Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Department of Neurosurgery, NeuroCenter, Kuopio University Hospital and Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Fluids Barriers CNS. 2023 Jun 5;20(1):40. doi: 10.1186/s12987-023-00440-5.
Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer's disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-β 1-42 (Aβ) to serve as predictors of shunt response.
We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC-MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness.
We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = - 0.46, log(fold change (FC)) = - 0.25, p < 0.001), ANXA4 (R = 0.46, log(FC) = 0.32, p < 0.001), MIF (R = -0.49, log(FC) = - 0.20, p < 0.001) and B3GAT2 (R = 0.54, log(FC) = 0.20, p < 0.001). In addition, five biomarker candidates were selected based on their strong correlation with gait speed change 1 year after shunt installation: ITGB1 (R = - 0.48, p < 0.001), YWHAG (R = - 0.41, p < 0.01), OLFM2 (R = 0.39, p < 0.01), TGFBI (R = - 0.38, p < 0.01), and DSG2 (R = 0.37, p < 0.01). Concentrations of the CSF AD core biomarkers did not differ significantly with shunt responsiveness.
FABP3, MIF, ANXA4, B3GAT2, ITGB1, YWHAG, OLFM2, TGFBI and DSG2 in CSF are promising prognostic biomarker candidates to predict shunt responsiveness in iNPH patients.
特发性正常压力脑积水（iNPH）是一种成人脑积水，其临床特征为进行性步态障碍、认知功能障碍和尿失禁。目前的标准治疗方法是手术安装脑脊液分流管。然而，只有一部分患者的症状从分流手术中得到缓解。因此，本前瞻性探索性蛋白质组学研究的目的是确定预测 iNPH 患者分流反应的预后性 CSF 生物标志物。此外，我们评估了核心阿尔茨海默病（AD）脑脊液生物标志物磷酸化（p）-tau、总（t）-tau 和淀粉样β 1-42（Aβ）作为分流反应预测因子的能力。
我们对 68 例 iNPH 患者术前腰椎 CSF 进行了串联质量标签（TMT）蛋白质组学分析。CSF 样本用 TMTpro 试剂进行酶切消化。TMT 多标签样品在碱性 pH 值下通过反相色谱法在 24 个串联馏分中进行分离，并在 Orbitrap Lumos 质谱仪上通过液相色谱-质谱（LC-MS）进行分析。鉴定蛋白的相对丰度与（i）iNPH 分级量表（iNPHGS）和（ii）术后 1 年从基线到手术的步态速度变化相关，以确定对分流反应的预测因子。
我们确定了四个与 iNPHGS 临床改善相关性最强的 CSF 生物标志物候选物，并且在分流反应性 iNPH 患者与分流无反应性 iNPH 患者中，这四个生物标志物在术后 1 年发生了显著变化：脂肪酸结合蛋白 3（FABP3）（R=-0.46，log（FC）=-0.25，p<0.001）、膜联蛋白 A4（ANXA4）（R=0.46，log（FC）=0.32，p<0.001）、巨噬细胞移动抑制因子（MIF）（R=-0.49，log（FC）=-0.20，p<0.001）和 B3GAT2（R=0.54，log（FC）=0.20，p<0.001）。此外，基于与分流安装后 1 年步态速度变化的强相关性，选择了五个生物标志物候选物：整合素β 1（ITGB1）（R=-0.48，p<0.001）、Y 盒结合蛋白 1（YWHAG）（R=-0.41，p<0.01）、寡霉素结合蛋白 2（OLFM2）（R=0.39，p<0.01）、转化生长因子β诱导蛋白 1（TGFBI）（R=-0.38，p<0.01）和桥粒芯糖蛋白 2（DSG2）（R=0.37，p<0.01）。CSF 中 AD 核心生物标志物的浓度与分流反应性无显著差异。
CSF 中的脂肪酸结合蛋白 3（FABP3）、巨噬细胞移动抑制因子（MIF）、膜联蛋白 A4（ANXA4）、B3GAT2、整合素β 1（ITGB1）、Y 盒结合蛋白 1（YWHAG）、寡霉素结合蛋白 2（OLFM2）、转化生长因子β诱导蛋白 1（TGFBI）和桥粒芯糖蛋白 2（DSG2）是预测 iNPH 患者分流反应的有前途的预后性 CSF 生物标志物候选物。
