To investigate the association of serum Neurofilament light (sNfL) with compartmental brain volumes in patients with multiple sclerosis (pwMS).

Gray matter (GM) pathology is associated with physical and cognitive impairment in pwMS. Increased sNfL, indicating neuroaxonal damage, has been described in MS and was related to the development of global brain atrophy. However, sNfL’s relation to MRI-based measures of distinct brain volumes, in particular the GM, is still poorly investigated.

We included 109 pwMS (38.1±11.7 years, 63.3% female, including 16 patients with clinically isolated syndromes (CIS), 72 relapsing-remitting MS (RRMS) and 21 progressive MS (PMS)) and 17 non-inflammatory neurological controls (NC). sNfL levels were measured by an ultrasensitive Single Molecule Array (Simoa®). In MS, we assessed whole and compartmental normalized and lesion-filled brain volumes and T2 lesion loads based on 3T MRI data, using T2-FLAIR and T1-weighted structural scans.

In the entire cohort, sNfL levels correlated with age (r=0.329, p<0.001). sNfL was elevated in RRMS (p=0.019) and PMS (p<0.010) vs. NC, as well as in PMS vs. CIS (p=0.035). Similarly, we found decreased brain volumes in PMS vs. CIS and RRMS (both p≤0.001) and increased white matter lesion volume (both p<0.05). In deep GM, basal ganglia and thalamus volumes were decreased similarly (all p<0.05). Only in patients with PMS sNfL correlated negatively with whole brain volume after correcting for age (r=–0.571, p=0.008). This was mainly driven by the correlation with volumes of the total GM (r=–0.615, p=0.004), cortical GM (r=–0.664, p=0.001) and the basal ganglia (r=–0.571, p=0.011).

Although sNfL is already increased in earlier phases of MS, our data indicate that its relation to brain tissue damage, in particular GM pathology, may become apparent only in more advanced, progressive forms of the disease. Further analysis of longitudinal MRI and clinical data is currently ongoing to confirm and extend our results.