CNS Deficits: Interaction of Age and Alcoholism

酒精中毒的神经病理学的神经放射学征象有相当大的变异性， 有些人的大脑会大量萎缩，而其他人则几乎没有明显的影响。总的关系 终生酒精剂量和脑组织体积收缩或CSF空间扩张通常是难以理解的， 并不能解释畸形的主要原因Wernicke's尸检发生率 脑病（WE）相关病变，在生活中未被发现，表明对高血压的低估。 酗酒者普遍缺乏营养（尤其是硫胺素）。此外，神经放射学 不复杂的发现（即，非健忘症）酗酒者出现的分级版本时，我们看到， 发展为遗忘性科尔萨科夫综合征（KS或WKS）。人类的文学作品中 提到“酒精的神经毒性”，但几乎没有直接支持这一说法， 提问：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 酒精性神经病变的基础 动物模型显示，酒精中毒后急性神经元坏死，但在酒精中的剂量非常高 幼稚动物，有时死亡率很高。酒精的影响主要在 以其神经可塑性、神经发生和独特的感受性而闻名 对环境的侮辱。在啮齿类动物中进行的硫胺素缺乏研究一致地产生大量的脑 病理学，包括白色物质和皮质病变，典型的人类酗酒者在体内和尸检，但 也有一个标志性的病变模式，涉及乳头丘脑束，包括乳头体， 穹窿、丘脑前核以及上级和下丘和前上级蚓部。 我们建议使用高分辨率结构磁共振技术建立一个平移动物模型 成像（MRI）和扩散张量成像（DTI）检查硫胺素缺乏症，建模为对照 饮食加吡啶硫胺诱导的硫胺素缺乏症（PITD），急性酒精狂欢治疗及其 老鼠的互动我们还将研究反复持续酗酒的WKS高危酗酒者， 关于狂欢期间营养不良的历史报道。最重要的假设是， 缺乏对观察到的神经病理学的贡献与酒精本身一样大或更大， 该组合是协同破坏性的。我们提出四个具体目标： 具体目标1：测量神经放射学可检测的发展，程度，位置和恢复 反复发作的PITD导致的脑损伤。 具体目标2：测量连续5天急性酒精对海马和海马伞的影响 大吃老鼠 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：从大鼠到人类的转化：识别营养缺乏的神经放射学体征 在人类酗酒者中与酗酒相关的畸形。

There is considerable variability in the neuroradiologicalsigns 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 underappreciation 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.