G-ratio distribution within the healthy population: the effect of age and gender
Mara Cercignani1,2, Giovanni Giulietti3, Nick Dowell4, Matthew Gabel4, Rebecca Broad4, P Nigel Leigh4, Neil Harrison4, and Marco Bozzali3

1Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, United Kingdom, 2Neuroimaging Laboratory, Santa Lucia Foundation, Rome, Italy, 3Santa Lucia Foundation, Rome, Italy, 4Brighton and Sussex Medical School, Brighton, United Kingdom


This paper investigates the variability of the g-ratio (the ratio of the inner to the outer diameter of a myelinated axon) as a function of age and gender in the healthy population. By combining magnetization transfer and diffusion MRI, the mean g-ratio of 20 white matter tracts was estimated, revealing no gender differences, and a systematic increase with age. Righ vs left hemisphere differences were also detected.


It has been recently demonstrated that the average voxel g-ratio, i.e., the ratio of the inner to the outer diameter of a myelinated axon, can be estimated in-vivo using a combination of magnetization transfer (MT-) and diffusion (d-) MRI [1]. The g-ratio is an index of axonal myelination, related to the physiology and function of an axon, and therefore is a potentially useful biomarker in a number of neurological conditions. Before characterising changes in the g-ratio caused by disease, however, it would be useful to have access to some normative data. The aim of this work is to explore the anatomical distribution of the g-ratio within the human brain, and its variability in the healthy population as a function of age and gender.


Data from 36 right-handed healthy participants (M/F=16/20, mean age=44.2 years, range: 20-76 years) were acquired on a 1.5T MRI scanner, including multi-shell diffusion-weighted data (10 b=0 volumes, 9 directions with b=300 smm-2 30 directions with b=800 smm-2, and 60 diffusion directions with b=2400 smm-2), optimised for neurite orientation dispersion and density imaging (NODDI, [2]), and a quantitative MT protocol based on balanced steady-state free precession (bSSFP), as described in [3]. A T1-mapping sequence was also acquired. Total acquisition time was approximately half an hour. Quantitative MT data were analysed using in-house software, yielding a voxel-wise estimation of the macromolecular pool size ratio, F. dMRI data were analysed using the NODDI toolbox [2], to yield maps of the volume of the intra-cellular water compartment (Vic) and the isotropic component (Viso). Quantitative MT and NODDI data were non-linearly co-registered using the Advanced Normalization Tools (ANTs) 1.9.x to bring all maps into the same space. g-ratio maps were computed as previously described [1,4] then warped into MNI space. The JHU white-matter tractography atlas, available with FSL, was then used to extract unbiased masks of 20 white matter tracts (thresholded at 20% and binarized). The mean tract g-ratios were estimated for every participant, and effects of gender, age and hemisphere explored.


The g-ratio was significantly correlated with age for each of the tracts studied (Spearman correlation coefficient, p<0.01) but no gender effect was observed. When plotting the mean g-ratio against age, most tracts showed a quadratic dependency, with g-ratio increasing between 20 and 60 years of age, and then reaching a plateau (see Fig 1 for an example, in the cortico-spinal tract). The only tract that did not show this trend was the superior longitudinal fasciculus (SLF) (Fig 2). Significant (p<0.05) inter-hemisphere differences were observed for most tracts with the exception of the SLF, the hippocampal part of the cingulum bundle, and the inferior longitudinal fasciculus. After Bonferroni correction, the laterality effect was still significant for the anterior thalamic radiation, the cingulum bundle and the uncinated fasciculus, with higher values in the right hemisphere compared to the left. Laterality seems to be maintained throughout the life span (Fig 3).


Our data indicate that the g-ratio varies throughout the life span following an inverted U-curve. The most likely interpretation is a subtle but consistent reduction in myelin throughout adulthood, until, around the age of 60, the density of axons begins to decrease, leading to an overall stabilisation of the g-ratio. While higher g-ratio in adolescent boys compared to girls has been suggested [5], we did not observe any gender effect in adults. The evidence of a laterality effect in some of the studied tracts is intriguing and deserves further investigation.


No acknowledgement found.


1) Stikov et al. In vivo histology of the myelin g-ratio with magnetic resonance imaging. Neuroimage 2015, 4:368-73; 2) Zhang H, et al. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage. 2012, 61:1000-16. 3) Gloor et al., Quantitative magnetization transfer imaging using balanced SSFP. Magn Reson Med. 2008, 60:691-700; 4) Cercignani et al., Mapping the g-ratio within MS lesions. Proc ISMRM 2015, # 1402; 5) Paus & Toro. Could sex differences in white matter be explained by g ratio?Front. Neuroanat. 3, 14. http://dx.doi.org/10.3389/neuro.05.014.2009.


Fig 1. Mean g-ratio as a function of age in the cortico-spinal tract. The lines represent a quadratic polynomial fit. Very similar trends were found for most of the other white matter tracts

Fig 2. Mean g-ratio as a function of age in the superior longitudinal fasciculus. This was the only tract where the g-ratio did not show a tendency towards a plateau after 60 years of age.

Fig 3. Mean g-ratio as a function of age in the anterior thalamic radiations. The data indicate a systematic offset between left and right tract, throughout the life-span.

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