Plasma neurofilament light levels show elevation prior to diagnosis of sporadic motor neuron disease in the UK Biobank cohort

ObjectiveMotor neuron disease (MND) is a debilitating neurodegenerative disease with profound unmet need. In pre-symptomatic mutation carriers, elevations in neurofilament light (NfL) precede symptom onset, however, the presence and timing of elevation is much more difficult to study in sporadic cases. MethodsUsing the UK Biobank cohort, we tested whether plasma NfL predicted risk of diagnosis of sporadic MND using survival analysis. ResultsWe identified 241 MND patients with pre-diagnosis NfL data, of which 203 (84%) lacked predicted loss of function or deleterious missense variants in established ALS genes. A total of 42,752 controls without MND were obtained from a random sample of UK Biobank participants. At two years pre-diagnosis, we found that NfL levels in patients exceeded the 95th percentile of controls and that patients could be discriminated from controls at high accuracy (AUC = 0.95 (95% CI 0.89-1.01)). In participants with hospital record follow-up after study enrollment, a 2-fold increase in NfL levels was associated with a 3.4 fold risk of receiving an MND diagnosis per year (95% CI 2.9-3.9, P = 4 x 10-64)). DiscussionOur findings show that NfL can identify sporadic MND as early as 2 years prior to diagnosis.