CNS Deficits: Interaction of Age and Alcoholism

中枢神经系统缺陷：年龄和酗酒的相互作用

• 批准号: 7883726
• 负责人: Adolf Pfefferbaum
• 金额: $ 39.84万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883726
• 关键词: Accounting; Acute; Affect; Age; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Animals; Anterior; Anterior Nuclear Group; Area; Autopsy; Brain; Brain Injuries; Brain Pathology; Brain region; Caliber; Cell Nucleus; Cerebellar vermis structure; Cognitive; Corpus Callosum; Development; Diffusion Magnetic Resonance Imaging; Dose; Dysmorphology; Ethanol; Fiber; Fimbria of hippocampus; Goals; High Prevalence; Hippocampus (Brain); Human; Image; Incidence; Individual; Individual Differences; Inferior; Inferior Colliculus; Lesion; Life; Literature; Location; Magnetic Resonance Imaging; Malnutrition; Measures; Modeling; Motor; Myelin; Necrosis; Neuronal Plasticity; Neurons; Nutritional status; Pathology; Pattern; Predisposition; Pyrithiamine; Rattus; Recording of previous events; Recovery; Reporting; Resolution; Risk; Rodent; Site; Source; System; Testing; Thalamic structure; Thiamine; Thiamine Deficiency; Translations; Wernicke Encephalopathy; Wernicke-Korsakoff Syndrome; alcohol effect; alcohol exposure; anterior commissure; base; binge drinking; brain tissue; density; dietary control; drinking; fimbria; frontal lobe; in vivo; mortality; neurogenesis; neuropathology; neurotoxic; neurotoxicity; nutrition; problem drinker; white matter

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.

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； 有些人大脑严重萎缩，另一些人则几乎没有明显的影响。道达尔之间的关系 终生酒精剂量和脑组织体积缩小或脑脊液间隙扩张通常难以捉摸 不占畸形的很大一部分。韦尼克氏病的尸检发病率 脑病(WE)相关的损害，在生活中没有被发现，暗示着对高 酗酒者中营养缺乏(尤其是硫胺素)的盛行率。此外，神经放射学 不复杂的(即非健忘症)酗酒者的发现看起来像是我们看到的那些的分级版本 进展为健忘性Korsakoff综合征(KS或WKS)。人类的文学作品中夹杂着 提到“酒精的神经毒性”，但几乎没有直接支持这一断言和以下内容 问题：如果营养充足，酒精有神经毒性吗？或者反复进行亚临床营养 酒精缺乏是人类酒精神经病理的基础吗？ 动物模型显示酗酒后急性神经元坏死，但在非常高剂量的酒精中 幼稚的动物，有时会有显著的死亡率。酒精的影响主要在 海马-内嗅觉-嗅觉回路，以其神经可塑性、神经发生和独特的敏感性而闻名 对环境的侮辱。啮齿类动物的硫胺素缺乏研究持续产生大量的大脑 病理，包括白质和皮质损害，在活体和尸检中是典型的人类酒精中毒，但 也有涉及乳丘脑束的标志性病变模式，包括乳头体， 穹隆、丘脑前核、上、下丘和前上蛔核。 我们建议利用高分辨率结构磁共振技术开发一种平移动物模型 磁共振成像(MRI)和扩散张量成像(DTI)检查硫胺素缺乏症，模拟为对照 饮食加吡硫胺硫胺致硫胺素缺乏症(PITD)、急性酗酒治疗及其临床意义 大鼠之间的相互作用。我们还将研究WKS高危酗酒者，他们反复持续酗酒和 关于狂欢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，并且 这一组合具有协同破坏性。我们提出了四个具体目标： 具体目标1：测量可检测的神经放射学疾病的发展、程度、位置和恢复 反复发作的PITD对大鼠的脑损伤。 特定目标2：测量重复5天急性酒精对海马体和海马伞的影响 狂欢于老鼠之中。 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：从大鼠到人的转化：确定营养缺乏的神经放射学迹象 人类酗酒者中与酒精中毒相关的畸形。