CNS Deficits: Interaction of Age and Alcoholism

描述（由申请人提供）：酒精中毒的神经病理学的神经放射学体征有相当大的差异;一些人有大量的脑萎缩，而另一些人几乎没有明显的影响。终生酒精剂量与脑组织体积缩小或CSF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（特别是硫胺素）的高患病率的低估。此外，无并发症的神经放射学发现（即，非失忆型）酗酒者与我们发展为失忆型科尔萨科夫综合征（KS或WKS）时所见的酗酒者相比，表现出了不同程度的差异。人类文献中有很多关于“酒精的神经毒性”的参考文献，但几乎没有直接支持这一论断，并提出了以下问题：如果营养充足，酒精是否具有神经毒性，或者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，酒精中毒后，急性神经元坏死，但在非常高的剂量酒精幼稚动物，有时与显着的死亡率。酒精的影响主要是在大脑皮层-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。啮齿类动物中硫胺素缺乏症的研究一致产生大量的脑病理学，包括白色物质和皮质病变，这是体内和尸检中人类酗酒者的典型病变，但也有涉及乳头体丘脑束的特征性病变模式，包括乳头体、穹窿、丘脑前核，以及上级和下丘以及前上级蚓部。我们建议建立一个翻译的动物模型，使用高分辨率结构磁共振成像（MRI）和扩散张量成像（DTI）检查硫胺素缺乏症，模拟为控制饮食加吡啶硫胺诱导的硫胺素缺乏症（PITD），急性酗酒治疗及其相互作用的大鼠。我们还将研究WKS的风险酗酒者反复持续酗酒和历史报告的营养不良，在狂欢。总体假设是，营养缺乏对所观察到的神经病理学的贡献与酒精本身一样大或更大，并且两者的组合具有协同破坏性。我们提出四个具体目标：具体目标1：测量大鼠反复发作PITD后神经放射学可检测脑损伤的发展、程度、位置和恢复。具体目标2：测量大鼠连续5天急性酒精狂欢对海马和海马伞的影响。具体目标3：在酒精狂欢和硫胺素缺乏的大鼠中建立人类饮酒模型。具体目标4：从大鼠到人类的翻译：识别人类酗酒者中营养缺乏复合酒精中毒相关畸形的神经放射学体征。

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.