Brain and cord myelin water imaging: a progressive multiple sclerosis biomarker

Abstract

ObjectivesConventional magnetic resonance imaging (MRI) is used to diagnose and monitor inflammatory disease in relapsing remitting (RR) multiple sclerosis (MS). In the less common primary progressive (PP) form of MS, in which focal inflammation is less evident, biomarkers are still needed to enable evaluation of novel therapies in clinical trials. Our objective was to characterize the association — across the brain and cervical spinal cord — between clinical disability measures in PPMS and two potential biomarkers (one for myelin, and one for atrophy, both resulting from the same imaging technique).MethodsMulti-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) MRI of the brain and cervical spinal cord were obtained for 15 PPMS patients and 11 matched controls. Data were analysed to estimate the signal related to myelin water (VFM), as well as volume measurements. MS disability was assessed using the Multiple Sclerosis Functional Composite score, which includes measures of cognitive processing (Paced Auditory Serial Addition Test), manual dexterity (9-Hole Peg Test) and ambulatory function (Timed 25-Foot Walk); and the Expanded Disability Status Scale.ResultsBrain and spinal cord volumes were different in PPMS compared to controls, particularly ventricular (+ 46%, p = 0.0006) and cervical spinal cord volume (− 16%, p = 0.0001). Brain and spinal cord myelin (VFM) were also reduced in PPMS (brain: − 11%, p = 0.01; spine: − 19%, p = 0.000004). Cognitive processing correlated with brain ventricular volume (p = 0.009). Manual dexterity correlated with brain ventricular volume (p = 0.007), and both brain and spinal cord VFM (p = 0.01 and 0.06, respectively). Ambulation correlated with spinal cord volume (p = 0.04) and spinal cord VFM (p = 0.04).InterpretationIn this study we demonstrated that mcDESPOT can be used to measure myelin and atrophy in the brain and spinal cord. Results correlate well with clinical disability scores in PPMS representing cognitive, fine motor and ambulatory disability.

A multiparametric analysis of white matter maturation during late childhood and adolescence

“…VF m provides increased specificity to myelin over DTI, and is sensitive to age‐related processes in myelin in our sample. VF m 's sensitivity to myelin has been validated histologically in healthy and cuprizone‐treated mice (Wood et al, ) and the shaking pup model (Hurley et al, ), along with in vivo studies of multiple sclerosis (Kolind et al, ; Kolind et al, ), and it shows good reproducibility within and across sites (Laule & Moore, ). Previous imaging studies using the same measure have shown rapid myelination during infancy (Deoni et al, ; Deoni et al, ), and histological studies have shown continued myelination into adolescence (Benes, ; Yakovlev & Lecours, ), but this is the first study to demonstrate VF m trends in late childhood and adolescence, and the first to show ongoing myelination in vivo.…”

“…VF m 's sensitivity to myelin has been validated histologically in healthy and cuprizone-treated mice (Wood et al, 2016) and the shaking pup model (Hurley et al, 2010), along with in vivo studies of multiple sclerosis (Kolind et al, 2012;Kolind et al, 2015), and it shows good reproducibility within and across sites (Laule & Moore, 2018). Previous imaging studies using the same measure have shown rapid myelination during infancy (Deoni et al, 2011;Deoni et al, 2012), and histological studies have shown continued myelination into adolescence (Benes, 1989;Yakovlev & Lecours, 1967) (Krogsrud et al, 2016), but further research is needed to investigate this possibility.…”

Advances in noninvasive myelin imaging

“…Caution should therefore be taken when comparing in‐vivo results with formalin fixed ex‐vivo histology (Schmierer et al, ). In another study, MWF and volume of the brain and spinal cord of primary progressive MS patients and healthy controls were obtained using mcDESPOT (Kolind et al, ). Changes in brain volume (suggested to indicate atrophy) were found to correlate with cognitive processing, evaluated using Paced Auditory Serial Addition Test and dexterity, evaluated using the 9‐Hole Peg Test (9‐HPT).…”

“…Changes in brain volume (suggested to indicate atrophy) were found to correlate with cognitive processing, evaluated using Paced Auditory Serial Addition Test and dexterity, evaluated using the 9‐Hole Peg Test (9‐HPT). MWF (indicating myelin) was found to correlate with 9‐HPT performance in the corpus callosum (Kolind et al, ). The MWF and f B however, have been found to only partially correlate, indicating that one or both measures may not specifically measure myelin but could also be affected by other factors such as axonal loss or inflammation (Tozer et al, ).…”

Rapid simultaneous high-resolution mapping of myelin water fraction and relaxation times in human brain using BMC-mcDESPOT

“…Finally, mcDESPOT makes use of conventional MR acquisition sequences, namely, fully balanced steady state free precession (bSSFP) and spoiled gradient recalled echo (SPGR), widely available on clinical MRI systems. Overall, then, mcDESPOT is particularly attractive for clinical investigations (26, 30, 45). …”