Mosconi Lisa, Berti Valentina, Quinn Crystal, McHugh Pauline, Petrongolo Gabriella, Osorio Ricardo S, Connaughty Christopher, Pupi Alberto, Vallabhajosula Shankar, Isaacson Richard S, de Leon Mony J, Swerdlow Russell H, Brinton Roberta Diaz
Department of Neurology, Weill Cornell Medical College, New York, NY, United States of America.
Department of Psychiatry, New York University School of Medicine, New York, NY, United States of America.
PLoS One. 2017 Oct 10;12(10):e0185926. doi: 10.1371/journal.pone.0185926. eCollection 2017.
After advanced age, female sex is the major risk factor for Alzheimer's disease (AD). The biological mechanisms underlying the increased AD risk in women remain largely undetermined. Preclinical studies identified the perimenopause to menopause transition, a neuroendocrine transition state unique to the female, as a sex-specific risk factor for AD. In animals, estrogenic regulation of cerebral glucose metabolism (CMRglc) falters during perimenopause. This is evident in glucose hypometabolism and decline in mitochondrial efficiency which is sustained thereafter. This study bridges basic to clinical science to characterize brain bioenergetics in a cohort of forty-three, 40-60 year-old clinically and cognitively normal women at different endocrine transition stages including premenopause (controls, CNT, n = 15), perimenopause (PERI, n = 14) and postmenopause (MENO, n = 14). All participants received clinical, laboratory and neuropsychological examinations, 18F-fluoro-deoxyglucose (FDG)-Positron Emission Tomography (PET) FDG-PET scans to estimate CMRglc, and platelet mitochondrial cytochrome oxidase (COX) activity measures. Statistical parametric mapping and multiple regression models were used to examine clinical, CMRglc and COX data across groups. As expected, the MENO group was older than PERI and controls. Groups were otherwise comparable for clinical measures and distribution of APOE4 genotype. Both MENO and PERI groups exhibited reduced CMRglc in AD-vulnerable regions which was correlated with decline in mitochondrial COX activity compared to CNT (p's<0.001). A gradient in biomarker abnormalities was most pronounced in MENO, intermediate in PERI, and lowest in CNT (p<0.001). Biomarkers correlated with immediate and delayed memory scores (Pearson's 0.26≤r≤0.32, p≤0.05). These findings validate earlier preclinical findings and indicate emergence of bioenergetic deficits in perimenopausal and postmenopausal women, suggesting that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.
步入老年后，女性性别是阿尔茨海默病（AD）的主要风险因素。女性患AD风险增加背后的生物学机制在很大程度上仍未明确。临床前研究确定围绝经期到绝经的转变，这是女性特有的一种神经内分泌转变状态，是AD的一个性别特异性风险因素。在动物中，围绝经期期间雌激素对脑葡萄糖代谢（CMRglc）的调节出现紊乱。这在葡萄糖低代谢和线粒体效率下降中很明显，且此后持续存在。本研究将基础科学与临床科学联系起来，以表征43名40 - 60岁临床和认知正常的女性队列在不同内分泌转变阶段（包括绝经前（对照组，CNT，n = 15）、围绝经期（PERI，n = 14）和绝经后（MENO，n = 14））的脑生物能量学特征。所有参与者均接受了临床、实验室和神经心理学检查、18F - 氟脱氧葡萄糖（FDG）-正电子发射断层扫描（PET）FDG - PET扫描以估计CMRglc，以及血小板线粒体细胞色素氧化酶（COX）活性测量。使用统计参数映射和多元回归模型来检查各组的临床、CMRglc和COX数据。正如预期的那样，MENO组比PERI组和对照组年龄更大。在临床测量和APOE4基因型分布方面，各组在其他方面具有可比性。与CNT组相比，MENO组和PERI组在AD易损区域均表现出CMRglc降低，这与线粒体COX活性下降相关（p值<0.001）。生物标志物异常的梯度在MENO组中最为明显，在PERI组中居中，在CNT组中最低（p<0.001）。生物标志物与即时和延迟记忆评分相关（Pearson相关系数0.26≤r≤0.32，p≤0.05）。这些发现验证了早期临床前研究结果，并表明围绝经期和绝经后女性出现了生物能量缺陷，这表明女性治疗干预的最佳时机是在内分泌衰老过程的早期。
