Activated Microglia Contribute to Neurofilament Light Levels in Multiple Sclerosis

Article

The strongest associations observed in the study were between microglial activation at the rim of chronic T1 hyperintense lesion and in the perilesional normal appearing white matter and serum neurofilament light.

Maija Saraste, PhD, Department of Neurology, University of Turku

Maija Saraste, PhD

A recently published study of patients with multiple sclerosis (MS) identified an association between increased brain innate immune cell activation and serum neurofilament light (sNfL) in this patient population. Above all, the findings emphasize the link between neuronal damage and microglial activation in MS, as well as highlight the role of rim-active lesions in promoting neuronal damage.

Led by Maija Saraste, PhD, Department of Neurology, University of Turku, the trial aimed to evaluate the association between serum NfL and translocator protein (TSPO)-PET-measurable microglial activation in patients with MS. Comprised of 44 individuals with MS and 24 age- and sex-matched controls, distribution volume ratio (DVR) was used to evaluate specific TSPO-binding radioligand [11C]PK11195-binding, while single molecule assays were used to measure sNfL levels.

The median time difference between imaging and sampling was 12 days. At baseline, the median sNfL level of patients with MS was 19.0 (IQR, 9.1-24.3) pg/mL. In comparison with HC, [11C]PK11195-binding in the whole brain (1.20 vs 1.18; P = .015) was increased in the MS cohort, as well as higher level of radioligand binding in the NAWM compared with the white matter of HCs (1.20 vs 1.18; P = .026). Brain DVR values correlated with DVR values in the normal appearing white matter (NAWM)(r = 0.75; P <.001), rim lesion, and perilesional NAWM.

In the analysis, higher levels of sNfL in individuals with high brain (DVR) correlated with increased [11C]PK11195-DVR in NAWM (r = 0.48; P = .036) and perilesional NAWM (r = 0.58, P = 0.009), at the lesion rim (r = 0.59, P = 0.008) and in T1 hypointensive lesions (r = 0.49, P = 0.034). Of note, all correlations, except T1 DVR, were sustained in partial age-correlated correction analyses.

Using an FDR-corrected univariate linear regression model, increased levels of sNfL were associated with higher DVR in the lesion rim (estimate, 0.49; 95% CI, 0.15-0.83; P [FDR] = 0.04) and perilesional NAWM (estimate, 0.48; 95% CI, 0.14-0.83; P [FDR] = 0.04). Additionally, these observations were observed with a higher number of rim-active and overall-active lesions (estimate, 0.46 [95% CI, 0.10-0.81] P [FDR] = 0.4; estimate, 0.47 [95% CI, 0.12-0.82; P [FDR] = 0.04) and with larger volume of rim-active lesions (estimate, 0.50; 95% CI, 0.17-0.84; P [FDR] = 0.04). The volume of rim-active lesions accounted for 37 %, and [11C]PK11195-DVR at the lesion rim for 35% of the variance in sNfL. In addition, increased sNfL associated with larger T1 lesion load.

"The strongest associations were observed between microglial activation at the rim of chronic T1 hypointense lesions and in the perilesional NAWM and sNfL. NfL is now considered the most promising biomarker candidate for nervous system damage-related pathology in MS,” Saraste et al wrote. "Most pronounced changes in NfL levels are seen in association with focal inflammatory lesion-induced axonal damage."

They added, "More modest, but significant alterations are seen in the context of smoldering disease and MS disease progression.” Our study cohort had no concurrent gadolinium-enhancing lesions or recent relapses. Hence, the increases in sNfL concentration observed in this cohort are most likely associated with the smoldering disease process."

When looking at the specific association between sNfL and different lesion subtypes, results showed that increased levels correlated with a larger proportion of lesions containing activated microglia and a smaller proportion of inactive lesions (ρ = 0.64, p = 0.003 and ρ = –0.64, p = 0.003, respectively). Investigators also observed correlations between sNfL and both the number and volume of lesions containing activated microglia (ρ = 0.6, p = 0.006 and ρ = 0.57, p = 0.012, respectively), whereas there was no correlation between sNfL and the number or volume of inactive lesions (ρ = 0.12, p = 0.63 and ρ = −0.028, p = 0.91).

REFERENCE
1. Saraste M, Matilainen M, Vuorimaa A, et al. Association of serum neurofilament light with microglial activation in multiple sclerosis. J Neurol Neurosurg Psychiatry. Published oline May 2, 2023. doi:10.1136/jnnp-2023-331051
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