Quantitative MRI to Study In Vivo Brain Manganese Deposition and Mn Neurotoxicity
Occupational exposure to Manganese, such as in welding, can cause motor and cognitive deficits that resemble Parkinson’s disease. In order to better understand the dose-effect relationship and to assess safe limits of exposure, it is important to understand the spatial and temporal dynamics of Mn deposition in the human brain upon inhalation of Mn fumes. Magnetic resonance image is a non-invasive tool to visualize and measure the accumulation of manganese (Mn) in the human brain. Due to the paramagnetic property of Mn, the presence of Mn in a particular brain region linearly increases the MR relaxation rates R1 and R2*, which causes the signal intensity in T1-weighted images to increase, thus showing brain areas with increased Mn deposition as hyperintensities. Quantitative mapping techniques allow the direct measurement of R1 and R2* relaxation rate in multiple brain areas and were thus used in this thesis to visualize and quantify Mn deposition in the brain of welders exposed to Mn. Despite Mn accumulation being most prominent in basal ganglia structures, increasing evidence shows that the cerebral cortex is also involved in Mn neurotoxicity. Yet, the dynamics of Mn accumulation in different brain regions are not yet understood. Furthermore, a better understanding of potential confounders in MR quantitative mapping, e.g. due to other metals such as iron, is necessary to estimate in vivo brain Mn levels, and to study the relationship of imaging parameters, such as R1 and R2*, with Mn exposure as well as with neurobehavioral outcomes. My thesis seeks to address these problems by (1) developing an optimized image processing protocol that enables the whole-brain visualization of significantly increased Mn deposition in a Mn-exposed group versus unexposed subjects, (2) studying the dynamics of Mn deposition and reversal in a longitudinal study on an animal model, and (3) studying the effects of metal mixtures of Mn and iron (Fe) on the relaxation rates R1 and R2 to develop a model for metal quantification. To visualize Mn deposition in the brain, image processing steps such as registration, normalization and smoothing were optimized to prevent unnecessary distortion while preserving the original quantitative information from the R1 maps. The resulting Mn deposition map showed Mn accumulation not only in the basal ganglia region but also in the frontal, parietal and temporal cortex. The 3D whole-brain approach allowed an overview of the Mn distribution along the white matter tract. Regions with significant deposition of Mn were used as seeds to measure the correlation with neurobehavioral exam scores, showing an association of brain areas with increased Mn deposition with working memory deficits and impairment in visuomotor function. To study the dynamics of Mn accumulation, the R1 mapping technique was applied in a study of non-human primates with chronic exposure to Mn. In this study, the longitudinal time course of brain Mn accumulation over a long-term (66-81 wks) Mn administration, as well as the wash-out of Mn after cessation of Mn administration were evaluated. The results demonstrate regionally different dynamics of Mn uptake and wash-out in a model of chronic Mn exposure. The continuously increasing R1 values in the globus pallidus during exposure suggest the possibility of continuous accumulation of Mn in subcortical regions. The hyperintensities found in T1-weighted images after the cessation of Mn exposure also demonstrate the slowness of Mn elimination in these regions. Structures like the substantia nigra, one of the primary brain structures affected by pathology in PD, seem to have a different saturation and faster wash-out rate, which underlines the regional differences of uptake and wash-out for different brain regions. Mn has been known for a long time as a contrast agent for MRI. Equally, R2* has been shown in the literature to correlate with iron content in brain, liver and heart. However, little is known about the interaction between Mn and Fe and its combined effect on relaxation rates R1 and R2*. Yet, next to Mn, welding fumes contain a large amount of Fe to which welders are also exposed. To study the relaxivity of Mn and Fe, and its potential interaction, mixtures in aqueous solution as well as in an environment mimicking brain tissue were studied. Linear mathematical models were expanded by adding interaction factors to describe the changes of R1 under conditions with various combinations of manganese, iron, and fetal bovine serum (FBS). Our results are in line with previous reports of relaxivity for Mn and Fe. They further suggest that a model including only linear terms for Mn and Fe already explains the R1 data with good accuracy in aqueous solution. However, when metals are solved in FBS complex binding with the protein occurs, resulting in a higher relaxivity than in aqueous solution. Competition for the binding sites with Fe decreased the high relaxivity of Mn and thus the effect of Fe on the quantification of Mn by R1 mapping should not be neglected. Using the experimental relaxivity of R1 and R2*, the brain Mn and Fe concentrations were estimated. Overall, this thesis provided a visualization tool to display Mn deposition in the human brain, revealed the longitudinal dynamics of Mn accumulation in non-human primates under chronic Mn exposure, explored the relationship between Mn deposition and neurobehavior, and studied the effect of Mn-Fe interaction on relaxivity processes.
Dydak, Purdue University.
Medical imaging|Health sciences|Neurosciences|Physiology
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