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）：睾丸激素（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有关。随着时间的流逝，低水平的水平与患阿尔茨海默氏病（AD）的风险增加有关。这些发现表明，t水平较低的男性对与年龄相关的认知下降和AD的风险最大，因此最有可能受益于补充T，以防止AD或与年龄相关的认知能力下降。在我们的实验室和其他研究中，当在超时性治疗期（6-12周）中，在thephysiologicy或Peak水平上进行评估时，在t t t t theflestement或eugonadal的男性以及男性都表现出认知的改善。尚不清楚t补充t在更长的治疗期（6个月）中，还是使用提供稳定状态的经皮配方，生理剂量水平将导致老年男性的有益认知变化，从而有可能因轻度认知障碍（MCI）和/或低T水平而导致认知能力下降的风险下降。除行为变化外，T还可以减少因对病理生物学生物标志物（例如β-淀粉样蛋白（AFT）1-40，42和TAU）的影响而导致的进一步认知下降，这被认为与AD的发作和疾病进展有关。动物和人类研究都表明，AR.40，42的血浆和大脑水平具有雄激素的反应。由于雄激素可以预防转基因APOE小鼠观察到的认知下降，因此雄激素也可能在调节MCI个体的AD发作和进展中发挥作用。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T的认知，情绪和脑脊液（CSF）生物标志物反应。拟议的研究基于我们以前的发现，通过在更长的时间（6个月）中检查认知反应，并评估这些认知变化是否在生理范围内观察到这些认知变化，并使用新的经皮凝胶制剂来达到稳态剂量水平。该项目是一个新型的询问领域，适合针对预防和治疗与年龄相关的认知下降和阿尔茨海默氏病（AD）的试验临床试验的PAR-05-021的目标和标准。鉴于T水平较低的老年男性的发生率随着年龄的增长而增加，因此MCI和AD的风险也会增加，因此对该人群的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方法和/或可以与现有药物结合使用的治疗方法。此外，这项研究的结果将为计划，更大的补充剂或选择性雄激素受体调节剂（SARMS）提供有价值的信息。