MECHANISMS OF NEURODEGENERATION AND REGENERATION IN POST-STROKE SURVIVORS

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DESCRIPTION (provided by applicant): Stroke is the third major cause of morbidity and mortality in older people, with a prevalence of approximately 10% in those over 75 years, and has similarly high costs for society. Prospective assessments of our post-stroke cohort (n=400) suggests 25% of stroke survivors develop dementia as an immediate consequence of infarction or haemorrhage. However, in those stroke survivors who do not develop immediate cognitive impairment, the risk of developing dementia at 3 years or longer after the stroke is almost 10-fold greater than for age- matched controls. Cognitive function also continues to improve for up to 15 months after a stroke in over a third of the survivors. Understanding the risk factors and mechanisms for the delayed dementia and cognitive improvement are critical for selective recruitment to clinical trials, and has important implications for the prognosis and rehabilitation of stroke patients. We have collected post-mortem brains from these prospectively assessed stroke survivors and propose i) histopathological and immunocytochemical analyses to examine markers of angiogenesis and neurogenesis (neurovascular unit) against the burden of sclerosis, oxidative damage and Alzheimer type of lesions in the medial temporal lobe of post-stroke improvers and decliners, and ii) the application of large-scale fluorescence-difference (DiGE) proteomics and mass spectrometry to define protein changes in the brains from post-stroke survivors who declined and improved in cognition. Brain tissue will be available from at least 60 prospectively assessed survivors. The proteomic profiles will be explored in the hippocampal CA1 and dentate gyrus cells, which will be bulk isolated and for further scrutiny by Laser Capture Microdissection. These investigations are based on the hypotheses that improvers will express growth promoting or signalling markers of neurogenesis (neural stem cells) and angiogenseis (vascular/ progenitor cells). The proposed research will uncover neuronal-vascular interactions that may relate to cognitive improvement and functional recovery in the post-stroke survivors. This work relates to delayed dementia after stroke but also neurodegenerative dementia which affects nearly 10% of elderly over age 75 years. This will impact on neurodegenerative mechanisms associated with common dementing disorders including Alzheimer's disease and dementia with Lewy bodies besides vascular dementia, leading towards rational preventative or treatment strategies based on vascular protection.