Abstract
Improvements in acute stroke treatment, including EVT and critical care management, have increased survival rates post-stroke. However, many stroke survivors have significant post-stroke disability and cognitive impairment. Despite this, the chronic progression and long-term sequelae of ischemic stroke pathology remains understudied. Methods: We examined the chronicity of neurobehavioral recovery and progressive neuropathology in young male (3 month) and middle-aged male and female (14 month) C57Bl/6 mice at 3 and 6 months after a 60-minute transient middle cerebral artery occlusion (tMCAO) or sham surgery ( n = 10-20/group ). Behavioral testing included NORT, fear conditioning (FC), and tail suspension. Immunohistochemistry (IHC) was performed on mouse brains, as well as post-mortem human brain samples from patients with a chronic infarct ( n = 6/group ), to assess demyelination (MBP), neuronal apoptosis (TUNEL/NeuN), and amyloid burden (Aβ-42). Flow cytometry was performed on the ipsilateral mouse brain hemisphere. RNA isolated from the ipsilateral hemisphere was sent for gene profiling. Results: In both young and middle-aged mice, depressive-like behavior persisted for 6 months post-stroke (PS) (p= <0.0001), while cognitive function progressively worsened from 3 to 6 months, as seen by a reduction in the NORT (p=.0063) and FC (p=.0084). MRI imaging and IHC revealed cerebral atrophy, significant demyelination (mouse, p=.0361; human, p =.0001), and increased microglial density (p=.0059) in the hippocampus of both human and mice. TUNEL/NeuN staining showed ongoing neuronal degeneration in the human hippocampus, distal to the chronic infarct. Human chronic stroke hippocampus had increased amyloid burden compared to age-matched controls (p=.0677). Cytometric anyalses revealed disease-associated microglial (DAM) phenotypes were marked by increased senescence, cytokine production, and an altered redox state. Transcriptomic data showed significant chronic upregulation of DAM genes. Conclusion: Our findings demonstrate that ischemic stroke accelerates inflamm-aging and premature senescence within the chronic infarct microenvironment. Cellular senescence and chronic disease signatures may contribute to progressive cognitive impairment post-stroke. Identification of secondary injury processes, and late pathological events post-stroke, allude to a neurodegenerative etiology and may offer viable targets for delayed treatment to prevent further neurological decline.
Published Version
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