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Age-Related Microstructural Alterations in Human Corpus Callosum Measured by High-Gradient Diffusion MRI
Qiuyun Fan1,2, Qiyuan Tian1,2, Ned A Ohringer1,2, Aapo A Nummenmaa1,2, Thomas Witzel1,2, Sean M Tobyne2,3, Eric C Klawiter2,3, Bruce R Rosen1,2,4, Lawrence L Wald1,2,4, David H Salat1,2, and Susie Y Huang1,2,4

1Radiology, Massachusetts General Hospital, Charlestown, MA, United States, 2Harvard Medical School, Boston, MA, United States, 3Neurology, Massachusetts General Hospital, Charlestown, MA, United States, 4Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, United States

Synopsis

Cerebral white matter exhibits degenerative changes during normal aging. Noninvasive approaches to measure these microstructural alterations would be invaluable for understanding the substrate and regional variability of age-related white matter degenerations. Recent advances in diffusion MRI have leveraged high gradient strengths to increase sensitivity toward axonal size and density in living human brains. Here, we examined the relationship between age and microstructural properties measured using high-gradient diffusion MRI. We observed an increase in apparent axon diameter and decrease in density with advancing age in the corpus callosum, with changes most pronounced in the genu and relatively absent in the splenium.

Introduction

Alterations in fiber composition within the corpus callosum interfere with the efficiency of interhemispheric transfer in older adults and likely contribute to cognitive aging.1,2 On histology, an increase in the number of large myelinated callosal fibers has been observed with increasing age,3 with less myelinated fibers in the genu found to be particularly susceptible to the deleterious effects of aging4,5. These trends have been corroborated on numerous neuroimaging studies6-13. DTI offers useful insight into the microstructural properties of white matter but is not specific to axonal and myelin integrity. Noninvasive approaches to estimate axon diameter and density in the living human brain would be invaluable for understanding the microstructural substrate of age-related white matter changes.

In recent years, a number of advanced diffusion MRI techniques for inferring axon diameter and packing density have become more readily translated to studying white matter structure in the living human brain, largely through the availability of higher gradient strengths on human MRI scanners.14,15 The goal of this study is to explore age-related differences in apparent axon diameter and density estimated using high-gradient diffusion MRI in the corpus callosum.

Methods

Participants A total of 36 healthy, cognitively normal adults (aged 22-72, 23F) participated in this study.

Data Acquisition Imaging data were acquired on the 3T Connectome scanner equipped with 300 mT/m maximum gradient strength14,16,17 using a custom-made 64-channel phased array head coil18 for signal reception. Sagittal 2-mm isotropic resolution diffusion-weighted spin-echo EPI images were acquired with whole brain coverage. The following parameters were used: TR/TE = 4000/77ms, δ=8ms, Δ=19/49ms, 8 diffusion gradient strengths linearly spaced from 30-290mT/m per Δ, 32-64 diffusion directions, parallel imaging (R=2) and simultaneous multislice (MB=2). Five b=0 images with reversed phase encoding direction were acquired for distortion correction.

Data Analysis Diffusion data were corrected for gradient nonlinearity17, motion, susceptibility and eddy current distortions using the TOPUP and EDDY tools in FSL19-21. A previously validated method22 was employed for the voxel-wise fitting for axon diameter, restricted and hindered volume fraction, and hindered diffusivity using Markov-Chain Monte-Carlo (MCMC) sampling. Corpus callosum masks were created from FreeSurfer labels and manually edited to ensure exclusion of voxels outside the corpus callosum (e.g., fornix and CSF). The corpus callosum was further divided into five sub-sections, which were derived from evenly spaced partitions along the primary eigenaxis using FreeSurfer’s automatic labeling23. Correlation analyses were performed between age and the ROI-averaged axonal metrics.

Results

Figure 1 shows representative maps of apparent axon diameter, restricted volume fraction and axon density in younger and older adult participants. Apparent axon diameter and axon density were significantly correlated with age in the whole corpus callosum (Figure 2a,b). While the previously reported correlations between FA and age were replicated in the cerebral white matter (Figure 2d), no significant correlation was observed for the corpus callosum (Figure 2c). Similar analyses in sub-regions of the corpus callosum showed the strongest age-related effects in the axonal metrics in the genu of the corpus callosum (Figure 3). Increased apparent axon diameter and decreased axon density were found in the forceps minor but not in the forceps major (Figure 4). The relationship between the axonal microstructural metrics and more widely studied DTI metrics related to aging are shown in Figure 5.

Discussion

We observed regionally selective, age-related microstructural axonal differences in the corpus callosum and adjacent white matter tracts estimated from high-gradient diffusion MRI. A global increase in apparent axon diameter and decrease in axon density was seen throughout the corpus callosum with increasing age, with the effect being most pronounced in the genu of the corpus callosum. The findings were mirrored by similar trends in the adjacent forceps minor and forceps major.

Our results support the hypothesis that select fiber bundles are preferentially affected by aging, and that these trends follow a regional distribution that reflects the selective vulnerability of certain anterior fiber bundles to age-related degeneration. More importantly, the axonal imaging metrics provide unique and complimentary regional markers of microstructural changes relative to DTI. This approach offers a more specific microstructural interpretation of the axonal changes underpinning the previously noted age-related differences in FA within anterior versus posterior fiber bundles, suggesting that the underlying substrate of age-related degeneration may relate to fiber size and packing density.

Acknowledgements

This work was funded by a National Institutes of Health Blueprint for Neuroscience Research Grant U01MH093765, as well as National Institutes of Health funding from the National Center for Research Resources P41EB015896, National Institute of Biomedical Imaging and Bioengineering R01EB006847 and R00EB015445, National Institute of Neurological Disorders and Stroke K23NS096056, and K23NS078044, and Instrumentation Grants S10-RR023401, S10-RR023043, and S10-RR019307. Funding support was also received from the National Multiple Sclerosis Society, the American Heart Association Postdoctoral Fellowship Award (17POST33670452), a Radiological Society of North America Research Resident Grant (RR1427), the Conrad N. Hilton Foundation (17330) and the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery Fellowship Award and Claflin Distinguished Scholar Award.

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Figures

Figure 1. Exemplary maps of apparent axon diameter, restricted volume fraction, and axon density in a healthy young adult (female, a-c) and a healthy older adult (male, d-f). The maps for both participants showed smaller apparent axon diameter and higher axon density in the genu and splenium of the corpus callosum compared to the posterior body. Furthermore, the apparent axon diameter estimates appeared larger, and the axon density appeared generally reduced throughout the corpus callosum in the older participant compared to the younger participant, while the restricted volume fraction was relatively constant between the younger and older adults.

Figure 2. Correlations of diffusion metrics in the whole corpus callosum and cerebral white matter with age. (a) Axon diameter increased with age, and (b) axon density decreased with age. (c) No significant correlation was found between FA and age in the corpus callosum. (d) FA of the cerebral white matter (WM) decreased with age. Pearson’s linear correlation controlling for gender was used to report the correlation coefficients (r) and significance level (p) after correcting for multiple comparisons using the false discovery rate method.

Figure 3. Correlation of apparent axon diameter and axon density with age in the five segments of the corpus callosum as illustrated in the insets. (Top) Overall, apparent axon diameter increased with age, with the strongest correlation found in the genu of the corpus callosum. (Bottom) Axon density decreased with age throughout the corpus callosum, with the correlations reaching the level of significance in the genu and posterior body. No correlation was found between apparent axon diameter or axon density with age in the splenium. NS: Not significant.

Figure 4. Correlation of apparent axon diameter and axon density with age in the forceps major and forceps minor. Apparent axon diameter increased and axon density decreased with increasing age in the forceps minor. By comparison, in the forceps major, no significant correlation was seen between age and axon diameter or axon density. NS: Not significant.

Figure 5. Correlation of DTI metrics and apparent axon diameter, restricted volume fraction, and axon density across all five segments of the corpus callosum. The scatterplots were generated by pooling together all voxels in the corpus callosum of all subjects. No significant correlation was observed between apparent axon diameter and DTI metrics including FA, AD, RD and MD. On the other hand, a strong positive correlation was identified between restricted volume fraction and FA and RD, and a moderate correlation was appreciated between axon density and DTI metrics including FA, RD and AD. p-values labeled in the figures are uncorrected for multiple comparisons.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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