Quantitative Estimates of Myelin Volume Fraction from T2 and Magnetization Transfer
Kathryn L West1,2, Nathaniel D Kelm1,2, Daniel F Gochberg2,3, Robert P Carson4, Kevin C Ess4, and Mark D Does1,2

1Biomedical Engineering, Vanderbilt University, Nashville, TN, United States, 2Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States, 3Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, United States, 4Neurology, Vanderbilt University, Nashville, TN, United States

Synopsis

Multiexponential T2 and quantitative magnetization transfer experiments provide quantitative measures of myelin water fraction (MWF) and bound pool fraction (BPF), respectively. These measures are known to correlate with myelin content in white matter; however discrepancies between the two have been shown. We display that by correcting for all proton pools contributing to MWF and BPF in white matter, we are able to show similar absolute measures of myelin content from MWF and BPF that are nearly equal to each other and close to myelin content measured by quantitative histology.

Purpose

Myelin water fraction (MWF) derived from multiexponential T2 (MET2) and bound pool fraction (BPF) resulting from quantitative magnetization transfer (qMT) experiments are known to correlate with myelin content in white matter (1,2). However, comparative studies have shown discrepancies between these two measures (3–5), which raises the question of how exactly these quantitative measures should be interpreted. Here we test the relationships between MET2, qMT, and myelin volume fraction (as measured by electron microscopy), in the context of a four-pool model of protons in white matter.

Methods

Mouse brains from control (n=6) and two models of tuberous sclerosis complex (Rictor CKO, n=3 and TSC, n=3) were perfusion-fixed and loaded with 1mM of Gadolinium (Magnevist) for high resolution 3D Extended Phase Graph (EPG)-compliant MET2 and inversion-recovery prepared 3D fast spin echo qMT studies at 15.2 T with 150µm isotropic resolution for both. Myelin water fraction (MWF) was obtained from voxel-wise T2-spectra fitting of MET2 data and bound pool fraction (BPF) was extracted voxel-wise from qMT data as previously described (6). Histology was performed using transmission electron microscopy on 4 regions of white matter from each brain. Histologic images were carefully segmented to obtain measures of myelin volume fraction (fHIST), as shown in Fig 1.

We use a four-pool model (Fig 2) to describe the fractions of water and macromolecular protons in non-myelin (a and b, respectively) and myelin (c and d, respectively) tissues. We assume approximately equal proton densities in each pool (7) and a + b + c + d = 1, therefore the myelin volume fraction = c + d. Assuming no exchange of magnetization between the myelin and non-myelin proton pools, MWF = d/(b+d), and from the standard binary spin pool qMT model, assuming identical biexponential recovery rates of longitudinal magnetization, BPF = a+c. We then define fMET2 and fMT as measures of myelin volume fraction (i.e., = c + d) which are expressible in terms of MWF and BPF, respectively.

Using literature values of water mass fractions in myelin (ρm = d/(c+d) = 0.44) and non-myelin (ρn= b/(a+b) = 0.82) components of white matter (8), MWF can be written in terms of the myelin volume fraction (fMET­2 = c+d) as shown in Eq. II, which can then be solved to express fMET­2 as a function of MWF as shown in Eq. III.

Similarly for qMT analysis, we first use the linear correlation between BPF and fHIST (Fig 3), to determine the contribution of the non-myelin macromolecular proton fraction (a) to BPF. Then, using water mass fraction in myelin, ρm, again, the myelin volume fraction (fMT = c+d) can be expressed in terms of BPF as shown in Eq. V.

Results

Fig 1 displays qualitative decreases in fHIST in representative segmented myelin images from control, Rictor CKO, and TSC brains. Fig 3 (top) displays MWF (black x) and BPF (blue dot) versus fHIST with BPF offset (a) and the line of unity (gray, dashed). While all measures display good correlation, with gradual decreases in myelin content, as expected in models, the absolute values of MWF, BPF and fHIST do not agree. Fig 3 (bottom) shows fMET­2 (black x) and fMT (blue dot) versus fHIST, which shows strong linear correlation between fMET­2 and fMT (R = 0.89) and each to fHIST (R = 0.8 and 0.83 for fMET­2 and fMT, respectively). Additionally, fMET­2, fMT, and fHIST exhibit good agreement in absolute measures of myelin content, with fMET­2 and fMT displaying nearly identical results. However, it is apparent that both fMET­2 and fMT underestimate fHIST, which may reflect a systematic overestimation of fHIST from histological image analysis, or, for fMET­2 at least, this could be explained by intercompartmental water exchange (5,9).

Conclusion

By correcting for all proton pools contributing to MWF and BPF, we are able to show similar absolute measures of myelin content (fMET2 and fMT) that are nearly equal to each other and close to myelin content measured by quantitative histology (fHIST). This displays that BPF can be as specific to myelin content as MWF, which is important because BPF is generally a higher precision measurement. However, if accurate measures of myelin volume fraction rather than simply correlative measures are needed, for example for measuring g-ratio (10,11) conversion of BPF to fMT relies on accounting for the contribution from non-myelin macromolecular protons, which may not be the same across all tissues or subjects.

Acknowledgements

NIH EB001744 and NSF GRFP DGE-0909667

References

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Figures

Figure 1. Examples of quantiative histology analysis of (left) original transmission electron microscopy images to (right) segmented myelin images to obtain myelin volume fraction in (top) control, (middle) Rictor CKO, and (bottom) TSC animals.


Figure 2. Four-pool model of white matter containing water and macromolecular protons in non-myelin tissue (a and b, respectively) and water and macromolecular protons in myelin (c and d, respectively). Equations I-V describe the steps taken to obtain measures MWF and BPF comparable to histology based on the model.


Figure; 3. (Top) MWF (black x) and BPF (blue dot) versus fHIST and (bottom) fMET2 (black x) and fMT (blue dot) versus fHIST with line of unity (gray, dashed).




Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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