Neurocognitive function varies by IDH1 genetic mutation status in patients with malignant glioma prior to surgical resection

Abstract

Background.Patients with malignant gliomas present with variation in neurocognitive function (NCF) not attributable to lesion size or location alone. A potential contributor is the rate at which tumors grow, or "lesion momentum." Isocitrate dehydrogenase 1 wild type (IDH1-WT) are more proliferative and aggressive than IDH1-mutant (IDH1-M) tumors. We hypothesized that patients with IDH1-WT would exhibit worse NCF than patients with IDH1-M tumors. Methods.Comprehensive NCF testing was completed in 119 patients with malignant glioma prior to surgical resection. IDH1 status was determined with immunohistochemistry and sequencing. Rates of impairment and mean test performances were compared by IDH1.Results. NCF impairment was significantly more frequent in patients with IDH1-WT tumors in memory, processing speed, visuoconstruction, language, executive functioning, and manual dexterity. Mean performances of patients with IDH1-WT were also significantly lower than those with IDH1-M tumors on measures of learning and memory, processing speed, language, executive functioning, and dexterity. Lesion volume was not statistically different between IDH1-WT and IDH1-M tumors. Tumor and lesion volume on T1-weighted and fluid attenuated inversion recovery MRI were significantly associated with most NCF tests in patients with IDH1-WT, but only significantly associated with a single measure in patients with IDH1-M tumors. Conclusion.Patients with IDH1-WT show reduced NCF compared with those with IDH1-M malignant gliomas. Lesion volume is inversely associated with NCF for patients with IDH1-WT, but not IDH1-M tumors. These findings are consistent with the hypothesis that patients with IDH1-WT tumors present with more severe NCF impairment due to greater lesion momentum, which may impede compensatory neuroplasticity and cerebral reorganization.

Understanding cognitive functioning in glioma patients: The relevance of IDH‐mutation status and functional connectivity

“…The same group investigated cortical thickness covariation as a neural correlate of this difference, showing that thickness covariation patterns indeed differ between subgroups and associate with cognition (Kesler et al, ). This provides a first insight into possible mechanisms underlying IDH‐mutation‐related cognitive differences and also suggests that tumor growth rate might contribute to cognitive problems (Klein, ; Wefel et al, ). However, the observed group differences in covarying cortical thickness were not corrected for age or presence of epilepsy.…”

“…Wefel and colleagues were the first to describe worse cognitive performance in patients with IDH‐wt glioma compared to patients with IDH‐mut glioma (Wefel et al, ). The same group investigated cortical thickness covariation as a neural correlate of this difference, showing that thickness covariation patterns indeed differ between subgroups and associate with cognition (Kesler et al, ).…”

“…An important marker for survival in patient with diffuse glioma is isocitrate dehydrogenase (IDH) mutation (IDH‐mut), which is associated with better prognosis but higher epilepsy prevalence (Chen et al, ; Yan et al, ). Patients with wildtype glioma (IDH‐wt) are generally older and more often have cognitive deficits (Wefel, Noll, Rao, & Cahill, ), even though they less often have epileptic seizures that are generally linked to poorer cognitive functioning (Chen et al, ; Klein, Engelberts, et al, ). Although the relevance of IDH status for survival is relatively straightforward (Yan et al, ), the higher occurrence of cognitive deficits at diagnosis in patients with IDH‐wt glioma as compared to patients with IDH‐mut glioma is incompletely understood.…”

The effect of IDH1 mutation on the structural connectome in malignant astrocytoma

“…We also included education level considering its significant independent contribution, as a proxy of cognitive reserve [42], to cognitive outcome following cancer [43] and other neurologic conditions. Age and histology were not included in this or any other models given that these variables reflect the known etiologic and pathologic differences associated with IDH1 subtypes [7, 44]. …”

“…We recently demonstrated that patients with wild type malignant gliomas show greater cognitive dysfunction compared to their mutant counterparts [7]. Additionally, greater lesion size was associated with worse cognition almost exclusively in patients with wild type tumors.…”