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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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睾丸激素早在三十几岁就开始下降，并在中年后期有所贡献。许多与男性衰老相关的生理和心理疾病。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种疾病干预措施可能产生最大效果睾酮下降的程度。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，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。我们认为 ADT 会对认知造成负担。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。我们追踪 AlzD 敏感认知能力的变化。在目标 3 中，AD 遗传风险较高的个体中的风险更大。 Aβ 和 tau 的测量受 ADT 的影响，我们将利用基于 CSF 的金标准测量，并且来自血浆的神经源性外泌体，用于获取 Aβ40、Aβ42、总 tau 和磷酸化 tau 的水平。我们追求的是，在 ADT 过程中，我们将观察到 Aβ 和 tau 水平的显着变化，并且这些变化对于那些患有阿尔茨海默氏症（AlzD）遗传风险较高的人来说会更加明显。 Aβ 和 tau 蛋白的变化与认知表现和认知努力的相关性更强对于阿尔茨海默氏症 (AlzD) 遗传风险较高的患者，将在治疗前进行评估，然后在 6 点和 6 点再次进行评估。 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研究提供了一个结果。一个宝贵的机会来检查单一阿尔茨海默病风险因素（睾酮水平）变化的影响。与此相反，睾酮水平在临床上显着下降可能需要数年或数十年才能显现出来。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因此，拟议的研究将在一段时间内分析阿尔茨海默病相关过程的标记。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。