Brain Morbidity in Treatment-Naive Alcoholics

描述(申请人提供)：在最初五年的工作中，我们表明，对接受治疗的酗酒者的便利样本的研究体现了一种偏见，即所谓的伯克森谬误，因为接受治疗的阿尔茨海默病患者不同于一般人群中的接受治疗的幼稚的阿尔茨海默病患者，后者构成了酗酒者的大多数。我们研究了21-50岁积极饮酒治疗的幼稚AD(TNAD)和年龄和性别可比的对照组，并将他们与我们正在进行的另一项长期戒酒治疗AD(ATAD)研究进行了比较。我们发现，对于开始滥用饮酒后最初阶段的酒精摄入量，TNAD并不是简单地治疗在疾病进展早期观察到的AD，而是包括初始重度酒精摄入量低于ATAD的亚群。在精神共病方面，我们发现与非酒精对照组(NAC)相比，TNAD有更多的精神障碍，但比ATAD更少精神障碍。我们还发现，与ATAD相比，TNAD在MRI上有更正常的脑结构，尽管经常大量饮酒，但TNAD在认知上是正常的。在目前的提案中，我们将研究35-60岁的TNAD，他们中的大多数人会比我们以前的TNAD酗酒更长时间(并且一生的酒精总摄入量要高得多)。这项研究的主要目标是：1)确定35-60岁的TNAD与年龄相当的NAC以及短期和长期的ATAD(从我们的待定项目中获得)在大脑结构和功能上是否不同；2)确定35-60岁的TNAD是否与NAC以及短期和长期的ATAD在共病情绪、焦虑和外化障碍的诊断、症状和特征的存在和严重程度上不同；3)确定与TNAD的大脑结构和功能损害相关的因素(包括共病情绪、焦虑和外化障碍的诊断、症状和特征的存在和严重程度，作为功能储备指标的发病前脑大小(以MRI上的脑室容量为指标)，饮酒的模式和严重程度，戒断症状的频率(包括严重程度)，以及易感因素，如酒精问题家族史或电生理和行为终末表型酒精中毒标记物)；4)确定男性和女性在这些比较中是否存在差异；以及5)确定伴随药物滥用/依赖对这些比较的影响。公共卫生相关性我们之前已经表明，30岁未戒酒的酒精依赖者介于非酒精对照组和接受治疗的酒精依赖者之间。在目前的提案中，我们计划继续这项工作，研究35-60岁治疗幼稚酒精依赖的个人。这些人一生中的酒精负担应该比之前研究的30年前的样本要大得多。此外，我们还纳入了一组未接受治疗的药物和酒精依赖者的样本，为美国人群提供更大的普适性，并测试伴随药物依赖与更严重的AD、更严重的精神共病以及更严重的认知和脑结构疾病相关的假说。这些中年的TNAD约占所有酗酒者的40%，绝大多数人从未寻求治疗。由于美国的大多数酒精中毒研究都使用方便的酒鬼样本进行治疗(占所有酒鬼的少数)，因此拟议的研究对于了解AD对美国人群的影响是必不可少的。

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.