Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.
Neurol Neurochir Pol. 2023;57(4):379-386. doi: 10.5603/PJNNS.a2023.0053. Epub 2023 Aug 1.
Our study assessed changes in concentrations of serum markers for brain damage and blood-brain barrier (BBB) dysfunction in untreated and treated Wilson's disease (WD) patients, and examined correlations between these changes and neurological impairment.
These results hold the potential to determine BBB impairment and neurological advancement in WD to develop the most effective treatment for patients with severe neurological deterioration.
The study groups included 171 patients with WD (77 with hepatic and 94 with neurological manifestations), treated either for up to 5 or 15 years, and 88 healthy controls. Serum concentrations of intercellular adhesion molecule 1 (ICAM1), P-selectin, matrix metallopeptidase 9 (MMP9), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein B (S100B) were measured before and during anti-copper treatment. The Unified Wilson's disease Rating Scale (UWDRS) was used to assess neurological advancement.
ICAM1 concentrations were elevated before and during anti-copper treatment compared to controls (p < 0.01), but therapy led to substantial decreases both in patients with hepatic (p < 0.01) and in patients with neurological manifestations (p < < 0.05). P-selectin concentrations remained elevated before and during treatment (p < 0.05) regardless of the treatment duration and disease form. MMP9 concentrations before treatment were lower (p < 0.05), but reached control levels during treatment. GFAP concentrations were significantly elevated only in untreated patients with neurological symptoms in the longer-treated group compared to controls (p < 0.05). A significant reduction during treatment was observed only in the shorter-treated neurological group (p < 0.05). No substantial changes were observed in S100B. Only ICAM1 concentrations positively correlated (r = 0.27, p < 0.001) with the UWDRS.
Our results provide evidence of endothelial activation in WD. However, inconclusive GFAP results, and no increase in S100B, do not allow us to conclude whether the reactive gliosis is not prominent or alternatively whether the BBB is disrupted. Elevated ICAM1 concentrations and their correlation with neurological advancement indicate BBB impairment. A decrease in ICAM1 during treatment suggests that the inflammatory process is reduced, and the BBB partially repaired. Decreased MMP9 concentrations may be the result of active liver fibrosis and higher copper concentrations. Elevated P-selectin concentrations indicate a systemic inflammatory process.
我们的研究评估了未经治疗和治疗的威尔逊病（WD）患者血清脑损伤和血脑屏障（BBB）功能障碍标志物浓度的变化，并检查了这些变化与神经损伤之间的相关性。
这些结果有可能确定 WD 中的 BBB 损伤和神经进展，为严重神经恶化的患者制定最有效的治疗方法。
研究组包括 171 例 WD 患者（77 例肝型和 94 例神经型），分别接受长达 5 年或 15 年的治疗，以及 88 例健康对照者。在抗铜治疗前和治疗期间测量细胞间黏附分子 1（ICAM1）、P-选择素、基质金属蛋白酶 9（MMP9）、胶质纤维酸性蛋白（GFAP）和 S100 钙结合蛋白 B（S100B）的血清浓度。使用统一的威尔逊病评定量表（UWDRS）评估神经进展。
与对照组相比，ICAM1 浓度在抗铜治疗前和治疗期间均升高（p<0.01），但治疗后肝型（p<0.01）和神经型患者（p<0.05）的浓度均显著降低。P-选择素浓度在治疗前和治疗期间均升高（p<0.05），与治疗持续时间和疾病形式无关。治疗前 MMP9 浓度较低（p<0.05），但治疗期间达到对照水平。仅在未经治疗的神经症状较长组的患者中，GFAP 浓度在治疗期间显著升高（与对照组相比，p<0.05）。在较短治疗的神经组中仅观察到治疗期间的显著降低（p<0.05）。S100B 未观察到明显变化。只有 ICAM1 浓度与 UWDRS 呈正相关（r=0.27，p<0.001）。
我们的结果提供了 WD 中内皮细胞激活的证据。然而，GFAP 结果不确定，S100B 无升高，这并不允许我们得出结论是反应性神经胶质增生不明显，还是 BBB 被破坏。升高的 ICAM1 浓度及其与神经进展的相关性表明 BBB 损伤。治疗期间 ICAM1 浓度的降低表明炎症过程减少，BBB 部分修复。MMP9 浓度降低可能是由于活动性肝纤维化和较高的铜浓度。升高的 P-选择素浓度表明存在全身性炎症过程。
