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

Abstract

Mutation of the IDH1 gene is associated with differences in malignant astrocytoma growth characteristics that impact phenotypic severity, including cognitive impairment. We previously demonstrated greater cognitive impairment in patients with IDH1 wild type tumor compared to those with IDH1 mutant, and therefore we hypothesized that brain network organization would be lower in patients with wild type tumors. Volumetric, T1-weighted MRI scans were obtained retrospectively from 35 patients with IDH1 mutant and 32 patients with wild type malignant astrocytoma (mean age = 45 ± 14 years) and used to extract individual level, gray matter connectomes. Graph theoretical analysis was then applied to measure efficiency and other connectome properties for each patient. Cognitive performance was categorized as impaired or not and random forest classification was used to explore factors associated with cognitive impairment. Patients with wild type tumor demonstrated significantly lower network efficiency in several medial frontal, posterior parietal and subcortical regions (p < 0.05, corrected for multiple comparisons). Patients with wild type tumor also demonstrated significantly higher incidence of cognitive impairment (p = 0.03). Random forest analysis indicated that network efficiency was inversely, though nonlinearly associated with cognitive impairment in both groups (p < 0.0001). Cognitive reserve appeared to mediate this relationship in patients with mutant tumor suggesting greater neuroplasticity and/or benefit from neuroprotective factors. Tumor volume was the greatest contributor to cognitive impairment in patients with wild type tumor, supporting our hypothesis that greater lesion momentum between grades may cause more disconnection of core neurocircuitry and consequently lower efficiency of information processing.

Keywords: Astrocytoma; Cognition; Connectome; IDH1; MRI.

Fig. 1

Nodal (regional) efficiency. Patients with wild type tumor showed significantly (p < 0.05, FDR corrected) lower efficiency in multiple brain regions compared to mutant (blue) as well as one area of higher efficiency (purple). Color bar indicates log(p value). Regions are shown overlaid on a Montreal Neurological Institute 152 standard template from BrainNet Viewer [65]

Fig. 2

Cumulative degree distribution power-law fit. Patients with mutant tumor demonstrated a good fit to the power-law (red line). However, patients with wild type tumor demonstrated a significantly poorer fit (p < 0.03) indicating fewer hubs and a disrupted information processing core

Fig. 3

Predictors of cognitive impairment. Random forest classification indicated that global efficiency (arbitrary units) and education (years) were the most important predictors of cognitive impairment in patients with mutant tumor while tumor volume (cc cubic centimeters) was the greatest contributor to cognitive impairment in patients with wild type tumor