Testosterone Supplementation in Men with MCI

患有 MCI 的男性补充睾酮

• 批准号: 7447396
• 负责人: MONIQUE CHERRIER
• 金额: $ 31.75万
• 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/7447396
• 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（由申请人提供）：自然年龄相关的睾酮(T)下降与独立于健康状况的认知能力下降有关。长期的低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，睾酮水平低的男性最容易出现与年龄相关的认知能力下降和AD，因此最有可能从补充睾酮中获益，以预防AD的发展或与年龄相关的认知能力下降。我们实验室的研究以及其他研究都支持性腺功能低下和性腺功能正常的男性，以及男性在短期治疗期间（6-12周）补充T后，在超生理或峰值水平进行评估时，表现出认知改善。目前尚不清楚，在较长的治疗期（6个月）内补充睾酮或使用经皮制剂提供稳定的生理剂量水平，是否会对因轻度认知障碍（MCI）和/或低睾酮水平而有进一步认知能力下降风险的老年男性产生有益的认知变化。除了行为改变外，T可能通过对病理生理生物标志物（如β -淀粉样蛋白（Aft） 1- 40,42和tau）的影响而进一步减少认知能力下降，这些生物标志物被认为与AD的发病和疾病进展有关。动物和人类研究都表明，血浆和脑中的ar . 40,42水平对雄激素有反应。雄激素也可能通过与载脂蛋白E*4 （APOE*4）的相互作用，在MCI个体中调节AD的发生和进展，因为雄激素可以保护转基因APOE小鼠的认知能力下降。该研究将检测轻度认知障碍（MCI）和低血清T水平老年男性对补充T的认知、情绪和脑脊液（CSF）生物标志物的反应。我们提出的研究建立在我们之前的研究结果的基础上，通过检查更长时间（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是否达到稳定的剂量水平。该项目是一个新颖的研究领域，符合PAR-05-021的目标和标准，用于预防和治疗与年龄相关的认知能力下降和阿尔茨海默病（AD）的试点临床试验。鉴于老年男性低T水平的发病率随着年龄的增长而增加，MCI和AD的风险也随之增加，在这一人群中进行潜在的治疗干预对公共卫生的影响是巨大的。补充睾酮的治疗益处可能提供另一种可能的治疗方案和/或可以与现有药物联合使用的治疗方案。此外，本研究的结果将为计划提供有价值的信息，未来更大规模的T补充剂或选择性雄激素受体调节剂（SARMs）的试验。