帕金森病伴发不宁腿综合征的临床特征及神经病理生化机制

Parkinson's disease with restless legs syndrome:clinical features,pathological proteins and neurotransmitters

目的初步探讨帕金森病(PD)伴发不宁腿综合征(RLS)的临床特征以及神经病理蛋白和神经递质水平的变化。方法收集连续就诊于北京天坛医院老年病科和神经内科的PD患者186例,将患者分为PD伴发RLS组(简称RLS组)和PD非伴发RLS(简称NRLS)组,采用不宁腿综合征评定量表(RLS-RS)评价RLS的临床表现及严重程度;采用酶联免疫吸附法检测脑脊液神经病理蛋白(包括α-突触核蛋白寡聚体、总Tau及不同部位磷酸化tau蛋白)水平,采用高效液相色谱检测脑脊液神经递质(包括多巴胺、乙酰胆碱、肾上腺素和5-羟色胺)的水平。分析各神经病理蛋白及神经递质与RLS-RS评分的关系。结果 (1)186例PD患者RLS的发生率为42.47%;RLS组的病程明显长于NRLS组(P<0.05)。(2)RLS组Hoehn-Yahr分期及UPDRSⅢ评分均明显高于NRLS组(均P<0.05)。(3)RLS组患者汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)、匹茨堡睡眠质量指数量表(PSQI)和疲劳严重程度量表(FSS)评分均高于NRLS组(均P<0.01),而两组间蒙特利尔认知评估量表(MoCA)、改良淡漠评定量表(MAES)和爱泼沃斯思睡量表(ESS)评分比较差异无统计学意义(P>0.05)。(4)RLS组脑脊液α-突触核蛋白寡聚体水平明显高于NRLS组〔(0.31±0.09)ng/mL比(0.21±0.08)ng/mL,P<0.05〕。RLS组RLS-RS评分与脑脊液α-突触核蛋白寡聚体水平呈正相关(r=0.355,P<0.01)。(5)RLS组脑脊液多巴胺和5-羟色胺水平明显低于NRLS组〔(5.53±3.67)pg/mL比(7.97±4.85)pg/mL,P<0.01;(13.23±8.14)pg/mL比(19.21±7.50)pg/mL,P<0.01〕。RLS组RLS-RS严重度评分与脑脊液多巴胺和5-羟色胺水平呈负相关(r=-0.274,P<0.01;r=-0.360,P<0.01)。(6)脑脊液α-突触核蛋白寡聚体水平与多巴胺以及5-羟色胺水平无相关性(r=-0.119,P=0.362;r=-0.127,P=0.327)。结论 RLS是PD常见的非运动症状之一,PD伴发RLS患者的运动症状更重,非运动症状中焦虑、抑郁、疲劳更重,睡眠质量更差。PD-RLS脑内α-突触核蛋白寡聚体沉积可能是PD-RLS的发生机制,多巴胺缺乏可能是PD-RLS的神经生化基础。

Objective To explore the relationships between restless legs syndrome（RLS）and clinical features,pathological proteins and neurotransmitters in patients with Parkinson＇s disease（PD）.Methods 186 PD patients were collected and divided into the RLS group and non-RLS（NRLS）groups according to the scores of RLS-rating scale（RLS-RS）and a comparison study was conducted by measuring pathological proteins（α-synuclein oligomer,total-Tau,phosphorylation-Tau）using enzyme linked immunosorbent assay（ELISA）,and neurotransmitters（dopamine,acetylcholine,adrenaline and 5-hydroxytryptaphane）using high-performance liquid chromatography.Results（1）42.47% of PD patients were accompanied with RLS.The RLS group had significantly longer disease duration than the NRLS group（P〈0.05）.（2）There were significant differences in Hoehn-Yahr Stage and UPDRS Ⅲ score between the RLS and NRLS groups（P〈0.05）.（3）The scores of Hamilton anxiety scale（HAMA）,Hamilton depression scale（HAMD）,fatigue severity scale（FSS）and Pittsburgh Sleep Quality Index（PSQI）in the RLS group were significantly increased comparing with those in the NRLS group（P〈0.05）.The scores of Montreal Cognitive Assessment（MoCA）,modified indifference rating scal（MAES）and Epworth Sleeping Scale（ESS）were not significantly different between the two groups（P〉0.05）.（4）α-synuclein oligomer levels in cerebrospinal fluid（CSF）in the PD-RLS group were elevated compared to PD-NRLS group [（0.31±0.09）ng/mL vs.（0.21±0.08）ng/mL,P〈0.05）.RLS-RS score was increased with the elevatedα-synuclein oligomer level in CSF（r=0.355,P〈0.01）.（5）Dopamine（DA）and serotonin（5-HT）levels in CSF in the PD-RLS group were decreased compared to PD-NRLS group[（5.53±3.67）pg/mL vs.（7.97±4.85）pg/mL,P〈0.01;（13.23±8.14）pg/mL vs.（19.21±7.50）pg/mL,P〈0.01;respectively].RLS-RS score was increased with the decreased DA and 5-HT levels in CSF（r=-0.274,P〈0.01;r=-0.360,P〈0.01;respectively）.（6）The level ofα-synuclein oligomers in CSF was not significantly correlated with the levels of DA and 5-HT transmitters（r=-0.119,P=0.362;r=-0.127,P=0.327）.Conclusions RLS is one of the common non-motor symptoms（NMS）in PD,which is associated with the severity of motor symptoms.PD patients with RLS have more NMS,among them,anxiety,depression,fatigue and sleep disorder are more prominent than the PD-NRLS group.PD patients with RLS present deposition ofα-synuclein,which may be the potential mechanism of PD in patients with RLS.The lack of DA in the brain may be the main transmitter disturbance of RLS in PD patients.