Temporal Patterning of Neurofilament Light as a Blood-Based Biomarker for Stroke: A Systematic Review and Meta-Analysis

Damage to axons is a core feature of ischemic stroke and cerebrovascular disease. The burden of axonal injury is correlated with the acute clinical deficits, the underlying burden of ischemic brain injury, the prognosis of recovery, and may be a meaningful therapeutic target for brain repair. Neurofilament light chain (NfL) has been identified as a blood-based biomarker that reflects neuroaxonal damage resulting from stroke. However, the utility of NfL as a blood-based biomarker in stroke is confounded by studies examining different temporal windows and patient populations. We conducted a systematic review and meta-analysis to verify the utility of blood NfL as a diagnostic, prognostic, and monitoring stroke biomarker. Nineteen studies reporting serum/plasma NfL values for a total of 4,237 distinct patients with stroke were identified. Using available summary data from the 10 studies that employed a common immunoassay platform, we utilized random effects linear mixed modeling and weighted averages to create a phasic model of serum/plasma NfL values in distinct time periods of acute stroke. Weighted averages show that blood NfL levels vary significantly across three distinct temporal epochs of acute (0–7 days), subacute (9–90 days), and chronic (>90 days) stroke with a steep peak in the early subacute period between 14 and 21 days after stroke. Blood NfL values can function as a diagnostic biomarker in distinguishing acute ischemic stroke from transient ischemic attack as well as amongst other cerebrovascular subtypes. Release of NfL into the bloodstream after stroke follows a distinct temporal dynamic that lags several weeks behind stroke onset and reliably associates with a stroke diagnosis despite some variability based on stroke subtype and severity. Identification of these temporal dynamics and the contribution of co- existent cerebrovascular disease states can improve the value of NfL as a stroke biomarker.