Molecular features and tumor location interact to account for preoperative cognitive-emotional status in glioma

Integrated molecular profiling has revolutionized brain tumor classification, but its ability to explain preoperative cognitive-emotional phenotypes in glioma patients relative to traditional anatomical factors remains unclear. This study investigated whether molecular features interact with tumor location to influence neuropsychological status, and whether such effects are anatomically context-dependent.

We prospectively enrolled 101 newly diagnosed glioma patients and 52 matched healthy controls. All participants underwent comprehensive neuropsychological assessments. Using a hierarchical strategy, we first stratified patients by tumor location, then examined associations of molecular characteristics and clinical factors with cognitive-emotional measures within each anatomical subgroup. Finally, multivariable regression analyses with formal interaction terms were performed in the entire cohort to test molecular-location interactions.

No significant differences in cognitive or emotional function were observed between patients with deep insular versus superficial frontal-temporal-parietal tumors. However, within the deep insular subgroup, IDH mutation remained associated with distinct patterns of emotional and attentional function after correction for multiple comparisons. Within the superficial frontal subgroup, tumor grade and several specific molecular features showed domain-specific associations with empathy or working memory. Critically, multivariable regression confirmed significant molecular-location interactions: IDH × insular for negative affect and attentional control; grade × frontal and TERT × frontal for empathy; and 1p/19q × frontal for working memory. These findings indicate that molecular features and tumor location interact to explain neuropsychological outcomes more effectively than either factor alone.

Molecular influences on preoperative cognitive-emotional status in glioma are anatomically context-dependent. Molecular features and tumor location interact to shape neuropsychological outcomes, supporting an integrated framework that incorporates both molecular and anatomical information into preoperative evaluation and personalized management strategies.