Plasma Glial Fibrillary Acidic Protein and Neurofilament Light Are Elevated in Bipolar Depression: Evidence for Neuroprogression and Astrogliosis

Abstract

Background: Recent advances now allow detection of brain-specific proteins in blood, including neurofilament light chain (NfL), a marker of axonal pathology, and glial fibrillary acidic protein (GFAP), indicative of astrocytic activation. Given the evidence of astroglial pathology and neuronal dysfunction in bipolar disorder, and ongoing debates on neuroprogression, we investigated plasma NfL and GFAP levels in affected individuals. Methods: This study analysed plasma NfL and GFAP measured in 216 individuals using Simoa. We used bootstrapped general linear models (GLM) to compare plasma NfL and GFAP levels between people with bipolar depression (n = 120) and healthy controls (n = 96), adjusting for age, sex, and weight. We examined associations between these biomarkers and clinical variables while adjusting for multiple comparisons. For sensitivity analyses, predictors were evaluated using Bayesian model averaging (BMA). Results: Plasma GFAP (β = 0.21 [0.07, 0.35], p = 0.006) and NfL (β = 0.06 [0.01, 0.10], p = 0.028) were elevated in people with bipolar depression. Illness duration was positively associated with NfL (r = 2.97, p = 0.002), and further supported by BMA analysis (posterior inclusion probability, PIP = 0.85). Age of onset was positively associated with GFAP (r = 0.246 p = 0.041), which was also supported by BMA analysis (PIP = 0.67). Conclusions: These findings indicate increased plasma NfL and GFAP levels in bipolar disorder. Our findings support the neuroprogression hypothesis, where prolonged illness duration contributes to neuroaxonal damage. Elevated GFAP in those with later onset suggests a role for neuroinflammation, potentially linked to increased cardiovascular and metabolic comorbidities.