Blood D-serine levels correlate with aging and dopaminergic treatment in Parkinson's disease

Introduction: We recently described increased D- and L-serine concentrations in the striatum of MPTP-treated monkeys and human Parkinson’s disease (PD) brains and in the CSF of de novo living PD patients compared to controls. However, data regarding peripheral D-serine levels in PD are scarce. Here we assessed whether the serum levels of serine enantiomers and the other NMDA receptor-related aminoacids (i) differ between PD patients and HC and (ii) correlate with demographic, clinical features and dopaminergic treatment in PD. Methods: We recruited 83 consecutive PD patients and 41 age-matched healthy controls (HC). PD cohort underwent an extensive motor, cognitive, quality of life and antiparkinsonian treatment characterization. The serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. Results: In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine or the other NMDA receptor-stimulating aminoacids between PD and HC. D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC (r=0.313, p=0.004 and r=0.311, p=0.004, respectively). Moreover, we found that (i) D-serine and D-/Total serine, but not the other neuroactive aminoacids, increase with older age at PD onset (r=0.379, p<0.001 and r=0.325, p=0.003, respectively); (ii) higher LEDD correlate with lower levels of D-serine (r =-0.248, p=0.027) and the other excitatory aminoacids; (iii) MDS-UPDRS-III positively correlate with glycine (r=0.241, p=0.033). Finally, the addition of LEDD as covariate disclosed higher serum D-serine in PD compared to HC (Δ=38.7%; p=0.038). Conclusions: increased serum D-serine levels represent a putative biochemical signature of PD. The positive correlation between D-serine and age at PD onset supports the hypothesis that D-serine may play a neuroprotective role in PD by delaying the onset of the disease.引言：本团队近期已报道，与对照组相比，经1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的猴纹状体、帕金森病（PD）患者脑组织以及初诊PD患者脑脊液（CSF）中的D-丝氨酸与L-丝氨酸浓度均升高。然而，目前关于PD患者外周血D-丝氨酸水平的相关数据仍较为匮乏。本研究旨在探讨以下两个问题：①PD患者与健康对照（HC）之间，丝氨酸对映体及其他N-甲基-D-天冬氨酸（NMDA）受体相关氨基酸的血清水平是否存在差异；②PD患者体内上述氨基酸的血清水平是否与人口统计学特征、临床症状及多巴胺能治疗方案存在相关性。 方法：本研究共纳入83例连续性PD患者及41例年龄匹配的健康对照（HC）。对PD队列进行了全面的运动功能、认知能力、生活质量及抗帕金森病治疗方案的特征性评估。采用高效液相色谱法（High Performance Liquid Chromatography, HPLC）检测受试者血清中D-丝氨酸、L-丝氨酸、L-谷氨酸、L-谷氨酰胺、L-天冬氨酸、L-天冬酰胺及甘氨酸的水平。 结果：经年龄与性别校正后的分析显示，PD患者与HC之间，D-丝氨酸、L-丝氨酸及其他NMDA受体兴奋性氨基酸的血清水平均无显著差异。在PD患者中，D-丝氨酸水平及D-/总丝氨酸比值与年龄呈显著正相关（相关系数r=0.313，P=0.004；r=0.311，P=0.004），而HC组未观察到该相关性。此外，本研究还发现：①D-丝氨酸水平及D-/总丝氨酸比值随PD发病年龄的增加而升高（r=0.379，P<0.001；r=0.325，P=0.003），而其他神经活性氨基酸则无此趋势；②较高的左旋多巴等效日剂量（Levodopa Equivalent Daily Dose, LEDD）与较低的D-丝氨酸及其他兴奋性氨基酸水平相关（r=-0.248，P=0.027）；③运动障碍学会统一帕金森病评定量表第三部分（MDS-UPDRS-III）评分与甘氨酸水平呈正相关（r=0.241，P=0.033）。最后，以LEDD作为协变量进行校正分析后发现，PD患者的血清D-丝氨酸水平较HC组升高38.7%（P=0.038）。 结论：血清D-丝氨酸水平升高可作为PD潜在的生化标志物。D-丝氨酸水平与PD发病年龄的正相关关系支持了以下假说：D-丝氨酸可能通过延缓疾病发病时间在PD中发挥神经保护作用。