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

雄激素剥夺疗法对阿尔茨海默病临床前症状的影响

• 批准号: 10176322
• 负责人: Matthew S Panizzon
• 金额: $ 63.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176322
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Androgens; Androstenedione; Anemia; Animals; Biological Markers; Cardiovascular system; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Control Groups; Decreased Libido; Dementia; Disease; Endocrine; Episodic memory; Estradiol; Fatigue; Functional disorder; Genes; Genetic Risk; Goals; Gold; Health; High Density Lipoprotein Cholesterol; Human; IL8 gene; Individual; Insulin; Interleukin-1 beta; Interleukin-6; Intervention; Knowledge; LDL Cholesterol Lipoproteins; Link; Malignant neoplasm of prostate; Measures; Mediating; Medical; Metabolic; Motion; Mydriasis; Neurons; Neuropsychological Tests; Nonmetastatic; Pathogenesis; Pathway interactions; Performance; Physiological; Plasma; Population; Predisposition; Process; Prostate; Prostate Cancer therapy; Quantitative Genetics; Regulation; Resource Allocation; Resources; Risk; Risk Factors; Role; Symptoms; TNF gene; Task Performances; Taxes; Testing; Testosterone; Time; Treatment Side Effects; Triglycerides; Visuospatial; Weight Gain; age related; analog; androgen deprivation therapy; androgen sensitive; base; cancer therapy; cardiometabolism; clinically significant; cognitive ability; cognitive change; cognitive function; cognitive performance; cognitive testing; dehydroepiandrosterone; dementia risk; epidemiology study; exosome; fasting glucose; genome wide association study; human old age (65+); inflammatory marker; insight; lifestyle factors; male; men; middle age; novel; older men; pre-clinical; pro-brain natriuretic peptide (1-76); processing speed; psychologic; response; response biomarker; side effect; sulfated glycoprotein 2; tau Proteins; tau-1; treatment response

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.

项目概要 老年男性睾酮水平低与患阿尔茨海默病的风险增加有关 疾病（阿尔茨海默病）。睾丸激素早在三十几岁就开始下降，到中年后期就会下降 许多与男性衰老相关的生理和心理疾病。这些的时间安排 变化与 AlzD 的临床前阶段重叠，该阶段被定为治疗期间的最佳时间 哪些针对该疾病的干预措施可能会产生最大的效果。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——代表了显着的影响 尚未得到充分审查的知识差距。在拟议的研究中，我们将从认知角度进行检查 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，目的是阐明睾酮消耗的影响 AlzD 的临床前标志物。 ADT 是前列腺癌的常用治疗方法，并提供独特的治疗方法 通过该场景来研究睾酮急剧减少对临床前标志物的影响 阿尔兹D。尽管 ADT 是一种有效的癌症治疗方法，但它会带来多种副作用， 包括阿尔茨海默病（AlzD）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，并利用经过充分验证的认知努力、任务诱发的衡量标准 瞳孔扩张，以评估 ADT 带来的认知变化。我们假设 ADT 会对认知造成负担 资源，从而导致努力和绩效的变化。在目标 2 中，我们将测试是否存在多基因风险 AlzD 改变了 ADT 对认知的影响。我们假设 AlzD 敏感认知能力发生变化 对于 AD 遗传风险较高的个体来说，该值会更大。在目标 3 中，将确定 Aβ 和 tau 的测量受 ADT 的影响。我们将采用基于 CSF 的黄金标准措施，并且 从血浆中提取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 水平的显着变化，并且 对于阿尔茨海默病遗传风险较高的人来说，这些变化会更加明显。此外，我们假设 Aβ 和 tau 蛋白的变化与认知表现和认知努力的相关性更强 那些患有阿尔茨海默病（AlzD）的遗传风险较高的人。评估将在治疗前进行，然后在 6 点和 6 点再次进行。 12 个月的随访（总共 3 次评估）。这项针对独特临床人群的自然主义研究提供了 一个宝贵的机会来检查单个阿尔茨海默病风险因素（睾酮水平）变化的影响。在 与临床上睾酮水平显着下降可能需要数年或数十年的时间形成鲜明对比 标准人群中，我们将能够观察睾丸激素耗尽对一些最早的人群的影响 一段时间内阿尔茨海默病相关过程的标记。因此，拟议的研究将 为了解雄激素作用在阿尔茨海默病发病机制中的作用提供了新的见解。