Increased pregenual anterior cingulate glucose and lactate concentrations in major depressive disorder
Andreas Hock1,2, Jutta Ernst2, Anke Henning1,3, Erich Seifritz2, Heinz Boeker2, and Simone Grimm2,4

1Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, 2Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Zurich, Switzerland, 3Max Planck Institute for Biological Cybernetics, Tuebingen, Germany, 4Department of Psychiatry, Charité, Berlin, Germany

Synopsis

Proton magnetic resonance spectroscopy (1H-MRS) was used to test whether patients with major depressive disorder have increased glucose and lactate levels in the pregenual anterior cingulate cortex (PACC) compared to healthy controls. Therefore, forty healthy and depressed participants spectra were acquired from the PACC using a maximum echo JPRESS protocol. Results show significant increases of glucose and lactate in patients, which are also associated with depression severity. These findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate.

Purpose

There is ample evidence that glucose metabolism as assessed by 18F FDG PET in the pregenual anterior cingulate cortex (PACC) is increased in major depressive disorder (MDD) (1). Elevated cerebrospinal fluid (CSF) lactate concentrations in MDD patients might indicate that increased glycolytical metabolization of glucose to lactate either alone or in conjunction with mitochondrial dysfunction results in an accumulation of lactate and contribute to pathophysiological mechanisms of MDD. However, until now, no study investigated PACC glucose and lactate levels in MDD in vivo. In this work, J-resolved proton magnetic resonance spectroscopy (1H-MRS) was therefore used to test whether patients with MDD have increased PACC glucose and lactate levels.

Methods

In 20 patients with major depression (MD) and 20 age and sex matched healthy controls spectra were acquired from the PACC using a maximum echo JPRESS protocol (2) at 3T (Achieva, Philips Healthcare, Best, The Netherlands) (Figure 1) with a minimum echo time of TE=28 ms and a repetition time of TR=1600 ms. The echo increment to encode the indirect dimension was set to 2 ms. 100 steps were acquired obtaining 8 averages per TE. After zero and first order phase correction and visual artifact inspection (ghosting, bad water suppression, line shape distortions) data were quantified using Profit 2.0 (3). Based on the high-resolution 3D T1 weighted images the fraction of cerebral spinal fluid (CSF), grey matter (GM) and white matter (WM) were calculated using SPM8 and a custom written MATLAB script. The metabolite concentrations normalized to internal creatine were corrected for differences in volume tissue composition as previously reported (4, 5). All metabolite concentrations regardless of the Cramer-Rao Lower Bound (CRLB) value were included in the statistic (no CRLB threshold was used) with the exception of infinitely high CRLB values (in case a metabolite could not be fitted in a data set) to avoid bias towards higher concentrations (6).

Results

Data from one patient with comorbid diabetes was excluded from the analysis because chronic hyperglycemia might result in elevated brain glucose levels (7). In addition, two patient spectra had to be excluded because of insufficient data quality. The resulting groups consisted of 17 subjects with depression (mean age, 31.7 years; 10 females) and 20 control subjects (mean age, 28.1 years; 11 females). Data from 5 depressive and 7 healthy subjects were excluded from the glucose analysis and data from 3 depressive subjects were excluded from the lactate analysis because of infinitely high CRLB values. Results show significant increases of glucose and lactate in patients (Figure 2), which are also associated with depression severity (Figure 3). There was a significant positive correlation of symptom severity with glucose (r= .41, p = .038) and a trend for a correlation with lactate (r= .33, p = .051) concentrations (Figure 4).

Discussion

Our findings indicate impaired brain energy metabolism in MDD with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate. The here reported increases in glucose concentration in PACC are consistent with the increased glucose metabolism as measured by FDG PET in this area in depressive patients (1,8). The increased glucose concentration we report here in the PACC may therefore reflect heightened glucose supply to this region due to increased cerebral blood flow (CBF) (8). Targeting these metabolic disturbances may affect the balance of metabolic pathways regulating neuronal energetics and may result in an attenuation of the elevated basal activity of brain regions within the neural circuitry of depression.

Acknowledgements

Funding by the Swiss National Science Foundation (Grant No.: 143715) as well as the participation of all volunteers in the current study is gratefully acknowledged.

References

1. Pizzagalli DA. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 2011;36(1):183-206.

2. Schulte RF, Lange T, Beck J, Meier D, Boesiger P. Improved two-dimensional J-resolved spectroscopy. NMR in Biomedicine 2006;19(2):264-270.

3. Fuchs A, Boesiger P, Schulte RF, Henning A. ProFit revisited. Magn Reson Med 2014;71(2):458-468.

4. Gasparovic C, Song T, Devier D, Bockholt HJ, Caprihan A, Mullins PG, Posse S, Jung RE, Morrison LA. Use of tissue water as a concentration reference for proton spectroscopic imaging. Magnetic Resonance in Medicine 2006;55(6):1219-1226.

5. Zoelch N, Hock A, Scheidegger M, Hulka L, Quednow B, Henning A. Necessity of tissue volume composition correction for internal referencing. Proc Intl Soc Mag Reson Med, Toronto, Ontario, Canada 2015(7080).

6. Kreis R. The trouble with quality filtering based on relative Cramér-Rao lower bounds. Magn Reson Med 2015:n/a-n/a.

7. Jacob R, Fan X, Evans M, Dziura J, Sherwin R. Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no evidence for protective adaptation by the blood brain barrier. Metabolism 2002;51(12):1522-1524.

8. Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. European Neuropsychopharmacology 2002;12(6):527-544.

Figures

Fig. 1: T1 weighted image of one exemplary patient. Color overlays represent segmentation results for GM (red), WM (blue), and CSF (green). In addition, the voxel placement is shown in yellow (Figure created with MRIcron, Version 6.6.2013).

Fig. 2: (a) 2-dimensional J-press data from one exemplary patient, (b) Profit2 fit, (c) residuum of the fit, (d) Lactate (Lac) contribution to the fit, and (e) Glucose (Glc) contribution to the fit.

Fig. 3: (A) Mean glucose and (B) lactate concentrations (relative to creatine [Cr]) ±standard error of the mean measured in the magnetic resonance spectroscopic voxel depicted in the PACC in healthy controls and MDD patients.

Fig. 4: Association between symptom severity and glucose concentration in PACC.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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