Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis
Neurology | June 4, 2021
Maggi P, Kuhle J, Schädelin S, van der Meer F, Weigel M, Galbusera R, Mathias A, Lu PJ, Rahmanzadeh R, Benkert P, La Rosa F, Cuadra MB, Sati P, Théaudin M, Pot C, van Pesch V, Leppert D, Stadelmann C, Kappos L, Du Pasquier R, Reich DS, Absinta M and Granziera C
Objective To assess whether chronic white matter inflammation in multiple sclerosis (MS) patients – as detected in-vivo by paramagnetic rim MRI lesions (PRL) – is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuro-axonal damage.
Methods In 118 MS patients with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathological evaluation was performed in 25 MS lesions from 20 additional autopsy MS patients.
Results In univariable analyses, participants with ≥2 PRL (“PRL ≥2”, n=43) compared to those with ≤1 PRL (“PRL 0–1,” n=75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p<0.001) and higher MS disease severity scale (MSSS median, 4.3 and 2.4; p=0.003). In multivariable analyses, sNfL percentile levels were higher in PRL ≥2 cases (βadd: 16.3; 95% CI: 4.6–28.0; p<0.01), whereas disease-modifying treatment (DMT), EDSS, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRL (n=30; βadd: 30.4; 95% CI, 15.6–45.2; p<0.01). Subsequent multivariable analysis revealed that PRL ≥2 cases had also 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).
Interpretation Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in non-acute MS patients, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.