MECHANISMS OF NEURODEGENERATION AND REGENERATION IN POST-STROKE SURVIVORS

描述(申请人提供)：中风是老年人发病率和死亡率的第三大原因，在75岁以上的人中患病率约为10%，对社会也有同样高的成本。对我们的卒中后队列(n=400)的前瞻性评估表明，25%的卒中幸存者因梗塞或出血的直接后果而患上痴呆。然而，在那些没有立即出现认知障碍的中风幸存者中，中风后3年或更长时间患痴呆症的风险几乎是年龄匹配的对照组的10倍。超过三分之一的幸存者中风后，认知功能也在长达15个月的时间里继续改善。了解迟发性痴呆和认知改善的危险因素和机制对选择性招募临床试验至关重要，并对卒中患者的预后和康复具有重要意义。我们收集了这些前瞻性评估的中风幸存者的身体脑，并提出了i)组织病理学和免疫细胞化学分析，以检测血管生成和神经生成(神经血管单位)的标记物，以对抗中风后改善和衰退者内侧颞叶的硬化症、氧化损伤和阿尔茨海默型病变的负担，以及ii)应用大规模荧光差异(DGE)蛋白质组学和质谱仪来确定中风后幸存者大脑中认知功能下降和改善的蛋白质变化。将从至少60名预期评估的幸存者那里获得脑组织。蛋白质组图谱将在海马区CA1和齿状回细胞中进行探索，这些细胞将被大量分离并用于激光捕获显微解剖的进一步研究。这些研究是基于这样的假设，即促进剂将表达神经发生(神经干细胞)和血管生成(血管/祖细胞)的生长促进或信号标记。这项拟议的研究将揭示神经元-血管相互作用可能与中风后幸存者的认知改善和功能恢复有关。这项工作与中风后迟发性痴呆症有关，但也与神经退行性痴呆症有关，75岁以上的老年人中有近10%受到影响。这将影响到与常见痴呆相关的神经退化机制，包括阿尔茨海默病和路易体痴呆，以及血管性痴呆，导致基于血管保护的合理预防或治疗策略。

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.