Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo 31P and 7Li magnetic resonance spectroscopy

Kato, Takeshi; Takahashi, Saburo; Shioiri, Toshiki; Inubushi, Toshiro

doi:10.1016/0165-0327(93)90097-4

Cited by 219 publications

(113 citation statements)

References 22 publications

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“…Alterations in pH and lactate levels have been reported in bipolar disorder brain neuroimaging studies. [51][52][53][54] Alterations in Ca 2+ release and concentrations have been observed in lymphoblastic cell lines from bipolar patients, 55,56 which can implicate calcium homeostatic mechanisms operated by mitochondria or endoplasmic reticulum, or cellular signaling. Taken together, metabolic alterations in BPD possibly involve selective mitochondrial and apoptotic functions consistent with the present gene expression results.…”

Section: Mitochondrial Dna Gene Expression In Agonal State and Mood Dmentioning

confidence: 99%

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

et al. 2006

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Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe pathophysiology of depression and mania is largely unknown leaving open a question of which cellular pathway(s) to investigate. Gene expression screening is a powerful method for probing alterations in neural functions in mood disorder. Examining gene expression profiles has been extremely useful for establishing different phenotypes in cancer. [1][2][3] Various microarray profiles in mood disorder have been reported that use different microarray platforms, analysis methodology, regional differences, agonal factors and brain pH. [4][5][6][7][8][9][10][11][12][13][14] Presumably, a substantial heterogeneity in the pathophysiology of mood disorder coupled with small sample sizes and small fold changes contributes to the lack of consistency among the findings. 15 In five microarray studies a broad mitochondrial dysfunction was reported in neuropsychiatric disorders. 10,11,14,[16][17][18] One study of bipolar disorder (BPD) focused on a broad set of mitochondrial-related gene expression and found that in general, mitochondrial gene expression was predominantly decreased in BPD compared to controls in the dorsolateral pre-frontal cortex (DLPFC) when using Stanley samples...

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Section: Mitochondrial Dna Gene Expression In Agonal State and Mood Dmentioning

confidence: 99%

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

et al. 2006

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“…It may be possible to increase in vivo sensitivity through a 7 Li-{ 1 H} nuclear Overhauser enhancement 52 or by dynamic nuclear polarization via water protons. 53 A potentially powerful feature of MRS is the ability to measure simultaneously the local tissue concentration of Li by 7 Li MRS and related changes in brain metabolism by 1 H or 31 P MRS. 54,55 Future 1 H or 31 P MRS studies of subjects on Li therapy would greatly benefit from the additional measurement of local Li concentration.…”

Section: Future Prospectsmentioning

confidence: 99%

Biomedical applications of7Li NMR

Komoroski

2005

NMR Biomed.

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The biomedical applications of 7 Li MRS and MRI have been progressing slowly. The interest derives primarily from the clinical use of Li to treat bipolar disorder. One area of concern is the nature of ionic transport and binding, so as to elucidate the mechanism(s) of therapeutic action and toxicity. Another is the development of a non-invasive, in vivo analytical tool to measure brain Li concentration and environment in humans, both as an adjunct to treatment and as a mechanistic probe. Here we review the most recent progress toward these goals.

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“…We have proposed the mitochondrial dysfunction hypothesis of bipolar disorder [Kato and Kato, 2000] based on the following lines of evidence; altered brain energy metabolism in patients with bipolar disorder detected by phosphorus-31 magnetic resonance spectroscopy [Kato et al, 1993], increased ratio of the mitochondrial DNA (mtDNA) deletion in the brains of patients with bipolar disorder [Kato et al, 1997], association with mtDNA polymorphisms causing amino acid substitutions in the subunits of complex I (NADH:ubiquinone oxidoreductase) . On the other hand, several studies have also suggested that mitochondrial dysfunction underlies the pathophysiology of schizophrenia [Kato, 2001;BenShachar, 2002;Ben-Shachar and Laifenfeld, 2004].…”

Section: Introductionmentioning

confidence: 99%

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population

Washizuka

Kametani

Sasaki

et al. 2006

American J of Med Genetics Pt B

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Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11-13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, -3542G > A and -602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, -3542G > A and -602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter-individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia.

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Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo 31P and 7Li magnetic resonance spectroscopy

Cited by 219 publications

References 22 publications

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

Biomedical applications of7Li NMR

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population

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