Functional neuroimaging biomarkers of impaired neurocognition after proton beam radiotherapy for brain tumors in...

Proton beam radiotherapy (PBRT) is a mainstay in treatment of pediatric brain tumors and may reduce risk of neurotoxicity. We hypothesized that dose-dependent effects on resting-state networks (RSNs) would manifest as impaired neurocognition and quality of life (QoL) in pediatric patients undergoing PBRT.

Patients and age- and sex-matched healthy controls (HCs) were prospectively enrolled and underwent resting-state functional connectivity (FC) MRI and neurocognitive tests (NIH Toolbox, PROMIS QoL Questionnaire) at 3-5 months post-PBRT. Functional connectivity within and between RSNs (default mode network [DMN], dorsal attention network [DAN], executive central network [ECN], salience network [SN]) was compared. One-sample t-tests assessed average RSN-specific FC. Group-level analysis used paired t-tests (q = 0.05).

Twenty-eight participants (14 patients, 14 HCs; median age 14 years) were analyzed. Compared to HCs, patients displayed worse attention/executive function (P = .018), working memory (P = .011), and processing speed (P = .047). Patients had lower within-network FC in DMN (P = .013) and SN (P = .026). Patients had disrupted anticorrelation between DMN and SN, and less local efficiency of RSNs (corrected P < .05). Higher brain volume receiving ≥20 Gy, left hippocampus mean dose, and left temporal lobe mean dose were associated with RSN disruption in DMN and SN (|r|≥0.70). Lower SN FC was associated with poorer processing speed (P = .049). On multivariable analysis, ECN FC was associated with working memory (P = .016) and patients had worse working memory vs HCs (P = .009).

Compared to HCs, pediatric patients after PBRT displayed significant disruption in several RSNs, notably between SN and DMN critical in neurocognitive control. Dose-dependent neurocognition and QoL impairment warrant further investigation for mitigation.