Abstract
<title>Abstract</title> <p>Perineuronal nets (PNNs) are specialized extracellular matrix structures that stabilize synaptic connections and regulate neuroplasticity in brain circuits involved in reward, cognition, and impulse control. Brevican (BCAN) and neurocan (NCAN), two key chondroitin sulfate proteoglycans of PNNs, may serve as peripheral indicators of CNS matrix integrity. We measured plasma BCAN and NCAN concentrations in 209 patients with alcohol use disorder (AUD) and 52 age- and sex-matched controls. Group differences were assessed using nonparametric tests, ANCOVA adjusted for age and BMI, principal component analysis (PCA), and Spearman correlations with clinical, cognitive, neurotrophic, tryptophan-pathway, and inflammatory markers. Patients with AUD showed significantly lower BCAN and NCAN levels than controls, independently of sex and cognitive impairment, indicating a generalized AUD-related effect rather than a consequence of cognitive decline. PCA identified a single component defined exclusively by both proteoglycans, supporting a common PNN-related signal. BCAN and NCAN were negatively associated with age; BCAN also correlated inversely with AUD severity and duration, whereas NCAN was associated with age at diagnosis and illness duration. Neither marker was significantly influenced by psychiatric comorbidity, comorbid substance use disorder, or psychotropic medication. Both proteoglycans were associated with neurotrophic factors (IGF-1, GCSF, VEGFA), tryptophan metabolites (kynurenine, kynurenic acid, serotonin), and inflammatory markers (TNF-α, MIP-1α). These findings provide the first evidence of reduced circulating BCAN and NCAN in AUD, consistent with alcohol-related PNN degradation and highlighting their potential as accessible biomarkers of neuroplastic disruption and disease chronicity and their relevance for understanding relapse vulnerability and guiding future therapeutic strategies targeting matrix restoration.</p>