Testosterone Supplementation in Men with MCI

患有 MCI 的男性补充睾酮

• 批准号: 7264932
• 负责人: MONIQUE CHERRIER
• 金额: $ 30.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264932
• 关键词: Age; Age-associated memory impairment; Aggressive behavior; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Androgens; Animals; Anxiety; Apolipoprotein E; Area; Behavior; Behavioral; Biological Markers; Brain; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Development; Dimensions; Disease; Disease Progression; Dose; Drug Formulations; Epidemiologic Studies; Equipment and supply inventories; Future; Gel; Goals; Health Status; Hormones; Hypogonadism; Impaired cognition; Incidence; Individual; Injection of therapeutic agent; Laboratories; Measures; Memory; Mental Depression; Methods; Moods; Mus; Onset of illness; Outcome; Participant; Patients; Pharmaceutical Preparations; Physiological; Placebos; Plasma; Population; Preparation; Prevention; Public Health; Questionnaires; Range; Rate; Research; Research Design; Research Personnel; Risk; Role; Route; Score; Serum; Site; Suggestion; Supplementation; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Thinking; Time; Transgenic Organisms; Universities; Washington; Week; age related; apolipoprotein E-4; cognitive change; geriatric depression; human study; men; mild neurocognitive impairment; neuropsychiatry; novel; older men; prevent; programs; response; selective androgen receptor modulator; tau Proteins; tau-1; treatment duration

DESCRIPTION (provided by applicant): Natural age related declines in testosterone (T) are associated with decrements in cognitive abilities independent of health status. Low T levels over time are associated with increased risk for developing Alzheimer's disease (AD). These findings suggest that men with low T levels are most at risk for age-related cognitive decline and AD and therefore most likely to benefit from T supplementation to prevent the development of AD or age-associated cognitive decline. Studies in our laboratory as well as others provide support that both hypogonadal and eugonadal men, and men demonstrate cognitive improvements from T supplementation for brief treatment periods (6-12 weeks), when assessed at a supraphysiological or peak level. It is unknown whether T supplementation over a longer treatment period (6 months) or using a percutaneous formulation that provides a steady state, physiological dose level will result in beneficial cognitive changes in older men at risk for further cognitive decline from either mild cognitive impairment (MCI) and/or low T levels. In addition to behavioral changes, T may reduce further cognitive decline due to effects on pathophysiological biomarkers such as beta-amyloid (Aft) 1-40, 42 and tau which are thought to be related to onset and disease progression in AD. Both animal and human studies indicate that plasma and brain levels of AR.40, 42 are androgen responsive. Androgens may also have a role in modulating AD onset and progression in MCI individuals due to interactions with apolipoprotein E*4 (APOE*4) as androgens protect against the cognitive declines observed in transgenic APOE mice. The proposed study will examine cognitive, mood and cerebrospinal fluid (CSF) biomarker response to T supplementation in older men with mild cognitive impairment (MCI) and low serum T levels. The proposed study builds on our previous findings by examining cognitive response over a longer period of time (6 months) and assess whether these cognitive changes are observed within a physiologic range, and steady state dose level achieved using a new percutaneous gel preparation. This project is a novel area of inquiry that fits the goals and criteria of PAR-05-021 for pilot clinical trials directed toward the prevention and treatment of age-associated cognitive decline and Alzheimer's disease (AD). Given that the incidence of older men with low T levels increases with age as does the risk for MCI and AD, the public health implications of a potential therapeutic intervention in this population are tremendous. A therapeutic benefit of T supplementation may provide another possible treatment alternative and/or one that can be combined with existing medications. Further, results of this study will provide valuable information for planning, larger future trials of T supplementation or selective androgen receptor modulators (SARMs).

描述(申请人提供)：与自然年龄相关的睾酮(T)下降与认知能力的下降有关，与健康状况无关。随着时间的推移，低T水平与患阿尔茨海默病(AD)的风险增加有关。这些发现表明，T水平低的男性最有可能患上与年龄相关的认知下降和AD，因此最有可能从补充T来预防AD的发展或与年龄相关的认知下降中受益。我们实验室和其他实验室的研究支持，性腺功能减退和优性腺功能低下的男性和男性在短暂的治疗期间(6-12周)，当被评估为超生理水平或高峰水平时，T补充显示出认知能力的改善。目前尚不清楚，在更长的治疗期(6个月)内补充T，或者使用提供稳定状态、生理剂量水平的经皮制剂，是否会导致有可能因轻度认知障碍(MCI)和/或低T水平而进一步认知下降的老年男性的有益认知变化。除了行为改变外，T还可能通过影响病理生理生物标记物如β-淀粉样蛋白(AFT)1-40、42和tau而减少进一步的认知能力下降，这些生物标志物被认为与AD的发病和疾病进展有关。动物和人类的研究都表明，血浆和大脑中AR.40、42的水平与雄激素有关。雄激素还可能通过与载脂蛋白E*4(APOE*4)的相互作用而在MCI患者中调节AD的发生和发展，因为雄激素可以保护转基因APOE小鼠的认知能力下降。这项拟议的研究将检测患有轻度认知障碍(MCI)和血清T水平低的老年男性对补充T的认知、情绪和脑脊液(CSF)生物标记物的反应。这项拟议的研究建立在我们之前的发现基础上，通过检测较长时间(6个月)的认知反应，并评估这些认知变化是否在生理范围内观察到，以及使用新的经皮凝胶制剂实现的稳定剂量水平。该项目是一个新的研究领域，符合PAR-05-021关于预防和治疗年龄相关性认知下降和阿尔茨海默病(AD)的试点临床试验的目标和标准。鉴于低T水平的老年男性的发病率随着年龄的增长而增加，MCI和AD的风险也随着年龄的增加而增加，潜在的治疗干预对这一人群的公共健康影响是巨大的。补充T的治疗益处可能提供另一种可能的治疗选择和/或可以与现有药物相结合的治疗方法。此外，这项研究的结果将为T补充或选择性雄激素受体调节剂(SARM)的规划和未来更大规模的试验提供有价值的信息。