Biomarker for Cognitive Impairment in Chronic Alcoholism

慢性酒精中毒认知障碍的生物标志物

• 批准号: 8137365
• 负责人: Richard James McClure
• 金额: $ 40.08万
• 依托单位: PHFR, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137365
• 关键词: Acute; Age; Alcoholism; Alcohols; Anterior; Autopsy; Basal Ganglia; Bayesian Method; Biological Markers; Brain; Brain imaging; Brain region; Budgets; Butyric Acids; Caliber; Caring; Chemical Shift Imaging; Chemicals; Chin; Cholesterol; Chronic; Chronic Schizophrenia; Clinical; Code; Cognition; Cognitive; Cognitive deficits; Color; Computer software; Data; Data Analyses; Data Set; Databases; Diagnosis; Dimensions; Disease; Disease Progression; Doctor of Philosophy; Ethanol; Fingerprint; Fourier Transform; Frequencies; Funding; Future; Gait; Gangliosides; Glutamates; Grant; Gray unit of radiation dose; Health; Health Professional; Human; Image; Impaired cognition; Impairment; Individual; Individual Differences; Inferior; Institution; Lead; Left; Life; Limb Ataxia; Link; Lipids; Lipoproteins; Lower Extremity; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manufacturer Name; Maps; Marketing; Measures; Membrane; Memory; Metabolic; Metabolism; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; N-acetylaspartate; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neuropsychological Tests; Nicotine; Occipital lobe; Outcome; Outcome Measure; Output; Parietal Lobe; Patients; Performance; Personal Communication; Phase; Phospholipid Metabolism; Phospholipids; Phosphorylation; Population Control; Positioning Attribute; Prefrontal Cortex; Process; Progress Reports; Property; Protein Dephosphorylation; Proteins; Proteomics; Publishing; Research; Research Personnel; Residual state; Resolution; Risk; Sample Size; Scanning; Schedule; Schizophrenia; Scientist; Sensitivity and Specificity; Signal Transduction; Slice; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Smoker; Smoking; Software Design; Specificity; Statistical Methods; Subgroup; Sum; Synapses; Synaptic Membranes; Synaptic Vesicles; System; Temporal Lobe; Testing; Therapeutic; Time; Tissues; Training; Transport Vesicles; Treatment Protocols; United States National Institutes of Health; Visuospatial; Water; Width; Work; base; brain tissue; cognitive change; design; executive function; glycosylation; gray matter; heuristics; in vivo; inorganic phosphate; insight; interest; magnetic resonance spectroscopic imaging; metabolomics; middle age; motor deficit; neuropsychiatry; neuropsychological; non-smoker; novel; prevent; problem drinker; programs; receptor function; regional difference; relating to nervous system; repaired; response; software development; success; sugar; two-dimensional; verification and validation

DESCRIPTION (provided by applicant): Previous work has identified a subgroup of chronic alcoholism subjects with severe, generalized cognitive impairment and a very poor outcome. What is critically lacking are brain molecular biomarkers that antedate both the cognitive impairment and the earliest, most minimal brain structural changes. Given the increased morbidity associated with cognitive impairment in chronic alcoholism subjects, further insights into the molecular basis for the cognitive changes are essential and could lead to future therapeutic and preventative measures as well as the ability to monitor neuromolecular responses to those therapeutic measures. The purpose of Phase I of the present SBIR Phase I/Phase II Fast Track application is to analyze existing NIH-funded multi-voxel 31P and 1H magnetic resonance spectroscopic imaging data sets to refine brain molecular biomarkers for neural membrane degeneration demonstrated in our STTR Phase I application. The STTR Phase I data strongly suggests it is the brain membrane phospholipid degeneration in the absence of adequate repair that results in cognitive impairment in chronic alcoholism. The neuromolecular biomarkers will reflect molecular changes that antecede brain structural changes observed by quantitative MRI-based neuromorphometrics and will predict which subjects with chronic alcoholism are at increased risk to develop cognitive impairment. Phase II of this proposal will focus on developing a software package in partnership with SterlingTech Software for analyses of MRSI data obtained from individual subjects to be compared to a normative basis set, analyze the data for abnormalities found in comparison with the normative basis set, and display changes in the individual subject. The proposed approach is unique because it directly and non-invasively measures critical aspects of brain molecular composition and metabolism in living subjects, specifically: 1) key aspects of membrane phospholipid metabolism; 2) utilization of high-energy phosphates; 3) dynamic aspects of protein phosphorylation - dephosphorylation; 4) the number of brain synaptic and transport vesicles; 5) key intermediates in the glycosylation of lipids and proteins; and 6) a marker of neuronal integrity. Since cognitive deficits are present in other neuropsychiatric disorders, for example chronic schizophrenia, a comparison of molecular measures associated with cognitive impairment in chronic schizophrenia with those of chronic alcoholism will help to establish the specificity of the biomarker for cognitive impairment in alcoholism. Brain molecular biomarkers which could distinguish molecular findings associated with cognitive impairment in chronic alcoholism from that observed in other neuropsychiatric disorders would be of great theoretical and practical clinical importance. PUBLIC HEALTH RELEVANCE: Brain molecular biomarkers such as proposed in this application could be used to guide further understanding of the molecular underpinnings of cognitive impairment in chronic alcoholism This will enhance future therapeutic and preventative approaches designed to repair or prevent neural membrane damage observed in alcoholism. The molecular biomarkers will be used to develop a software package in partnership with SterlingTech Software that will analyze individual 31P and 1H magnetic resonance spectroscopic imaging data and produce a color-coded brain image showing how that subject compares to a control population. The software package will be commercialized and marketed to corporations (primarily MR manufacturers), institutions, and individuals worldwide.

描述（由申请人提供）：以前的工作已经确定了一个慢性酒精中毒受试者的亚组，具有严重的，普遍的认知障碍和非常差的结果。严重缺乏的是脑分子生物标志物，这些生物标志物既抗认知障碍，也是最早，最小的大脑结构变化。鉴于与慢性酒精中毒受试者认知障碍相关的发病率增加，对认知变化的分子基础的进一步见解至关重要，并且可能导致未来的治疗和预防措施以及监测对这些治疗方法的神经分子反应的能力。当前SBIR I/II期快速轨道应用I期I期的目的是分析现有的NIH资助的多素31P和1H磁共振光谱成像数据集，以优化我们在Sttr I期应用中显示的神经膜变性的脑分子生物标志物。 STTR I期数据强烈表明，在没有适当修复的情况下，它是脑膜磷脂变性，导致慢性酒精中毒的认知障碍。神经分子生物标志物将反映通过基于定量MRI的神经形态图观察到的脑结构变化的分子变化，并将预测哪些患有慢性酒精中毒的受试者有增加认知障碍的风险。该提案的第二阶段将重点介绍与Sterlingtech软件合作开发软件包，以分析从单个受试者获得的MRSI数据与规范基础集进行比较，分析与规范基集相比发现的异常数据的数据，并显示个人受试者的变化。所提出的方法是独特的，因为它直接和非侵入性测量了生物中脑分子组成和代谢的关键方面，特别是：1）膜磷脂代谢的关键方面； 2）利用高能磷酸盐； 3）蛋白质磷酸化的动态方面 - 去磷酸化； 4）大脑突触和运输囊泡的数量； 5）脂质和蛋白质糖基化的关键中间体； 6）神经元完整性的标志。由于认知缺陷存在于其他神经精神疾病中，例如慢性精神分裂症，因此比较了与慢性精神分裂症认知障碍相关的分子测量，将有助于确定生物标志物在酒精中毒中认知障碍的特异性。可以区分与慢性酒精中毒的认知障碍与在其他神经精神疾病中观察到的分子发现相关的分子发现的脑分子生物标志物将具有极大的理论和实际临床重要性。公共卫生相关性：本应用中提出的脑分子生物标志物可以用于指导对慢性酒精中毒认知障碍的分子基础的进一步了解，这将增强未来的治疗和预防方法，旨在修复或防止酒精中毒中观察到的神经膜损害。分子生物标志物将用于与Sterlingtech软件合作开发软件包，该软件将分析单个31p和1H磁共振光谱成像数据并产生颜色编码的大脑图像，以表明该受试者如何与对照人群相比。该软件包将被商业化并销售给公司（主要是制造商MR），机构和全球个人。