Sex Differences and Alcohol Dependence: Hippocampal Neurochemistry and Function

描述（由申请人提供）：体内磁共振波谱（MRS）已被用于检查各种酒精人群中细胞健康、完整性和代谢的变化，尽管几乎没有MRS研究包括足够数量的女性来检查酒精对大脑代谢物影响的性别差异。这项新提议旨在比较22-45岁酒精依赖（ALC）男性和女性在早期戒酒（5-10天）中检查的内侧颞叶（MTL）区域中的GABA和谷氨酸代谢物水平，以及空间和文字记忆功能，以及报告最小酒精使用史的健康年龄和性别匹配的对照受试者（NALC）。为了研究月经周期阶段对脑代谢物的影响，NALC女性将在其月经周期的卵泡期和黄体期进行纵向测试（通过唾液激素测定证实）。此外，将对NALC男性亚组进行两次扫描，以评估MRS重测信度。我们将在4.0特斯拉下应用单体素质子（1H）MRS，使用MEGAPRESS和2D-JPRESS（分别针对GABA和谷氨酸的检测和定量优化的序列）测量MTL代谢物，以最大限度地减少与峰重叠和MTL对场不均匀性敏感性相关的方法学挑战。代谢物数据将检查相对于海马介导的记忆功能，一个领域的认知，不仅表现出性别差异，但也在酗酒人群受损。本研究的结果将建立健康NALC成年人记忆功能的神经化学相关性谱，这可能依赖于月经周期（具体目标1，2）。纳入ALC患者，特别是最近脱毒的患者，将提供基线数据（探索性目的），用于设计未来的酗酒者纵向研究，检查MTL GABA和谷氨酸的变化以及认知功能的相关改善。这些发现不仅可以建立与成功康复相关的神经化学相关性，而且还可以确定复发风险增加的潜在标志物。 公共卫生相关性：我们提出的研究的总体目标是比较在早期戒酒中检查的22-45岁酒精依赖（ALC）男性和女性中，内侧颞叶（MTL）区域（包含海马）中的GABA和谷氨酸代谢物水平以及空间和文字记忆功能，和健康的年龄和性别匹配的比较对象（NALC），通过应用高场（4.0特斯拉）体内磁共振波谱（MRS）技术结合语言和空间学习和记忆的神经心理学评估。为了研究月经周期阶段对脑代谢物的影响，NALC女性将在其月经周期的卵泡期和黄体期进行纵向测试（通过唾液激素测定证实）。这项研究的结果将建立健康NALC成年人记忆功能的神经化学相关性的概况，这可能是月经周期依赖性的，但纳入ALC患者也将提供基线数据，这些数据将用于设计未来的酗酒者纵向研究，该研究将检查MTL GABA和谷氨酸的变化以及认知功能的相关改善，这些发现不仅可以建立与成功康复相关的神经化学相关性，而且还可以确定复发风险增加的潜在标志物。

DESCRIPTION (provided by applicant): In vivo magnetic resonance spectroscopy (MRS) has been used to examine alterations in cellular health, integrity and metabolism across a variety of alcoholic populations, although almost no MRS studies have included sufficient numbers of women to examine sex differences in the impact of alcohol on cerebral metabolites. This novel proposal aims to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence (5-10 days), and healthy age- and sex-matched comparison subjects (NALC) reporting a minimal alcohol use history. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). Furthermore, a subset of NALC men will be scanned twice to assess MRS test-retest reliability. We will apply single voxel proton (1H) MRS at 4.0 Tesla to measure MTL metabolites using MEGAPRESS and 2D-JPRESS, sequences optimized for detection and quantification of GABA and glutamate, respectively, to minimize methodological challenges associated with peak overlap and susceptibility of the MTL to field inhomogeneities. Metabolite data will be examined relative to hippocampal-mediated memory function, an area of cognition that has not only demonstrated sex differences, but also is impaired in alcoholic populations. The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent (Specific Aims 1,2). Inclusion of ALC patients, especially those who are recently detoxified, will provide baseline data (Exploratory Aim) that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function. Those findings could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse. PUBLIC HEALTH RELEVANCE: The overall aim of our proposed study is to compare GABA and glutamate metabolite levels in a region of the medial temporal lobe (MTL) that contains the hippocampus, and spatial and verbal memory function in 22-45 year old alcohol dependent (ALC) men and women examined in early abstinence, and healthy age- and sex-matched comparison subjects (NALC) by applying high field (4.0 Tesla) in vivo magnetic resonance spectroscopy (MRS) techniques in conjunction with neuropsychological assessment of verbal and spatial learning and memory. To investigate the effects of menstrual cycle phase on brain metabolites, NALC women will be tested longitudinally, in both follicular and luteal phases of their menstrual cycle (confirmed by salivary hormone assays). The results of this study will establish profiles of neurochemical correlates of memory function in healthy NALC adults, which may be menstrual cycle dependent, but also inclusion of ALC patients will provide baseline data that will be used to design a future longitudinal study in alcoholics that examines MTL GABA and glutamate changes and associated improvements in cognitive function, findings that could not only establish neurochemical correlates associated with successful recovery, but also identify potential markers of increased risk for relapse.