Phosphorus magnetic resonance spectroscopy studies in schizophrenia

Yüksel, Çağrı; Tegin, Cuneyt; O’Connor, Lauren K.; Du, Fei; Ahat, Ezgi; Cohen, Bruce M.; Öngür, Döst

doi:10.1016/j.jpsychires.2015.06.014

Cited by 31 publications

(19 citation statements)

References 66 publications

(218 reference statements)

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“…Indices of mitochondrial bioenergetics include high-energy phosphates, including phosphocreatine (PCr) and adenosine triphosphate (ATP). While 31 P MRS studies have reported abnormalities in phospholipid metabolism and/or mitochondrial bioenergetics in patients with bipolar disorder (Yildiz et al, 2001), major depressive disorder (MDD)(Kato et al, 1992; Volz et al, 1998), and schizophrenia (Yuksel et al, 2015), the underlying risk factors remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo 31P MRS study

Lindquist

Asch

Schurdak

et al. 2017

Journal of Psychiatric Research

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Evidence from 31P magnetic resonance spectroscopy (31P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using 31P MRS. During the peri-adolescent period (P21–P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n=20), a diet fortified with preformed DHA (fish oil, FO, n=20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n=20). On P90, 31P MRS was performed under isoflurane anesthetic using a 7T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (−17%, p≤0.0001) and significantly higher in rats fed the FO diet (+14%, p≤0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present 31P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism.

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Section: Introductionmentioning

confidence: 99%

Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo 31P MRS study

Lindquist

Asch

Schurdak

et al. 2017

Journal of Psychiatric Research

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“…Our results, however, do not suggest significant abnormalities in ATP with normal Pi/ATP, PME/ATP and PDE/ATP ratios, consistent with past studies in psychotic disorders (Stanley et al, 1995; Volz et al, 1998). Fourth, the reduction found in PCr should be interpreted with caution in view of the discrepancies between 31 P MRS studies in both patients with first episode and chronic psychotic disorders, which may be due in part to differences in methodology (Yuksel et al, 2015b). Fifth, with regards to NAD metabolite measures, while NAD+/NADH is the generally accepted index of redox state of cells (Blacker et al, 2014), NAD+/NADH alterations may also reflect upstream changes in other related redox pairs, including nicotinamide adenine dinucleotide phosphate (NADP+)/reduced NADPH and reduced glutathione/oxidized glutathione.…”

Section: Discussionmentioning

confidence: 99%

“…Brain parenchymal pH can also be measured in 31 P MRS using the chemical shift difference between PCr and Pi. Altered levels of these brain metabolites have been found in patients with psychotic disorders, revealing energy metabolism abnormalities and perturbed membrane phospholipid metabolism in the brain (Du et al, 2014; Nenadic et al, 2012; Pettegrew et al, 1991; Smesny et al, 2007; Yuksel et al, 2015a; Yuksel et al, 2015b). In a previous study using a 31 P magnetization transfer MRS approach (Du et al, 2014), we found new evidence of dysfunctional brain bioenergetics, specifically, a significant reduction in the forward rate constant of a critical enzyme involved in energy metabolism, creatine kinase, in the frontal lobe of patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we reported that brain parenchymal pH measured by 31 P MRS was significantly reduced in patients with schizophrenia, possibly indicating a reduced ratio of oxidative phosphorylation to glycolysis, leading to lactic acid build up. Despite intriguing observations, however, no abnormalities in HEPs or phospholipid metabolites have been reported consistently enough in the 31 P MRS literature (Yuksel et al, 2015b). In particular, there are few studies that have used 31 P MRS to investigate brain abnormalities in unaffected relatives of patients with psychotic disorders (Keshavan et al, 2003; Klemm et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Brain bioenergetics and redox state measured by 31 P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders

Chouinard

Kim

Valeri

et al. 2017

Schizophrenia Research

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Background Brain bioenergetic anomalies and redox dysregulation have been implicated in the pathophysiology of psychotic disorders. The present study examined brain energy-related metabolites and the balance between nicotinamide adenine dinucleotide metabolites (oxidized NAD+ and reduced NADH) using 31P-magnetic resonance spectroscopy (31P-MRS) in unaffected siblings, compared to first episode psychosis (FEP) patients and healthy controls. Methods 21 unaffected siblings, 32 FEP patients (including schizophrenia spectrum and affective psychoses), and 21 controls underwent 31P-MRS in the frontal lobe (6×6×4 cm3) on a 4T MR scanner, using custom-designed dual-tuned surface coil with outer volume suppression. Brain parenchymal pH and steady-state metabolite ratios of high energy phosphate compounds were measured. NAD+ and NADH levels were determined using a 31P-MRS fitting algorithm. 13 unaffected sibling-patient pairs were related; other patients and siblings were unrelated. ANCOVA analyses were used to examine 31P-MRS measures, with age and gender as covariates. Results The phosphocreatine/adenosine triphosphate ratio was significantly reduced in both unaffected siblings and FEP patients, compared to controls. NAD+/NADH ratio was significantly reduced in patients compared to siblings and controls, with siblings showing a reduction in NAD+/NADH compared to controls that was not statistically significant. Compared to patients and controls, siblings showed significantly reduced levels of NAD+. Siblings did not differ from patients or controls on brain pH. Discussion Our results indicate that unaffected siblings show some, but not all the same abnormalities in brain energy metabolites and redox state as FEP patients. Thus, 31P-MRS studies may identify factors related both to risk and expression of psychosis.

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“…P hosphorus magnetic resonance spectroscopy ( 31 P-MRS) provides insight into bioenergetic impairment and mitochondrial dysfunction in vivo under various physiological and pathological conditions. [1][2][3][4][5] Major phosphorus-containing metabolites related to bioenergetics detected by in vivo 31 P-MRS include phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) with the a-, b-, and c-resonances. These metabolites compose a chemical exchange network (PCr$ATP$Pi) catalyzed by the enzymes creatine kinase (CK) and ATP synthase (ATPase).…”

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confidence: 99%

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

Kim

Chen

Öngür

et al. 2017

Magnetic Resonance Imaging

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Purpose: The metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and in-organic phosphate (Pi) are biochemically coupled. Their pool sizes, assessed by their magnetization ratios, have been extensively studied and reflect bioenergetics status in vivo. However, most such studies have ignored chemical exchange and T 1 relaxation effects. In this work, we aimed to extend the T nom 1 method to simultaneously quantify the reaction rate constants as well as phosphorus metabolite pool size ratios under partially relaxed conditions. Materials and Methods: Modified Bloch-McConnell equations were used to simulate the effects of chemical exchanges on T 1 relaxation times and magnetization ratios among PCr, c-ATP, and Pi. The T nom 1 method with iteration approach was used to measure both reaction constants and metabolite pool size ratios. To validate our method, in vivo data from rat brains (N 5 8) at 9.4 Tesla were acquired under two conditions, i.e., approximately full relaxation (TR 5 9 s) and partial relaxation (TR 5 3 s). We compared metabolite pool size ratios and reaction constants before and after correcting the chemical exchange and T 1 relaxation effects. Results: There were significant errors in underestimation of PCr/cATP by 12 % (P 5 0.03) and overestimation of ATP/Pi ratios by 14 % (P 5 0.04) when not considering chemical exchange effects. These errors were minimized using our iteration approach, resulting in no significant differences (PCr/cATP, P 5 0.47; ATP/Pi, P 5 0.81) in metabolite pool size ratios and reaction constants between the two measurements (i.e., short versus long TR conditions). Conclusion: Our method can facilitate broad biomedical applications of 31 P magnetization saturation transfer spectroscopy, requiring high temporal and/or spatial resolution for assessment of altered bioenergetics. P hosphorus magnetic resonance spectroscopy ( 31 P-MRS) provides insight into bioenergetic impairment and mitochondrial dysfunction in vivo under various physiological and pathological conditions. 1-5 Major phosphorus-containing metabolites related to bioenergetics detected by in vivo 31 P-MRS include phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine triphosphate (ATP) with the a-, b-, and c-resonances. These metabolites compose a chemical exchange network (PCr$ATP$Pi) catalyzed by the enzymes creatine kinase (CK) and ATP synthase (ATPase). These chemical reactions are crucial for regulating ATP metabolism and maintaining normal ATP functionality. The phosphorus metabolite levels or pool sizes assessed by their magnetization ratios such as PCr to c-ATP (PCr/c-ATP), c-ATP to Pi (c-ATP/Pi), and PCr to Pi (PCr/Pi) have been extensively studied in various disease states in vivo, for instance in the brain, 6-8 heart, 9,10 and muscle. 2,11 For measuring phosphorus-containing metabolite levels using a conventional MRS approach, Ernst and Anderson 12 suggested that large improvements in signal-to-noise ratio (SNR) per unit sampling time could be achieved by the use of short inter-pulse del...

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Phosphorus magnetic resonance spectroscopy studies in schizophrenia

Cited by 31 publications

References 66 publications

Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo 31P MRS study

Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo 31P MRS study

Brain bioenergetics and redox state measured by 31 P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders

Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo

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