A New Advanced MRI Biomarker 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.

Figure 1

Design of the in vivo and postmortem parts of the study. MS = multiple sclerosis; PMS = progressive multiple sclerosis; QSM = quantitative susceptibility mapping; RRMS = relapsing‐remitting multiple sclerosis. [Color figure can be viewed at www.annalsofneurology.org]

Figure 2

QSM lesion types and their distribution in patients with MS. (A–E) Exemplary QSM lesion types (A = iso‐intense, B = hypo‐intense, C = hyperintense, D = hypo‐rim, E = PRL). Table in Figure 2: distribution of the different QSM lesion types (%) in patients with RRMS and PMS. PMS = progressive multiple sclerosis; QSM = quantitative susceptibility mapping; RRMS = relapsing‐remitting multiple sclerosis. [Color figure can be viewed at www.annalsofneurology.org]

Figure 3

Lesions excluded from the QSM classification. (A) Confluent lesions; (B) lesions crossed by one/more vessels; (C) lesions in artifacts area. Lesions are magnified in a rectangle on the bottom right and indicated with a red arrow. QSM = quantitative susceptibility mapping. [Color figure can be viewed at www.annalsofneurology.org]

Figure 4

Quantitative susceptibility, MWF, and NDI in QSM lesion types. (A) Average susceptibility in WMLs, NAWM, and WM‐HCs. (B) Lesion‐wise relative susceptibility of WMLs compared to PPWM. (C) Comparison of mean relative susceptibility values among QSM lesion types. (D–F) Comparison of susceptibility, MWF, and NDI values among QSM lesion types. (G–I) GMM clustering of WMLs using mean lesion MWF, NDI, and susceptibility. *p < 0.05; **p < 0.001; ***p < 0.0001. GMM = Gaussian Mixture Model; MWF = myelin water fraction; NAWM = normal‐appearing white matter; NDI = neurite density index; ppb = parts per billion; PPWM = peri‐plaque white matter; QSM = quantitative susceptibility mapping; WM = white matter; WM‐HCs = white matter healthy controls; WML = white matter lesions. [Color figure can be viewed at www.annalsofneurology.org]

Figure 5

Lesion size comparison across QSM lesion types. *p < 0.05; **p < 0.001; ***p < 0.0001. Iso = iso‐intense; ns = not significant; QSM = quantitative susceptibility mapping.

Figure 6

MWF changes in iso‐ and hypo‐intense lesions at follow‐up (TP2) compared to baseline (TP1). (A) MWF increases in the majority of lesions that are hyperintense at TP1 and iso‐intense at TP2. (B) MWF is stable in lesions that are iso‐intense at TP1 and hypo‐intense at TP2. MWF = myelin water fraction; TP1 = timepoint1; TP2 = timepoint2. [Color figure can be viewed at www.annalsofneurology.org]

Figure 7

Histopathology and postmortem QSM of remyelinated lesions. A1–D1: MBP (brown)‐MHC II (blue) double IHC in exemplary fully (B‐1) or partially (A1, C1, D1) remyelinated lesions. A2–D2: DAB‐enhanced TBB (brown) ‐ MHC II (blue) staining showing macrophages/activated microglia containing (D1; red arrow) or lacking iron (A1–C1; yellow arrow); A3–D3: BCAS1 IHC showing non‐compact myelin and, in D‐3, newly formed myelinating oligodendrocytes; A4–D4: postmortem QSM showing fully (B‐1) or partially (A1, C1, D1) remyelinated lesions. [Color figure can be viewed at www.annalsofneurology.org]

Figure 8

Histopathology and postmortem QSM of chronic inactive and chronic active lesions. E1–F1: MBP ‐ MHC II staining of chronic inactive lesions. E2–F2: TBB (brown) ‐ MHC II (blue) staining of macrophages/activated microglia containing (E2; red arrow) or lacking iron (F2; yellow arrow). E‐3, F‐3: Postmortem QSM showing a corresponding hyperintensity for chronic inactive lesions. G1–H1: MBP ‐ MHC II IHC of chronic active lesions showing extensive demyelination. G2–H2: TBB (brown) ‐ MHC II (blue) staining showing iron‐laden macrophages/activated microglia at the lesion edge (red arrow). G‐3, H‐3: Postmortem QSM revealing a hyperintense paramagnetic rim in chronic active lesions. BCAS1 = breast carcinoma‐amplified sequence 1; IHC = immunohistochemistry; MBP = myelin basic protein; MHC II = major histocompatibility complex II; QSM = quantitative susceptibility mapping; TBB = DAB‐enhancedTurnbull's blue. [Color figure can be viewed at www.annalsofneurology.org]