Neuronal changes in the hippocampus of post-stroke survivors

Abstract

Background: Delayed post-stroke dementia (PSD) affects up to 50% of all stroke survivors, developing months or years after the initial stroke. However, the underlying mechanisms which cause PSD are unclear. Hippocampal atrophy is associated with PSD and vascular dementia, and hippocampal neurons are known to be particularly vulnerable in stroke and cerebrovascular disease. This work aimed to identify neuropathological characteristics and mechanisms contributing to cognitive decline in post-stroke survivors, focusing on the involvement of regional specific hippocampal neurons. Methods: Post-mortem brain tissue from the prospective CogFAST study was analyzed to compare pathological changes in stroke survivors who developed PSD with those who maintained normal cognitive function (PSND). Tissue from elderly controls and pathologically defined dementia groups lzheimer’s disease ( D) vascular dementia (VaD), mixed AD with VaD (MD); were also analysed for comparison with different disease aetiologies. Histological and immunohistochemical staining with quantitative image analysis and 3D morphometric analysis was carried out in paraffin-embedded sections, and protein immunoblotting was used in frozen hippocampal tissue. Key findings: Neuronal volumes in hippocampal subfields CA1-4 were reduced in PSD, VaD and AD subjects compared to elderly controls and PSND. Neuronal volume was also related to post-stroke cognitive function. There were no differences in dendritic length-density, hippocampal myelin loss, or autophagy markers between PSD and PSND. However, neuronal volumes were related to hippocampal tau pathology burden, reactive astrocyte density and myelin density in the alveus. Interestingly, the PSND subjects had greater burden of hippocampal amyloid-β than PSD. There were no quantitative differences in markers for astrocytes or microglia between the post-stroke groups. Conclusion: These findings suggest that neuronal volume loss is associated with post- stroke and ageing-related dementia. There were no relationships between the observed neuronal changes and AD pathology in stroke survivors, suggesting an important role for cerebrovascular disease processes.