Objective

To investigate serum biomarkers of progression in inactive primary progressive multiple sclerosis (PPMS).

Methods

We measured protein biomarkers (growth differentiation factor-15 (GDF-15), dickkopf-1 (DKK-1), neuron specific enolase (NSE) and cathepsin-D) in serum samples from 39 patients with inactive PPMS included in a clinical trial enrolling people with PPMS (clinicaltrials.gov identifier NCT02913157) and investigated the association of these biomarker levels with clinical disability at baseline and during follow-up. We then performed a meta-analysis of publicly available transcriptomic datasets to investigate the gene expression of these biomarkers in the CNS in progressive MS.

Results

When compared with healthy controls, people with PPMS had higher serum levels of GDF-15, DKK-1 and cathepsin-D at baseline. These findings match those in our meta-analysis which found increased expression of GDF-15 and cathepsin-D in the CNS in progressive MS. At baseline, elevated serum DKK-1 was associated with worse Expanded Disability Status Scale (EDSS) and nine-hole peg test (9HPT) scores. None of the other biomarkers levels significantly correlated with EDSS, Timed 25-Foot Walk Test (T25FWT), 9HPT, or cognitive measures. However, serum GDF-15 and cathepsin-D were higher at baseline in participants who developed worsening disability. Our receiver operating characteristic curve showed that higher serum GDF-15 and cathepsin-D at baseline significantly discriminated between participants who worsened in T25FWT and 9HPT and those who remained stable.

Conclusions

Patients with PPMS have altered levels of GDF-15, DKK-1 and cathepsin-D in serum, and GDF-15 and cathepsin-D may have predictive value in progression free of inflammatory activity in PPMS.

中文翻译：

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非活动性原发性进行性多发性硬化症残疾恶化的生物标志物

客观的

研究非活动性原发性进行性多发性硬化症 (PPMS) 进展的血清生物标志物。

方法

我们测量了临床试验中 39 名非活动性 PPMS 患者血清样本中的蛋白质生物标志物（生长分化因子-15 (GDF-15)、dickkopf-1 (DKK-1)、神经元特异性烯醇化酶 (NSE) 和组织蛋白酶-D）招募 PPMS 患者（clinicaltrials.gov标识符NCT02913157 ），并在基线和随访期间调查这些生物标志物水平与临床残疾的关联。然后，我们对公开的转录组数据集进行了荟萃分析，以研究进行性多发性硬化症中枢神经系统中这些生物标志物的基因表达。

结果

与健康对照者相比，PPMS 患者基线时的 GDF-15、DKK-1 和组织蛋白酶-D 血清水平较高。这些结果与我们的荟萃分析中的结果相符，荟萃分析发现进行性多发性硬化症的中枢神经系统中 GDF-15 和组织蛋白酶-D 的表达增加。在基线时，血清 DKK-1 升高与扩展残疾状态量表 (EDSS) 和九孔钉测试 (9HPT) 评分较差相关。其他生物标志物水平均未与 EDSS、定时 25 英尺步行测试 (T25FWT)、9HPT 或认知测量显着相关。然而，残疾状况恶化的参与者的基线时血清 GDF-15 和组织蛋白酶-D 较高。我们的受试者工作特征曲线显示，基线时较高的血清 GDF-15 和组织蛋白酶-D 可以显着区分 T25FWT 和 9HPT 恶化的参与者与保持稳定的参与者。

结论

PPMS 患者血清中 GDF-15、DKK-1 和组织蛋白酶-D 水平发生改变，GDF-15 和组织蛋白酶-D 可能对 PPMS 的无炎症活动进展具有预测价值。