Abstract
Immunohistochemical data based on isocitrate–dehydrogenase (IDH) mutation status have redefined glioma as a whole-brain disease, while occult tumor cell invasion along white matter fibers is inapparent in conventional magnetic resonance imaging (MRI). The functional and prognostic impact of focal glioma may however relate to the extent of white matter involvement. We used diffusion tensor imaging (DTI) to investigate microstructural characteristics of whole-brain normal-appearing white matter (NAWM) in relation to cognitive functions as potential surrogates for occult white matter involvement in glioma. Twenty patients (12 IDH-mutated) and 20 individually matched controls were preoperatively examined using DTI combined with a standardized neuropsychological examination. Tumor lesions including perifocal edema were masked, and fractional anisotropy (FA) as well as mean, radial, and axial diffusivity (MD, RD, and AD, respectively) of the remaining whole-brain NAWM were determined by using Tract-Based Spatial Statistics and histogram analyses. The relationship between extratumoral white matter integrity and cognitive performance was examined using partial correlation analyses controlling for age, education, and lesion volumes. In patients, mean FA and AD were decreased as compared to controls, which agrees with the notion of microstructural impairment of NAWM in glioma patients. Patients performed worse in all cognitive domains tested, and higher anisotropy and lower MD and RD values of NAWM were associated with better cognitive performance. In additional analyses, IDH-mutated and IDH-wildtype patients were compared. Patients with IDH-mutation showed higher FA, but lower MD, AD, and RD values as compared to IDH-wildtype patients, suggesting a better preserved microstructural integrity of NAWM, which may relate to a less infiltrative nature of IDH-mutated gliomas. Diffusion-based phenotyping and monitoring microstructural integrity of extratumoral whole-brain NAWM may aid in estimating occult white matter involvement and should be considered as a complementary biomarker in glioma.
Highlights
While the extent of tumor resection is regarded as an important therapy-dependent prognostic factor, the infiltrative nature of diffuse glioma remains a diagnostic and therapeutic problem and an obstacle to curative treatment
normal-appearing white matter (NAWM) of patients and controls differed in anisotropy, with significantly lower fractional anisotropy (FA) and axial diffusivity (AD) values in patients compared to controls (FAM : MPAT = 0.42 and MCG = 0.43 units, t = 1.85, p = 0.04, effect sizes (ES) = –=49, CI = [−1.12–0.14]; ADM : MPAT = 1.17 and MCG = 1.18 mm2/s, t = 2.01, p = 0.03, ES = –=49, CI = [−1.12– 0.14])
Significant group differences in cognitive performance were found for verbal learning and task switching (VLMT_rec: MPAT = 47 and MCG = 57 words, t = 2.65, p = 0.01, ES = –=91, CI = [−1.64 to −0.18]; TMT_RTexe: MPAT = 43 and MCG = 23 s, t = −2.54, p = 0.01, ES = 0.98, CI = [0.19–1.76])
Summary
While the extent of tumor resection is regarded as an important therapy-dependent prognostic factor, the infiltrative nature of diffuse glioma remains a diagnostic and therapeutic problem and an obstacle to curative treatment. Occult tumor cell invasion has thereby been delineated even in areas remote to the primary tumor site, which had macro- and microscopically appeared unaffected [2] These findings have redefined cerebral glioma as a systemic rather than focal brain disease, which is supported by cellular observations of diffusively invading tumor cells expanding to extensive intracerebral networks [3]. As diffuse infiltrative glioma growth has histologically been characterized to occur typically along white matter (WM) tracts [4], diffusion tensor imaging (DTI) appears of particular interest It provides indirect information about the microstructural WM architecture and its integrity in vivo, based on water diffusion properties in the intra- and extracellular space [5]. While higher FA and AD in WM have been linked to preserved fiber integrity, increases in MD and RD have been related to structural disintegration [12]
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