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

项目总结 老年男性的睾酮水平低与患阿尔茨海默氏症的风险增加有关 疾病(阿尔茨海默病)。睾丸激素的下降早在35岁左右就开始了，到中年后期才开始下降。 许多与男性衰老相关的生理和心理方面的抱怨。这些措施的时机 变化与阿尔茨海默病的临床前阶段重叠，这段时间被定为 哪种干预措施对这种疾病可能有最大的效果。睾丸激素下降的程度 影响阿尔茨海默病的临床前标志物-认知、β-淀粉样蛋白(A-β)和tau-代表显著 尚未充分研究的知识鸿沟。在拟议的研究中，我们将从认知角度审视 接受雄激素剥夺疗法(ADT)治疗非转移性前列腺癌的正常男性，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是前列腺癌的一种常用治疗方法，它提供了一种独特的 研究严重的睾丸素缺乏对临床前标志物的影响 老年痴呆症。虽然ADT是一种有效的癌症治疗方法，但它与各种副作用有关， 包括增加患阿尔茨海默病的风险。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，并利用一种经过充分验证的认知努力量度--任务诱发 散瞳，以评估ADT带来的认知变化。我们假设ADT将对认知征税 资源，从而导致工作和绩效的变化。在目标2中，我们将测试是否存在多基因风险 阿尔茨海默病会改变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 阿尔茨海默病的遗传风险较大的个体将会更大。在目标3中，将确定 A、β和tau的测量受到ADT的影响。我们将采用基于证券交易基金的黄金标准措施，以及 从血浆中获取神经元来源的外切体以获得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，并且 这些变化在阿尔茨海默病遗传风险较高的人中会更加明显。此外，我们假设 Aβ和tau的变化将与认知表现和认知努力更强地相关 那些遗传风险较高的人患阿尔茨海默病。评估将在治疗前进行，然后在6点和6点再次进行 12个月随访(共三次评估)。这项对独特临床人群的自然主义研究提供了一种 这是研究单一阿尔茨海默病风险因素(睾丸激素水平)变化的影响的宝贵机会。在……里面 相比之下，临床上睾丸激素的显著下降可能需要几年或几十年的时间才能显现出来 标准人群中，我们将能够观察到睾酮耗竭对一些最早的影响 阿尔茨海默病相关过程的标记在一段浓缩的时间内。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.