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Elevated cerebrospinal fluid homocysteine is associated with blood-brain barrier disruption in amyotrophic lateral sclerosis patients.

肌萎缩侧索硬化患者脑脊液同型半胱氨酸升高与血脑屏障破坏相关。

  • 影响因子:1.76
  • DOI:10.1007/s10072-020-04292-x
  • 作者列表:"Wu Y","Yang X","Li X","Wang H","Wang T
  • 发表时间:2020-02-21
Abstract

OBJECTIVES:Homocysteine (Hcy) has been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). Although the CSF Hcy changes were explored in patients with ALS previously, the outcomes were inconsistent, and the permeability of the blood-brain barrier (BBB) may involve in the process. The aim of this study was to investigate the relationship between concentration of Hcy and BBB integrity indicated by CSF/serum albumin ratio (Qalb). METHODS:CSF and plasma/serum levels of Hcy, folate, and vitamin B12 and other biochemical biomarkers such as albumin, β2-microglobulin, high sensitive-C reactive protein (hs-CRP), microalbumin, immunoglobulin G (IgG), IgM, IgA, and complement 3 and 4 were analyzed in all 31 ALS patients and 34 controls. Routine CSF analysis including cells/leukocytes count, total protein, glucose, and chlorides were also performed. RESULTS:CSF Hcy levels (0.50 ± 0.46 vs 0.25 ± 0.27 μmol/L) and Qalb (8.09 ± 3.03 vs 6.39 ± 2.21) were significantly higher in the ALS group than that in controls (P < 0.05). The generalized linear mixed model analysis showed that the CSF Hcy was positively correlated with Qalb in ALS patients (P < 0.05). CONCLUSIONS:BBB permeability is increased in ALS patients. CSF Hcy level is associated with BBB integrity. Qalb is a significantly independent predisposing factor for CSF Hcy.

摘要

目的: 同型半胱氨酸 (Hcy) 已被证明与肌萎缩侧索硬化 (ALS) 的发病机制有关。尽管既往在 ALS 患者中探索了 CSF Hcy 的变化,但结果不一致,血脑屏障 (BBB) 的通透性可能参与了这一过程。本研究旨在探讨 Hcy 浓度与脑脊液/血清白蛋白比值 (Qalb) 提示的血脑屏障完整性的关系。 方法: 检测 CSF 和血浆/血清 Hcy 、叶酸、维生素 B12 等生化标志物如白蛋白、 β 2-微球蛋白、高敏 C 反应蛋白 (hs-CRP) 、微量白蛋白、对 31 例 ALS 患者和 34 例对照组进行免疫球蛋白 G (IgG) 、 IgM 、 IgA 和补体 3 、 4 分析。还进行常规 CSF 分析,包括细胞/白细胞计数、总蛋白、葡萄糖和氯化物。 结果: CSF Hcy 水平 (0.50 ± 0.46 vs 0.25 ± 0.27 μ mol/L) 和 Qalb (8.09 ± 3.03 vs 6.39 ± 2.21) ALS 组明显高于对照组 (p <0.05)。广义线性混合模型分析显示,ALS 患者 CSF Hcy 与 Qalb 呈正相关 (p <0.05)。 结论: ALS 患者 BBB 通透性增加。CSF Hcy 水平与 BBB 完整性相关。Qalb 是 CSF Hcy 的独立易感因素。

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发表时间:2020-01-01
DOI:10.1111/bpa.12761
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

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影响因子:3.66
发表时间:2020-01-24
DOI:10.3233/JAD-191069
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

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