ABSTRACT Narcolepsy is a chronic sleep-wake disorder usually diagnosed by polysomnography, multiple sleep latency testing, and laboratory assessment. One such laboratory approach involves measuring hypocretin-1 in cerebrospinal fluid. Deficiency of this neuropeptide is characteristic of narcolepsy. However, reliance on its measurement has limitations related to invasiveness, restricted availability, and variable sensitivity across disease phenotypes. Reliance on a single biomarker for the diagnosis of any disease has several drawbacks, including the limited availability of that biomarker and variability in disease outcomes. Emerging biomarkers beyond hypocretin-1 span genetic, immune, molecular, neurophysiological, and neuroimaging domains. Genetic associations, particularly HLA-related risk and T-cell receptor variants, support an autoimmune contribution to disease pathogenesis. Autoantibodies and molecular biomarkers, on the other hand, are still in their early stages due to inconsistent replication and poor validation. Neurophysiological and imaging data provide essential mechanistic insights, but their diagnostic specificity is limited. The integration of numerous biomarkers may increase diagnostic accuracy and disease subtype identification. Heterogeneity in study design, assay methodology, and cohort characteristics continues to impede clinical translation. Future research should target longitudinal validation, assay standardization, and collaborative registries to help establish clinically relevant biomarker-driven diagnostic frameworks.
Reddy et al. (2026) studied this question.