Elevated polyglutamylation and tau phosphorylation levels are associated with cognitive impairment at diagnosis in patients with primary central nervous system lymphoma

Background Primary central nervous system lymphoma (PCNSL) often manifests with cognitive impairment or nonspecific symptoms, which can delay diagnosis and worsen prognosis. However, the mechanisms underlying these neurological manifestations remain poorly understood. Previous studies have shown that polyglutamylation, a posttranslational modification, is associated with better responses to methotrexate-based chemotherapy in patients with PCNSL. Moreover, excessive polyglutamylation in neurons has been implicated in neurodegeneration via phosphorylated tau accumulation. This study aimed to elucidate the relationship between polyglutamylation, phosphorylated tau, and cognitive impairment in PCNSL. Methods We retrospectively analyzed 140 patients with histologically confirmed PCNSL treated at our institution between 2001 and 2022. Cognitive status at hospital admission was assessed using the Clinical Dementia Rating (CDR) scale. Immunohistochemical analysis of tumor specimens was performed to quantify the polyglutamylation and phosphorylated tau levels. Furthermore, in vitro studies with PCNSL cell lines were conducted to investigate whether the pharmacological upregulation of polyglutamylation by a histone deacetylase inhibitor promotes tau phosphorylation. Statistical analyses examined associations among polyglutamylation status, cognitive impairment, tau phosphorylation, and clinical outcomes. Results High polyglutamylation levels were observed in 59% of tumor samples, and this factor was independently associated with cognitive impairment at diagnosis (odds ratio: 4.35, 95% confidence interval 1.47–12.9, p = 0.0080). Immunohistochemical analysis demonstrated that tumors with elevated polyglutamylation showed significantly higher phosphorylated tau levels. In vitro experiments confirmed that increased polyglutamylation levels in PCNSL cells led to enhanced tau phosphorylation in PCNSL cell lines. Conclusions High polyglutamylation levels in PCNSL were associated with cognitive impairment and increased tau phosphorylation at diagnosis. These findings suggest that polyglutamylation may contribute to neurocognitive symptoms by promoting tau pathology. Elucidating this mechanism may provide novel insights into PCNSL pathophysiology and may inform future studies on disease mechanisms and potential treatment targets.