Retinal Imaging with Optical Coherence Tomography as a Biomarker for Manganese Neurotoxicity

使用光学相干断层扫描进行视网膜成像作为锰神经毒性的生物标志物

• 批准号: 9097720
• 负责人: JAY S SCHNEIDER
• 金额: $ 19.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097720
• 关键词: Adult; Adverse effects; Alzheimer like pathology; Alzheimer' s Disease; Animals; Area; Behavioral; Biological; Biological Markers; Brain; Brain Injuries; Carbohydrates; Chronic; Cognitive; Data; Detection; Deterioration; Development; Dose; Early Diagnosis; Environmental Exposure; Environmental and Occupational Exposure; Evolution; Exhibits; Exposure to; Eye; Functional disorder; Health; Human; Image; Imaging Techniques; Impaired cognition; Injection of therapeutic agent; Intoxication; Lead; Learning; Lipids; MPTP Poisoning; Manganese; Measurement; Measures; Memory; Monkeys; Morphology; Motor; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurologic Dysfunctions; Neuropsychological Tests; Nutrient; Occupational Exposure; Optical Coherence Tomography; Outcome; Parietal; Pathology; Pattern; Performance; Play; Process; Reaction Time; Reporting; Retina; Retinal; Rodent; Role; Symptoms; Synaptic Transmission; System; Thick; Time; Toxicant exposure; Toxicology; Trace metal; Visual; Visuospatial; brain health; cofactor; cognitive development; early onset; in vivo; indexing; interest; mild cognitive impairment; molecular imaging; motor disorder; neurobehavioral; neuropsychological; neurotoxic; neurotoxicity; nonhuman primate; potential biomarker; protein aggregation; protein metabolism; radiotracer; rapid technique; relating to nervous system; tau Proteins

 DESCRIPTION (provided by applicant): Manganese (Mn) is an essential trace metal nutrient that is important as a cofactor for a number of enzymatic processes in the brain. However, excess Mn can be neurotoxic. The degree to which chronic environmental or occupational exposures to Mn in adults cause neurological dysfunction is an area of considerable interest. Exposures at high levels are known to cause a variety of adverse neurological effects whereas more recently, a number of studies have reported neuropsychological dysfunction resulting from lower level chronic exposures. Much has been learned about the basic toxicology of Mn from exposure studies in rodents, and more recently, from Mn exposures in nonhuman primates, a species whose behavioral repertoire more closely resembles that generated by the human neurobehavioral system. While earlier non-human primate studies primarily examined the outcomes from relatively high level, short-term exposures, often resulting in severe motor dysfunction, studies conducted in our lab over the last several years have documented a variety of neurocognitive deficits resulting from chronic to exposure to Mn at levels in the range of those reported for human environmental or occupational exposures. Although humans and nonhuman primates can exhibit Mn- induced neuropsychological deficits and neuropsychological testing can indicate the presence of brain injury consequent to Mn exposure, its sensitivity to detecting early brain injury related to Mn exposure remains to be demonstrated. A variety of in vivo structural and molecular imaging techniques have been suggested as potential biomarkers of Mn neurotoxicity, however, all are expensive to perform, are time consuming, are invasive (for example, requiring radiotracer injections), and some require specialized facilities and expertise not available at all centers. We propose here that optical coherence tomography (OCT), a noninvasive, non-contact, reproducible, easy to perform, rapid technique that allows imaging of all of layers of the retina, along with measurement of thickness and volume of specific retinal layers, may serve as a biomarker to detect the early onset and progression of Mn neurotoxicity. Preliminary studies in our lab show that monkeys with chronic exposure to Mn have specific changes in their retinas detected by OCT and that the magnitude of at least some of the changes corresponds to the duration of Mn exposure. The studies proposed in this exploratory R21 application will extend these preliminary findings and have the following aim: Using optical coherence tomography, study the evolution of changes in retinal morphology associated with chronic exposure to Mn and associate these changes with neurocognitive readouts and post-mortem indices of neurodegenerative changes in the brain and retina. Hypothesis: Mn-exposed monkeys will develop retinal abnormalities over time, detectable with OCT imaging, and specific changes in the retina may correspond with cognitive impairment and amounts of cumulative Mn exposure. We propose that retinal thickness/volume changes may be a sensitive indicator of Mn intoxication and may precede the development of cognitive disturbances.

 描述（由申请人提供）：锰 (Mn) 是一种必需的微量金属营养素，作为大脑中许多酶促过程的重要辅助因子，然而，过量的锰可能具有神经毒性。成人接触锰会导致神经功能障碍是一个令人非常感兴趣的领域，已知高浓度的锰会导致各种不良的神经系统影响，而最近，许多研究报告了低浓度的慢性锰导致的神经心理功能障碍。通过对啮齿类动物的接触研究，以及最近对非人类灵长类动物的接触，人们对锰的基本毒理学有了很多了解，该物种的行为特征与人类神经行为系统产生的特征更为相似，而早期的非人类灵长类动物的行为特征更接近于人类神经行为系统。灵长类动物研究主要检查相对高水平、短期暴露的结果，通常会导致严重的运动功能障碍，我们实验室在过去几年中进行的研究记录了由于长期暴露于锰含量在这些范围内 尽管人类和非人类灵长类动物可能表现出锰引起的神经心理缺陷，并且神经心理学测试可以表明存在锰暴露引起的脑损伤，但其检测与锰暴露相关的早期脑损伤的敏感性仍有待证明。各种体内结构和分子成像技术已被建议作为锰神经毒性的潜在生物标志物，然而，所有这些技术执行起来都很昂贵、耗时、具有侵入性（例如，需要放射性示踪剂）注射），有些需要所有中心都没有的专门设施和专业知识，我们在这里建议使用光学相干断层扫描（OCT），这是一种无创、非接触、可重复、易于执行的快速技术，可以对所有层进行成像。视网膜以及特定视网膜层的厚度和体积的测量可以作为检测锰神经毒性早期发作和进展的生物标志物。我们实验室的初步研究表明，长期接触锰的猴子患有锰神经毒性。通过 OCT 检测到他们视网膜的具体变化，并且至少某些变化的幅度与 Mn 暴露的持续时间相对应。此探索性 R21 应用中提出的研究将扩展这些初步发现，并具有以下目标：使用光学相干断层扫描。 ，研究与长期接触锰相关的视网膜形态变化的演变，并将这些变化与神经认知读数和大脑和视网膜神经退行性变化的死后指标联系起来。随着时间的推移，接触锰的猴子会出现视网膜异常，可通过 OCT 成像检测到，视网膜的特定变化可能与认知障碍和累积锰暴露量相对应，我们认为视网膜厚度/体积变化可能是锰中毒的敏感指标。并且可能先于认知障碍的发展。