The Biological Basis of Alcohol-and Smoking-Induced Brain Injury

描述(由申请人提供)：慢性吸烟在酒精使用障碍(AUD)中非常常见。然而，长期吸烟对酒精依赖者体内脑损伤测量的影响尚未被研究。因此，尚不清楚酒精依赖所描述的全面脑萎缩、细胞膜和微结构损伤、神经代谢紊乱、脑血流量低和神经认知功能障碍是否完全归因于长期饮酒，或者长期吸烟是否影响了这些指标。我们正在进行的磁共振(MR)和认知研究的初步结果表明，长期吸烟似乎会加剧酒精导致的脑形态、神经化学和血液流动的异常，并可能对神经元和细胞膜/髓鞘完整性的替代标记物的恢复以及短期戒酒期间神经认知的某些方面产生不利影响。因此，这一竞争性延续的主要目标是在接受治疗的酒精依赖者中测试(I)长期吸烟化合物是否会导致酒精引起的神经生物学脑损伤，(Ii)慢性吸烟的影响是否在功能上显著，以及(Iii)在戒酒期间，长期吸烟是否会影响酒精引起的神经生物学和神经认知功能障碍的恢复。我们将继续采用一种综合的方法，将来自不同磁共振模式的信息和神经认知测试纵向结合在同一个人身上，以评估长期吸烟对接受酒精依赖治疗的个人的神经生物学和功能影响。具体地说，我们将继续进行纵向1.5特斯拉磁共振研究，以量化局部脑结构、脑代谢物(反映神经元和髓鞘活性)和局部脑血流量，并重复全面的神经认知测试。此外，在强磁场(4T)下进行的新的磁共振研究将改善脑血流和扩散数据的质量，并将测量皮质谷氨酸和Y-氨基丁酸的水平，这两种氨基酸在物质依赖的启动和维持中起关键作用。MR衍生指标和神经认知指标的关系将确定神经生物学指标的功能相关性及其随时间的变化，并测试长期吸烟对酒精中毒患者功能神经回路的影响。这项申请是对PA-05-074的响应，因为拟议的研究将提高我们对酒精和吸烟诱导的脑损伤及其戒酒后的潜在可逆性的理解。到目前为止，长期吸烟可能对这些神经生物学过程及其认知和临床后果有重大贡献，但尚未被认识到。从这项转化性研究中获得的知识可以直接用于公共教育，用于AUD的药理学和行为干预的新方法，以及监测治疗结果。

DESCRIPTION (provided by applicant): Chronic cigarette smoking is very common in alcohol use disorders (AUD). Nevertheless, the effects of chronic smoking on in-vivo measures of brain injury in alcohol-dependent individuals have not been studied. Thus, it is unknown if the full extent of brain atrophy, cell membrane and microstructural injury, derangement of neurometabolism, low cerebral blood flow, and neurocognitive dysfunction described in alcohol dependence are solely attributable to chronic alcohol use, or if chronic smoking influences these measures. Preliminary results from our ongoing magnetic resonance (MR) and cognitive studies indicate that chronic smoking appears to exacerbate alcohol-induced abnormalities in brain morphology, neurochemistry, and blood flow, and may adversely affect recovery of surrogate markers of neuronal and cell membrane/myelin integrity as well as aspects of neurocognition during short-term abstinence from alcohol. The main goal of this competing continuation is therefore to test in treated alcohol dependent individuals (i) if chronic smoking compounds alcohol-induced neurobiological brain injury, (ii) if chronic smoking effects are functionally significant, and (iii) if chronic smoking influences recovery of alcohol-induced neurobiological and neurocognitive dysfunction during abstinence from alcohol. We will continue to apply an integrative approach of combining information from different MR modalities and neurocognitive testing in the same individual longitudinally to assess the neurobiological and functional consequences of chronic smoking in treated alcohol-dependent individuals. Specifically, we will continue our longitudinal 1.5 Tesla MR studies to quantitate regional brain structure, brain metabolites (reflecting neuronal and myelin viability), and regional cerebral blood flow as well as repeat comprehensive neurocognitive testing. In addition, new MR studies at high magnetic field (4T) will improve the quality of cerebral blood flow and diffusion data, and will measure cortical levels of glutamate and Y-aminobutyric acid, amino acids critically involved in the initiation and maintenance of substance dependence. Relationships of MR-derived and neurocognitive measures will determine the functional relevance of neurobiological measures and their changes over time and test the effects of chronic smoking on functional neurocircuitry in alcoholism. This application is responsive to PA-05-074 in that the proposed research will improve our understanding of the mechanisms underlying alcohol- and smoking induced brain injury and its potential reversibility with abstinence from alcohol. Chronic smoking may have hitherto unrecognized but significant contributions to these neurobiological processes and their cognitive and clinical consequences. The knowledge to be gained from this translational research can be used directly for public education, in new approaches to pharmacologic and behavioral interventions for AUD, and in monitoring treatment outcome.