CNS Deficits: Interaction of Age and Alcoholism

描述（由申请人提供）：酒精中毒神经病理的神经放射学征象有相当大的可变性；一些人有严重的脑萎缩，而另一些人几乎没有明显的影响。一生总酒精剂量与脑组织体积缩小或脑脊液空间扩张之间的关系通常是难以捉摸的，并且不能解释畸形的实质性部分。韦尼克脑病（WE）相关病变的尸检发生率在生活中未被发现，表明对酗酒者中营养缺乏症（尤其是硫胺素）的高患病率的认识不足。此外，当WE发展为健忘性Korsakoff综合征（KS或WKS）时，无并发症（即无健忘性）酗酒者的神经放射学表现为分级版本。人类文献中有很多关于“酒精的神经毒性”的说法，但很少有直接的证据支持这一论断，并提出了以下问题：如果营养充足，酒精是否具有神经毒性，还是反复发作的亚临床营养缺乏是人类酒精性神经病理学的基础？动物模型显示狂饮酒精后急性神经元坏死，但在酒精初始动物中非常高的剂量，有时具有显著的死亡率。酒精的影响主要是在海马-内嗅-嗅觉回路中描述的，该回路以其神经可塑性、神经发生和对环境损伤的独特易感性而闻名。在啮齿类动物中进行的硫胺素缺乏症研究始终会产生大量的脑部病理，包括白质和皮质损伤，这是体内和尸检中人类酗酒者的典型症状，但也有一个标志性的损伤模式，涉及到乳丘束，包括乳状体、穹窿、丘脑前核，以及上丘和下丘和前上蚓。我们建议建立一个翻译动物模型，利用高分辨率结构磁共振成像（MRI）和扩散张量成像（DTI）来检查硫胺素缺乏症，模拟大鼠控制饮食加硫胺素诱导的硫胺素缺乏症（PITD），急性暴饮乙醇治疗及其相互作用。我们还将研究反复持续狂饮的wks高危酗酒者，以及在狂饮期间营养不良的历史报告。最重要的假设是，营养缺乏对观察到的神经病理学的贡献与酒精本身一样大，甚至更大，两者的结合是协同破坏的。我们提出了四个具体目标：具体目标1：测量大鼠反复发作PITD时神经放射学可检测的脑损伤的发展，程度，位置和恢复。专项目的2：测定5天急性酒精暴饮对大鼠海马和脑皮层的影响。具体目标3：模拟人类饮酒的大鼠联合酗酒和硫胺素缺乏症。具体目标4：从大鼠到人类的转化：确定人类酗酒者营养缺乏复合酒精相关畸形的神经放射学迹象。

DESCRIPTION (provided by applicant): There is considerable variability in the neuroradiological signs of neuropathology of alcoholism; some individuals have massive brain shrinkage and others little demonstrable effect. A relationship between total lifetime alcohol dose and brain tissue volume shrinkage or CSF space expansion is typically elusive and does not account for a substantial portion of the dysmorphology. Autopsy incidence of Wernicke's encephalopathy (WE) associated lesions, undetected in life, suggests an under appreciation of the high prevalence of nutritional deficiency (especially thiamine) among alcoholics. Further, the neuroradiological findings of uncomplicated (i.e., nonamnesic) alcoholics appear as a graded version of those seen when WE progresses to the amnesic Korsakoff syndrome (KS or WKS). The human literature is sprinkled with references to the "neurotoxicity of alcohol" but with little direct support for this assertion and with the following questions begged: is alcohol neurotoxic if nutrition is adequate, or do repeated bouts of subclinical nutritional deficiency underlie human alcoholic neuropathology? Animal models demonstrate acute neuronal necrosis after binge alcohol, but at very high doses in alcohol naive animals, sometimes with significant mortality. Alcohol effects are primarily described in the hippocampal-entorhinal-olfactory circuit, known for its neuroplasticity, neurogenesis and unique susceptibility to environmental insult. Thiamine deficiency studies in rodents consistently produce substantial brain pathology, including white matter and cortical lesions, typical of human alcoholics in vivo and at autopsy, but also have a signature lesion pattern involving the mammillothalamic tract, including the mammillary bodies, fornix, anterior thalamic nuclei, in addition to the superior and inferior colliculi and anterior superior vermis. We propose to develop a translational animal model, using high resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to examine thiamine deficiency, modeled as controlled dietary plus pyrithiamine-induced thiamine deficiency (PITD), acute binge ethanol treatment and their interaction in rats. We will also study WKS-at-risk alcoholics with repeated sustained binge drinking and historical reporting of poor nutrition during the binges. The overarching hypothesis is that nutritional deficiency makes as great or greater contribution than alcohol per se to the observed neuropathology, and the combination is synergistically damaging. We propose four specific aims: Specific Aim 1: Measure the development, extent, location and recovery of neuroradiologically-detectable brain damage with repeated bouts of PITD in rats. Specific Aim 2: Measure the effects on the hippocampus and fimbria of repeated 5-day, acute alcohol binge in rats. Specific Aim 3: Model human drinking in rats with combined alcohol binges plus thiamine deficiency. Specific Aim 4: Translation from rats to humans: Identify neuroradiological signs of nutritional deficiency compounding alcoholism-related dysmorphology in human alcoholics.