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: 9364864
• 负责人: Matthew S Panizzon
• 金额: $ 65.48万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364864
• 关键词: Adverse effects; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; 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; 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; Triglycerides; Visuospatial; Weight Gain; age related; analog; androgen deprivation therapy; androgen sensitive; base; cancer therapy; clinically significant; cognitive ability; cognitive change; cognitive function; cognitive performance; cognitive testing; dehydroepiandrosterone; epidemiology study; exosome; fasting glucose; genome wide association study; 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; sulfated glycoprotein 2; tau Proteins; tau-1; treatment response; Adverse effects; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; 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; 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; Triglycerides; Visuospatial; Weight Gain; age related; analog; androgen deprivation therapy; androgen sensitive; base; cancer therapy; clinically significant; cognitive ability; cognitive change; cognitive function; cognitive performance; cognitive testing; dehydroepiandrosterone; epidemiology study; exosome; fasting glucose; genome wide association study; 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; 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.

项目摘要 老年男性的睾丸激素水平较低，与发展阿尔茨海默氏症的风险增加有关 疾病（ALZD）。睾丸激素的下降早在三十年代中期开始，到中期年龄贡献 与男性衰老有关的许多身体和心理投诉。这些的时间 变化与ALZD的临床前阶段重叠，这个时期是作为最佳时间的目标 对该疾病的干预措施可能最大。睾丸激素下降的程度 影响ALZD的临床前标记 - 认知，β-淀粉样蛋白（Aβ）和TAU - 代表着重要的 尚未得到充分检查的知识差距。在拟议的研究中，我们将在认知上检查 接受雄激素剥夺疗法（ADT）的正常男性针对非转移性前列腺癌以及 非ADT前列腺癌阳性对照组，目的是确定睾丸激素部署的影响 在ALZD的临床前标记上。 ADT是前列腺癌的常用治疗方法，并提供独特 研究急性睾丸激素耗竭对临床前标记的影响 尽管ADT是一种有效的癌症治疗，但它与多种副作用有关 包括增加ALZD的风险。在AIM 1中，我们将表征ADT对认知功能的影响。 我们将评估一系列认知测试，并利用经过良好验证的认知工作的测量 学生词典，以评估ADT带来的认知变化。我们假设ADT将对认知征税 资源，导致努力和绩效的变化。在AIM 2中，我们将测试多基因的风险 ALZD改变了ADT对认知的影响。我们假设ALZD敏感认知能力的变化 对AD的遗传风险更大的个体将更大。在AIM 3中，将确定在多大程度上 Aβ和TAU的度量受ADT的影响。我们将利用基于黄金标准CSF的措施，并 从血浆到获得Aβ40，Aβ42，Total-TAU和磷酸化的TAU水平的神经源性外泌体。 我们假设在ADT过程中，我们将观察到Aβ和TAU水平的重大变化，并且 这些变化在ALZD遗传风险更大的人中会更明显。而且，我们假设 Aβ和TAU的变化将与认知表现和认知努力更加密切相关 那些对ALZD遗传风险更大的人。评估将进行预处理，然后在6点再次进行 12个月的随访（总共三个评估）。这项对独特临床人群的自然主义研究提供了 有价值的机会来检查单个ALZD风险因素（睾丸激素水平）中变化的影响。在 与表现出临床上显着下降的临床显着下降可能需要的几年或数十年形成对比 标准人群，我们将能够观察睾丸激素耗竭对最早的某些 在凝结的时间段内，与ALZD相关的过程的标记。结果，拟议的研究将 对雄激素作用在ALZD发病机理中的作用提供新的见解。