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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 42: 12-23, 2014 NIHMSID581478

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.

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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:

2. DWI Images:

3. FA Images:

4. Color FA Images:


Supplementary Data:

1. Minimum deformation template for control animals - FA:

2. Minimum deformation template for control animals - DWI:

3. Corrected p values 12 mg/Kg versus controls for FA:

4. Corrected p values 8 mg/Kg versus controls for FA:

5. Corrected p values 12 mg/Kg versus controls for DBM:

6. Corrected p values 8 mg/Kg versus controls for DBM:

7. Mask for MDT control average:


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:

2. Effect sizes for 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:

4. Effect sizes morphometric change: control group versus 12 mg/Kg treated rat group:


Acknowledgement

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. We are particularly grateful to the members of the ISLI / HESI Project Committee on Imaging for Translational Safety Assessment for advice in choosing the test compound and design of the protocol. We are also grateful to James Cook and Sally Zimney at the Duke Center for In Vivo Microscopy for technical assistance in image processing and help in preparing the manuscript.

Funding:

Dosing, tissue preparation, scanning, and image analysis were performed at the Duke Center for In Vivo Microscopy, an NIH/NIBIB national Biomedical Technology Resource Center (P41 EB015897), with additional support from NIA K01 AG041211 (to A. Badea).


 


 

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