Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration.
Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration.
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N-乙酰葡萄糖的标记与进行性多发性硬化和神经变性的关联。
DOI：
10.1001/jamaneurol.2021.1116
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发表时间：
2021-07-01
期刊：
影响因子：
29
通讯作者：
Demetriou M
中科院分区：
文献类型：
--
作者：
Brandt AU;Sy M;Bellmann-Strobl J;Newton BL;Pawling J;Zimmermann HG;Yu Z;Chien C;Dörr J;Wuerfel JT;Dennis JW;Paul F;Demetriou M
多发性硬化症患者血清n -乙酰氨基葡萄糖（GlcNAc）浓度是否发生改变？这项横断面研究发现，患有进行性多发性硬化症亚型和更严重疾病的患者血清中GlcNAc标志物水平降低。此外，GlcNAc是n -聚糖分支的限速底物，已被证明可以调节免疫活性和髓鞘形成。这项研究表明，GlcNAc和n -聚糖分支与多发性硬化症有关，特别是与进行性多发性硬化症有关。n -聚糖分支调节细胞表面受体的可用性，其在小鼠中的缺乏促进炎症性脱髓鞘，髓鞘形成减少和神经变性。n -乙酰氨基葡萄糖（GlcNAc）是n -聚糖分支的限速底物，但据我们所知，多发性硬化症（MS）患者的内源性血清水平尚不清楚。为了研究MS患者内源性血清GlcNAc水平的标志物，在美国和德国的2个MS学术中心进行了横断面发现研究和横断面验证研究。这项发现研究在2010年4月20日至2013年6月21日期间从门诊诊所招募了54名多发性硬化症患者以及66名健康对照者。验证性研究从2007年4月9日至2016年2月29日在MS学术研究中心的筛查访问中招募了180名MS患者。分析2013年12月2日至2015年3月2日的血清样本。统计时间为2020年2月23日至2021年3月18日。血清中GlcNAc及其立体异构体，称为n -乙酰己糖胺（HexNAc）的水平，采用靶向串联质谱法进行评估。次要结果（验证性研究）包括影像学和临床疾病标志物。该发现队列包括66名健康对照（38名女性，平均[SD]年龄42岁），33名复发-缓解型MS患者（RRMS， 25名女性，平均[SD]年龄50岁）和21名进行性MS患者（PMS， 14名女性，平均[SD]年龄55岁）。验证性队列包括125例RRMS患者（83例女性，平均[SD]年龄40岁）和55例经前综合征患者（22例女性，平均[SD]年龄49[80]岁）。在发现队列中，健康对照组血清中GlcNAc及其立体异构体（HexNAc）的平均（SD）水平为710 (174)nM， RRMS患者血清中GlcNAc及其立体异构体（HexNAc）的平均（SD）水平为682 (173)nM, P =。PMS患者与健康对照（平均[SD]水平，548 [101]nM; P = 9.55 × 10−9）和RRMS患者（P = 1.83 × 10−4）相比，PMS患者的水平明显降低。RRMS患者（平均[SD]水平，709 [193]nM）与PMS患者（平均[SD]水平，405 [161]nM, P = 7.6 × 10−18）之间的差异在独立验证队列中得到证实。较低的HexNAc血清水平与较差的扩展残疾状态量表评分相关（ρ = -0.485; P = 4.73 × 10 - 12），与较低的丘脑体积相关(t = 1.7；视网膜神经纤维层较薄（B = 0.012 [SE = 7.5 × 10−11];P = 0.008）。较低的基线血清HexNAc水平与18个月时较大的脑容量损失百分比相关（t = 1.8; P = 0.04）。该研究提示GlcNAc及其立体异构体（HexNAc）的缺乏可能是经前综合征的生物标志物。先前的临床前、人类遗传和离体人体机制研究表明，n -聚糖分支和/或GlcNAc可能减少促炎反应，促进髓磷脂修复，并减少神经退行性变。综上所述，这些数据表明，GlcNAc缺乏可能与多发性硬化症（MS）患者的疾病进展和神经退行性变有关。这项横断面研究调查了多发性硬化症（MS）患者内源性血清n -乙酰氨基葡萄糖水平的标志物。
Is the serum concentration of N-acetylglucosamine (GlcNAc) altered in patients with multiple sclerosis? This cross-sectional study found that patients with a progressive multiple sclerosis subtype and more severe disease have reduced serum levels of a marker of GlcNAc. In addition, GlcNAc is a rate-limiting substrate for N-glycan branching, which has been shown to regulate immunoactivity and myelination. This study suggests that GlcNAc and N-glycan branching are associated with multiple sclerosis in general and progressive multiple sclerosis in particular. N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown. To investigate a marker of endogenous serum GlcNAc levels in patients with MS. A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021. Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers. The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10−9) and patients with RRMS (P = 1.83 × 10−4). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10−18) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = –0.485; P = 4.73 × 10−12), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10−11]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04). This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS. This cross-sectional study investigates a marker of endogenous serum N-acetylglucosamine levels in patients with multiple sclerosis (MS).
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影响因子：
64.5
作者：
Lau, Ken S.;Partridge, Emily A.;Dennis, James W.
通讯作者：
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