Study of serum cystatin C levels in patients with vascular cognitive impairment
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摘要:
目的 明确血清胱抑素C(CysC)在血管性认知障碍(VCI)患者中的表达,探讨两者间的相关性及CysC的临床预测价值。 方法 纳入蚌埠医学院第一附属医院2021年1月—2022年2月诊治的VCI患者96例。根据患者日常生活能力及蒙特利尔认知量表(MoCA)评分将患者分为血管性痴呆(VaD)组(35例)和血管性认知障碍非痴呆(VCIND)组(61例),另选取83例认知和颅脑CT/MRI均表现正常的健康老人为对照(NC)组。比较3组基线资料及CysC水平,分析CysC与VCI患者总体认知及特定认知域的关系,采用二元logistic回归分析和ROC曲线评估VCI发生的相关危险因素及CysC对其发生的预测价值。 结果 3组年龄、高血压、糖尿病、卒中史、CysC和MoCA评分差异有统计学意义(均P < 0.05);NC组、VCIND组和VaD组CysC表达水平依次升高,两两比较差异有统计学意义(均P < 0.05);CysC与VCI患者MoCA总评分以及视空间与执行力、命名、计算与注意力、语言、定向、延迟记忆呈负相关关系(均P < 0.05);Logistic回归分析显示CysC表达升高可能是VCI发生的独立危险因素(P < 0.05);ROC曲线分析显示CysC预测VCI发生的AUC为0.758,灵敏度为70.8%,特异度为77.1%,最佳截断值为0.99 mg/L。 结论 血清胱抑素C在VCI中高表达并与认知损害严重程度相关,是认知障碍发生的独立影响因素,有望成为VCI早期评估的生物学指标。 Abstract:Objective To determine the expression of serum cystatin C (CysC) in patients with vascular cognitive impairment (VCI), and to explore the correlation between them and the clinical predictive value of CysC. Methods This study included 96 patients with VCI who were enrolled in the First Affiliated Hospital of Bengbu Medical College from January 2021 to February 2022. They were divided into vascular dementia group (VaD, n=35) and vascular cognitive impairment without dementia group (VCIND, n=61) according to the Montreal Cognitive Assessment (MoCA) and ability of daily living (ADL) scores. In addition, 83 healthy elderly with normal cognitive function and brain MRI/CT were selected as normal controls (NC group). Baseline data and serum CysC levels were compared to analyse the relationship of CysC with overall cognition and its specific cognitive domains in patients with VCI. Binary logistic regression and ROC curves were used to evaluate VCI-related risk factors and the predictive value of CysC for the occurrence of VCI. Results Significant differences in age, history of hypertension, diabetes, stroke, MoCA scores and CysC were found among the three groups (all P < 0.05). The serum CysC expression increased sequentially in the NC, VCIND and VaD groups, and the differences were statistically significant (all P < 0.05). CysC was negatively correlated with MoCA overall cognition, visual space and executive function, naming, attention and computation, language, delayed memory and orientation in the VCI group (all P < 0.05). The results of multivariate logistic regression model indicated that higher levels of CysC were independent risk factors for VCI (P < 0.05). ROC curve analysis showed that the area under curve (AUC) for predicting the occurrence of VCI by serum CysC level was 0.758, the sensitivity was 70.8%, the specificity was 77.1% and the optimal cut-off value was 0.99 mg/L. Conclusion Serum CysC is highly expressed in VCI and is related to the severity of cognitive impairment. It is an independent influencing factor of cognitive impairment and is expected to become a biological indicator for early assessment of VCI. -
Key words:
- Vascular cognitive impairment /
- Cystatin C /
- Alzheimer' s disease /
- Cognitive function
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表 1 3组研究对象一般资料及MoCA评分比较
Table 1. Comparison of general information and MoCA scores among the three groups
项目 NC组(n=83) VCIND组(n=61) VaD组(n=35) 统计量 P值 性别(男/女, 例) 40/43 28/33 17/18 0.095c 0.954 年龄(x±s, 岁) 66.48±6.97 68.05±7.36 71.00±6.51ab 5.111d 0.007 BMI(x±s) 24.58±2.99 24.22±3.28 23.73±3.89 0.835d 0.435 受教育年限(x±s, 年) 9.01±2.32 8.62±3.04 7.98±2.80 0.345d 0.693 吸烟史[例(%)] 18(21.68) 18(29.50) 8(22.85) 1.230c 0.541 饮酒史[例(%)] 11(13.25) 11(18.03) 5(14.28) 0.649c 0.723 高血压史[例(%)] 39(46.98) 41(67.21)a 31(88.57)ab 19.134c < 0.001 糖尿病史[例(%)] 15(18.07) 29(47.54)a 17(48.57)a 17.659c < 0.001 高脂血症[例(%)] 28(33.73) 31(50.81) 16(45.71) 4.476c 0.107 卒中史[例(%)] 13(15.66) 32(52.45)a 30(85.71)ab 53.865c < 0.001 TC(x±s, mmol/L) 3.84±0.94 3.70±1.06 3.82±1.21 0.312d 0.732 TG[M(P25, P75), mmol/L] 1.21(0.87, 1.70) 1.34(0.88, 1.77) 1.16(0.78, 1.76) 0.848e 0.654 LDL-C(x±s, mmol/L) 2.38±0.68 2.15±0.79 2.17±0.71 2.000d 0.138 HDL-C(x±s, mmol/L) 1.02±0.28 1.00±0.24 0.98±0.26 0.378d 0.686 FBG[M(P25, P75), mmol/L] 5.19(4.69, 6.05) 5.36(4.69, 6.84) 5.72(4.63, 8.22) 1.909e 0.385 UA[M(P25, P75), μmol/L] 304(255, 335) 285(234, 335) 271(211, 336) 2.164e 0.339 BUN(x±s, mmol/L) 6.53±1.06 6.82±0.98 7.09±1.72 0.820d 0.441 SCr(x±s, μmol/L) 69.32±15.06 71.56±16.54 73.68±21.43 1.529d 0.219 CysC(x±s, mg/L) 0.85±0.32 1.07±0.32a 1.29±0.63ab 9.662d < 0.001 MoCA评分[M(P25, P75), 分] 28(27, 28) 18(13, 20)a 10(8, 14)ab 148.693e < 0.001 注:与NC组比较,aP < 0.05;与VCIND组比较,bP < 0.05。c为χ2值,d为t值,e为H值。 表 2 VCI患者血清CysC与MoCA及特定认知域的相关性分析
Table 2. Correlation analysis of serum CysC with MoCA and specific cognitive domains in patients with VCI
项目 MoCA 视空间与执行 命名 注意 计算 语言 抽象 延迟记忆 定向 r值 -0.472 -0.380 -0.230 -0.269 -0.274 -0.311 -0.164 -0.363 -0.303 P值 < 0.001 < 0.001 0.024 0.008 0.007 0.002 0.110 < 0.001 0.003 表 3 VCI发生的多因素logistic回归分析
Table 3. Multivariate logistic regression analysis of VCI occurrence
模型 B SE Wald χ2 P值 OR值 95% CI 单变量分析 2.476 0.577 18.423 < 0.001 11.898 3.840~36.862 多变量模型1 1.533 0.644 5.662 0.017 4.630 1.310~16.360 多变量模型2 1.706 0.729 5.472 0.019 5.507 1.319~23.001 -
[1] DICHGANS M, LEYS D. Vascular cognitive impairment[J]. Circ Res, 2017, 120(3): 573-591. doi: 10.1161/CIRCRESAHA.116.308426 [2] LIVINGSTON G, HUNTLEY J, SOMMERLAD A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission[J]. Lancet, 2020, 396(10248): 413-446. doi: 10.1016/S0140-6736(20)30367-6 [3] LEES J S, WELSH C E, CELIS-MORALES C A, et al. Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease[J]. Nat Med, 2019, 25(11): 1753-1760. doi: 10.1038/s41591-019-0627-8 [4] ROTHENBACHER D, REHM M, IACOVIELLO L, et al. Contribution of cystatin C and creatinine-based definitions of chronic kidney disease to cardiovascular risk assessment in 20 population-based and 3 disease cohorts: the BiomarCaRE project[J]. BMC Med, 2020, 18(1): 300. doi: 10.1186/s12916-020-01776-7 [5] VIGGIANO D, WAGNER C A, MARTINO G, et al. Mechanisms of cognitive dysfunction in CKD[J]. Nat Rev Nephrol, 2020, 16(8): 452-469. VIGGIANO D, WAGNER C A, MARTINO G, et al. Mechanisms of cognitive dysfunction in CKD[J]. Nat Rev Nephrol, 2020, 16(8): 452-469. doi: 10.1038/s41581-020-0266-9 [6] CUI Z Z, CAO G Z, WANG Y Y, et al. Effects of cystatin C on cognitive impairment in older Chinese adults[J]. Am J Alzheimers Dis Other Demen, 2020, 35: 1533317520965101. DOI: 10.1177/1533317520965101. [7] CHEN X P, HUANG Y, BAO T, et al. Changes in serum cystatin C levels and the associations with cognitive function in Alzheimer's disease patients[J]. Front Aging Neurosci, 2022, 13: 790939. DOI: 10.3389/fnagi.2021.790939. [8] GHIDONI R, BENUSSI L, GLIONNA M, et al. Plasma cystatin C and risk of developing Alzheimer's disease in subjects with mild cognitive impairment[J]. J Alzheimers Dis, 2010, 22(3): 985-991. doi: 10.3233/JAD-2010-101095 [9] 中国医师协会神经内科分会认知障碍专业委员会, 《中国血管性认知障碍诊治指南》编写组. 2019年中国血管性认知障碍诊治指南[J]. 中华医学杂志, 2019, 99(35): 2737-2744. doi: 10.3760/cma.j.issn.0376-2491.2019.35.005Cognitive Disorders Professional Committee, Neurology Branch, Chinese Medical Doctor Association, Writing group of Chinese Guidelines for the diagnosis and treatment of vascular cognitive Impairment. Guidelines for Diagnosis and Treatment of vascular cognitive Impairment in China, 2019[J]. 中华医学杂志, 2019, 99(35): 2737-2744. doi: 10.3760/cma.j.issn.0376-2491.2019.35.005 [10] 甘露, 刘涛, 王淑华, 等. 中文版简明精神状态量表与蒙特利尔认知评估量表临床应用进展[J]. 中国康复医学杂志, 2017, 32(7): 842-845. doi: 10.3969/j.issn.1001-1242.2017.07.026GAN L, LIU T, WANG S H, et al. Clinical application of the Chinese version of the concise mental state scale and the montreal cognitive assessment scale[J]. Chinese Journal of Rehabilitation Medicine, 2017, 32(7): 842-845. doi: 10.3969/j.issn.1001-1242.2017.07.026 [11] BOLAND J R. DSM-5 (R) guidebook: the essential companion to the diagnostic and statistical manual of mental disorders, 5th edition[J]. J Psychiatr Pract, 2015, 21(2): 171-173. doi: 10.1097/01.pra.0000462610.04264.fa [12] ZENG Q, HUANG Z H, WEI L L, et al. Correlations of serum cystatin C level and gene polymorphism with vascular cognitive impairment after acute cerebral infarction[J]. Neurol Sci, 2019, 40(5): 1049-1054. doi: 10.1007/s10072-019-03777-8 [13] 叶明, 陈育华, 刘晓林, 等. 帕金森病患者血清半胱氨酸蛋白酶抑制剂C水平的变化及其临床意义[J]. 中华全科医学, 2016, 14(12): 2004-2007. doi: 10.16766/j.cnki.issn.1674-4152.2016.12.010YE M, CHEN Y H, LIU X L, et al. The clinical significance of serum cystatin C level change in Parkinson's disease[J]. Chinese Journal of General Practice, 2016, 14(12): 2004-2007. doi: 10.16766/j.cnki.issn.1674-4152.2016.12.010 [14] YAO T T, SONG G P, LI Y H, et al. Chronic kidney disease correlates with MRI findings of cerebral small vessel disease[J]. Ren Fail, 2021, 43(1): 255-263. doi: 10.1080/0886022X.2021.1873804 [15] DUAN J H, MARCELLUS K A, QIN X K, et al. Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons[J]. Mol Cell Neurosci, 2018, 89: 1-8. doi: 10.1016/j.mcn.2018.03.009 [16] PERLENFEIN T J, MURPHY R M. A mechanistic model to predict effects of cathepsin B and cystatin C on β-amyloid aggregation and degradation[J]. J Biol Chem, 2017, 292(51): 21071-21082. doi: 10.1074/jbc.M117.811448 [17] SHEIKH A M, WADA Y, TABASSUM S, et al. Aggregation of cystatin C changes its inhibitory functions on protease activities and amyloid β fibril formation[J]. Int J Mol Sci, 2021, 22(18): 9682. doi: 10.3390/ijms22189682 [18] FANG Z P, FENG Y, LI Y H, et al. Neuroprotective autophagic flux induced by hyperbaric oxygen preconditioning is mediated by cystatin C[J]. Neurosci Bull, 2019, 35(2): 336-346. doi: 10.1007/s12264-018-0313-8 [19] WU H X, DU Q N, DAI Q Y, et al. Cysteine protease cathepsins in atherosclerotic cardiovascular diseases[J]. J Atheroscler Thromb, 2018, 25(2): 111-123. doi: 10.5551/jat.RV17016 [20] ZHANG Y R, SUN L. Cystatin C in cerebrovascular disorders[J]. Curr Neurovasc Res, 2017, 14(4): 406-414.