Imaging G-Ratio in Multiple Sclerosis Using High-Gradient Diffusion MRI and Macromolecular Tissue Volume

Abstract

BACKGROUND AND PURPOSE: Remyelination represents an area of great therapeutic interest in multiple sclerosis but currently lacks a robust imaging marker. The purpose of this study was to use high-gradient diffusion MRI and macromolecular tissue volume imaging to obtain estimates of axonal volume fraction, myelin volume fraction, and the imaging g-ratio in patients with MS and healthy controls and to explore their relationship to neurologic disability in MS. MATERIALS AND METHODS:Thirty individuals with MS (23 relapsing-remitting MS, 7 progressive MS) and 19 age-matched healthy controls were scanned on a 3T MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Macromolecular tissue volume imaging was performed to quantify the myelin volume fraction. Diffusion data were fitted to a 3-compartment model of white matter using a spheric mean approach to yield estimates of axonal volume fraction. The imaging g-ratio was calculated from the ratio of myelin volume fraction and axonal volume fraction. Imaging metrics were compared between groups using 2-sided t tests with a Bonferroni correction. RESULTS:The mean g-ratio was significantly elevated in lesions compared with normal-appearing WM (0.74 vs 0.67, P , .001). Axonal volume fraction (0.17 vs 0.23, P , .001) and myelin volume fraction (0.17 vs 0.25, P , .001) were significantly lower in lesions than normal-appearing WM. Myelin volume fraction was lower in normal-appearing WM compared with that in healthy controls (0.25 vs 0.27, P = .009). Disability, as measured by the Expanded Disability Status Scale, was significantly associated with myelin volume fraction (b = -40.5, P = .001) and axonal volume fraction (b = -41.0, P = .016) in normal-appearing WM. CONCLUSIONS:The imaging g-ratio may serve as a biomarker for the relative degree of axonal and myelin loss in MS.ABBREVIATIONS: AVF 4 axonal volume fraction; EDSS 4 Expanded Disability Status Scale; HC 4 healthy controls; MSFC 4 multiple sclerosis functional composite; MTV 4 macromolecular tissue volume; MVF 4 myelin volume fraction; NAWM 4 normal-appearing white matter; NODDI 4 neurite orientation dispersion and density imaging; PMS 4 progressive MS; qMT 4 quantitative magnetization transfer; RRMS 4 relapsing-remitting MS M ultiple sclerosis is a disease of the CNS characterized by inflammatory demyelination and axonal loss. Demyelination predisposes axons to immune-mediated injury, resulting in axonal loss that is thought to be the substrate of permanent disability. 1 Myelin repair occurs to a variable extent, and promoting remyelination represents an area of great therapeutic interest. 2,3 Unfortunately, conventional MRI is unable to distinguish remyelination from myelin loss and axonal damage. This lack of sensitivity and specificity highlights the need for more specific imaging approaches.

Characterization of multiple sclerosis lesions with distinct clinical correlates through quantitative diffusion MRI

“…3 ). B-type lesions are thought to be associated with more severe demyelination and axonal damage ( Yu et al, 2019 ). Therefore, the classification proposed would provide information regarding inflammatory destruction or the ability for neurorepair in a given patient, potentially representing a useful biomarker for phase II clinical trials.…”

Towards in vivo g-ratio mapping using MRI: Unifying myelin and diffusion imaging

“…( Assaf et al, 2008 ; Alexander et al, 2010 ; Huang et al, 2016 )). This has been used by Duval et al for g-ratio mapping in the spinal cord ( Duval et al, 2017 ) and by Yu et al ( Yu et al, 2019 ) in patients with multiple sclerosis. However, such a protocol requires more extensive (and time-consuming) data acquisition.…”

“…Despite the challenges associated with accurate measurement and calibration of the MVF and AVF, many studies have exploited the potential of in vivo g-ratio weighted imaging for a variety of different applications (see Table 1 for full details). These have ranged from g-ratio mapping in infants ( Melbourne et al, 2016 ) and children ( Dean et al, 2016 ) to healthy adults ( Mohammadi et al, 2015 ; Mancini et al, 2018 ; Berman et al, 2019 ; Drakesmith et al, 2019a ), during healthy aging ( Cercignani et al, 2017 ; Berman et al, 2018 ) and as a result of pathological change ( Hagiwara et al, 2017 ; Hori et al, 2018 ; Kamagata et al, 2019 ; Yu et al, 2019 ).…”

“…LA.3, LA.4, LA.5, LM.1, LM.6, LM.8 Kamagata et al, 2019 DWI2 (NODDI) MPM with multi-echo SPGR (MTsat) 14C;14P The brain network topology was assessed using g-ratio as a marker for the connectivity strength, comparison between healthy controls and patients with multiple sclerosis. LA.3, LA.4, LM.1, LM.2, LM.9 Yu et al, 2019 DWI17.8 (3CM) SPGR (MTV) 19C; 30P g-ratio and axon diameter mapping in patients with multiple sclerosis and healthy controls. LA.6, LM.4, LM.9 Berman et al, 2019 DWI1 (DTI) SPGR (MTV) 37C Estimating conduction velocities in fibre pathways using g-ratio and tractography in 37 subjects (20 younger and 17 older humans).…”

Age‐related estimates of aggregate g‐ratio of white matter structures assessed using quantitative magnetic resonance neuroimaging

“…Electron microscopy is the gold standard technique to measure the g-ratio; this limits investigations to ex vivo measures. To address this, new clinical magnetic resonance imaging (MRI)-based methods have been introduced for whole-brain in vivo mapping of the g-ratio and have shown that the g-ratio could represent a sensitive and specific biomarker of neurodevelopment and neurodegeneration (Berman, West, Does, Yeatman, & Mezer, 2018;Campbell et al, 2017;Cercignani et al, 2017;Colgan et al, 2016;Dean et al, 2016;Mustafi et al, 2019;Parker et al, 2018;Yu et al, 2019). The original approach was introduced by Stikov and colleagues and is based on measuring the axonal and myelin volume fractions in a voxel, instead of for individual fibers, and assuming a uniform g-ratio for all fibers (Stikov et al, 2011); this has come to be known as the "aggregate g-ratio" (Stikov et al, 2015), the calculation of which requires an estimation of myelin volume fraction (MVF) and axonal volume fraction (AVF).…”