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Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression

View Article: PubMed Central - PubMed

ABSTRACT

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-α to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

No MeSH data available.


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Association between plasma C-reactive protein (CRP) and the left basal ganglia glutamate in depressed patients. Plasma CRP was positively associated with the left basal ganglia absolute glutamate in both a linear (a) and step-wise manner (b), in medication-free patients with major depressive disorder. (a) Increased log plasma CRP correlated and log left basal ganglia absolute glutamate concentrations in depressed subjects after controlling for age, sex, race, smoking status, body mass index and 17-item Hamilton Depression Rating Scale scores (β=0.36, t=2.57, P=0.014). (b) Group-wise comparison of log left basal ganglia absolute glutamate concentrations among patients grouped by CRP revealed a significant main effect of group (F[2,43]=4.42, P=0.018). *P<0.025.
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fig1: Association between plasma C-reactive protein (CRP) and the left basal ganglia glutamate in depressed patients. Plasma CRP was positively associated with the left basal ganglia absolute glutamate in both a linear (a) and step-wise manner (b), in medication-free patients with major depressive disorder. (a) Increased log plasma CRP correlated and log left basal ganglia absolute glutamate concentrations in depressed subjects after controlling for age, sex, race, smoking status, body mass index and 17-item Hamilton Depression Rating Scale scores (β=0.36, t=2.57, P=0.014). (b) Group-wise comparison of log left basal ganglia absolute glutamate concentrations among patients grouped by CRP revealed a significant main effect of group (F[2,43]=4.42, P=0.018). *P<0.025.

Mentions: Log CRP was the only significant predictor of log left basal ganglia glutamate after exclusion of covariates (β=0.36, t=2.57, P=0.01, Cohen's f2=0.33, power=0.95; Figure 1). One-way ANOVA also revealed a significant main effect of CRP group on log left basal ganglia glutamate (F[2,43]=4.42, P=0.02, d=0.90, power=0.80), with the high CRP group (>3 mg l−1, n=14) exhibiting significantly greater log glutamate concentrations than the low CRP group (<1 mg l−1, n=22; mean difference=0.062, SE=0.021, Pcorr=0.02, d=1.15, power=0.95; Figure 1). This relationship remained significant after controlling for covariates including body mass index, which was the only covariate which differed among CRP groups (high CRP group: 38.7±7.1; medium CRP group: 32.6±7.2; low CRP group: 26.5±4.3; F[2,49]=17.7, P<0.001). Although log plasma CRP was highly correlated with log CSF CRP (r=0.87, P<0.001, d=3.53), log CSF CRP did not predict log left basal ganglia glutamate concentrations (β=0.29, t=1.8, P=0.085, Cohen's f2=0.09, power=0.49), albeit the analysis was underpowered. No significant associations were found between log plasma or log CSF CRP and log absolute glutamate concentrations in the dACC using linear regression or ANOVA (P=NS). Therefore, the dACC was not considered in further analyses.


Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression
Association between plasma C-reactive protein (CRP) and the left basal ganglia glutamate in depressed patients. Plasma CRP was positively associated with the left basal ganglia absolute glutamate in both a linear (a) and step-wise manner (b), in medication-free patients with major depressive disorder. (a) Increased log plasma CRP correlated and log left basal ganglia absolute glutamate concentrations in depressed subjects after controlling for age, sex, race, smoking status, body mass index and 17-item Hamilton Depression Rating Scale scores (β=0.36, t=2.57, P=0.014). (b) Group-wise comparison of log left basal ganglia absolute glutamate concentrations among patients grouped by CRP revealed a significant main effect of group (F[2,43]=4.42, P=0.018). *P<0.025.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940313&req=5

fig1: Association between plasma C-reactive protein (CRP) and the left basal ganglia glutamate in depressed patients. Plasma CRP was positively associated with the left basal ganglia absolute glutamate in both a linear (a) and step-wise manner (b), in medication-free patients with major depressive disorder. (a) Increased log plasma CRP correlated and log left basal ganglia absolute glutamate concentrations in depressed subjects after controlling for age, sex, race, smoking status, body mass index and 17-item Hamilton Depression Rating Scale scores (β=0.36, t=2.57, P=0.014). (b) Group-wise comparison of log left basal ganglia absolute glutamate concentrations among patients grouped by CRP revealed a significant main effect of group (F[2,43]=4.42, P=0.018). *P<0.025.
Mentions: Log CRP was the only significant predictor of log left basal ganglia glutamate after exclusion of covariates (β=0.36, t=2.57, P=0.01, Cohen's f2=0.33, power=0.95; Figure 1). One-way ANOVA also revealed a significant main effect of CRP group on log left basal ganglia glutamate (F[2,43]=4.42, P=0.02, d=0.90, power=0.80), with the high CRP group (>3 mg l−1, n=14) exhibiting significantly greater log glutamate concentrations than the low CRP group (<1 mg l−1, n=22; mean difference=0.062, SE=0.021, Pcorr=0.02, d=1.15, power=0.95; Figure 1). This relationship remained significant after controlling for covariates including body mass index, which was the only covariate which differed among CRP groups (high CRP group: 38.7±7.1; medium CRP group: 32.6±7.2; low CRP group: 26.5±4.3; F[2,49]=17.7, P<0.001). Although log plasma CRP was highly correlated with log CSF CRP (r=0.87, P<0.001, d=3.53), log CSF CRP did not predict log left basal ganglia glutamate concentrations (β=0.29, t=1.8, P=0.085, Cohen's f2=0.09, power=0.49), albeit the analysis was underpowered. No significant associations were found between log plasma or log CSF CRP and log absolute glutamate concentrations in the dACC using linear regression or ANOVA (P=NS). Therefore, the dACC was not considered in further analyses.

View Article: PubMed Central - PubMed

ABSTRACT

Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-&alpha; to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP.

No MeSH data available.


Related in: MedlinePlus