Clinical Significance of Tryptophan Metabolism in the Nontumoral Hemisphere in Patients with Malignant Glioma

Abstract

Alpha-11C-methyl-L-tryptophan positron emission tomography (AMT-PET) allows evaluation of brain serotonin synthesis and can also track upregulation of the immunosuppressive kynurenine pathway in tumor tissue. Increased AMT uptake is a hallmark of World Health Organization grade III–IV gliomas. Our recent study also suggested decreased frontal cortical AMT uptake in glioma patients contralateral to the tumor. The clinical significance of extratumoral tryptophan metabolism has not been established. In the present study, we investigated clinical correlates of tryptophan metabolic abnormalities in the non-tumoral hemisphere of glioma patients. Methods Standardized AMT uptake values (SUV) and the uptake rate constant of AMT (K [mL/g/min], a measure proportional to serotonin synthesis in non-tumoral gray matter) were quantified in the frontal and temporal cortex as well as thalamus in the non-tumoral hemisphere in 77 AMT-PET scans of 66 patients (41 males; mean age: 55±15 years) with grade III–IV gliomas. These AMT values were determined pre-treatment in 35 and post-treatment in 42 patients and were correlated with clinical variables and survival. Results AMT uptake in the thalamus showed a moderate age-related increase pre-treatment (SUV, r=0.39, p=0.02) but decrease post-treatment (K, r=−0.33; p=0.057). Females had higher thalamic SUVs pre-treatment (p=0.037) and higher thalamic (p=0.013) and frontal cortical K values (p=0.023) post-treatment. In the post-treatment glioma group, high thalamic SUVs and high thalamo-cortical SUV ratios were associated with short survival in Cox regression analysis. The thalamo-cortical ratio remained strongly prognostic (p<0.01) when clinical predictors, including age, glioma grade, and time since radiotherapy were entered in the regression model. Long interval between radiotherapy and post-treatment AMT-PET as well as high radiation dose affecting the thalamus were associated with lower contralateral thalamic or cortical AMT uptake values. Conclusions These observations provide evidence for altered tryptophan uptake in contralateral cortical and thalamic brain regions in glioma patients after initial therapy, suggesting treatment effects on the serotonergic system. Low thalamic tryptophan uptake appears to be a strong, independent predictor of long survival in patients with previous glioma treatment.

Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

“…This highlights the potential for serotonin receptor activation to promote GBM growth and invasion [179]. This is in line with PET scanning observation showing serotonin binding to various receptors [218] and tryptophan uptake correlated with decreased survival of patients [219]. The tumor source of serotonin may come from the platelet aggregation of the thrombotic environment of GBM.…”

Imaging cerebral tryptophan metabolism in brain tumor-associated depression

“…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.…”

“…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.…”

“…Application of AMT-PET has also been studied in brain tumor imaging: AMT is accumulated in various brain tumors, and kinetic AMT-PET parameters are able to differentiate various brain tumor types, assess glioma proliferative activity, and estimate IDO and tryptophan 2,3-dioxygenase expression in both gliomas and meningiomas [ 27 – 32 ]. Interestingly, our recent studies in patients with brain tumors who underwent AMT-PET scan also demonstrated abnormal AMT uptake and kinetics in non-tumoral brain regions contralateral to the tumor [ 33 , 34 ]. In patients with post-treatment malignant gliomas, altered AMT uptake in the contralateral cortex and thalamus was observed, and high thalamic uptake was a predictor of shorter survival [ 34 ].…”

“…Interestingly, our recent studies in patients with brain tumors who underwent AMT-PET scan also demonstrated abnormal AMT uptake and kinetics in non-tumoral brain regions contralateral to the tumor [ 33 , 34 ]. In patients with post-treatment malignant gliomas, altered AMT uptake in the contralateral cortex and thalamus was observed, and high thalamic uptake was a predictor of shorter survival [ 34 ].…”