Brain Metabolite Abnormalities in the White Matter of Elderly Schizophrenic Subjects: Implication for Glial Dysfunction

Chang, Linda; Friedman, Joseph I.; Ernst, Thomas; Zhong, Kai; Tsopelas, Nicholas D.; Davis, Kenneth L.

doi:10.1016/j.biopsych.2007.05.025

Cited by 92 publications

(114 citation statements)

References 67 publications

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“…Previous studies have reported conflicting data on Glu levels in schizophrenia patients, including: increased Glu levels in left dorsolateral prefrontal cortex in first episode schizophrenia patients, 74 decreased levels of Glu and Gln in left anterior cingulate cortex of medicated patients with schizophrenia, 46 increased levels of Glu in prefrontal cortex and hippocampus of schizophrenia patients, 75 and increased Glx levels in multiple WM regions in elderly schizophrenia patients. 61 The observed reductions in Glu levels among probands are consistent with the N-methyl D-aspartate (NMDA) receptor hypofunction model of schizophrenia, which assumes decreased glutamatergic neurotransmission. However, direct measurement of Glu neurotransmission is not possible because 1 H MRS measures both metabolic and vesicular Glu.…”

Section: Discussionsupporting

confidence: 62%

Proton MRS in twin pairs discordant for schizophrenia

et al. 2008

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Proton magnetic resonance spectroscopy ( 1 H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE = 3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine þ phosphocreatine (Cr), glycerophosphocholine þ phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that 1 H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

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Section: Discussionsupporting

confidence: 62%

Proton MRS in twin pairs discordant for schizophrenia

et al. 2008

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“…This result is incompatible with a neurodegenerative hypothesis of 17 schizophrenia [28] but may indicate either decreased glial content or more dysfunctional glia in more severe disease [30].…”

Section: Discussioncontrasting

confidence: 61%

Magnetic resonance spectroscopy investigations of functionally defined language areas in schizophrenia patients with and without auditory hallucinations

et al. 2014

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Background: Cerebral dysfunction occurring in mental disorders can show metabolic disturbances which are limited to circumscribed brain areas. Auditory hallucinations have been shown to be related to defined cortical areas linked to specific language functions. Here, we investigated if the study of metabolic changes in auditory hallucinations requires a functional rather than an anatomical definition of their location and size to allow a reliable investigation by magnetic resonance spectroscopy (MRS). Methods: Schizophrenia patients with (AH; n=12) and without hallucinations (NH; n=8) and healthy controls (HC; n=11) underwent a verbal fluency task in functional MRI (fMRI) to functionally define Broca's and Wernicke's areas. Left and right Heschl's gyrus were defined anatomically. Results: The mean distances in native space between the fMRI-defined regions and a corresponding anatomically defined area were 12.4±6.1 mm (range: 2.7-36.1 mm) for Broca's area and 16.8±6.2 mm (range:4.5-26.4 mm) for Wernicke's area, respectively. Hence, the spatial variance was of similar extent as the size of the investigated regions. Splitting the investigations into a single voxel examination in the frontal brain and a spectroscopic imaging part for the more homogeneous field areas led to good spectral quality for almost all spectra. In Broca's area, there was a significant group effect (p = 0.03) with lower levels of N-acetyl-aspartate (NAA) in NH compared to HC (p = 0.02). There were positive associations of NAA levels in the left Heschl's gyrus with total (p = 0.03) and negative (p = 0.006) PANSS scores. In Broca's area, there was a negative association of myo-inositol levels with total PANSS scores (p = 0.008). Conclusion: This study supports the neurodegenerative hypothesis of schizophrenia only in a frontal region whereas the results obtained from temporal regions are in contrast to the majority of previous studies. Future research should test the hypothesis raised by this study that a functional definition of language regions is needed if neurochemical imbalances are expected to be restricted to functional foci. Highlights

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“…Previous MRS studies of glutamate in the white matter in schizophrenia found higher glutamate levels in acute psychosis (Ota et al, 2012) and elderly schizophrenia patients (Chang et al, 2007). In rodents, systemic administration of kynurenine significantly decreased extracellular glutamate levels in the prefrontal cortex Konradsson-Geuken et al, 2010).…”

Section: Introductionmentioning

confidence: 92%

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

Chiappelli

Postolache

Kochunov

et al. 2016

Neuropsychopharmacol

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Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (po0.001), and kynurenine/tryptophan ratios were correspondingly higher (p = 0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r = 0.347, p = 0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r = − 0.391 and − 0.350 respectively, p = 0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/ kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

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Brain Metabolite Abnormalities in the White Matter of Elderly Schizophrenic Subjects: Implication for Glial Dysfunction

Cited by 92 publications

References 67 publications

Proton MRS in twin pairs discordant for schizophrenia

Proton MRS in twin pairs discordant for schizophrenia

Magnetic resonance spectroscopy investigations of functionally defined language areas in schizophrenia patients with and without auditory hallucinations

Tryptophan Metabolism and White Matter Integrity in Schizophrenia

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