Effects of mixed metal exposures on MRI diffusion features in the medial temporal lobe

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Abstract Background Environmental exposure to metal mixtures is common and may be associated with increased risk for neurodegenerative disorders including Alzheimer’s disease Objective This study examined associations of mixed metal exposures with medial temporal lobe (MTL) MRI structural metrics and neuropsychological performance. Methods Metal exposure history, whole blood metal, and neuropsychological tests were obtained from subjects with/without a history of mixed metal exposure from welding fumes (42 exposed subjects; 31 controls). MTL structures (hippocampus, entorhinal and parahippocampal cortices) were assessed by morphologic (volume, cortical thickness) and diffusion tensor imaging [mean (MD), axial (AD), radial diffusivity (RD), and fractional anisotropy (FA)] metrics. In exposed subjects, correlation, multiple linear, Bayesian kernel machine regression, and mediation analyses were employed to examine effects of single- or mixed-metal predictor(s) and their interactions on MTL structural and neuropsychological metrics; and on the path from metal exposure to neuropsychological consequences. Results Compared to controls, exposed subjects had higher blood Cu, Fe, K, Mn, Pb, Se, and Zn levels (p’s<0.026) and poorer performance in processing/psychomotor speed, executive, and visuospatial domains (p’s<0.046). Exposed subjects displayed higher MD, AD, and RD in all MTL ROIs (p’s<0.040) and lower FA in entorhinal and parahippocampal cortices (p’s<0.033), but not morphological differences. Long-term mixed-metal exposure history indirectly predicted lower processing speed performance via lower parahippocampal FA (p=0.023). Higher whole blood Mn and Cu predicted higher entorhinal diffusivity (p’s<0.043) and lower Delayed Story Recall performance (p=0.007) without overall metal mixture or interaction effects. Discussion Mixed metal exposure predicted MTL structural and neuropsychological features that are similar to Alzheimer’s disease at-risk populations. These data warrant follow-up as they may illuminate the path for environmental exposure to Alzheimer’s disease-related health outcomes. Highlights Mixed metal exposed subjects through welding fumes had higher blood Cu, Fe, K, Mn, Pb, Se, and Zn levels than controls. Exposed subjects had higher diffusion tensor imaging (DTI) mean (MD), axial (AD), radial (RD) diffusivity values in all medial temporal lobe (MTL) regions of interest (ROI) (hippocampus, entorhinal and parahippocampal cortices) and lower fractional anisotropy (FA) in the entorhinal and parahippocampal cortices without significant morphologic differences. Long-term mixed metal exposure history predicted altered MTL DTI metrics (lower parahippocampal FA and higher hippocampal RD). Across correlation, multiple linear, and Bayesian kernel machine regression analyses, higher whole blood Mn and Cu levels predicted higher entorhinal diffusivity values and lower Delayed Story Recall performance, features resembling Alzheimer’s disease at-risk populations. MTL DTI metrics mediate, at least partially, the effects of metal exposure on cognitive performance.

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