Imaging cerebral tryptophan metabolism in brain tumor-associated depression

Edit Bosnyák, David O Kamson, Michael E Behen, Geoffrey R Barger, Sandeep Mittal, Csaba Juhász, Edit Bosnyák, David O Kamson, Michael E Behen, Geoffrey R Barger, Sandeep Mittal, Csaba Juhász

Abstract

Background: Depression in patients with brain tumors is associated with impaired quality of life and shorter survival. Altered metabolism of tryptophan to serotonin and kynurenine metabolites may play a role in tumor-associated depression. Our recent studies with alpha[(11)C]methyl-L-tryptophan (AMT)-PET in brain tumor patients indicated abnormal tryptophan metabolism not only in the tumor mass but also in normal-appearing contralateral brain. In the present study, we explored if tryptophan metabolism in such brain regions is associated with depression.

Methods: Twenty-one patients (mean age: 57 years) with a brain tumor (10 meningiomas, 8 gliomas, and 3 brain metastases) underwent AMT-PET scanning. MRI and AMT-PET images were co-registered, and AMT kinetic parameters, including volume of distribution (VD', an estimate of net tryptophan transport) and K (unidirectional uptake, related to tryptophan metabolism), were measured in the tumor mass and in unaffected cortical and subcortical regions contralateral to the tumor. Depression scores (based on the Beck Depression Inventory-II [BDI-II]) were correlated with tumor size, grade, type, and AMT-PET variables.

Results: The mean BDI-II score was 12 ± 10 (range: 2-33); clinical levels of depression were identified in seven patients (33 %). High BDI-II scores were most strongly associated with high thalamic AMT K values both in the whole group (Spearman's rho = 0.63, p = 0.004) and in the subgroup of 18 primary brain tumors (r = 0.68, p = 0.004). Frontal and striatal VD' values were higher in the depressed subgroup than in non-depressed patients (p < 0.05); the group difference was even more robust when moderately/severely depressed patients were compared to patients with no/mild depression (frontal: p = 0.005; striatal: p < 0.001). Tumor size, grade, and tumor type were not related to depression scores.

Conclusions: Abnormalities of tryptophan transport and metabolism in the thalamus, striatum, and frontal cortex, measured by PET, are associated with depression in patients with brain tumor. These changes may indicate an imbalance between the serotonin and kynurenine pathways and serve as a molecular imaging marker of brain tumor-associated depression.

Trial registration: ClinicalTrials.gov NCT02367469.

Keywords: Brain tumor; Cortical; Depression; Kynurenine; Magnetic resonance imaging; Positron emission tomography; Serotonin; Striatum; Thalamus; Tryptophan.

Figures

Fig. 1
Fig. 1
AMT-PET/T1-Gad MRI fusion images of a patient (#10) with left frontal WHO grade 2 glioma. Contralateral frontal, parietal, and temporal cortical, as well as thalamic and striatal regions of interest used for analysis, are outlined in red
Fig. 2
Fig. 2
Positive correlation between thalamus AMT K values and BDI-II depression scores (Spearman’s rho = 0.63, p = 0.004)
Fig. 3
Fig. 3
Comparison of AMT-PET variables in patients with no/mild depression vs. moderate/severe depression. Frontal and striatal AMT volume of distribution (VD’) values were significantly higher in patients with moderate/severe depression (frontal VD’: 0.43 vs. 0.31, p = 0.005; striatal VD’: 0.61 vs. 0.35, p < 0.001)

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