Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: An in vivo 1 H MRS study

MOOD-CNS Program, Division of Mood and Anxiety Disorders, Department of Psychiatry, The University of Texas Health Science Center at San Antonio, TX 78229, USA.
Bipolar Disorders (Impact Factor: 4.97). 06/2007; 9(s1):119-127. DOI: 10.1111/j.1399-5618.2007.00454.x
Source: PubMed


While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr).
Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference.
BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites.
These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.

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    • "It is suggested that the glutamate elevation in BD subjects represents a shift in energy redox state from oxidative phosphorylation toward glycolysis (Dager et al., 2004). On the other hand, there are a number of studies that show no differences in glutamate levels in similar brain areas between BD patients and healthy controls (Frey et al., 2007; Port et al., 2008; Kaufman et al., 2009; Senaratne et al., 2009). Other studies even reported decreased glutamate levels in the frontal white matter bilaterally and the right lentiform nucleus of BD patients (Port et al., 2008) or in the ACC of pediatric offspring of parents with BD (Singh et al., 2010). "
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    ABSTRACT: There has been growing support for dysfunctions of the excitatory glutamatergic system and its implications for the psychophysiology of schizophrenia. However, previous studies reported mixed results regarding glutamate concentrations in schizophrenia with varying deviations across brain regions. We used an optimized proton magnetic resonance spectroscopy procedure to measure absolute glutamate concentrations in the left hippocampal region and the anterior cingulate cortex (ACC) in 29 medicated patients with schizophrenia and in 29 control participants without mental disorder. The glutamate concentrations were significantly lower in the ACC but higher in the hippocampus of patients compared to controls. ACC and hippocampal glutamate concentrations correlated positively in patients but not in controls. ACC glutamate was weakly associated with Clinical Global Impression score and duration of illness in patients. Glutamate concentrations in schizophrenia deviate from controls and show associations with disease severity. A higher concentration of hippocampal glutamate in schizophrenia compared to controls is shown. The association between ACC and hippocampus glutamate concentrations in patients with schizophrenia suggests an abnormal coupling of excitatory systems compared to controls as predicted by previous glutamate models of schizophrenia. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Schizophrenia Bulletin 09/2015; DOI:10.1093/schbul/sbv124 · 8.45 Impact Factor
    • "However, there are a few studies that found reduced tCr levels in dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus and basal ganglia of schizophrenia patients (Ohrmann et al., 2005; Ohrmann et al., 2007; Ongur et al., 2009). In addition, the literature is not conclusive about the concentrations of Cr and Ins for patients with bipolar disorder (Yildiz-Yesiloglu and Ankerst, 2006; Frey et al., 2007; Theberge et al., 2007; Ongur et al., 2009; Silverstone and McGrath, 2009; Kraguljac et al., 2012a; Sikoglu et al., 2013). The decrease in tNAA, tCr and Ins that we observed in patients with bipolar disorder compared to healthy participants may be a region specific disturbance in this disorder, as we investigated an understudied brain area, i.e. the left superior temporal cortex. "
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    ABSTRACT: Background: Superior temporal cortices include brain regions dedicated to auditory processing and several lines of evidence suggest structural and functional abnormalities in both schizophrenia and bipolar disorder within this brain region. However, possible glutamatergic dysfunction within this region has not been investigated in adult patients. Methods: Thirty patients with schizophrenia (38.67 ± 12.46 years of age), 28 euthymic patients with bipolar I disorder (35.32 ± 9.12 years of age), and 30 age-, gender- and education- matched healthy controls were enrolled. Proton Magnetic Resonance Spectroscopy data were acquired using a 3.0T Siemens MAGNETOM TIM Trio MR system and single voxel Point Resolved Spectroscopy Sequence (PRESS) in order to quantify brain metabolites within the left and right Heschl Gyrus and Planum Temporale of superior temporal cortices. Results: There were significant abnormalities in Glutamate (Glu) (F(2,78)=8.52, p<0.0001), n- Acetyl Aspartate (tNAA) (F(2,81)=5.73, p=0.005), Creatine (tCr) (F(2,83)=5.91, p=0.004) and Inositol (Ins) (F(2,82)=8.49, p<0.0001) concentrations in the left superior temporal cortex. In general, metabolite levels were lower for bipolar disorder patients when compared to healthy participants. Moreover, patients with bipolar disorder exhibited significantly lower tCr and Ins concentrations when compared to schizophrenia patients. In addition, we have found significant correlations between the superior temporal cortex metabolites and clinical measures. Conclusion: As the left auditory cortices are associated with language and speech, left hemisphere specific abnormalities may have clinical significance. Our findings are suggestive of shared glutamatergic abnormalities in schizophrenia and bipolar disorder.
    Schizophrenia Research 02/2015; 161(2-3). DOI:10.1016/j.schres.2014.11.012 · 3.92 Impact Factor
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    • "A number of investigators have utilized neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to investigate the pathophysiology of the MRC in BP as well as magnetic resonance spectroscopy (MRS) to investigate neurochemical abnormalities within the MRC. This report focuses on MRS abnormalities in BPD and BPM. 1 H MRS studies have reported exciting findings regarding molecular abnormalities in BP (Strakowski et al., 2000; Moore and Galloway, 2002; Yildiz-Yesiloglu and Ankerst, 2006; Dager et al., 2008) such as decreased phosphotidyl inositol (Kim et al., 2005), decreases and increases in choline levels (Moore et al., 2000; Cecil et al., 2002; Frey et al., 2007; Michael et al., 2009; Senaratne et al., 2009), decreased or normal N-acetylaspartate (NAA) (Winsberg et al., 2000; Brambilla et al., 2004; Dager et al., 2004; Gallelli et al., 2005; Frye et al., 2007a), elevated gray matter lactate (Dager et al., 2004; Stork and Renshaw, 2005), decreased or unchanged γ-aminobutyric acid (GABA) (Bhagwagar et al., 2007; Kaufman et al., 2009), and elevated Glx (glutamate+glutamine) concentrations (Dager et al., 2004; Michael et al., 2009; Yüksel and Öngür, 2010). 31 P MRS studies have reported increased phosphomonester (Kato et al., 1991; Volz et al., 1998; Yildiz et al., 2001; Silverstone et al., 2002) levels and decreased phosphocreatinine (Kato et al., 1995; Murashita et al., 2000) levels the BPD phase. "
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    ABSTRACT: The neurobiology and neurochemistry of bipolar disorder and its different phases are poorly understood. This study investigated metabolite abnormalities in both unmedicated bipolar depression as well as mania using 2D (1)H magnetic resonance spectroscopy imaging (MRSI). MRSI data were obtained from 24 unmedicated bipolar disorder (BP) subjects (12 (hypo)manic (BPM)) and 12 depressed (BPD), and 20 closely matched healthy controls. 2D (1)H MRSI data were collected from a 15-mm axial slice placed along the anterior commissure-posterior commissure (AC-PC) line to measure brain metabolites bilaterally in the thalamus and also the anterior and posterior cingulate cortex (ACC and PCC). Brain Lac/Cr levels were significantly increased in the BP group as a whole compared to healthy controls. Glutamate abnormalities varied across bipolar state as well as brain region: significantly increased Glx/Cr values were found in the left thalamus in BPD, but BPM had decreased Glu/Cr and Glx/Cr levels in the PCC when compared to healthy controls and decreased Glu/Cr levels even when compared to the BPD subjects group. The findings of the study point to state-related abnormalities of oxidative and glutamate metabolism in bipolar disorder.
    06/2013; 213(3). DOI:10.1016/j.pscychresns.2013.02.008
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