Cortical thickness in the anterior cingulate correlates with apoptotic markers in cultured fibroblasts in first-episode schizophrenia individuals

Introduction: Structural abnormalities such cortical thickness (CTH) reductions across frontal and temporal lobes are common in individuals with early schizophrenia [1,2], yet the pathophysiology underlying these findings is poorly understood. First-episode schizophrenia (FES) patients show increased susceptibility to apoptosis [3]; and peripheral markers of apoptotic susceptibility correlate with regional brain volume and metabolites (e.g. glutamate) in FES and healthy controls (HC), consistently with the neuroprogressive theories around the onset of the disease [4]. Aim: To test the correlation between cortical thickness and markers of apoptotic susceptibility measured in cultured fibroblasts from FES and HC. Methods: FES individuals (according to DSM-IV-TR criteria) were recruited from the psychiatry inpatient unit in Hospital Clinic. All patients were antipsychotic-naïve at the time of inclusion. HC with no Axis I psychiatric disorders, were recruited from the same geographical area. All participants underwent a comprehensive socio-demographic and clinical evaluation. Exclusion criteria comprised intellectual disability, neurological illness, substance use disorders and chronic drug treatment. The study was approved by the local Ethical Review Board. High-resolution structural MRI images were acquired on a 3Tesla scanner. Images were pre-processed using automated procedures implemented in FreeSurfer 5.3.0; cortical parcellation was based on the Desikan-Killiany brain atlas. CTH was computed for each region of interest. Hallmarks of apoptotic susceptibility were measured in fibroblast cultures obtained from skin biopsies of all subjects after inducing apoptosis with staurosporine (STS) 0.25 and 0.5μM. Based on previous findings from our group [4] we selected chromatin condensation (CC; 6h after STS induction at doses of 0.25 and 0.5μM) as marker of apoptotic susceptibility and three brain regions (anterior cingulate, right postcentral gyrus and the superior temporal cortex) for the correlation analyses. Partial correlations controlling for the time of experiment when the apoptotic hallmarks were measured were conducted to examine the relationship between apoptotic markers and CTH. Significance was set at p<.05, corrected using the false discovery rate (FDR). Results: Seventeen subjects were included: 7 HC and 11 FES; with mean ages: 22.8±0.9 and 23.5±1.1 (t = -0.47, p = 0.641); age range: 19-29 years; gender( %male): 57.1 % and 54.5 %, (χ2 = 0.01, p = 0.914). No significant differences in global CTH between groups were found (2.71cm and 2.70cm; t = 0.017, p = 0.867). A significant negative correlation between CTH in the left anterior cingulate and CC after apoptosis induction with STS 0.25μM was found (r = -0.80; pFDR = 0.04) in the FES group. No significant correlations were found in HC. Discussion: Individuals with FES showed a significant negative correlation between peripheral apoptotic markers (CC) and CTH in the left anterior cingulate. These findings expand previous data of increased apoptotic susceptibility in FES compared to HC, where CC correlated negatively with glutamate levels in the cingulate cortex [4]. Overall, the present data support the hypothesis of an increased vulnerability to proapoptotic stimuli in FES, which may play a role in the structural abnormalities, characterized by accelerated loss of CTH found in schizophrenia.