Multi-Modal Imaging of Psychostimulant Effects on Executive Function Post-RRSO

项目摘要：完成双侧输卵管卵巢切除术(RRSO)后降低风险 生育已成为预防妇科和乳腺癌的标准护理 BRCA1或BRCA2基因突变携带者。尽管手术降低了因 癌症增加了75%以上，了解了这一过程和随后的影响 性腺功能减退症对大脑结构、功能和神经递质系统的影响有限。更年期 40岁之前与随后的几年中认知能力显著下降有关， 如果女性不补充雌激素(E2)，患痴呆症的风险几乎增加2倍 然而，由于癌症风险增加，对于许多RRSO后的女性来说，E2不是一种选择。 对接受RRSO的一大群女性的系统评估表明 RRSO的执行功能(EF)缺陷，严重程度与年龄呈负相关。作为 前额叶皮质受到E2丢失的影响，对工作记忆和其他EFS至关重要 建议研究精神刺激剂的生物学和行为影响 100例35~55岁女性RRSO EF术后左旋糖胺(LDX)的应用 投诉。参与者将接受多模式成像(功能磁共振 光谱学，功能磁共振成像；和质子磁共振波谱，使用超 心理刺激剂6周疗程前后7特斯拉的高磁场强度 左旋苯丙胺(LDX；Vyvanse®)或安慰剂，在穿越前进行为期3周的冲洗 转到另一种情况。我们的首要目标是确定LDX治疗对 大脑功能(神经激活和化学)与主观和客观有关 EFS的衡量标准包括1)工作的组织和活跃，2)注意力和专注力， 3)警觉性、努力程度、处理速度，4)管理情感干扰，5)工作 记忆，访问回忆。虽然非常规的精神刺激剂的使用，这部小说 方法已经展示了改善新出现的EF困难的潜力 经历了自然更年期的妇女，并提供了关于 治疗作用的潜在机制，特别是LDX引起的背外侧区改变 前额叶皮质(DlPFC)谷氨酸(Glut)水平。

Project Summary: Risk-reduction bilateral salpingo-oophorectomy (RRSO) after completion of childbearing has become the standard-of-care for prevention of gynecologic and breast cancer in BRCA1 or BRCA2 gene mutation carriers. Although surgery reduces the risk of death due to cancer by over 75%, knowledge regarding the impact of this procedure and subsequent hypogonadism on brain structure, function and neurotransmitter systems is limited. Menopause before the age of 40 is associated with significant cognitive decline in the years that follow and an almost 2-fold increased risk of dementia if a woman does not supplement with estradiol (E2) However, E2 is not an option for many post-RRSO women due to enhanced risk of cancer. Systematic assessment of a large group of women who underwent RRSO suggests subjective deficits in executive functions (EF), with severity inversely correlated with age at RRSO. As the prefrontal cortex is impacted by loss of E2 and is critical for working memory and other EFs, we propose to examine the biological and behavioral impact of the psychostimulant lisdexamfetamine (LDX) in 100 women between the ages of 35 and 55 with post-RRSO EF complaints. Participants will undergo multi-modal imaging (functional magnetic resonance spectroscopy, fMRI; and proton magnetic resonance spectroscopy, 1H-MRS) using the ultra- high magnetic field strength of 7 Tesla pre and post a 6-week course of the psychostimulant lisdexamphetamine (LDX; Vyvanse®) or placebo followed by a 3-week washout before crossing over to the other condition. Our overarching aim is to determine the impact of LDX treatment on brain function (neural activation and chemistry) as it relates to subjective and objective measures of EFs such as 1) organization and activation for work, 2) attention and concentration, 3) alertness, effort, processing speed, 4) managing affective interference, and 5) working memory, accessing recall. While an unconventional use of psychostimulants, this novel approach has already demonstrated the potential to improve new-onset EF difficulties among women who underwent a natural menopause and has provided important information regarding a potential mechanism of therapeutic action, specifically LDX-induced changes in dorsolateral prefrontal cortex (dlPFC) glutamate (GLUT) levels.