Decreased brain PME/PDE ratio in bipolar disorder: a preliminary (31) P magnetic resonance spectroscopy study.

OBJECTIVES: The aim of the present study was to measure brain phosphorus-31 magnetic resonance spectroscopy ((31) P MRS) metabolite levels and the creatine kinase reaction forward rate constant (kf ) in subjects with bipolar disorder (BD). METHODS: Subjects with bipolar euthymia (n = 14) or depression (n = 11) were recruited. Healthy comparison subjects (HC) (n = 23) were recruited and matched to subjects with BD on age, gender, and educational level. All studies were performed on a 3-Tesla clinical magnetic resonance imaging system using a (31) P/(1) H double-tuned volume head coil. (31) P spectra were acquired without (1) H-decoupling using magnetization-transfer image-selected in vivo spectroscopy. Metabolite ratios from a brain region that includes the frontal lobe, corpus callosum, thalamus, and occipital lobe are expressed as a percentage of the total phosphorus (TP) signal. Brain pH was also investigated. RESULTS: Beta-nucleoside-triphosphate (ß-NTP/TP) in subjects with bipolar depression was positively correlated with kf (p = 0.039, r(2) = 0.39); similar correlations were not observed in bipolar euthymia or HC. In addition, no differences in kf and brain pH were observed among the three diagnostic groups. A decrease in the ratio of phosphomonoesters to phosphodiesters (PME/PDE) was observed in subjects with bipolar depression relative to HC (p = 0.032). We also observed a trend toward an inverse correlation in bipolar depression characterized by decreased phosphocreatine and increased depression severity. CONCLUSIONS: In our sample, kf was not altered in the euthymic or depressed mood state in BD. However, decreased PME/PDE in subjects with bipolar depression was consistent with differences in membrane turnover. These data provide preliminary support for alterations in phospholipid metabolism and mitochondrial function in bipolar depression.

Effect of altitude on brain intracellular pH and inorganic phosphate levels.

Normal brain activity is associated with task-related pH changes. Although central nervous system syndromes associated with significant acidosis and alkalosis are well understood, the effects of less dramatic and chronic changes in brain pH are uncertain. One environmental factor known to alter brain pH is the extreme, acute change in altitude encountered by mountaineers. However, the effect of long-term exposure to moderate altitude has not been studied. The aim of this two-site study was to measure brain intracellular pH and phosphate-bearing metabolite levels at two altitudes in healthy volunteers, using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS). Increased brain pH and reduced inorganic phosphate (Pi) levels were found in healthy subjects who were long-term residents of Salt Lake City, UT (4720ft/1438m), compared with residents of Belmont, MA (20ft/6m). Brain intracellular pH at the altitude of 4720ft was more alkaline than that observed near sea level. In addition, the ratio of inorganic phosphate to total phosphate signal also shifted toward lower values in the Salt Lake City region compared with the Belmont area. These results suggest that long-term residence at moderate altitude is associated with brain chemical changes.

Decreased frontal lobe phosphocreatine levels in methamphetamine users.

BACKGROUND: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and ß-nucleoside triphosphate (ß-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter. METHODS: Study participants consisted of 51 METH (age=32.8±6.7) and 23 healthy comparison (age=31.1±7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored. RESULTS: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub-analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1±1.0g) of METH use than males (1.4±1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02). CONCLUSIONS: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels.

Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study.

OBJECTIVES: To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). METHODS: We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (ß-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. RESULTS: Analysis of covariance, including age as a covariate, revealed differences in PCr (p=0.037), Pi (p=0.017), and PCr/Pi (p=0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p=0.038) and medicated BD (24%; p=0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p=0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p=0.013) and with medicated BD (39%; p=0.002). No differences in ß-NTP or pH were observed. CONCLUSIONS: Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n-acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD.

Cocaine use in the past year is associated with altitude of residence.

OBJECTIVES: Recently, increased rates of suicide in US counties at higher altitudes have been noted. Because of the documented association between cocaine use and suicide, we hypothesized that there would be a correlation between incidence of cocaine use and altitude of residence. METHODS: Cocaine use data were obtained from the Substate Substance Abuse Estimates from the 1999-2001 National Surveys on Drug Use and Health. Data related to the percentages of people 12 years or older who used cocaine in the past year. Average elevation for US counties was calculated using the Shuttle Radar Topography Mission elevation data set, and subject region elevation was calculated by averaging the weighted elevations of each region's relevant counties. The correlation between elevation of a substate region and incidence of cocaine use in that region was calculated using Pearson correlation coefficients. RESULTS: A significant correlation exists between mean altitude of a substate region and incidence of cocaine use in that region (r = 0.34; P < 0.0001). Regression analysis controlling for age, sex, race, education level, income, unemployment, and population density was performed. Altitude remained a significant factor (P = 0.007), whereas male sex (P = 0.008) and possessing less than a college education (P < 0.0001) were also significant predictors of self-reported cocaine use in the past year. It is important to note that cocaine use was assessed in isolation of other drugs of abuse, an additional confounding variable. CONCLUSIONS: This study demonstrates a significant correlation between altitude of substate region of residence and incidence of cocaine use. It is possible that stress response due to hypoxia is responsible; however, this requires further investigation. However, because other substance use was not assessed, specificity of this association is unknown. In addition, this correlation may help explain the increased rate of suicide in areas of higher elevation.

Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study.

BACKGROUND: Adolescent major depressive disorder (MDD) is a life-threatening brain disease with limited interventions. Treatment resistance is common, and the illness burden is disproportionately borne by females. 31-Phosphorus magnetic resonance spectroscopy ((31)P MRS) is a translational method for in vivo measurement of brain energy metabolites. METHODS: We recruited 5 female adolescents who had been on fluoxetine (Prozac®) for ≥ 8 weeks, but continued meet diagnostic criteria for MDD with a Children's Depression Rating Scale-Revised (CDRS-R) raw score ≥ 40. Treatment response was measured with the CDRS-R. (31)P MRS brain scans were performed at baseline, and repeated following adjunctive creatine 4 g daily for 8 weeks. For comparison, 10 healthy female adolescents underwent identical brain scans performed 8 weeks apart. RESULTS: The mean CDRS-R score declined from 69 to 30.6, a decrease of 56%. Participants experienced no Serious Adverse Events, suicide attempts, hospitalizations or intentional self-harm. There were no unresolved treatment-emergent adverse effects or laboratory abnormalities. MDD participants' baseline CDRS-R score was correlated with baseline pH (p=0.04), and was negatively correlated with beta-nucleoside triphosphate (ß-NTP) concentration (p=0.03). Compared to healthy controls, creatine-treated adolescents demonstrated a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31)P MRS brain scans. LIMITATIONS: Lack of placebo control; and small sample size. CONCLUSIONS: Further study of creatine as an adjunctive treatment for adolescents with SSRI-resistant MDD is warranted.