Abstract
Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.
Highlights
Schizophrenia (SZ) and bipolar disorder (BD) are severe mental illnesses (SMIs) each affecting approximately 1% of the population (Kahn et al, 2015; Vieta et al, 2018)
We further aimed to explore whether putative case-control differences in circulating Neuron-specific enolase (NSE) are dependent on total grey matter volume (TGMV)
We found no effect of diurnal variation comparing non-fasting levels in individuals at 8 am and 4 pm [n = 6, within-patient coefficient of variation (CV) = 16%, p = 0.43] or postprandial variation comparing fasting and non-fasting samples at 8 am (n = 6, within-patient CV = 12%, p = 0.38)
Summary
Schizophrenia (SZ) and bipolar disorder (BD) are severe mental illnesses (SMIs) each affecting approximately 1% of the population (Kahn et al, 2015; Vieta et al, 2018). Increased cerebrospinal fluid (CSF) and circulating (plasma/ serum) NSE concentrations indicate neuronal damage (Haque et al, 2018; Isgro et al, 2015). Elevated NSE reflects neuronal damage after traumatic brain injury (Cheng, Yuan, Yang, Wang, & Liu, 2014) and may indicate oxidative damage underlying neurodegenerative disorders (Haque et al, 2018). If SMIs are neurodegenerative disorders with ongoing neuronal damage, circulating NSE levels might be increased. We hypothesise that circulating NSE concentrations in adult and adolescent patients with SMI are either increased (indicating progressive neuronal damage) or decreased (suggesting neural maturation disturbance). As neurons are the main cells producing NSE (Marangos & Schmechel, 1987), it has been hypothesised, but never shown, that smaller grey matter volume is associated with reduced circulating NSE concentrations (Hoffmann et al, 2017). In a population-based study, Hoffmann et al reported no significant association (Hoffmann et al, 2017), but to the best of our knowledge, this has not been investigated in SMI
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