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

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 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.