Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology
G. Allan Johnson1,2, Evan Calabrese1,2, Peter B. Little3, Laurence Hedlund1, Yi Qi 1, Alexandra Badea1
1Center for In Vivo Microscopy, Department of Radiology, Duke University Medical Center
2Biomedical Engineering, Duke University
3Neuropathology Consultant, EPL Inc., Research Triangle Park, NC
Neurotoxicology, 11;42C:12-23 2014. PMCID: PMC4053477
The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E)-stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time-consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/Kg and 12 mg/Kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain.<
Supplementary Data:
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Representative Images:
Adult rat brain imaged at 7.1T using magnetic resonance histology, in conjunction with active staining.
1. Conventional MR imaging: View Conventional MR imaging in CIVMVoxPort
2. DWI Images: View DWI Images in CIVMVoxPort
3. FA Images: View FA Images in CIVMVoxPort
4. Color FA Images: View Color FA Images in CIVMVoxPort
More Supplementary Data:
1. Minimum deformation template for control animals - FA: View FA in CIVMVoxPort
2. Minimum deformation template for control animals - DWI: View DWI Images in CIVMVoxPort
3. Corrected p values 12 mg/Kg versus controls for FA: View Color FA Images in CIVMVoxPort
4. Corrected p values 8 mg/Kg versus controls for FA: View q values 8 mg/Kg FA Images in CIVMVoxPort
5. Corrected p values 12 mg/Kg versus controls for DBM: View q values 12 mg/Kg DBM Images in CIVMVoxPort
6. Corrected p values 8 mg/Kg versus controls for DBM: View q values 8 mg/Kg DBM Images in CIVMVoxPort
7. Mask for MDT control average: View MDT controls brain mask Images in CIVMVoxPort
Supplementary Movies:
Note: For optimal quality, please download the following videos, and view them from your local computer.
1. Effect sizes for fractional anisotropy differences: control group versus 8 mg/Kg treated rat group:
View fractional anisotropy differences: control group versus 8 mg/Kg treated rat group
2. Effect sizes for fractional anisotropy differences: control group versus 12 mg/Kg treated rat group:
View fractional anisotropy differences: control group versus 12 mg/Kg treated rat group
3. Effect sizes for morphometric changes: control group versus 8 mg/Kg treated rat group:
View morphometric changes: control group versus 8 mg/Kg
4. Effect sizes morphometric change: control group versus 12 mg/Kg treated rat group:
View morphometric changes: control group versus 12 mg/Kg
Acknowledgements:
We are grateful to Dr. Robert Sills and Dr. Jean Harry at NIEHS for support in histopathology and useful discussions in understanding the effects of trimethyltin.
