基于定量磁化率源分离的多发性硬化病灶微结构表型分型及其临床相关性

Abstract

Background: Quantitative susceptibility mapping (QSM) exhibits phase cancellation between paramagnetic (e.g. iron) and diamagnetic (e.g. myelin/protein) sources, obscuring microstructural lesion heterogeneity in multiple sclerosis (MS). We evaluated whether biophysical χ-separation identifies clinically meaningful lesion phenotypes and whether reduced echo sampling preserves microstructural sensitivity. Methods: In this cross-sectional study of 183 people with multiple sclerosis (PwMS), we analyzed 3327 quality-controlled white matter lesions using 3T MRI with a five-echo gradient-recalled echo sequence (GRE5) and a subsampled two-echo dataset (GRE2). A hybrid framework combining unsupervised clustering on whole-lesion paramagnetic (χpara) and diamagnetic (χdia) features with rule-based compartmental edge-core gradient assignment resolved MS lesion phenotypes. Intralesional microstructural properties were evaluated using linear mixed-effects models. Multivariable linear regressions assessed associations with physical disability (Expanded Disability Status Scale, EDSS; n = 158), cognitive processing speed (Symbol Digit Modalities Test, SDMT; n = 79), and disease duration (DD; n = 161), with sensitivity models adjusting for total lesion volume, count, or DD. Results: The framework identified four reproducible lesion phenotypes (Adjusted Rand Index = 0.924): Type 1 (22.7%; preserved χdia), Type 2 (32.9%; high χpara without positive edge-core gradient), Type 3 (35.8%; attenuated χdia), and Type 4 (8.6%; high χpara with a positive edge-core paramagnetic gradient). Higher EDSS was selectively associated with more negative signed χdia within Type 4 lesions (whole: β = -0.37, q = 0.020; core: β = -0.37, q = 0.006; edge: β = -0.34, q = 0.030) and Type 2 edge (β = -0.33, q = 0.044). Type 4 core associations remained robust across sensitivity models adjusting for total lesion volume (β = -0.35, q = 0.004), total lesion count (β = -0.37, q = 0.008), and DD (β = -0.32, q = 0.033). Abbreviated GRE2 attenuated Type 4 compartmental associations to non-significance (all q greater than 0.05; core: β = -0.20, q = 0.215). Conclusions: Quantitative χ-separation identified four internally stable susceptibility-defined MS lesion phenotypes, revealing disability-associated tissue heterogeneity beyond total lesion burden. Higher EDSS was associated with more negative diamagnetic measures within Type 4 cores after adjustment for lesion burden, pointing toward complex intralesional non-myelin tissue remodeling or reactive astrogliosis. Two-echo subsampling may influence compartment-specific clinical associations. By uncoupling susceptibility sources, χ-separation provides a quantitative framework for characterizing disability-associated lesion heterogeneity.

Competing Interest Statement

EMH, MA, H-GS, FS, EGG, and EdA have nothing to disclose. NMO had a predoctoral Rio Hortega fellowship from the Instituto de Salud Carlos III (CM21/00018), has been awarded an ECTRIMS-MAGNIMS Research Fellowship 2024, and also received speaking honoraria and travel expenses from Merck and Roche. JS-G receives research support from the Instituto de Salud Carlos III, co-funded by the European Union (PI19/0950, PI22/0750, PI25/01664), has participated in events funded by Merck, Roche, BMS, Sanofi, Novartis, Neuraxpharm, and Cobel-Darou in the last 36 months, and is a member of the ECTRIMS Executive Board and Editor-in-Chief of the Multiple Sclerosis Journal. AR serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, and Biogen, has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers, and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigacion en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain. DP receives research support from the Instituto de Salud Carlos III, co-funded by the European Union (PI18/00823, PI22/01709).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The study protocol was approved by the local institutional review board (Vall d'Hebron Hospital Universitari), and all participants provided written informed consent in accordance with the Declaration of Helsinki.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors. The methodological processing pipeline (xseparation-bids) will be made publicly available at https://github.com/eloydelas/xseparation-bids upon peer-reviewed publication.