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

描述（由申请人提供）：超过60%接受酒精使用障碍（AUD）治疗的个体在治疗6个月内复发。这项竞争性更新的主要目标是确定在AUD治疗个体中预测危险饮酒复发的显著神经生物学和神经心理学因素。识别这些复发风险因素对于更好地理解复发和持续戒断的机制至关重要，并将有助于识别最容易复发的个体。这些知识最终将为更个性化的干预措施的发展提供信息，以提高AUD治疗的疗效，降低酒精相关的死亡率。在目前的资助期内，通过最先进的磁共振（MR）方法和神经认知评估，我们已经证明在寻求酗酒（ALC）治疗的同时慢性吸烟与复合神经生物学和神经认知功能障碍有关。我们进一步表明，长期吸烟阻碍了戒酒期间神经生物学和神经认知的恢复。此外，初步的回顾性分析显示，在清醒早期的脑形态学、神经元完整性、血流和处理速度的区域测量区分了保持清醒的个体（戒酒者）和在治疗后12个月内恢复危险饮酒的个体（复吸者）。其中一些指标也能显著预测复发，基于核磁共振的脑奖励系统（BRS）组成部分的神经生物学指标与复发患者治疗后饮酒的严重程度密切相关。在这篇修订后的论文中，我们假设，包括BRS“自上而下”组成部分的大脑区域的神经生物学异常，以及执行技能、奖励相关决策、冒险、冲动控制和处理速度方面的相关神经认知缺陷，预示着AUD治疗后1年内的复发。我们建议通过最先进的高场磁共振方法（代谢物浓度、形态学、灌注、扩散）、奖励相关决策、风险承担、冲动控制和其他神经认知领域的测量，对治疗后12个月内的酒精消耗进行纵向研究，收集DNA进行储存，并选择基因分型以探索复发表型。然后，我们将确定基线和3个月随访时的横截面测量和纵向变化测量来区分未来的复吸者和未来的戒酒者，并确定哪些因素或其组合准确地预测复吸与戒酒。这项研究将为AUD个体和亚组建立一个更全面和综合的生物心理社会复发风险概况。本研究对于AUD的治疗具有重要的临床意义，为将有限的治疗资源集中在最易复发的人群上，从而提高AUD的整体治疗效果，降低AUD的死亡率提供了重要的新信息。

DESCRIPTION (provided by applicant): More than 60% of individuals treated for alcohol use disorders (AUD) relapse within 6 months of treatment. The primary goal of this competitive renewal is to determine salient neurobiological and neuropsychological factors that predict relapse to hazardous alcohol consumption in individuals treated for AUD. Identification of such relapse risk factors is pivotal for a better understanding of mechanisms of relapse and sustained abstinence and will facilitate identification of individuals with greatest relapse vulnerability. Sch knowledge will ultimately inform the development of more personalized interventions to increase the efficacy of AUD treatment and reduce alcohol-related mortality. In the current grant period, via state-of-the-art magnetic resonance (MR) methods and neurocognitive assessments, we have demonstrated that concurrent chronic cigarette smoking in treatment seeking alcoholics (ALC) is associated with compounded neurobiological and neurocognitive dysfunction. We have further shown that neurobiological and neurocognitive recovery during abstinence from alcohol is hampered by chronic cigarette smoking. In addition, preliminary retrospective analyses revealed that regional measures of brain morphology, neuronal integrity and blood flow as well as processing speed early in sobriety discriminated individuals who maintained sobriety (abstainers) from those who resumed hazardous drinking within 12 months following treatment (relapsers). Some of these measures also significantly predicted relapse, and MR-based neurobiological measures of components of the brain reward system (BRS) were strongly related to the severity of post-treatment alcohol consumption in relapsers. In this revised renewal, we postulate that neurobiological abnormalities in brain regions that include the 'top-down' components of the BRS and related neurocognitive deficits in executive skills, reward-related decision-making, risk taking, impulse control, and processing speed predict relapse within 1 year following treatment for AUD. We propose to study longitudinally over three months 100 ALC by state-of-the-art high-field MR methods (metabolite concentrations, morphology, perfusion, diffusion), measurements of reward-related decision-making, risk taking, impulse control and other neurocognitive domains, to quantitate alcohol consumption over 12 months following treatment, and to collect DNA for banking and select genotyping to explore the relapse phenotype. We will then determine what cross-sectional measures at baseline and 3-month-follow-up and what longitudinal change measures distinguish future relapsers from future abstainers, and determine which of these factors or combinations thereof accurately predict relapse vs. abstinence. This research will establish a more comprehensive and integrated biopsychosocial relapse risk profile for AUD individuals and subgroups. The research is of high clinical significance in AUD treatment, as it will provide critical new information for focusing limited treatment resources on those with greatest relapse vulnerability, thereby increasing overall AUD treatment efficacy and reducing mortality in AUD.