Sex Differences and Alcohol Dependence: Hippocampal Neurochemistry and Function

性别差异和酒精依赖：海马神经化学和功能

• 批准号: 8131619
• 负责人: MARISA M SILVERI
• 金额: $ 18.98万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131619
• 关键词: Abstinence; Accidents; Adult; Age; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Area; Biological Assay; Blood alcohol level measurement; Brain; Cerebrum; Cognition; Cognitive deficits; Consumption; Data; Death Rate; Detection; Dose; Ethanol Metabolism; Exhibits; Female; Future; Gender; Glutamates; Health; Heart Diseases; Hippocampus (Brain); Hormonal Change; Hormones; Incidence; Learning; Left; Liver Cirrhosis; Longitudinal Studies; Luteal Phase; Magnetic Resonance Spectroscopy; Measures; Medial; Mediating; Memory; Menstrual cycle; Metabolism; Modeling; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Patients; Performance; Phase; Population; Predisposition; Protons; Recording of previous events; Recovery; Relapse; Relative (related person); Reporting; Research; Risk; Salivary; Scanning; Sedation procedure; Sex Characteristics; Stroke; Suicide; System; Techniques; Temporal Lobe; Testing; Verbal Learning; Woman; alcohol consequences; alcohol related problem; alcohol use disorder; binge drinking; cognitive function; design; drinking; drinking onset; gamma-Aminobutyric Acid; in vivo; men; neurochemistry; neuropsychological; novel; problem drinker; proliferative phase Menstrual cycle; public health relevance; sex

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.

描述（由申请人提供）：体内磁共振光谱（MRS）已用于检查各种酒精种群中细胞健康，完整性和代谢的改变，尽管几乎没有MRS研究包括足够的女性来检查性别差异酒精对脑代谢产物的影响。这项新颖的建议旨在比较包含海马的内侧颞叶（MTL）区域中的GABA和谷氨酸代谢物水平，以及22-45岁的酒精（ALC）男性和女性在早期检查的空间和言语记忆功能禁欲（5-10天），以及健康的年龄和性别匹配比较主题（NALC），报告了最少的酒精使用历史。为了研究月经循环阶段对脑代谢产物的影响，将在其月经周期的卵泡和黄体阶段进行纵向测试NALC妇女（通过唾液激素测定确认）。此外，将两次扫描NALC男性的子集，以评估MRS测试可靠性。我们将在4.0 tesla处应用单个体素质子（1H）MRS，以使用巨型和2D jpress测量MTL代谢物，优化用于检测和定量GABA和GABA和谷氨酸的序列，以最大程度地减少与MTL的峰值重叠和敏感性相关的方法学挑战对现场不均匀性。相对于海马介导的记忆函数，将检查代谢物数据，这是一个认知领域，不仅表现出性别差异，而且在酒精饮料中也受到了损害。这项研究的结果将在健康的NALC成年人中建立记忆功能的神经化学相关性的谱，这可能是月经周期依赖性的（具体目的1,2）。包括ALC患者，尤其是最近被解毒的患者，将提供基线数据（探索性目的），该数据将用于设计未来的酒精中毒纵向研究，该研究检查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恢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。 公共卫生相关性：我们拟议的研究的总体目的是比较包含海马的内侧颞叶（MTL）区域中的GABA和谷氨酸代谢物水平，以及22-45岁的酒精含量（ ALC）在早期禁欲中检查的男性和女性，以及通过在体内磁共振光谱（MRS）技术中应用高领域（4.0 Tesla），并与言语和空间学习的神经心理学评估一起，在体内磁共振光谱（MRS）中应用高领域（4.0 TESLA）。和内存。为了研究月经循环阶段对脑代谢产物的影响，将在其月经周期的卵泡和黄体阶段进行纵向测试NALC妇女（通过唾液激素测定确认）。这项研究的结果将在健康的NALC成年人中建立记忆功能的神经化学相关性的概况，这可能是月经周期的，但是纳入ALC患者的结果也将提供基线数据，这些数据将用于设计未来的纵向研究，以检查研究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恢复相关的神经化学相关性，而且还确定了增加复发风险增加的潜在标志。