Age-dependent associations between plasma neurofilament light chain protein and symptom severity in treatment-resistant Schizophrenia: a moderation analysis

Background and objectives Treatment-resistant schizophrenia (TRS) is a severe subtype of schizophrenia. While negative and disorganised symptoms have been associated with cognitive dysfunction, the underlying neurobiological mechanisms remain unclear. Plasma neurofilament light chain protein (NfL), a biomarker of neuroaxonal damage, has shown promising associations in TRS. This study investigates the interrelationships between symptomatology, cognition, and NfL in TRS. Methods Eighty-two clozapine-treated TRS participants were assessed using the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Cognitive functions were evaluated using the Cambridge Neuropsychological Test Automated Battery and Wisconsin Card Sorting Test. Plasma NfL concentrations were measured using a Single Molecule Array assay. General linear models and moderation analyses were employed. Results In younger participants, NfL levels negatively correlated with excited factor (r = -0.26, 95% confidence interval [CI] = [-0.47, -0.04]), whereas in older participants, NfL levels positively correlated with blunted affect (r [95% CI] = 0.27 [0.05, 0.47]). Disorganised (unstandardised beta [B] = -0.07, 95% CI = [-0.11, -0.02]) and positive (B [95% CI] = -0.04 [-0.07, -0.005]) factors were significant predictors of executive dysfunction, independent of NfL levels. Importantly, NfL moderated the relationship between positive formal thought disorder and executive dysfunction (B [95% CI = 0.02 [0.001, 0.05]). Conclusions These findings suggest distinct age-related neurobiological trajectories in TRS. While symptom-cognition relationships were relatively independent of NfL, its moderation effects point to potential compensatory or maladaptive responses that vary by illness stages.