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

描述（由申请人提供）：长期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个体脑损伤的体内测量的影响尚未研究。因此，目前尚不清楚酒精依赖中描述的脑萎缩、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的全部程度是否完全归因于长期饮酒，或者长期吸烟是否影响这些指标。我们正在进行的磁共振（MR）和认知研究的初步结果表明，慢性吸烟似乎加剧了酒精诱导的脑形态学，神经化学和血流异常，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的神经认知方面产生不利影响。因此，这一竞争性继续的主要目标是在接受治疗的酒精依赖个体中测试（i）慢性吸烟是否复合酒精诱导的神经生物学脑损伤，（ii）慢性吸烟的影响是否具有功能意义，以及（iii）慢性吸烟是否影响戒酒期间酒精诱导的神经生物学和神经认知功能障碍的恢复。我们将继续应用一种综合的方法，结合不同的MR模式和神经认知测试在同一个人纵向的信息，以评估慢性吸烟治疗酒精依赖个体的神经生物学和功能的后果。具体来说，我们将继续我们的纵向1.5特斯拉MR研究，以定量局部脑结构，脑代谢物（反映神经元和髓鞘活力），局部脑血流量以及重复全面的神经认知测试。此外，在高磁场（4 T）下的新MR研究将提高脑血流和扩散数据的质量，并将测量谷氨酸和Y-氨基丁酸的皮质水平，这些氨基酸与物质依赖的启动和维持密切相关。MR衍生和神经认知测量的关系将确定神经生物学测量的功能相关性及其随时间的变化，并测试慢性吸烟对酒精中毒功能神经回路的影响。本申请响应PA-05-074，因为拟定的研究将提高我们对酒精和吸烟诱导脑损伤的潜在机制及其在戒酒后的潜在可逆性的理解。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迄今未被认识但重要的贡献。从这项转化研究中获得的知识可以直接用于公众教育，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.