Abstract
BackgroundGlutamatergic dysfunction, deregulated mitochondrial metabolism and alterations of membrane phospholipids are considered as core pathology of psychosis, and have been studied in schizophrenic illness using magnetic resonance spectroscopy (MRS). Combining 1H- and 31P-MRS, this study investigates these aspects in Ultra-high risk (UHR-T) patients right after transition to psychosis (T0) and after a two years interval (T1) in a naturalistic longitudinal design, including treatment as usual by cognitive-behavioral therapy (CBT) and pharmacotherapy with second generation antipsychotics.MethodsWe applied 3 T chemical shift imaging (3D 31P-MRS, 2D 1H-MRS) and hippocampal single-voxel 1H-MRS in 29 neuroleptic-naïve UHR-T patients and 27 healthy controls matched for age and gender. Glutamate (Glu) and N-acetyl-aspartate (NAA) reflect neuronal functioning, phosphocreatine (PCr), adenosine triphosphate (ATP) and NAA indicate mitochondrial function and energy metabolism, and phosphomono- and diester indicate the balance of phospholipid synthesis (PME) and -breakdown (PDE). Psychopathology was assessed using the CAARMS, BPRS-E and SCL-90-R. Generalized linear mixed models were used to examine case-control differences in metabolite changes over time, and associations with clinical improvement.ResultsAt T0, cross-sectional analysis revealed decreased NAA, Glu and PME levels in the left dorsolateral prefrontal cortex (DLPFC) and thalamus of UHR-T patients as well as higher PCr and lower PDE levels in the right hippocampus. (ii) Follow-up analysis (T1) showed in patients a significant increase of Glu in the bilateral DLPFC and the right thalamus, while a decrease of PCr was observed in the right hippocampus.DiscussionThe observed metabolite pattern at T0 likely reflects a hypofunction of glutamatergic neurons and a disturbance of membrane phospholipid turnover in fronto-thalamo-hippocampal networks during the first acute onset phase of psychotic illness. The pattern of changes at T1 is suggestive for an improvement of neuronal functioning in these networks that is caused by therapy, and presumably underlies the observed clinical improvement in terms of negative symptoms and cognitive impairment.
Highlights
The current study aimed to identify shared and distinct brain structure abnormalities and their relationships with circadian gene expression in patients with bipolar depression and unipolar major depression
Our findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis
A total of 103 subjects participated in this study, including 32 patients with bipolar depression (BDP), 26 patients with unipolar depression (UDP) and age, sex-matched 35 healthy controls were conducted brain structural magnetic resonance imaging scans and used optimized voxel-based morphometry to explore group differences in regional gray matter volume (GMV)
Summary
Thirty patients were diagnosed with schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder or a long-term unspecified nonorganic psychosis during follow-up, while 23 patients achieved complete remission. Eight patient samples showed autoreactivity to the N-terminal fragment of the PAGE protein family (PAGE2B/PAGE2/PAGE5), whereas no such autoreactivity was seen among the controls. PAGE autoreactivity was associated with a significantly increased risk of being diagnosed with schizophrenia during follow-up (odds ratio 6.7). An antisera raised against the N-terminal fragment stained an unknown extracellular target in human cortical brain tissue (Zandian et al, Transl Psychiatry 7: e1177; doi:10.1038/tp.2017.160). Two other putative new autoantibodies found primarily among the patients, and rarely in the controls, will be discussed at the meeting. Discussion: Our findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis. Chengcheng Zhang*,1, Peiyan Ni1, Tao Li1 1West China Hospital, Sichuan University
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