Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state

A novel radiotracer, [¹¹C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [¹¹C]SL25.1188, to measure MAO-B V_T, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B V_T (F_(2,37.42) = 4.56, p = 0.02, Cohen's f = 0.49), controlling for tobacco (F _(1,37.42) = 5.37, p = 0.03) and cannabis use (F_(1,37.42) = 5.11, p = 0.03) with significantly lower MAO-B V_T in CHR compared to HV (Cohen's d = 0.99). We report a significant cannabis effect on MAO-B V_T (F_(1,39.19) = 12.57, p = 0.001, Cohen's f = 0.57), with a significant group-by-cannabis interaction (F_(2,37.30) = 3.82, p = 0.03, Cohen's f = 0.45), indicating lower MAO-B V_T in cannabis-using clinical groups. Lower MAO-B V_T levels were more robust in striatal than cortical regions, in both clinical groups (F_(12,46.84) = 2.08, p = 0.04, Cohen's f = 0.73) and in cannabis users (F_(6,46.84) = 6.42, p < 0.001, Cohen's f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.