Testosterone Supplementation in Men with MCI

描述（由申请人提供）：睾酮（T）的自然年龄相关下降与独立于健康状况的认知能力下降相关。随着时间的推移，低T水平与发展阿尔茨海默病（AD）的风险增加有关。这些研究结果表明，T水平低的男性最有可能患上与年龄相关的认知能力下降和AD，因此最有可能从T补充剂中获益，以预防AD或与年龄相关的认知能力下降的发展。我们实验室的研究以及其他研究提供了支持，即性腺功能减退和性腺功能正常的男性，以及男性在超生理或峰值水平评估时，在短暂的治疗期（6-12周）内补充T后表现出认知改善。目前尚不清楚在较长的治疗期（6个月）内补充T或使用提供稳态生理剂量水平的经皮制剂是否会导致轻度认知障碍（MCI）和/或低T水平导致进一步认知下降风险的老年男性的有益认知变化。除了行为改变之外，T还可以减少进一步的认知下降，这是由于对病理生理学生物标志物的影响，例如β-淀粉样蛋白（Aft）1-40，42和tau，这些生物标志物被认为与AD的发病和疾病进展有关。动物和人类研究均表明，血浆和脑中AR. 40、42的水平是雄激素反应性的。由于雄激素与载脂蛋白E*4（APOE*4）的相互作用，雄激素也可能在调节MCI个体的AD发作和进展中发挥作用，因为雄激素可防止转基因APOE小鼠中观察到的认知下降。这项拟议的研究将检查患有轻度认知障碍（MCI）和低血清T水平的老年男性对T补充剂的认知，情绪和脑脊液（CSF）生物标志物反应。拟议的研究建立在我们以前的研究结果的基础上，通过检查较长时间（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达到的稳态剂量水平。该项目是一个新的调查领域，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。鉴于低T水平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长而增加，因此在这一人群中进行潜在治疗干预的公共卫生影响是巨大的。补充T的治疗益处可以提供另一种可能的治疗替代方案和/或可以与现有药物组合的治疗方案。此外，这项研究的结果将为计划，更大的未来试验T补充剂或选择性雄激素受体调节剂（SARM）提供有价值的信息。

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).