著下降可能需要几年或几十年的时间来表现相反， 标准人群中，我们将能够观察到睾丸激素消耗对一些最早的 AlzD相关过程的标志物。因此，拟议的研究将 为雄激素在阿尔茨海默病发病机制中的作用提供了新的见解。

PROJECT SUMMARY Low levels of testosterone in older men have been associated with an increased risk of developing Alzheimer's disease (AlzD). Declines in testosterone begin as early as the mid-thirties, and by late-middle age contribute to many of the physiological and psychological complaints associated with male aging. The timing of these changes overlaps with the preclinical stage of AlzD, a period that has been targeted as the optimal time during which interventions for the disease may have the greatest effect. The degree to which declines in testosterone influence the preclinical markers of AlzD – cognition, beta-amyloid (Aβ), and tau – represents a significant knowledge gap that has yet to be adequately examined. In the proposed study we will examine cognitively normal men undergoing androgen deprivation therapy (ADT) for non-metastatic prostate cancer, as well as a non-ADT prostate cancer positive control group, with the goal of clarifying the effects of testosterone depletion on preclinical markers of AlzD. ADT is a commonly used treatment for prostate cancer, and offers a unique scenario through which to study the impact of dramatic testosterone depletion on the preclinical markers of AlzD. Although ADT is an effective cancer treatment, it is associated with a wide variety of side effects, including an increased risk for AlzD. In Aim 1, we will characterize the effects of ADT on cognitive function. We will assess an array of cognitive tests, and utilize a well validated measure of cognitive effort, task-evoked pupil dilation, to assess cognitive changes brought on by ADT. We hypothesize that ADT will tax cognitive resources, resulting in changes in effort and performance. In Aim 2, we will test whether the polygenic risk for AlzD alters the effects of ADT on cognition. We hypothesize that changes in AlzD sensitive cognitive abilities will be greater in individuals at greater genetic risk for AD. In Aim 3, will determine the extent to which measures of Aβ and tau are influenced by ADT. We will utilize gold standard CSF based measures, and neuronally-derived exosomes from plasma to acquire levels of Aβ40, Aβ42, total-tau, and phosphorylated-tau. We hypothesize that over the course of ADT we will observe significant changes in Aβ and tau levels, and that these changes will be more pronounced in those at greater genetic risk for AlzD. Moreover, we hypothesize that changes in Aβ and tau will be more strongly correlated with cognitive performance and cognitive effort in those at greater genetic risk for AlzD. Assessments will be conducted pre-treatment, and then again at 6 and 12 month follow-ups (three assessments in total). This naturalistic study of a unique clinical population offers a valuable opportunity to examine the impact of changes in a single AlzD risk factor (testosterone level). In contrast to the years or decades that it might take for clinically significant declines in testosterone to manifest in standard populations, we will be able to observe the impact of testosterone depletion on some of the earliest markers of AlzD-related processes over a condensed period of time. As a result, the proposed study will provide novel insights into the role of androgen action in the pathogenesis of AlzD.