Abstract Post-stroke cognitive impairment is a severe sequela of cerebral ischemia, with its underlying mechanisms remaining elusive and specific diagnostic biomarkers currently lacking. Growing evidence suggests that secondary neurodegeneration is closely associated with post-stroke cognitive impairment, although its metabolic basis has not been fully elucidated. Therefore, this study aimed to investigate the spatiotemporal changes and metabolic characteristics of secondary neurodegeneration and cognitive function after cortical stroke. We established a photothrombotic mouse model for post-stroke cognitive impairment research and conducted longitudinal assessments with final endpoints at 14, 32, and 84 days postsurgery. Voxel-based morphometry analysis of whole-brain regions using magnetic resonance imaging revealed that only the hippocampus exhibited gray matter alterations consistent with secondary neurodegeneration pathology. Morris water maze and open field tests demonstrated persistent impairments in recent and remote memory, along with anxietylike behaviors in photothrombotic mice. Untargeted metabolomic and lipidomic analyses were established to comprehensively characterize secondary neurodegeneration-related metabolic disturbances in the hippocampus, highlighting pathophysiological mechanisms involving oxidative stress, lipid peroxidation, neurotransmitter dysregulation, and disrupted energy metabolism. These important mechanisms were verified by immunohistochemistry, immunofluorescence staining, and real-time polymerase chain reaction. The screened potential biomarker, N -acetylneuraminic acid, was validated via targeted metabolomics in both photothrombotic mouse serum and 148 clinical samples, showing significant elevation in both cohorts. Receiver operating characteristic curve analysis and decision curve analysis confirmed the clinical utility of N -acetylneuraminic acid in diagnosing post-stroke cognitive impairment (area under the curve = 0.951, 95% confidence interval: 0.903–0.980). Flow cytometry and immunofluorescence staining revealed that N -acetylneuraminic acid activates microglia-driven neuroinflammation and oxidative stress. Our findings elucidate a potential pathological mechanism of post-stroke cognitive impairment: cortical stroke induces hippocampal accumulation of N -acetylneuraminic acid, which promotes microglial oxidative stress and inflammation, thereby triggering hippocampal secondary neurodegeneration and leading to persistent cognitive deficits. Importantly, N -acetylneuraminic acid serves as a dual-functional biomarker capable of predicting post-stroke cognitive impairment progression while dynamically tracking secondary neurodegeneration.
Zhou et al. (Thu,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: