Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy,Diabetologia

当前位置： X-MOL 学术 › Diabetol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy
Diabetologia ( IF 8.4 ) Pub Date : 2021-09-03 , DOI: 10.1007/s00125-021-05557-6
Jakob Morgenstern ₁ , Jan B Groener _{1,

2,

3} , Johann M E Jende ₄ , Felix T Kurz ₄ , Alexander Strom _{2,

5} , Jens Göpfert ₆ , Zoltan Kender _{1,

2} , Maxime Le Marois ₁ , Maik Brune ₁ , Rohini Kuner ₇ , Stephan Herzig _{2,

8} , Michael Roden _{2,

5,

9} , Dan Ziegler _{2,

5,

9} , Martin Bendszus ₄ , Julia Szendroedi _{1,

2} , Peter Nawroth _{1,

2,

8} , Stefan Kopf _{1,

2} , Thomas Fleming _{1,

2}

Affiliation

Aims/hypothesis

The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein.

Methods

Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months.

Results

In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA_1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519).

Conclusions/interpretation

This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers.

Graphical abstract

中文翻译：

神经元特异性生物标志物可预测糖尿病周围神经病变患者的痛觉减退和痛觉过敏

目标/假设

对于每个人来说，糖尿病周围神经病变进展的个体风险很难预测。已知负责髓鞘形成过程的蛋白质突变会导致神经变性，并在糖尿病神经病变的实验模型中显示出改变。在一项前瞻性观察性人体试验研究中，我们研究了已在体外鉴定的髓鞘特异性循环 mRNA 靶标，以了解它们在诊断和预测糖尿病神经病变方面的能力。最有希望的候选者针对最近建立的神经损伤生物标志物神经丝轻链蛋白进行了测试。

方法

在高葡萄糖条件下培养雪旺氏细胞，并在细胞内和细胞外筛选各种髓鞘特异性基因的 mRNA。92 名 2 型糖尿病参与者和 30 名对照参与者被纳入并使用神经病变缺损评分、神经病变症状评分和神经传导研究以及基线和 12/24 个月随访后的定量感觉测试评估周围神经病变时期。对 37 名个体进行了坐骨神经的磁共振神经造影。在所有参与者的血清中测量了来自体外筛选的神经丝轻链蛋白和四种髓鞘特异性 mRNA 转录物。测试结果与特定神经病性缺陷的关联，

结果

在神经元雪旺细胞和人类神经切片中，髓鞘蛋白零被确定为生物标志物研究的最强候选者。糖尿病神经病变参与者的髓鞘蛋白 0 循环 mRNA 显着降低（p < 0.001），而糖尿病神经病变参与者的神经丝轻链蛋白水平升高（p < 0.05）。这两个变量都与改变的电生理学、分数各向异性和定量感官测试有关。在接受者操作特征曲线分析中，髓鞘蛋白零与标准模型（糖尿病持续时间、年龄、BMI、HbA _1c) 从 0.681 到 0.836 的 AUC 用于检测糖尿病周围神经病变。一项后续研究表明，神经丝轻链增加与痛觉过敏表型的发展有关（p < 0.05），而髓鞘蛋白零减少预示着痛觉减退（p < 0.001）和神经功能的进行性丧失提前 24 个月（HR 6.519)。