Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis.
Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis.
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DOI：
10.12688/wellcomeopenres.9967.2
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发表时间：
2016-11-15
影响因子：
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通讯作者：
Bangham CRM
中科院分区：
文献类型：
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作者：
Lewin A;Hamilton S;Witkover A;Langford P;Nicholas R;Chataway J;Bangham CRM
背景资料：继发性进行性多发性硬化症（SPMS）残疾的主要原因是进行性脑萎缩，其发病机制尚未完全了解。本研究的目的是确定SPMS脑萎缩的蛋白质生物标志物。 研究方法：我们使用表面增强激光解吸电离飞行时间质谱法对血清蛋白进行无偏搜索，其浓度与脑萎缩率相关，通过连续MRI扫描在2年内对140例SPMS患者进行了充分表征。 通过液相色谱-电喷雾串联质谱鉴定蛋白质种类。 结果如下：有显著（p<0.004）脑萎缩率与血清中15.1kDa和15.9kDa蛋白质浓度升高之间的相关性。串联质谱鉴定这些蛋白质为α-血红蛋白和β-血红蛋白，用ELISA法检测血清游离血红蛋白浓度，继发性进展型多发性硬化患者血清乳酸脱氢酶活性也显著升高（P<10 - 12）。 结论：实验结果与以下假设一致。在进行性多发性硬化症中，轻度慢性血管内溶血将血红蛋白释放到血清中;血红蛋白随后穿过受损的血脑屏障易位到中枢神经系统（CNS）中，在CNS中，血红蛋白及其分解产物（包括血红素和铁）促成神经变性和随后在进行性疾病中可见的脑萎缩。我们假设血红蛋白是铁的来源，铁在多发性硬化斑块中沿血管沿着沉积与神经退行性变有关，如果是这样，那么血红蛋白螯合剂，而不是游离血清铁螯合剂，可能有效地预防这种神经退行性变。
Background: A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods: We used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results: There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively. The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10 -12) in patients with secondary progressive multiple sclerosis. Conclusions: The results are consistent with the following hypothesis. In progressive multiple sclerosis, low-grade chronic intravascular haemolysis releases haemoglobin into the serum; the haemoglobin is subsequently translocated into the central nervous system (CNS) across the damaged blood-brain barrier. In the CNS, the haemoglobin and its breakdown products, including haem and iron, contribute to the neurodegeneration and consequent brain atrophy seen in progressive disease. We postulate that haemoglobin is a source of the iron whose deposition along blood vessels in multiple sclerosis plaques is associated with neurodegeneration. If so, then chelators of haemoglobin, rather than chelators of free serum iron, may be effective in preventing this neurodegeneration.