Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

BACKGROUND: In glioma patients, multimodality therapy and recurrent tumor can lead to structural brain tissue damage characterized by pathologic findings in MR and PET imaging. However, little is known about the impact of different types of damage on the fiber architecture of the affected white matter. PATIENTS AND METHODS: This study included 121 pretreated patients (median age, 52 years; ECOG performance score, 0 in 48%, 1-2 in 51%) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median follow-up time of 14 months (range, 1-214 months), anatomic MR and O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) PET images were acquired on a 3T hybrid PET/MR scanner. Post-therapeutic findings comprised resection cavities, regions with contrast enhancement or increased FET uptake and T2/FLAIR hyperintensities. Local fiber density was determined from high angular-resolution diffusion-weighted imaging and advanced tractography methods. A cohort of 121 healthy subjects selected from the 1000BRAINS study matched for age, gender and education served as a control group. RESULTS: Lesion types differed in both affected tissue volumes and relative fiber densities compared to control values (resection cavities: median volume 20.9 mL, fiber density 16% of controls; contrast-enhanced lesions: 7.9 mL, 43%; FET uptake areas: 30.3 mL, 49%; T2/FLAIR hyperintensities: 53.4 mL, 57%, p<0.001). In T2/FLAIR-hyperintense lesions caused by peritumoral edema due to recurrent glioma (n=27), relative fiber density was as low as in lesions associated with radiation-induced gliosis (n=13, 48% vs. 53%, p=0.17). In regions with pathologically increased FET uptake, local fiber density was inversely related (p=0.005) to the extent of uptake. Total fiber loss associated with contrast-enhanced lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on overall ECOG score. CONCLUSIONS: These results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients’ performance status due to the larger volume affected.