Elevated polyglutamylation and tau phosphorylation levels in patients with primary central nervous system lymphoma are related to cognitive decline and neuropsychiatric changes at disease onset

Primary central nervous system lymphoma (PCNSL) often presents with nonspecific cognitive decline and neuropsychiatric changes at onset, yet the underlying mechanisms remain poorly understood. Polyglutamylation, a posttranslational modification, is associated with better responses to methotrexate-based chemotherapy in patients with PCNSL. On the other hand, hyperglutamylation of microtubules in neurons has been implicated in neurodegeneration via the accumulation of phosphorylated tau. This study aimed to elucidate the relationship of polyglutamylation with cognitive decline and neuropsychiatric changes at PCNSL onset. We retrospectively analyzed 145 patients with PCNSL treated at our institution between 2001 and 2022. Polyglutamylation and phosphorylated tau were evaluated using immunohistochemistry. In vitro studies were performed to evaluate the causal relationship between polyglutamylation and tau phosphorylation in PCNSL cell lines. Cognitive decline and neuropsychiatric changes at disease onset were observed in 48.3% of patients, with multivariate analysis identifying high polyglutamylation levels as an independent risk factor (odds ratio: 7.34, p  < 0.001). Patient samples and cell lines consistently demonstrated a link between polyglutamylation and tau phosphorylation, implicating that polyglutamylation-induced tau phosphorylation may contribute to cognitive decline and neuropsychiatric changes. Our findings suggest that polyglutamylation contributes to neurocognitive dysfunction in PCNSL, and these results elucidate a novel aspect of PCNSL pathophysiology.