脑脊液甲壳质酶蛋白40与新发帕金森病患者认知功能变化的关系

Relationship between cerebrospinal fluid YKL-40 and cognitive function changes in patients with de novo Parkinson disease

目的探讨新发帕金森病(Parkinson disease,PD)患者脑脊液(cerebrospinal fluid,CSF)中甲壳质酶蛋白40(chitinase protein,YKL-40)与认知功能纵向变化的相关性。方法从帕金森进展标志物倡议(Parkinson Progression Marker Initiative,PPMI)数据库中筛选新发PD患者(PD组)和健康对照者(健康对照组),分别收集其基线及随访6个月、12个月、24个月、36个月和60个月的数据。将PD组分为认知功能正常组(Parkinson disease normally cognitive,PD-NC)、轻度认知功能障碍组(PD with mild cognitive impairment,PD-MCI)和痴呆组(PD with dementia,PD-D),比较各组的临床数据,并研究基线CSF YKL-40的浓度及YKL-40变化率与CSF生物标志物及临床认知评估量表结果纵向变化的相关性。结果共纳入PD组195例,健康对照组(healthy controls,HC)组88例,PD组基线CSF YKL-40水平(119.08 pg/mL)低于HC组(132.64 pg/mL),PD-MCI组CSF YKL-40水平(127.51 pg/mL)高于PD-NC组(114.77 pg/mL),差异有统计学意义(P<0.001)。在PD组中,基线CSF YKL-40与CSF Aβ_(42)(β=0.526,P<0.001)、T-tau(β=0.425,P<0.001)、P-tau(β=0.373,P<0.001)、α-syn(β=0.525,P<0.001)水平均呈正相关,与临床认知功能评估结果未发现相关。通过混合效应模型分析发现,PD组基线CSF YKL-40浓度越高,CSF T-tau(β=0.034,P=0.009)、P-tau(β=0.041,P=0.001)水平增高越快,而霍普金斯词语学习测验(Hopkins verba learning test,HVLT)-延迟回忆评分(β=-0.027,P=0.029)、HVLT-维持记忆评分(β=-0.030,P=0.022)下降越快。更高的CSF YKL-40变化率与CSF T-tau(β=0.045,P=0.001)、P-tau(β=0.053,P<0.001)水平更快增高和HVLT-延迟回忆评分(β=-0.026,P=0.049)更快下降相关。结论CSF YKL-40有希望成为监测新发PD患者认知功能下降严重程度的生物标志物。

Objective To investigate the correlation between chitinase protein(YKL-40)in cerebrospinal fluid(CSF)and longitudinal changes of cognitive function in patients with de novo Parkinson disease(PD).Methods PD group and healthy controls group were selected from the Parkinson Progression Markers Initiative(PPMI)database and their clinical data were collected at baseline,6 months,12 months,24 months,36 months and 60 months of follow-up.PD patients were divided into Parkinson disease normally cognitive(PD-NC),PD with mild cognitive impairment(PD-MCI),and Parkinson disease with dementia(PD-D)groups and comparison of clinical data between groups.We also investigated the correlation of baseline CSF YKL-40 concentration and rate of change in YKL-40 with longitudinal changes in other CSF biomarkers and clinical cognitive assessment results.Results A total of 195 patients were enrolled in PD group and 88 in healthy controls(HC)group.Baseline CSF YKL-40 levels in PD patients(119.08 pg/mL)were significantly lower than those in HC patients(132.64 pg/mL).The level of CSF YKL-40 in PD-MCI patients(127.51 pg/mL)was significantly higher than that in PD-NC patients(114.77 pg/ml)at baseline(P<0.001).In PD patients,baseline CSF YKL-40 was positively correlated with CSF Aβ42(β=0.526,P<0.001),T-tau(β=0.425,P<0.001),P-tau(β=0.373,P<0.001),andα-syn(β=0.525,P<0.001)levels,and was not correlated with clinical assessments of cognitive function.In mixed effect model analysis,we found that the higher the baseline CSF YKL-40 concentration in PD patients,the faster the increase of CSF T-tau(β=0.034,P=0.009)and P-tau(β=0.041,P=0.001)levels,and the faster the decrease of Hopkins verbal learning test(HVLT)delayed recall(β=-0.027,P=0.029)and HVLT retention(β=-0.030,P=0.022).We also found that higher rates of CSF YKL-40 change were associated with faster increases in CSF T-tau(β=0.045,P=0.001)and P-tau(β=0.053,P<0.001)levels and faster declines in HVLT Delayed Recall(β=-0.026,P=0.049).Conclusion Our study suggests that CSF YKL-40 holds promise as a biomarker that can monitor the severity of cognitive decline in patients with new-onset PD.