Brain Morbidity in Treatment-Naive Alcoholics

描述（由申请人提供）：在前五年的工作中，我们表明，对治疗过的酗酒者的便利样本的研究体现了一种偏见，称为“伯克森谬论”，因为治疗过的阿尔茨海默病个体不同于普通人群中治疗过的幼稚阿尔茨海默病个体，后者构成了大多数酗酒者。我们研究了21-50岁积极饮酒治疗的原发性AD （TNAD）和年龄和性别可比较的对照组，并将他们与我们正在进行的长期戒酒治疗AD （ATAD）的研究进行了比较。我们发现，在开始酗酒后最初阶段的酒精摄入量方面，在疾病进展的早期观察到的TNAD不是简单地治疗AD，而是包含一个亚群，其初始大量饮酒量低于ATAD。关于精神疾病的共病，我们发现TNAD比非酒精对照（NAC）有更多的精神疾病，但比ATAD有更少的精神疾病。我们还发现，在MRI上，TNAD患者的大脑结构比ATAD患者更正常，尽管频繁大量饮酒，TNAD患者的认知功能仍正常。在目前的提案中，我们将研究35- 60岁的TNAD，他们中的大多数人酗酒的时间更长（并且一生的酒精摄入量要比我们以前的TNAD高得多）。该研究的主要目标是：1)确定35-60岁TNAD患者的大脑结构和功能是否与年龄相当的NAC，以及短期和长期ATAD患者不同（将从我们正在进行的项目中获得）；2)确定35-60岁TNAD与NAC以及短期和长期ATAD在共病情绪、焦虑和外化障碍诊断、症状和特征的存在和严重程度上是否不同；3)确定与TNAD患者脑结构和功能损伤相关的因素(包括共病情绪、焦虑和外化障碍诊断的存在和严重程度、症状和特征、病前脑大小作为功能储备的衡量标准（通过MRI颅内穹顶容积指标）、饮酒的模式和严重程度、戒断症状的频率（包括严重程度）；和易感因素如酒精问题家族史或电生理和行为终表型酒精中毒标记)；4)确定男性和女性在这些比较中是否存在差异；5)确定伴随药物滥用/依赖对这些比较的影响。我们之前的研究表明，30岁未接受治疗的酒精依赖者介于非酒精对照者和接受治疗的酒精依赖者之间。在目前的建议中，我们计划继续这项工作，研究35 - 60岁的治疗初期酒精依赖个体。这些人的终生酒精负担应该比先前研究的30岁样本大得多。此外，我们纳入了治疗初期药物和酒精依赖个体的样本，为美国人群提供了更大的普遍性，并验证了伴随药物依赖与治疗初期AD更严重、更严重的精神合并症以及更大的认知和大脑结构发病率相关的假设。这些中年酗酒者约占所有酗酒者的40%，而且绝大多数人从不寻求治疗。由于美国大多数酒精中毒研究使用的是治疗中的酗酒者样本（占所有酗酒者的一小部分），因此拟议的研究对于了解AD对美国人群的影响至关重要。

DESCRIPTION (provided by applicant): In the first five years of work, we showed that the study of convenience samples of treated alcoholics embody a bias, called `Berkson's Fallacy', in that treated individuals with AD differ from treatment naive individuals with AD in the general population, who comprise the majority of alcoholics. We studied 21-50 year old actively drinking treatment naive AD (TNAD) and age and gender comparable controls, and compared them to our other ongoing study of long-term abstinent treated AD (ATAD). We showed that with regard to alcohol intake in the initial period after starting abusive drinking, TNAD were not simply treated AD observed earlier in the progression of the disease, but rather comprise a subpopulation with lower initial heavy alcohol consumption than ATAD. Regarding psychiatric comorbidity, we showed that TNAD had more psychiatric disorder than non-alcoholic controls (NAC), but less psychiatric disorder that ATAD. We also showed that TNAD have more normal brain structure on MRI than ATAD, and that TNAD are cognitively normal despite active heavy drinking. In the current proposal, we will study TNAD 35--60 years of age, most of whom would have drank abusively for longer periods (and have a much higher total lifetime alcohol intake) than our former TNAD. The major goals of the proposed research are: 1) to determine whether 35-60 year old TNAD differ in brain structure and function from age-comparable NAC, and from both short- and long-term ATAD (to be available from our pending project); 2) to determine whether 35-60 year old TNAD differ from NAC and from both short- and long-term ATAD in the presence and severity of comorbid mood, anxiety, and externalizing disorder diagnoses, symptoms and traits; 3) to determine the factors associated with impairments in brain structure and function in TNAD (including presence and severity of comorbid mood, anxiety, and externalizing disorder diagnoses, symptoms and traits, premorbid brain size as a measure of functional reserve (as indexed by intracranial vault volume on MRI), the pattern and severity of drinking, the frequency of withdrawal symptoms (including severity), and predisposing factors such as the family history of alcohol problems or electrophysiological and behavioral end phenotypic alcoholism markers)); 4) to determine whether men and women differ in these comparisons; and 5) to determine the effect of concomitant drug abuse/dependence on these comparisons. PUBLIC HEALTH RELEVANCE We have previously shown that 30-year old treatment-naive alcohol dependent individuals are intermediate between non-alcoholic controls and treated alcoholics. In the current proposal, we plan to continue this work, studying 35 - 60 year old treatment naive alcohol dependent individuals. Such individuals should have a much greater lifetime alcohol burden than the 30 year old samples studied previously. Additionally, we are including a sample of treatment-naive drug and alcohol dependent individuals, to provide greater generalizabilty to the U.S. population, and test the hypothesis that concomitant drug dependence is associated with more severe AD, greater psychiatric comorbidity, and greater cognitive and brain structural morbidity in treatment naive AD. These middle-aged TNAD comprise about 40% of all alcoholics, and the great majority never seek treatment. Since most studies of alcoholism in the U.S. use convenience samples of alcoholics in treatment (a minority of all alcoholics), the proposed studies are essential to understand the impact of AD on the US population.