Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Abstract

Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). We used 1H-MRS imaging to assess Glx and NAAc, as well as total-choline (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateral-parietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia.

Keywords: 1H-MRS; N-acetylaspartate; creatine; glutamate; schizophrenia; total-choline.

Fig. 1.

Proton magnetic resonance spectroscopy imaging (¹H-MRSI). A: ¹H-MRSI supraventricular axial slab with predominantly white matter (WM, yellow) and gray matter (GM, green) voxels. Regions anterior to central sulcus (CS, in red) are frontal. Regions posterior to CS are parietal. B: Sagittal view of A. C: Fitted spectrum (red line) from a predominantly GM voxel. Peak areas for glutamine plus glutamate (Glx), N-acetylaspartate compounds (NAAc), Cr (total-creatine), Ins (myo-inositol), and Cho (total-choline) are labeled. Top irregular line represents the residual signal. Lower continuous line represents the baseline used for fitting. D: Distribution of Glx values corresponding to the individual voxel’s GM tissue-fraction for the ¹H-MRSI from A; in yellow are predominantly WM and in green predominantly GM Glx values.

Fig. 2.

Increased glutamine plus glutamate (Glx) in schizophrenia compared to healthy controls in gray matter (F_1,197 = 19.5, P < .001) and white matter (F_1,197 = 5.9, P = .01), across age.

Fig. 3.

Increased N-acetylaspartate compounds (NAAc) in gray matter (GM, F_1,101 = 14.3, P < .001) but reduced in white matter (WM, F_1,101 = 62.2, P < .001) in older (≥35 y) schizophrenia compared with healthy controls. In younger schizophrenia subjects WM NAAc is also decreased (F_1,96 = 12.1, P < .001).

Fig. 4.

Opposite relationship between white matter N-acetylaspartate compounds (NAAc) (age-adjusted) and Measurement-and-Treatment-Research-to-Improve-Cognition-in-Schizophrenia (MATRICS) overall score in schizophrenia and healthy controls (F_1,571 = 27.9, P < .001).