In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy

Abstract

Importance: Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies.

Objective: To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy.

Design, setting, and participants: Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter).

Intervention: 31P magnetization transfer spectroscopy.

Main outcomes and measures: The primary outcome measure was the forward rate constant (k(f)) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester.

Results: A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder.

Conclusions and relevance: Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.

Figure 1.

T₂-weighted brain anatomic imaging (in the sagittal orientation) and the sensitivity profile (6×6×4 cm³) of the 7-cm ³¹P surface coil placed over the forehead. In order to delineate the ³¹P sensitivity region of the surface coil with outer-volume saturation in the current experiment, 1D profiles of Pi signal along three orthogonal dimensions were acquired from a phantom (14-cm diameter cylindrical bottle) with inorganic phosphate solution ([Pi] = 0.6 M and pH = 7.1).

Figure 2.

In vivo ³¹P spectra with 10-Hz line broadening in the absence and presence of saturating γ-ATP resonance (illustrated by the back arrows) demonstrated in left and right columns, respectively. The spectra on top and bottom rows were acquired from a representative SZ and HC subject, respectively. Saturation time was 12.28 s. All resonance peaks are labeled in the lowest spectrum. The magnetization of PCr was reduced by 56% and 43% for the HC and SZ subject, respectively. pH was calculated via pH = 6.77 + log{(δ–3.29)/(5.68–δ)} where δ is the distance between the chemical shifts of PCr and Pi. Note this distance is different in the SZ and HC groups (aligned by vertical lines across the two spectra), indicating parenchymal pH reduction in SZ.

Figure 3.

Dependence of the PCr signal on γ-ATP saturation time for SZ (diamond, n=26) and HC (circle, N=25). The peak integrals for PCr represent the normalized M_s/M₀ ratios. The intrinsic spin-lattice relaxation times of PCr (T₁^int) and the forward rate constants ($k_f^{PCr\to ATP}$) were determined from these data by regression analyses using the Equation 4 described above.

Figure 4.

The relationship between pH and the PCr/γ-ATP ratio in both HC (blue circles) and SZ (red diamond).