Krijnen_2026_Neurooncol.Adv_8_vdag123

BACKGROUND: Neurocognitive deficits are common in patients with diffuse glioma, compromising quality of life and prognosis. Neuroligin-3 is a postsynaptic activity-dependent protein, considered a key component of brain-glioma interactions, specifically at neurogliomal synapses. Neuroligin-3 may modulate neuronal and epileptic activity, contributing to both tumor growth and cognitive deficits. We aimed to investigate the relationship between intratumoral neuroligin-3 expression and neurocognitive functioning (NCF) in diffuse glioma patients, and to determine whether epilepsy modifies this relationship. METHODS: In this single-center retrospective study, adult patients with grades 2-4 diffuse glioma underwent neuropsychological assessment prior to awake surgery. Tissue microarray analysis was used to assess intratumoral neuroligin-3 expression. We examined the relation between NCF (attention and executive functioning, memory, language, visuospatial functioning and psychomotor speed) and neuroligin-3 expression, using multivariable logistic regression models adjusting for tumor grade, location and volume. Additionally, presence of epilepsy and its interaction term with neuroligin-3 expression were added to separate models. RESULTS: In total, 101 patients were included for analyses. Neuroligin-3 showed a protective effect on memory performance in all patients, not modified by epilepsy. Patients with neuroligin-3-positive high-grade and isocitrate dehydrogenase (IDH)-wild type glioma have a decreased risk of memory and attention and executive functioning deficits, again not modified by epilepsy. In low-grade and IDH-mutant glioma patients, neuroligin-3 expression was not associated with NCF. CONCLUSIONS: Intratumoral neuroligin-3 expression is an independent determinant of NCF, especially in the domain memory and in high-grade and IDH-wild type glioma. This protective effect was not modified by presence of epilepsy.