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ToxSci Advance Access originally published online on September 12, 2006
Toxicological Sciences 2006 94(2):351-358; doi:10.1093/toxsci/kfl106
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Evidence for Cortical Dysfunction and Widespread Manganese Accumulation in the Nonhuman Primate Brain following Chronic Manganese Exposure: A 1H-MRS and MRI Study

Tomás R. Guilarte*,1, Jennifer L. McGlothan*, Mahaveer Degaonkar{dagger}, Ming-Kai Chen*, Peter B. Barker{dagger}, Tore Syversen{ddagger} and Jay S. Schneider§

* Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205 {dagger} Department of Radiology, Johns Hopkins Hospital, Baltimore, Maryland 21205 {ddagger} Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway § Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Received July 13, 2006; accepted September 9, 2006

Exposure to high levels of manganese (Mn) is known to produce a complex neurological syndrome with psychiatric disturbances, cognitive impairment, and parkinsonian features. However, the neurobiological basis of chronic low-level Mn exposure is not well defined. We now provide evidence that exposure to levels of Mn that results in blood Mn concentrations in the upper range of environmental and occupational exposures and in certain medical conditions produces widespread Mn accumulation in the nonhuman primate brain as visualized by T1-weighted magnetic resonance imaging. Analysis of regional brain Mn distribution using a "pallidal index equivalent" indicates that this approach is not sensitive to changing levels of brain Mn measured in postmortem tissue. Evaluation of longitudinal 1H-magnetic resonance spectroscopy data revealed a significant decrease (p = 0.028) in the N-acetylaspartate (NAA)/creatine (Cr) ratio in the parietal cortex and a near significant decrease (p = 0.055) in frontal white matter (WM) at the end of the Mn exposure period relative to baseline. Choline/Cr or myo-Inositol/Cr ratios did not change at any time during Mn exposure. This indicates that the changes in the NAA/Cr ratio in the parietal cortex are not due to changes in Cr but in NAA levels. In summary, these findings suggest that during chronic Mn exposure a significant amount of the metal accumulates not only in the basal ganglia but also in WM and in cortical structures where it is likely to produce toxic effects. This is supported by a significantly decreased, in the parietal cortex, NAA/Cr ratio suggestive of ongoing neuronal degeneration or dysfunction.

Key Words: manganese; MRI; MRS; nonhuman primate; brain; basal ganglia; N-acetylaspartate.


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