Abstract DP002: Red blood cell BPGM deficiency may contribute to cognitive decline in stroke patients

Background: Cognitive impairment (CI) affects up to 60% of stroke survivors and is a major cause of morbidity and mortality after stroke. Red blood cells (RBCs), once thought to be passive oxygen carriers, are increasingly recognized as contributors to brain health. However, their role in post-stroke CI remains poorly understood. Method: 49 consecutive stroke patients were prospectively recruited under IRB-approved protocols. All the patients were non-anemic. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), with MoCA ≥ 26 defined as no cognitive impairment (NCI) and MoCA < 26 as CI. RBCs were sampled from all participants and the changes in RBC proteome between CI and NCI patients were profiled by mass spectrometry. Result: MoCA scores in stroke patients were inversely correlated with red cell distribution width (RDW) (r = -0.49, p < 0.001). ( Figure 1A ). Patients with CI (MoCA < 26) exhibited significantly higher RDW ( Figure 1B ), and this association remained independent of age, diabetes, hypertension, and hyperlipidemia (OR: 2.15, 95% CI: 1.02 ~ 4.55, p = 0.045) ( Table 1 ). Further RBC proteomics profiling revealed a significant reduction of glycolytic process in CI patients, with bisphosphoglycerate mutase (BPGM) showing the most dramatic decrease ( Figure 2A, 2B ). BPGM is a RBC-specific enzyme regulating the production of 2,3-bisphosphoglycerate (2,3-BPG) through the Rapoport-Luebering glycolytic shunt, which plays a crucial role in decreasing hemoglobin affinity for oxygen and facilitates oxygen release to tissues ( Figure 2C ). Consistent with reduced BPGM expression, CI patients exhibited lower 2,3-BPG levels compared to NCI individuals ( Figure 2B ). Importantly, BPGM and 2,3-BPG levels did not differ between NCI stroke patients and non-stroke controls ( Figure 2B ). Conclusion: RBC BPGM deficiency and reduced 2,3-BPG production may impair cerebral oxygen delivery and exacerbate hypoxic conditions following stroke, potentially contributing to cognitive decline. Our findings highlight a novel mechanism and biomarker for post-stroke cognitive impairment. Further studies are under way to validate these results in a larger patient cohort and explore the underlying mechanism.