Myelin biomarkers in the healthy adult brain: Correlation, reproducibility, and the effect of fiber orientation.

PURPOSE: We investigated the correlation, reproducibility, and effect of white matter fiber orientation for three myelin-sensitive MRI techniques: magnetization transfer ratio (MTR), inhomogeneous magnetization transfer ratio (ihMTR), and gradient and spin echo-derived myelin water fraction (MWF). METHODS: We measured the three metrics in 17 white and three deep grey matter regions in 17 healthy adults at 3 T. RESULTS: We found a strong correlation between ihMTR and MTR (r = 0.70, p < 0.001) and ihMTR and MWF (r = 0.79, p < 0.001), and a weaker correlation between MTR and MWF (r = 0.54, p < 0.001). The dynamic range in white matter was greatest for MWF (2.0%-27.5%), followed by MTR (14.4%-23.2%) and then ihMTR (1.2%-5.4%). The average scan-rescan coefficient of variation for white matter regions was 0.6% MTR, 0.3% ihMTR, and 0.7% MWF in metric units; however, when adjusted by the dynamic range, these became 6.3%, 6.1% and 2.8%, respectively. All three metrics varied with fiber direction: MWF and ihMTR were lower in white matter fibers perpendicular to B0 by 6% and 1%, respectively, compared with those parallel, whereas MTR was lower by 0.5% at about 40°, with the highest values at 90°. However, separating the apparent orientation dependence by white matter region revealed large dissimilarities in the trends, suggesting that real differences in myelination between regions are confounding the apparent orientation dependence measured using this method. CONCLUSION: The strong correlation between ihMTR and MWF suggests that these techniques are measuring the same myelination; however, the larger dynamic range of MWF may provide more power to detect small differences in myelin.

Nonaqueous magnetization following adiabatic and selective pulses in brain: T1 and cross-relaxation dynamics.

Inversion pulses are commonly employed in MRI for T 1 -weighted contrast and relaxation measurements. In the brain, it is often assumed that adiabatic pulses saturate the nonaqueous magnetization. We investigated this assumption using solid-state NMR to monitor the nonaqueous signal directly following adiabatic inversion and compared this with signals following hard and soft inversion pulses. The effects of the different preparations on relaxation dynamics were explored. Inversion recovery experiments were performed on ex vivo bovine and porcine brains using 360-MHz (8.4 T) and 200-MHz (4.7 T) NMR spectrometers, respectively, using broadband rectangular, adiabatic, and sinc inversion pulses as well as a long rectangular saturation pulse. Analogous human brain MRI experiments were performed at 3 T using single-slice echo-planar imaging. Relaxation data were fitted by mono- and biexponential decay models. Further fitting analysis was performed using only two inversion delay times. Adiabatic and sinc inversion left much of the nonaqueous magnetization along B 0 and resulted in biexponential relaxation. Saturation of both aqueous and nonaqueous magnetization components led to effectively monoexponential T 1 relaxation. Typical adiabatic inversion pulses do not, as has been widely assumed, saturate the nonaqueous proton magnetization in white matter. Unequal magnetization states in aqueous and nonaqueous 1 H reservoirs prepared by soft and adiabatic pulses result in biexponential T 1 relaxation. Both pools must be prepared in the same magnetization state (e.g., saturated or inverted) in order to observe consistent monoexponential relaxation.

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

PURPOSE: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T1D. METHODS: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining. RESULTS: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T2 peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 °C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR. CONCLUSIONS: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T1D components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.

Orientation dependence of inhomogeneous magnetization transfer and dipolar order relaxation rate in phospholipid bilayers.

Inhomogeneous magnetization transfer (ihMT) is a novel MRI technique used to measure white matter myelination in the brain and spinal cord. In the brain, ihMT has a strong orientation dependence which is likely to arise from the anisotropy of dipolar couplings between protons on oriented lipids in the myelin bilayers. We measured the orientation dependence of the second moment (M2) of the lineshape, dipolar order relaxation rate (R1D), and ihMT ratio (ihMTR) in an oriented phospholipid bilayer at 9.4 T. We found a strong orientation dependence in all three parameters. ihMTR and R1D were maximized when the bilayers were aligned perpendicular to B0 and minimized near the magic angle (∼54.7°). M2 followed an orientation dependence given by the second Legendre polynomial squared as predicted by the form of the secular dipolar Hamiltonian. These results were used to calculate the orientation dependence of R1D and ihMTR in a diffusionless myelin sheath model, which showed ihMTR was maximised for fibers perpendicular to B0 and minimised at 45°, similar to ex-vivo spinal cord with a larger prepulse frequency offset, but in contrast to in vivo brain findings. Adding fiber dispersion to this model smoothed the orientation dependence curve as expected. Our results suggest the importance of the effects of lipid diffusion and prepulse offset frequency on ihMTR.

International Spinal Cord Injury Biobank: A Biorepository and Resource for Translational Research.

Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

Learning-Challenged Youth Show an Abnormal Relationship Between Fronto-Parietal Myelination and Mathematical Ability.

BACKGROUND AND PURPOSE: Differences in the microstructure of fronto-parietal white matter tracts have been associated with mathematical achievement. However, much of the supporting evidence relies on nonspecific diffusion-weighted magnetic resonance imaging, making it difficult to isolate the role of myelin in math ability. METHODS: We used myelin water imaging to measure brain myelin. We related myelin water fraction (MWF) to Woodcock-Johnson III (WJ-III) basic math scores using region of interest (ROI) and tract-based spatial statistics (TBSS) analyses, in 14 typically developing and 36 learning challenged youth aged 9-17 years. RESULTS: The ROI analysis found a positive relationship between fronto-parietal MWF and math in typically developing youth, but not in learning challenged youth. The relationship between fronto-parietal MWF and math observed in typically developing youth was fully mediated by age. No group differences in fronto-parietal MWF were found between typically developing and learning challenged youth. TBSS also found no group differences in MWF values. TBSS indicated math-MWF relationships extend beyond fronto-parietal tracts to descending and ascending projection tracts in typically developing youth. TBSS identified math-MWF relationships in the cerebral peduncles of learning challenged youth. CONCLUSIONS: Our results suggest that in typically developing youth, brain myelination contributes to individual differences in basic math achievement. In contrast, youth with learning challenges appear to have less capacity to leverage myelin to improve math achievement.

Brain Myelin Water Fraction and Diffusion Tensor Imaging Atlases for 9-10 Year-Old Children.

BACKGROUND AND PURPOSE: Myelin water imaging (MWI) and diffusion tensor imaging (DTI) provide information about myelin and axon-related brain microstructure, which can be useful for investigating normal brain development and many childhood brain disorders. While pediatric DTI atlases exist, there are no pediatric MWI atlases available for the 9-10 years old age group. As myelination and structural development occurs throughout childhood and adolescence, studies of pediatric brain pathologies must use age-specific MWI and DTI healthy control data. We created atlases of myelin water fraction (MWF) and DTI metrics for healthy children aged 9-10 years for use as normative data in pediatric neuroimaging studies. METHODS: 3D-T1 , DTI, and MWI scans were acquired from 20 healthy children (mean age: 9.6 years, range: 9.2-10.3 years, 4 females). ANTs and FSL registration were used to create quantitative MWF and DTI atlases. Region of interest (ROI) analysis in nine white matter regions was used to compare pediatric MWF with adult MWF values from a recent study and to investigate the correlation between pediatric MWF and DTI metrics. RESULTS: Adults had significantly higher MWF than the pediatric cohort in seven of the nine white matter ROIs, but not in the genu of the corpus callosum or the cingulum. In the pediatric data, MWF correlated significantly with mean diffusivity, but not with axial diffusivity, radial diffusivity, or fractional anisotropy. CONCLUSIONS: Normative MWF and DTI metrics from a group of 9-10 year old healthy children provide a resource for comparison to pathologies. The age-specific atlases are ready for use in pediatric neuroimaging research and can be accessed: https://sourceforge.net/projects/pediatric-mri-myelin-diffusion/.