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（由适用提供）：锰（MN）是一种必需的痕量金属营养素，对于大脑中许多酶促过程而言，作为辅助因子很重要。但是，超过MN可以是神经毒性的。成年人在成年人中向MN暴露于MN导致神经功能障碍的程度是一个引人注目的领域。众所周知，高水平的暴露会引起各种不良神经系统作用，而最近，许多研究报告了较低慢性暴露导致的神经心理功能障碍。从啮齿动物的暴露研究中，从非人类隐私中的MN暴露中了解了MN的基本毒理学，这是一种行为库的物种，其行为库更相似地相似于人类神经行为系统。虽然早期的非人类隐私研究主要研究了相对较高水平的结果，但短期暴露通常会导致严重的运动功能障碍，但在过去几年中，我们的实验室进行的研究记录了各种神经认知缺陷，这是由于长期暴露于MN的慢性暴露于MN的水平。 尽管人类和非人类私人可以表现出MN引起的神经心理学缺陷，而神经心理学测试可以表明脑损伤对MN暴露的影响，但其对检测与MN暴露相关的早期脑损伤的敏感性尚待证明。已经提出了各种体内结构和分子成像技术作为Mn神经毒性的潜在生物标志物，但是，所有这些都昂贵，耗时，耗时均具有侵入性（例如，需要放射性注射剂），并且有些需要专业的设施和专业知识。我们在这里提出，光学相干断层扫描（OCT）是一种无创，非接触，可重现的，易于执行的，易于成像，可以对视网膜的所有层进行成像，并测量厚度和特定残留层的体积，可以作为生物标志物来检测MN神经毒性的早期发作和进展。在我们的实验室中，初步研究表明，慢性暴露于MN的猴子在OCT之前检测到的视网膜有特定的变化，并且至少某些变化的大小与MN暴露的持续时间相对应。在本探索性R21应用中提出的研究将扩展这些初步发现，并具有以下目的：使用光学相干断层扫描，研究与长期暴露于MN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神经认知的变化相关联，并将其与大脑和视网膜的神经变性变化相关联。假设：暴露于MN的猴子会随着时间的流逝而产生视网膜异常，可检测到OCT成像，视网膜的特定变化可能与认知障碍和累积MN暴露量相对应。我们建议视网膜厚度/体积变化可能是MN肠毒性的敏感指标，并且可能先于认知障碍的发展。