A Comparison of Magnetic Resonance Imaging Methods to Assess Multiple Sclerosis Lesions: Implications for Patient Characterization and Clinical Trial Design

Magnetic resonance imaging (MRI) is a sensitive imaging modality for identifying inflammatory and/or demyelinating lesions, which is critical for a clinical diagnosis of MS and evaluating drug responses. There are many unique means of probing brain tissue status, including conventional T1 and T2 weighted imaging (T1WI, T2WI), T2 fluid attenuated inversion recovery (FLAIR), magnetization transfer, myelin water fraction, diffusion tensor imaging (DTI), phase-sensitive inversion recovery and susceptibility weighted imaging (SWI), but no study has combined all of these modalities into a single well-controlled investigation. The goals of this study were to: compare different MRI measures for lesion visualization and quantification; evaluate the repeatability of various imaging methods in healthy controls; compare quantitative susceptibility mapping (QSM) with myelin water fraction; measure short-term longitudinal changes in the white matter of MS patients and map out the tissue properties of the white matter hyperintensities using STAGE (strategically acquired gradient echo imaging). Additionally, the outcomes of this study were anticipated to aid in the choice of an efficient imaging protocol reducing redundancy of information and alleviating patient burden. Of all the sequences used, T2 FLAIR and T2WI showed the most lesions. To differentiate the putative demyelinating lesions from inflammatory lesions, the fusion of SWI and T2 FLAIR was used. Our study suggests that a practical and efficient imaging protocol combining T2 FLAIR, T1WI and STAGE (with SWI and QSM) can be used to rapidly image MS patients to both find lesions and study the demyelinating and inflammatory characteristics of the lesions.

Myelin Water Fraction in Relation To Fractional Anisotropy and Reading in 10-Year-Old Children

Diffusion-weighted imaging studies have repeatedly shown that white matter correlates with reading throughout development. However, the neurobiological interpretation of this relationship is constrained by the limited microstructural specificity of diffusion imaging. A critical component of white matter microstructure is myelin, which can be investigated noninvasively using MRI. Here, diffusion-weighted as well as myelin water imaging were applied to examine the links of myelin water fraction (MWF) with fractional anisotropy (FA; a common diffusion index) and reading ability in 10-year-old children (n = 69). The results replicate previous reports on a positive relationship between FA and MWF, which is significant in dorsal but not ventral tracts. Moreover, our findings revealed a negative correlation between word reading and MWF in left reading-related white matter tracts. Altogether, this study contributes important insights into the role of myelin-related processes in the relationship between reading and white matter structure.

Quantitative susceptibility mapping captures chronic multiple sclerosis rim lesions with greater myelin damage: Comparison with high-pass filtered phase MRI

Background Chronic active MS lesions with paramagnetic rim can be identified by high-pass filtered (HPF) phase imaging or quantitative susceptibility mapping (QSM). Purpose The objective was to compare the ability of HPF and QSM to identify MS lesions with greater myelin damage and to distinguish MS patients with increased clinical disability. Material and Methods Eighty-six patients were scanned with gradient echo sequence for lesion rim detection and FAST-T2 sequence for myelin water fraction (MWF) mapping. Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images (HPF rim+/QSM rim+, HPF rim+/QSM rim-, HPF rim-/QSM rim+, HPF rim-/QSM rim-). A lesion-level linear mixed-effects model with MWF as outcome was used to compare myelin damage among the lesion groups. A multivariate patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the number of rim lesions (zero vs. one or more). Results Of 2229 lesions, 96 (8.8%) were HPF rim+/QSM rim+, 211 (9.5%) were HPF rim+/QSM rim-, and the remainder had no rim. Adjusting for other factors, HPF rim+/QSM rim+ lesions had on average significantly lower MWF than both HPF rim+/QSM rim- (p<0.001) and HPF rim-/QSM rim- (p<0.001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p=0.309). Having at least one QSM rim+ lesion was associated with an increase in EDSS compared to having no QSM rim+ lesions, holding all other factors constant (p=0.026). The relationship between having one or more HPF rim+ lesions vs. having no HPF rim+ lesions and EDSS was not statistically significant. Conclusion QSM identifies chronic MS lesions with paramagnetic rim that on average have greater myelin damage. QSM may be a valuable tool for studying the impact of rim lesions on clinical disability in MS.

Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy controls and normal-appearing MS tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P &lt; 0.0001) and peri-plaque white matter (P &lt; 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P &lt; 0.0001 and P &lt; 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P &lt; 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P &lt; 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P &lt; 0.01, beta=-10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patients cohort (P &lt; 0.01, beta=-3.60 and P &lt; 0.01, beta=0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior–posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7–85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers—genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.