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Imaging cerebral tryptophan metabolism in brain tumor-associated depression.

Bosnyák E, Kamson DO, Behen ME, Barger GR, Mittal S, Juhász C - EJNMMI Res (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Wayne State University, 3901 Beaubien Street, Detroit, MI, 48201, USA. drbosnyakedit@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig1: 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

Mentions: For visualization of AMT uptake in the brain, averaged activity images 30–55 min post-injection were created and converted to an AMT standardized uptake value (SUV) image. For quantification of AMT accumulation, a Patlak graphical analysis was performed using the dynamic brain PET images and blood input function [27, 36]. This approach provides two main kinetic parameters. The y-intercept of the Patlak plot yields the tracer’s apparent volume of distribution (VD’), which is tightly correlated with VD values derived from compartmental analysis [21, 27, 37]; AMT VD’ values are indicative of the net transport of tryptophan into the tissue of interest (tumor or cortex). The slope of the Patlak plot (K-complex or K) reflects the unidirectional uptake of the tracer into the tissue and correlates with tryptophan metabolism via the serotonin synthesis pathway in cortex [21, 22]. In brain tumors, with no evidence of serotonin synthesis, the most likely mechanism of an increase in AMT K-complex is tumoral accumulation in the form of either unmetabolized AMT or kynurenine metabolites. The advantages and limitations of using these kinetic AMT-PET parameters have been discussed previously [21, 27, 30]. For image analysis, the 3D Slicer 3.6.3 software suite was used (Brigham and Women’s Hospital, Inc.) as described previously [32, 34, 38, 39]. First, a transformation matrix was created by co-registration of the summed AMT-PET images to the T1-Gad volumetric image volumes (magnetization-prepared rapid gradient-echo [MPRAGE] protocol on Siemens or MPRAGE-equivalent sequence on GE and Philips scanners) as well as FLAIR images using the Fast Rigid Registration module. This transformation matrix was then applied to the summed AMT-PET image and to the dynamic AMT-PET images loaded via the 4D Image module of the 3D Slicer. Following fusion of the summed AMT-PET with MR images, the largest orthogonal diameters as well as maximum tumor area on T1-Gad (or T2/FLAIR images, if no enhancement was seen) were measured. Regions of interest (ROIs) were drawn on the tumor mass in tumor regions with contrast enhancement and/or T2/FLAIR signal changes on MRI. In addition, cortical and subcortical regions, contralateral to the tumor, were delineated and analyzed as described recently [34]; for the three tumors close to the midline, the tumor side was defined as the side with the larger tumor mass. In brief, regions of interest were segmented manually using the axial view of the PET/MRI fusion images (Fig. 1). The ROIs included gray matter voxels with AMT uptake: a single plane for the thalamus and striatum with the largest axial diameter and multiple planes (one to two planes apart) for the cortical ROIs including the frontal (three planes), temporal (two planes), and parietal (two planes) lobes. None of these ROIs showed abnormal contrast-enhancement or FLAIR signal on co-registered MR images. Similar to our previous study, the occipital cortex, which often shows high physiologic AMT uptake, was not included in the analyses. All tumoral and contralateral cortical and subcortical ROIs were applied on the co-registered AMT SUV as well as dynamic PET images, and AMT SUV as well as K and VD’ values from the Patlak analysis was obtained for each region.Fig. 1


Imaging cerebral tryptophan metabolism in brain tumor-associated depression.

Bosnyák E, Kamson DO, Behen ME, Barger GR, Mittal S, Juhász C - EJNMMI Res (2015)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608955&req=5

Fig1: 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
Mentions: For visualization of AMT uptake in the brain, averaged activity images 30–55 min post-injection were created and converted to an AMT standardized uptake value (SUV) image. For quantification of AMT accumulation, a Patlak graphical analysis was performed using the dynamic brain PET images and blood input function [27, 36]. This approach provides two main kinetic parameters. The y-intercept of the Patlak plot yields the tracer’s apparent volume of distribution (VD’), which is tightly correlated with VD values derived from compartmental analysis [21, 27, 37]; AMT VD’ values are indicative of the net transport of tryptophan into the tissue of interest (tumor or cortex). The slope of the Patlak plot (K-complex or K) reflects the unidirectional uptake of the tracer into the tissue and correlates with tryptophan metabolism via the serotonin synthesis pathway in cortex [21, 22]. In brain tumors, with no evidence of serotonin synthesis, the most likely mechanism of an increase in AMT K-complex is tumoral accumulation in the form of either unmetabolized AMT or kynurenine metabolites. The advantages and limitations of using these kinetic AMT-PET parameters have been discussed previously [21, 27, 30]. For image analysis, the 3D Slicer 3.6.3 software suite was used (Brigham and Women’s Hospital, Inc.) as described previously [32, 34, 38, 39]. First, a transformation matrix was created by co-registration of the summed AMT-PET images to the T1-Gad volumetric image volumes (magnetization-prepared rapid gradient-echo [MPRAGE] protocol on Siemens or MPRAGE-equivalent sequence on GE and Philips scanners) as well as FLAIR images using the Fast Rigid Registration module. This transformation matrix was then applied to the summed AMT-PET image and to the dynamic AMT-PET images loaded via the 4D Image module of the 3D Slicer. Following fusion of the summed AMT-PET with MR images, the largest orthogonal diameters as well as maximum tumor area on T1-Gad (or T2/FLAIR images, if no enhancement was seen) were measured. Regions of interest (ROIs) were drawn on the tumor mass in tumor regions with contrast enhancement and/or T2/FLAIR signal changes on MRI. In addition, cortical and subcortical regions, contralateral to the tumor, were delineated and analyzed as described recently [34]; for the three tumors close to the midline, the tumor side was defined as the side with the larger tumor mass. In brief, regions of interest were segmented manually using the axial view of the PET/MRI fusion images (Fig. 1). The ROIs included gray matter voxels with AMT uptake: a single plane for the thalamus and striatum with the largest axial diameter and multiple planes (one to two planes apart) for the cortical ROIs including the frontal (three planes), temporal (two planes), and parietal (two planes) lobes. None of these ROIs showed abnormal contrast-enhancement or FLAIR signal on co-registered MR images. Similar to our previous study, the occipital cortex, which often shows high physiologic AMT uptake, was not included in the analyses. All tumoral and contralateral cortical and subcortical ROIs were applied on the co-registered AMT SUV as well as dynamic PET images, and AMT SUV as well as K and VD’ values from the Patlak analysis was obtained for each region.Fig. 1

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Wayne State University, 3901 Beaubien Street, Detroit, MI, 48201, USA. drbosnyakedit@gmail.com.

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.

No MeSH data available.


Related in: MedlinePlus