Abstract
BACKGROUND: Combined chemoradiotherapy extends survival in high-grade glioma but may induce domain-specific neurocognitive deficits. The precise timing of greatest vulnerability and the hemispheric specificity of these effects remain unclear. We analyzed a novel longitudinal dataset in adult high-grade glioma patients to delineate critical post-treatment windows and hemisphere-dependent patterns of cognitive decline. MATERIAL AND METHODS: In this prospective study, 200 adult patients who underwent GTR surgery for high grade wild-type gliomas were given a comprehensive neuropsychological assessment at baseline and then again at 5 days, 1 month, 3 months, 6 months, and 12 months after completing concomitant radiochemotherapy and adjuvant chemiotherapy. The assessment included tasks such as Naming, the Token Test for comprehension, Semantic Fluency, Phonemic Fluency, Matrices of Attention, and the Trail Making Test A and B, as well as Praxis functions. Analyses were stratified by the irradiated hemisphere (left vs. right) to identify side-specific trajectories and to separate the effects of radiotherapy from those of chemotherapy. RESULTS: Patients undergoing concomitant radiochemotherapy typically experienced a disruption in their functional recovery one month after treatment. The greatest decline across all domains occurred one month post-treatment. Specifically Left-hemisphere irradiation yielded selective lack of recovery in language tests (during Naming, Token Test, Semantic Fluency, Phonemic Fluency), whereas right-hemisphere irradiation produced pronounced impairment in attention and executive measures (Matrices of Attention, Trail Making Test). In both right and left hemisphere a significant decrease of praxis performances recovery after post-rediotherapy were observed. In general, the most pronounced reduction in recovery is observed immediately following radiation therapy. However, a gradual improvement in recovery metrics is evident at the three-month mark, despite the ongoing administration of chemotherapy. CONCLUSION: Our findings identify the early post-radiotherapy period as the critical point for neurocognitive decline and demonstrate hemisphere-specific vulnerability. This evidence supports the development of hemisphere-targeted neuroprotective and rehabilitative strategies to mitigate radiotherapy-induced cognitive decline in high-grade glioma patients.