Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.
Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.
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DOI：
10.1093/braincomms/fcac202
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
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Pelizaeus-Merzbacher病是一种X连锁隐性中枢神经系统白质营养不良，由影响主要髓鞘蛋白、蛋白脂质蛋白1的突变引起。然而，对Pelizaeus-Merzbacher病最常见形式的蛋白质、蛋白脂质蛋白1复制的体内神经化学改变的程度知之甚少。磷磁共振波谱是唯一的体内技术，可以评估生物化学与高能磷酸盐和膜磷脂代谢在不同的皮质，皮质下和白色物质领域。在这项横断面研究中，全脑，多体素磷磁共振波谱采集在3 T的14例Pelizaeus-Merzbacher病与蛋白质，蛋白脂质蛋白1重复和23名健康对照（所有男性）。 合成代谢和分解代谢水平的膜磷脂（磷酸胆碱和磷酸乙醇胺，甘油磷酸乙醇胺和甘油磷酸胆碱，分别），以及磷酸肌酸，无机正磷酸盐和腺苷三磷酸水平相对于总磷磁共振波谱信号从12个不同的皮质和皮质下区域进行了比较。与对照组相比，与脑区无关，Pelizaeus Merzbacher病患者的磷酸胆碱、甘油磷酸乙醇胺和无机正磷酸盐水平显著降低（P = 0.0025，P < 0.0001和P = 0.0002），磷酸肌酸水平显著升高（P < 0.0001）。此外，磷酸肌酸存在显著的组-脑区相互作用，事后分析表明，与对照组相比，Pelizaeus-Merzbacher病患者的多个脑区（前部和后部白色物质、上级顶叶、后扣带回皮质、海马、枕叶皮质、纹状体和丘脑;所有P ≤ 0.0042）的磷酸肌酸水平显著更高。磷酸乙醇胺、甘油磷酸乙醇胺和三磷酸腺苷水平在组间无显著差异。首次报道了Pelizaeus-Merzbacher病患者磷磁共振波谱代谢物水平的广泛变化。具体而言，多个区域中磷酸肌酸的高能磷酸盐储存水平增加伴随无机正磷酸盐减少表明Pelizaeus-Merzbacher病中高能磷酸盐利用的广泛减少，并且膜磷脂代谢物缺乏表明Pelizaeus-Merzbacher病患者的神经递质含量/维持的广泛降解，包括轴突，皮质内的树突和星形胶质细胞以及白色物质内的髓鞘微结构和少突胶质细胞。这些结果提供了更深入的了解Pelizaeus-Merzbacher病的神经病理学方面的能量消耗和膜磷脂代谢物。未来的纵向研究有必要调查磷磁共振波谱作为替代生物标志物在监测Pelizaeus-Merzbacher病治疗干预中的效用。Pelizaeus-Merzbacher病是一种X连锁隐性脑白质营养不良，其体内神经化学改变的程度尚不清楚。在这项研究中，Laukka等人报告了与对照组相比，Pelizaeus-Merzbacher病患者使用磷磁共振波谱的广泛生化改变。结果表明Pelizaeus-Merzbacher病的能量消耗和膜磷脂代谢。
Pelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus–Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus–Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus–Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus–Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus–Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus–Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus–Merzbacher disease. The extent of the altered in vivo neurochemistry in Pelizaeus–Merzbacher disease, an X-linked recessive leucodystrophy, is poorly understood. In this study, Laukka et al. report widespread biochemical alterations in patients with Pelizaeus–Merzbacher disease compared with controls utilizing phosphorous magnetic resonance spectroscopy. Results implicate energy expenditure and membrane phospholipid metabolism in Pelizaeus–Merzbacher disease.
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影响因子：
6.2
作者：
Appikatla S;Bessert D;Lee I;Hüttemann M;Mullins C;Somayajulu-Nitu M;Yao F;Skoff RP
通讯作者：
Skoff RP
DOI：
10.1016/j.bpsc.2019.09.008
发表时间：
2020-03-01
影响因子：
5.9
作者：
Haszto, Connor S.;Stanley, Jeffrey A.;Prasad, Konasale M.
通讯作者：
Prasad, Konasale M.
影响因子：
14.5
作者：
Gruenenfelder, Fredrik, I;McLaughlin, Mark;Edgar, Julia M.
通讯作者：
Edgar, Julia M.
影响因子：
3.8
作者：
Pettegrew, JW;Klunk, WE;Stanley, JA
通讯作者：
Stanley, JA
影响因子：
4.7
作者：
Huettemann, Maik;Zhang, Zhan;Skoff, Robert P.
通讯作者：
Skoff, Robert P.