CNS Deficits: Interaction of Age and Alcoholism

描述(申请人提供)：酒精中毒的神经病理的神经放射学征象有相当大的变异性；一些人有大量的脑萎缩，而另一些人几乎没有明显的影响。终生酒精总剂量与脑组织体积缩小或脑脊液间隙扩张之间的关系通常难以捉摸，也不会占畸形的很大一部分。WerNicke脑病(WE)相关病变的尸检发病率在生活中未被发现，这表明人们对酗酒者中营养缺乏(特别是硫胺素)的高患病率认识不足。此外，不复杂(即非健忘症)酗酒者的神经放射学结果似乎是当我们进展为健忘性Korsakoff综合征(KS或WKS)时看到的分级版本。人类文献中零星地提到了“酒精的神经毒性”，但几乎没有直接支持这一断言，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否构成人类酒精神经病理的基础？动物模型显示出酗酒后的急性神经元坏死，但在酒精幼稚的动物中，剂量非常高，有时会显著死亡。酒精的影响主要是在海马体-内嗅觉-嗅觉回路中描述的，以其神经可塑性、神经发生和对环境侮辱的独特敏感性而闻名。对啮齿类动物的硫胺素缺乏研究始终会产生实质性的脑病理，包括白质和皮质损害，这在活体和尸检中是典型的人类酒精中毒，但也有一种标志性的损害模式，涉及乳丘脑束，包括乳头体、穹隆、丘脑前核，以及上、下丘和前上蠕虫。我们建议建立一种翻译动物模型，使用高分辨率结构磁共振成像(MRI)和扩散张量成像(DTI)来检测硫胺缺乏，模拟为控制饮食加吡硫胺硫胺诱导的硫胺缺乏(PITD)、急性酗酒治疗及其相互作用。我们还将研究WKS高危酗酒者，他们反复持续酗酒，并有在酗酒期间营养不良的历史报道。最重要的假设是，营养缺乏对观察到的神经病理的贡献与酒精本身一样大或更大，而且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：测量反复发作的PITD对神经放射学可检测到的脑损伤的发展、程度、位置和恢复情况。具体目标2：测定重复5天急性饮酒对大鼠海马区和海马伞的影响。具体目的3：建立酗酒加硫胺素缺乏的大鼠饮酒模型。具体目标4：从大鼠到人类的翻译：确定营养缺乏的神经放射学迹象，结合人类酗酒者与酒精中毒相关的畸形。

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.