Improvements in acute stroke treatment have increased survival rates. However, many stroke survivors have significant neurological deficits, and stroke remains a leading cause of long-term disability. Despite this, the chronic evolution of ischemic stroke pathology remains underexplored. We examined long-term neurobehavioral recovery and neuropathology of middle-aged (14-months) C57Bl/6 mice at 1-, 3- and 6-months after a 60-minute transient middle cerebral artery occlusion (tMCAO) or sham surgery. For tissue, cellular, and molecular analyses, we utilized immunohistochemistry, flow cytometry, and transcriptomics, respectively. We also assayed post-mortem human brain samples with chronic infarcts. In mice, cognitive function progressively worsened from 1 to 6-months after MCAO, as seen by a continual reduction in the discrimination index of the novel object recognition test (p=.0058). However, this effect was only apparent in older female stroke mice, while their male counterparts showed no significant changes over time. Deficits in memory retention at 6-months post-stroke (PS) were also observed in the fear-conditioning test (p=.0084). Brain atrophy was evident by MRI imaging at 2- and 6-months PS, with ventricular volume increasing over time. Furthermore, histopathology revealed significant demyelination (mouse, p=.0361; human, p =.0001), and increased gliosis (p=.0059) in the hippocampus and frontal cortex of both human and mice brains chronically after stroke. We observed microglia activation proximal to apoptotic neurons in the hippocampus of mice and humans PS, as shown by TUNEL assay. Disease-associated microglial (DAM) phenotypes were marked by increased proliferative status and senescent-like phenotypes, including elevated production of cytokines. Transcriptomic screening of mouse brains indicates upregulation of DAM genes and inflammatory pathways, while plasma proteomic analysis of 6-months PS plasma revealed similar patterns, indicating the systemic and far-reaching effects of post-stroke pathology. Our findings demonstrate that ischemic stroke accelerates inflamm-aging and induces premature senescence within the chronic infarct microenvironment. Cellular senescence and chronic neurodegenerative signatures likely underlie the progressive worsening of cognitive function late after stroke. The identification of active secondary injury mechanisms may result in the development of novel, delayed, treatment strategies for ischemic stroke.
Khan et al. (Thu,) studied this question.
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