Apoptotic markers in cultured fibroblasts correlate with brain metabolites and regional brain volume in antipsychotic-naive first-episode schizophrenia and healthy controls

Abstract

Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 μM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 μM: r = -0.90; P = 0.001; STS 0.25 μM: r = -0.73; P = 0.003), and between NAA and cells with CC (STS 0.5 μM induction r = -0.76; P = 0.002; STS 0.25 μM r = -0.62; P = 0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 μM; P < 0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness.

Figure 1

Spectroscopic voxel placement in the anterior cingulate (AC) cortex (a) and in the left thalamus (LT; b). Representative spectra of one control in the AC (c) and in the LT (d) and of one patient in the AC (e) and in the LT (f). Glx, glutamate+glutamine; NAA, N-acetylaspartate.

Figure 2

Partial correlation plots showing the association between the residualized values of apoptotic markers and metabolite concentrations after controlling for percentages of gray matter and for the time of experiement when the apoptotic hallmarks were measured. (a) Inverse correlation between anterior cingulate Glx (glutamate+glutamine) levels and chromatin condensation (CC) after apoptosis induction with staurosporine (STS) 0.5 μM in first-episode schizophrenia and controls (r=−0.90; P=0.001). (b) Inverse correlation between anterior cingulate N-acetylaspartate (NAA) levels and CC after apoptosis induction with STS 0.5 μM in first-episode schizophrenia and controls (r=−0.62; P=0.01). (c) Positive correlation between anterior cingulate glutamate+glutamine (Glx) and NAA levels in first-episode schizophrenia and controls (r=0.80; P=0.001). ●, First-episode schizophrenia; ○, controls.

Figure 3

Correlation of regional brain volume with chromatin condensation (CC) after apoptosis induction with staurosporine (STS) in first-episode schizophrenia (FES) and controls. (a) Significant negative correlation in the right superior temporal and in the right postcentral after apoptosis induction with STS 0.25 μM (P<0.001, family-wise error (FWE)-corrected at a cluster level). (b) Significant negative correlation in the right post-central region after apoptosis induction with STS 0.5 μM (P<0.001, FWE-corrected at a cluster level). Images are superimposed on selected slices of a normalized brain and are oriented following the neurological convention (right=right). Voxels with P<0.001 (uncorrected) are displayed. Color bar represents t-value.