Temporal Dynamics of Plasma Neurofilament Light in Blood Donors With Preclinical Multiple Sclerosis

Abstract

Background and objectives: Multiple sclerosis (MS) is a CNS disease, characterized by demyelination, inflammation, and neurodegeneration. Recent advances in technology allow measurement of the axonal damage marker neurofilament light chain in peripheral blood. Two studies have shown that patients with MS have elevated neurofilament light levels before their first symptom, but longitudinal studies are lacking. We aimed to investigate the intraindividual neurofilament light dynamics during the presymptomatic phase of MS.

Methods: The Danish Blood Donor Study (DBDS) has stored plasma samples from blood donors for more than 10 years. We identified DBDS participants, who had subsequently been diagnosed with MS, and included all samples donated before their first demyelinating symptom (median 5.00 samples per case). As controls, we included 2 healthy donors per case. Plasma levels of neurofilament light were measured and compared with quality-of-life data. We used a Bayesian approach to derive estimates for the percentage of cases with presymptomatic increased neurofilament light levels.

Results: We observed that 12 (17%, 95% CI 9%-28%) of 69 presymptomatic MS donors had intermittently increased neurofilament light levels preclinically. Increased levels were present up to 9 years before clinical onset, also in primary progressive MS. Healthy donors and presymptomatic MS donors with and without increased neurofilament light levels reported equally high physical and mental well-being. Model-based estimates suggested that 55% of cases (95% credible interval [28%-87%]) had experienced increased presymptomatic neurofilament light levels.

Discussion: Patients with MS periodically sustain axonal injury up to 9 years before clinical onset, even in primary progressive disease. This most likely represents asymptomatic disease activity. Some or even all patients are affected by this intermittent axonal injury, prompting the need for further studies of the presymptomatic phase in relation to prognosis and as a therapeutic window of opportunity.

Figure 1. Study Design

*One sample matched to the age of the cases at the time of the most recent donation, the other 2 approximately 3 months and 1 year apart, respectively. DBDS = The Danish Blood Donor Study; DMSR = The Danish Multiple Sclerosis Registry; MS = Multiple sclerosis; NPR = The Danish National Patient Registry; NPR No DD = Selection of individuals in NPR without demyelinating diagnoses; SFQ12 = The Short Form-12 Questionnaire; The MS Registry = The Danish Multiple Sclerosis Registry.

Figure 2. Neurofilament Light Levels Dynamics in Consecutive Healthy Donor samples

Neurofilament light ratio in relation to No. of months since earliest donation in healthy donors. The ratio of actual neurofilament light values to the predicted 97.5% upper reference limit is displayed on the y-axis, and the upper reference limit is denoted by the dashed line. Red triangle: increased neurofilament light level. Blue circle: neurofilament light level within the normal range.

Figure 3. Neurofilament Light Levels in Preclinical Multiple Sclerosis Donor Samples

(A) Neurofilament light ratio in relation to number of years to the first demyelinating symptom in all samples from presymptomatic MS donors. The ratio of actual neurofilament light values to the predicted 97.5% upper reference limit is displayed on the y-axis. The upper reference limit is denoted by the blue dashed line. Samples with levels more than 10% above the upper reference limit are highlighted in red; (B) neurofilament light ratio in relation to years to the first demyelinating symptom in presymptomatic MS donors with increased neurofilament light levels. Red: increased neurofilament light level. Blue: neurofilament light level within the normal range.