Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.
Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.
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DOI：
10.1093/brain/awu040
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Love S
中科院分区：
文献类型：
--
作者：
Barker R;Ashby EL;Wellington D;Barrow VM;Palmer JC;Kehoe PG;Esiri MM;Love S
脑白质低灌注症的病理生理学机制知之甚少。Barker等人。通过测量易受缺血影响的髓鞘蛋白，量化死前低灌注量，并评估血管调节因子在多大程度上保护或促进阿尔茨海默病和血管性痴呆的缺血性脑白质损伤。关于人脑中白质低灌流的影响因素和生理反应，人们知之甚少。我们以前发现，死后人脑组织中髓鞘相关糖蛋白与蛋白脂蛋白1的比率与死前脑缺血的程度有关。在西南痴呆脑库(布里斯托尔)的阿尔茨海默病(n=49)、血管性痴呆(n=17)和对照组(n=33)的年龄匹配的尸检队列中，我们现在研究了髓鞘相关糖蛋白与蛋白脂蛋白1的比率与其他几种参与调节白质血管和血流的蛋白质之间的关系。在三个队列中，白质血流灌注(髓鞘相关糖蛋白/蛋白脂蛋白1的比率)与血管收缩因子内皮素1的浓度呈正相关(P=0.0005)，与促血管生成蛋白血管内皮生长因子的浓度呈负相关(P=0.0015)。血管紧张素转换酶的活性没有改变，该酶催化血管收缩因子血管紧张素II的产生。在一个独立的(英国牛津)尸检队列(n=74)的额叶白质样本中，我们证实了髓鞘相关糖蛋白/蛋白脂蛋白1的比率与内皮素1和血管内皮生长因子之间的显著相关性。我们还通过测量第八因子相关抗原来评估布里斯托尔(英国)样本中的微血管密度，我们发现第八因子相关抗原水平与血管内皮生长因子水平相关(P=0.0487)，这表明血管内皮生长因子上调往往会增加白质中的血管密度。我们认为，在髓鞘相关糖蛋白/蛋白脂蛋白1比率降低的背景下，内皮素1的下调和血管内皮生长因子的上调可能是对脑白质灌注量减少的保护性生理反应。对布里斯托尔队列的进一步分析表明，与对照组相比，阿尔茨海默病患者脑白质中的内皮素-1含量降低(P<；0.05)，但在血管性痴呆患者中并没有，内皮素-1有升高的趋势，这可能反映了血管性痴呆患者脑白质血流的异常调节。我们的发现证明了死后测量髓鞘蛋白和血管功能介体的潜力，以评估参与阿尔茨海默病和血管性痴呆脑血流调节的生理和病理过程。
The pathophysiology of white matter hypoperfusion is poorly understood. Barker et al. quantify ante-mortem hypoperfusion by measuring myelin proteins differentially susceptible to ischaemia, and assess the extent to which vasoregulatory factors protect from or contribute to ischaemic white matter injury in Alzheimer’s disease and vascular dementia. Little is known about the contributors and physiological responses to white matter hypoperfusion in the human brain. We previously showed the ratio of myelin-associated glycoprotein to proteolipid protein 1 in post-mortem human brain tissue correlates with the degree of ante-mortem ischaemia. In age-matched post-mortem cohorts of Alzheimer’s disease (n = 49), vascular dementia (n = 17) and control brains (n = 33) from the South West Dementia Brain Bank (Bristol), we have now examined the relationship between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and several other proteins involved in regulating white matter vascularity and blood flow. Across the three cohorts, white matter perfusion, indicated by the ratio of myelin-associated glycoprotein to proteolipid protein 1, correlated positively with the concentration of the vasoconstrictor, endothelin 1 (P = 0.0005), and negatively with the concentration of the pro-angiogenic protein, vascular endothelial growth factor (P = 0.0015). The activity of angiotensin-converting enzyme, which catalyses production of the vasoconstrictor angiotensin II was not altered. In samples of frontal white matter from an independent (Oxford, UK) cohort of post-mortem brains (n = 74), we confirmed the significant correlations between the ratio of myelin-associated glycoprotein to proteolipid protein 1 and both endothelin 1 and vascular endothelial growth factor. We also assessed microvessel density in the Bristol (UK) samples, by measurement of factor VIII-related antigen, which we showed to correlate with immunohistochemical measurements of vessel density, and found factor VIII-related antigen levels to correlate with the level of vascular endothelial growth factor (P = 0.0487), suggesting that upregulation of vascular endothelial growth factor tends to increase vessel density in the white matter. We propose that downregulation of endothelin 1 and upregulation of vascular endothelial growth factor in the context of reduced ratio of myelin-associated glycoprotein to proteolipid protein 1 are likely to be protective physiological responses to reduced white matter perfusion. Further analysis of the Bristol cohort showed that endothelin 1 was reduced in the white matter in Alzheimer’s disease (P < 0.05) compared with control subjects, but not in vascular dementia, in which endothelin 1 tended to be elevated, perhaps reflecting abnormal regulation of white matter perfusion in vascular dementia. Our findings demonstrate the potential of post-mortem measurement of myelin proteins and mediators of vascular function, to assess physiological and pathological processes involved in the regulation of cerebral perfusion in Alzheimer’s disease and vascular dementia.
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