A New AdvancedMRIBiomarker for Remyelinated Lesions in Multiple Sclerosis

Abstract

Objectives Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS. Methods We performed 3 studies: (1) a cross‐sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso‐intense, hypo‐intense, hyperintense, lesions with hypo‐intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology‐QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions. Results At baseline, hypo‐ and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2‐year follow‐up, hypo‐/iso‐intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo‐/iso‐intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%). Interpretation These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486–502

Neurite Orientation Dispersion and Density Imaging in Multiple Sclerosis: A Systematic Review

“…Among the 24 studies, 18 studies had high quality (7–9 NOS scores), six studies had intermediate quality (4–6 NOS scores), and none were low‐quality studies (Table S1). Participants were age‐matched in four studies, 24,28,37,39 sex‐matched in one study 36 . Meanwhile, 15 studies controlled for both age and gender 16,18,23,26,27,29–31,33–35,40–43 …”

“…As expected, these studies applied a different range of analysis on the NODDI metrics. These approaches included grey matter-based spatial statistics (GBSS), 23 region-of-interest (ROI), 16,18,23,25,26,28,[30][31][32][33]35,36,[38][39][40]43,44 cortical surface mapping, 24,30 whole-brain analysis, 27 tract-based spatial statistics (TBSS), 28,29,31,33,34,37 and voxel-based analysis (VBA). 32,41,42 A more homogeneity was reported for the toolboxes used for this analysis.…”

Positron Emission Tomography with [18F]‐DPA‐714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression

“…In a recent classification of individual lesions based on quantitative susceptibility mapping (QSM) signal, 52% were characterized by diffuse hyperintensity, whereas 13% showed a perilesional rim. 52 When combined with histology, hyperintense QSM lesions were mostly inactive demyelinated lesions, but 28% still had an active neuroinflammatory component. 40 Combining TSPO-PET and multimodal MRI, it would therefore be intriguing to explore whether a subset of these hyperintense QSM lesions indeed corresponds to PET-defined CAL.…”

“…Whether quantitative MRI sequences may succeed in identifying these lesion subtypes remains an open question. In a recent classification of individual lesions based on quantitative susceptibility mapping (QSM) signal, 52% were characterized by diffuse hyperintensity, whereas 13% showed a perilesional rim 52 . When combined with histology, hyperintense QSM lesions were mostly inactive demyelinated lesions, but 28% still had an active neuroinflammatory component 40 .…”

From pathology to MRI and back: Clinically relevant biomarkers of multiple sclerosis lesions

“…In the context of MS, the ability to identify chronic inflammation (i.e., the paramagnetic rim) and estimate myelin content with the same image sequence makes the QSM-source separation approach an attractive potential myelin biomarker ( Shin et al, 2021 , Dimov et al, 2022 , Emmerich et al, 2021 ). Qualitative assessment of susceptibility changes on QSM-based imaging was recently suggested as a straightforward approach to distinguish remyelinated from demyelinated MS lesions ( Rahmanzadeh et al, 2022 ). Overall, advances in QSM analysis reinforce its potential as a tool for interrogating microstructural damage, and in particular myelin content in MS, though further improvements in image quality may be required.…”