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Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis
Pietro Maggi1, Jens Kuhle1, Sabine Schädelin1
1From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.
Objective:
To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.
Methods:
In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.
Results:
In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (βadd, 16.3; 95% confidence interval [CI], 4.6-28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; βadd, 30.4; 95% CI, 15.6-45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (βadd, 1.1; 95% CI, 0.3-1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively).
Conclusion:
Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
Insights
Paramagnetic rim lesions (PRLs) indicating chronic inflammation in multiple sclerosis (MS) are linked to higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage. This suggests PRLs contribute to MS severity and neurodegeneration.
Area of Science:
- Neuroimmunology
- Neuroimaging
- Neuropathology
Background:
- Multiple sclerosis (MS) is characterized by chronic white matter inflammation.
- Paramagnetic rim lesions (PRLs) are a specific MRI marker of chronic active white matter inflammation in MS.
- Serum neurofilament light chain (sNfL) is a sensitive biomarker of neuroaxonal damage.
Purpose of the Study:
- To investigate the association between in vivo detected chronic white matter inflammation (PRLs) and serum neurofilament light chain (sNfL) levels in patients with MS.
- To determine if PRLs correlate with disease severity markers in non-acute MS.
Main Methods:
- 118 patients with MS underwent 3D-submillimeter phase MRI and sNfL level analysis, excluding those with gadolinium-enhancing lesions or recent relapses.
- Histopathological evaluation of 25 MS lesions from 20 autopsy cases was performed.
- Statistical analyses included univariable and multivariable models to assess associations between PRLs, sNfL, and clinical/radiological parameters.
Main Results:
- Patients with ≥2 PRLs exhibited significantly higher age-adjusted sNfL percentiles and Multiple Sclerosis Severity Scale (MSSS) scores compared to those with ≤1 PRL.
- Multivariable analyses confirmed that higher PRL counts (≥2 and ≥4) were independently associated with increased sNfL levels and higher MSSS scores.
- Histopathology revealed greater acute axonal damage at the edge versus the center of both chronic active and smoldering MS lesions.
Conclusions:
- Chronic white matter inflammation, as indicated by PRLs, is associated with elevated sNfL levels and increased disease severity in non-acute MS.
- PRLs represent a clinically relevant marker of inflammation-driven neurodegeneration in MS.
- These findings highlight the role of chronic inflammation in ongoing axonal damage in MS.
