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

 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辅助因子非常重要。然而，过量的Mn可能具有神经毒性。在成年人中慢性环境或职业暴露于锰导致神经功能障碍的程度是一个相当感兴趣的领域。已知高水平的暴露会引起各种不利的神经影响，而最近，一些研究报告了较低水平的慢性暴露导致的神经心理功能障碍。从啮齿类动物暴露研究中，以及最近从非人灵长类动物（其行为库更接近于人类神经行为系统所产生的行为库的物种）的锰暴露中，已经了解到许多关于锰的基本毒理学的信息。虽然早期的非人灵长类动物研究主要检查了相对高水平的短期暴露的结果，通常导致严重的运动功能障碍，但在过去几年中，我们实验室进行的研究已经记录了长期暴露于Mn导致的各种神经认知缺陷，其水平范围为 报告了人类环境或职业暴露。尽管人类和非人灵长类动物可表现出Mn诱导的神经心理学缺陷，并且神经心理学测试可指示Mn暴露导致的脑损伤的存在，但其检测与Mn暴露相关的早期脑损伤的灵敏度仍有待证明。已经提出了多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，然而，所有这些都是昂贵的，耗时的，侵入性的（例如，需要放射性示踪剂注射），并且一些需要专业设施和专业知识，而不是在所有中心都可用。我们在这里提出，光学相干断层扫描（OCT），一种非侵入性，非接触，可重复，易于执行，快速的技术，允许成像的所有层的视网膜，沿着测量厚度和体积的特定视网膜层，可以作为一种生物标志物，以检测锰神经毒性的早期发作和进展。我们实验室的初步研究表明，长期暴露于锰的猴子有特定的变化，在他们的视网膜检测OCT和至少有一些变化的幅度对应于锰暴露的持续时间。在这项探索性R21申请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相关的视网膜形态学变化的演变，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尸检指标相关联。假设：锰暴露猴将随着时间的推移出现视网膜异常，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关。我们建议，视网膜厚度/体积的变化可能是锰中毒的敏感指标，并可能先于认知障碍的发展。

 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.