BACKGROUND: Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT). METHODS: Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, and 12 months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated. RESULTS: The optimal model identified 3 unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (P = .007) and a greater proportion of males (P <
.001)
the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (P-values <
.05)
and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory being the most vulnerable. Patients who declined reported greater symptoms of depression (P = .007) and poorer quality of life (P = .025). CONCLUSIONS: We identified 3 distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (eg, IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.