The European Academy of Neurology (EAN) annual congress included new research on neurofilament-light (NfL), an indicator of neuroaxonal damage and one of the more promising biomarkers in multiple sclerosis and other neurodegenerative conditions. Several recent publications have also presented interesting findings that suggest a role for NfL in MS diagnosis, prognosis and treatment selection.
At EAN, an Italian study examined NfL levels in CSF and serum for 90 patients (75 RRMS, 14 PMS, 1 RIS) over a median 32-month follow-up period (Zanoni et al. EAN 2020; abstract EPR1176). NfL levels were higher in patients with Gd+ lesions. NfL levels were modestly correlated with T2 lesion volume, but there was no correlation with clinical measures (relapses, disability worsening). An Austrian study compared NfL levels in 109 MS and matched non-inflammatory neurological controls (Buchmann et al. EAN 2020; abstract O2031). Serum NfL was correlated with total grey matter volume and lesion load in progressive MS, but not in RRMS or CIS.
A number of authors have reported that cortical GM damage occurs along an ‘outside-in’ gradient, which may be due to toxic factors released by B cells or other immune cells in meningeal follicle-like structures. A post-mortem study of SPMS patients reported that thalamic damage showed a similar pattern from the ependyma inward, with a gradient of microglial activation and neuronal loss (Marastoni et al. EAN 2020; abstract EPR2139). In patients with thalamic lesions, neuron density was decreased 42% at the sub-ependymal surface and 20% in the inner regions. NfL levels in CSF had a similar gradient, supporting the hypothesis that subcortical GM damage is due in part to intrathecal inflammation.
Three studies at EAN examined NfL changes with disease-modifying therapies. The effect of interferon-beta on NfL was examined using samples obtain in the REFLEX trial of CIS (Kuhle et al. EAN 2020; abstract EPR2132). At month 12, there was a significant reduction in serum NfL levels versus placebo with interferon-beta three times weekly but not with a two times weekly dosing. At month 24, fewer patients developed MS in the group with lower vs. higher baseline NfL levels (tiw 49.1% with lower sNfL vs. 75.2% with higher sNfL), indicating that higher baseline NfL is an indicator of a risk of earlier conversion to MS.
Two studies looked at the effect of ocrelizumab on NfL. In the OPERA (RMS) and ORATORIO (PPMS) trials, median baseline NfL levels were 10.6 pg/mL for RRMS patients and 10.8 pg/mL for PPMS patients (Bar-Or et al. EAN 2020; abstract EPR1150). At 96 weeks, median levels decreased to 6.7 pg/mL in RRMS patients and 8.8 pg/mL in PPMS patients treated with ocrelizumab. Results for the comparator groups (interferon-beta; placebo) in OPERA/ORATORIO were not available. The OBOE (Ocrelizumab Biomarker Outcome Evaluation) trial of RMS and PPMS reported a reduction in CSF NfL concentrations of 24% at 12 weeks and 47% at 24 weeks with ocrelizumab (Bar-Or et al. AAN 2020; abstract S24.002). A longer follow-up of the PPMS cohort found no decrease in NfL (CSF or serum) at 52 weeks; there was a trend to lower NfL concentrations in PPMS with versus without Gd+ lesions at baseline (Bar-Or et al. EAN 2020; abstract EPR1149).
Two groups have recently suggested that serum NfL can be used in MS diagnosis and treatment decision-making. The BartsMS group used NfL levels, along with clinical and MRI assessments, to guide treatment decisions in 203 MS patients (Smets et al. EAN 2020; abstract EPR3093). Elevated NfL levels had a greater influence on DMT decisions than clinical activity or MRI activity. For the progressive MS subset, 19.8% of DMT decisions were based only on NfL; in RRMS, 2.3% of treatment decisions were based on NfL in the absence of clinical or radiological disease activity. Patients with higher NfL levels were more likely to have their treatment switched. It should be noted, however, that 58% of patients in this sample did not have raised CSF NfL concentrations, nor was it apparent whether NfL-guided therapy improved outcomes.
A German longitudinal study obtained serum NfL values in 814 CIS/RRMS patients over a four-year follow-up period (Bittner et al. EBioMedicine 2020;56:102807; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380/pdf/main.pdf). Baseline NfL levels were 12.5 pg/mL in RRMS and 10.1 pg/mL in CIS (9.1 pg/mL in CIS patients according to McDonald 2017 criteria). Baseline NfL levels were higher in patients with >9 T2 lesions, Gd+ lesions or recent relapses. NfL was only weakly correlated with EDSS score or the presence of ring-enhancing lesions. Modelling to discriminate CIS from MS showed the predictive accuracy of OCB and/or Gd+ increased from 79% to 84% if serum NfL >31 pg/mL (90th percentile) was added. The authors proposed that NfL levels may be considered in future diagnostic criteria. Interestingly, treatment decisions in this sample reflected NfL levels. While clinicians were unaware of test results, NfL levels were lower in untreated patients (10.0 pg/mL) or those treated with a first-line DMT (10.5 pg/mL), and were highest in those receiving a higher-efficacy DMT (21.0 pg/mL). NfL levels were comparable (7.5-8.2 pg/mL) in all treatment groups after two years on therapy. As such, NfL appears to be predicted by the clinical gestalt based on disease activity. The authors noted, however, that it is unclear what underlying pathophysiologic process is reflected by NfL, and whether NfL provides a useful indication of the neurodegeneration underlying disease progression.