Nerattini Matilde, Williams Schantel, Andy Caroline, Carlton Caroline, Zarate Camila, Boneu Camila, Fauci Francesca, Ajila Trisha, Jett Steven, Battista Michael, Pahlajani Silky, Berti Valentina, Andrews Randolph, Matthews Dawn C, Dyke Jonathan P, Brinton Roberta Diaz, Mosconi Lisa
Department of Neurology, Weill Cornell Medicine, New York, NY, United States of America.
Department of Experimental and Clinical Biomedical Sciences, Nuclear Medicine Unit, University of Florence, Florence, Italy.
PLoS One. 2025 Jan 13;20(1):e0317303. doi: 10.1371/journal.pone.0317303. eCollection 2025.
Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer's disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35-65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes.
睾酮是一种重要的性类固醇激素，在两性的整个生命周期中，通过影响神经生理学和神经病理学来影响大脑健康。然而，该领域的人体研究有限，尤其是在女性中。本研究根据性别和绝经状态，考察了有患阿尔茨海默病（AD）风险的中年个体的睾酮水平、灰质体积（GMV）和脑血流量（CBF）之间的关联。294名认知正常的中年参与者组成的队列，其中83%为女性，年龄在35 - 65岁之间，有AD家族史和/或载脂蛋白Eε4（APOE - 4）基因型，接受了容积磁共振成像（MRI）以测量GMV，并采用磁共振动脉自旋标记（ASL）测量CBF。我们使用基于体素的分析和感兴趣区域来测试睾酮（总睾酮和游离睾酮）与脑成像结果之间的关联，并按性别和绝经状态进行分层。较高的总睾酮和游离睾酮水平与男性较大的GMV相关，在额叶和颞叶区域有峰值效应。相反，在女性中，较高的睾酮水平与较高的CBF相关，在额叶和边缘区域、皮质下区域及下丘脑有峰值效应。在女性中，睾酮与GMV之间的关联在绝经前和围绝经期阶段被观察到，但绝经后未观察到，而睾酮与CBF之间的关联从围绝经期阶段开始显著，且在未使用激素治疗的女性中更为明显。结果独立于年龄、APOE - 4状态、中年健康指标和性激素结合球蛋白水平。这些发现表明，睾酮在有AD风险的中年个体的AD易损区域具有性别特异性的神经生理效应，且在性别和绝经状态之间存在差异。这突出了进一步研究聚焦于睾酮对两性神经保护潜力的必要性。
