MECHANISMS OF NEURODEGENERATION AND REGENERATION IN POST-STROKE SURVIVORS

描述（由申请人提供）：中风是老年人发病和死亡的第三大主要原因，在75岁以上人群中的患病率约为10%，并且对社会产生同样高的成本。我们对卒中后队列（n=400）的前瞻性评估表明，25%的卒中幸存者发展为梗死或出血的直接后果痴呆。然而，在那些没有立即发生认知障碍的中风幸存者中，中风后3年或更长时间发生痴呆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在中风后的15个月内，认知功能也持续改善。了解迟发性痴呆和认知改善的危险因素和机制对于选择性招募临床试验至关重要，并对脑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死后大脑，并提出i）组织病理学和免疫细胞化学分析，以检查血管生成和神经发生的标志物（神经血管单位）对抗中风后改善者和衰退者内侧颞叶硬化、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（DiGE）蛋白质组学和质谱法来确定认知能力下降和改善的中风后幸存者的大脑中的蛋白质变化。将从至少60名前瞻性评估的幸存者中获得脑组织。将在海马CA 1和齿状回细胞中探索蛋白质组学特征，这些细胞将被大量分离，并通过激光捕获显微切割进行进一步检查。这些研究是基于这样的假设，即改良剂将表达神经发生（神经干细胞）和血管生成（血管/祖细胞）的生长促进或信号传导标志物。这项拟议中的研究将揭示可能与中风后幸存者的认知改善和功能恢复有关的神经血管相互作用。这项工作涉及中风后的迟发性痴呆，也涉及影响近10%的75岁以上老年人的神经退行性痴呆。这将影响与常见痴呆症相关的神经退行性机制，包括阿尔茨海默病和路易体痴呆，以及血管性痴呆，从而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.