Plasma Glial Fibrillary Acidic Protein and Neurofilament Light are Elevated in Bipolar Disorder: Evidence for Neuroprogression and Astrocytic Activation

ABSTRACT Importance: Recent methodological developments allow us to measure small amounts of brain-specific proteins in the blood, including neurofilament light chain (NfL), a marker of axonal pathology, and glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. Given the evidence of potential astroglial pathology and neuronal dysfunction in bipolar disorder, these markers may provide further insight into its pathophysiology. Objective: We investigated plasma NfL and GFAP levels in people with bipolar depression and compared them with unaffected individuals. Design, Setting, and Participants: This cross-sectional study included 216 individuals, of which 120 participants had bipolar depression and 96 healthy controls. The blood samples were analysed between November 2023 and April 2024. Main outcomes and measures: We used bootstrapped general linear models (GLM) to compare plasma NfL and GFAP levels between people with bipolar depression and healthy controls, adjusted adjusting for age, sex, and weight. We examined associations between these biomarkers and clinical variables, including mood symptom severity, past psychiatric history, and functioning, adjusting for multiple comparisons. For additional sensitivity analyses, predictors were evaluated using Bayesian model averaging (BMA). Results: GFAP and NfL levels in plasma were elevated in people with bipolar depression (n = 120) compared to healthy controls (n = 96) after adjusting for age, sex and weight. The duration of illness was positively associated with NfL. The BMA analysis also identified duration of illness as a strong predictor of NfL (Posterior Inclusion Probability, PIP = 0.85). Age of onset was positively associated with GFAP. The BMA analysis similarly found age of onset to be a moderately strong predictor (PIP = 0.67). Conclusions and Relevance: This study found elevated levels of plasma NfL and GFAP in bipolar depression compared to unaffected individuals, with significant associations with the duration of illness and age at onset, suggesting a degree of neuronal injury and astrocytic dysfunction in bipolar depression. These biomarkers may reflect specific illness stages, including neuroprogression and the later onset of bipolar disorder.