| BackgroundProgressive supranuclear palsy(PSP)is a kind of common Parkinson's superposition syndrome,accounting for about 7%of Parkinson's syndrome and 50%of atypical Parkinson's syndrome.Its characteristic clinical manifestations are vertical supranuclear gaze paralysis,pseudobulbar paralysis,postural instability and fall,axial dystonia,cognitive decline,and drug resistance to levodopa.The typical pathological changes of PSP is microtubule-associated protein-positive neuron fiber fibrosis(NFTs)in the globus pallidus,substantia nigra,locus coeruleus,oculomotor nuclei,and midbrain periaqueductal gray.The pathogenic mechanism of PSP is not fully understood,although genetic and epigenetic factors,oxidative injury and inflammation are thought to contribute to their development and progression.In recent years,neuroinflammation has been a hot topic and focus of PSP research.Evidence for activated glia in PSP raises the possibility that neuroinflammation,indeed,may be involved in its pathogenesis.Further clarification of this process and its regulatory mechanisms is the key to finding potential targets for disease modification therapy and delaying the progression of the disease process.YKL-40 is a 40kDa heparin and chitin-binding glycoprote also known as chitinase-3-like protein 1(CHI3L1).The abbreviation YKL-40 is based on the one letter code for the first three N-terminal amino acids-tyrosine(Y),lysine(K)and leucine(L)-and its molecular weight of 40kDa.The human CHI3L1 gene encoding for YKL-40 has been localized to chromosome 1q31-q32.Notably,YKL-40 shows a chitin-binding ability but does not possess any chitinase activity.YKL-40 plays a role in various cellular responses-including proliferation,differentiation,survival,and inflammation response.YKL-40 is expressed in macrophages and can be considered a specific differentiation marker for this cell type.Other cells that are able to express YKL-40 include mast cells,chondrocytes,fibroblasts,vascular smooth muscle cells,endothelial cells,astroglia,and microglia.YKL-40 is involved in the development and progression of several neurological diseases,including stroke,multiple sclerosis,traumatic brain injury,and dementia.Particularly,in multiple sclerosis(MS),the most important neuroinflammatory disease model in humans,CSF YKL-40 helped to predict the conversion to clinically definite MS in subjects with clinically isolated syndromes and discriminate primary progressive from relapsing remitting MS.As so far,little is known about the concentration of YKL-40 in the serum of PSP patient.Establishing a correlation between PSP pathology and cytokine alterations would be important not only in understanding the pathogenesis of the disease,but in considering cytokine-inhibitors or other anti-inflammatory agents as potential therapeutic strategies.Thus,the purpose of this study was to investigate the serum YKL-40 expression level in PSP patients.ObjectiveThis study detected the expression level of YKL-40 in the serum of PSP patients,investigated the association between YKL-40 and clinical parameters.In order to evaluate whether this cytokines can be used as a biological marker for diagnosis or monitoring of the development of PSP.Methods28 probable PSP patients and 26 age-matched healthy controls were enrolled.For the PSP subject,information regarding gender,age,disease duration,and age at onset of PSP symptoms were collected.The severity of PSP was evaluated according to the Progressive Supranuclear Palsy Rating Scale(PSPRS)score which was conducted during the off-medication phase.The severity of cognitive dysfunction was evaluated according to the Mini-mental State Examination(MMSE)score.Serum YKL-40 level was measured by enzyme-linked immunosorbent assays(ELISA).Univariate and multivariate analyses investigated correlations between YKL-40 and clinical characteristics,including disease severity by the PSPRS.Finally,use receiver operating characteristic(ROC)analysis evaluated the diagnostic value of YKL-40.Results1.1.Clinical data of PSP group and healthy control group28 probable PSP patients(15 males and 13 females)and 26 age-matched healthy controls(14 males and 12 females)were enrolled.There was no significant difference between the two groups in the gender and age(all P>0.05).2.Basic characteristics for PSP patients and controlsTo determine whether there was a significant difference in YKL-40 levels between the PSP patients and controls,we used a standard 2-sample t-test.The mean YKL-40 level of the PSP group(59.24 ng/mL)was nearly 1.5 fold that of the control group(42.12 ng/mL,P = 0.011).Moreover,when stratified into PSP-RS and PSP-P,the serum YKL-40 level in peripheral blood of PSP-RS group(65.09 ng/mL)was significantly higher than that of normal control group(41.62 ng/mL,P = 0.003).3.Clinical characteristics of men and women in the PSP groupThe serum YKL-40 levels of men and women in the PSP group was 61.00 ng/mL and 57.20 ng/mL,respectively(P = 0.713),and therefore statistically similar.Meanwhile,the male and female with PSP were statistically similar in age,disease duration,age at onset of PSP symptoms,MMSE score,and PSPRS score.4.Clinical characteristics of PSP-RS and PSP-PIn the PSP group,the serum YKL-40 level of PSP-RS patients(65.09 ng/mL)were significantly higher that of PSP-P patients(41.68 ng/mL,P = 0.041).At the same time,the disease duration of PSP-P patients was significant longer than that of PSP-RS patients(P = 0.003).The PSP-RS and PSP-P were statistically similar in age,age at onset of PSP symptoms,MMSE score,and PSPRS score.5.Associations between YKL-40 levels and clinical parameters in the PSP-RS groupIn PSP-RS group,the correlation analysis showed that the serum YKL-40 level was significantly and positively associated with PSPRS score(r = 0.566,P = 0.008).Nevertheless,no significant association was found between YKL-40 level and age(r=0.383,P = 0.086),age at onset of PSP symptoms(r = 0.275,P = 0.227),or MMSE score(r =-0.114,P = 0.624).6.The multiple linear regression analysis of PSPRS scoreIn PSP-RS group,we used univariate and multiple linear regression analyses to identify potential risk factors for severity of disease,as reflected by the PSPRS score.According to the results of the univariate analysis,the disease duration(?= 0.490,P ?0.024)and serum YKL-40 level(?=0.566,P =0.008)were significantly associated with PSPRS score.To adjust the disease duration,a stepwise multiple linear regression analysis was performed.The results revealed that serum YKL-40 level(??0.504,P = 0.033)were independent risk factors that correlated with PSPRS score.7.ROC curve analysis of serum YKL-40 as a possible PSP biomarkerWe than performed a ROC curve analysis,evaluating the utility of serum YKL-40 as a candidate marker for discriminating the PSP from the normal controls.For all PSP patients,an optimal cut-off value of 51.20ng/mL for serum YKL-40 was identified,and the AUC was 0.698(95%CI 0.558-0.815,P = 0.0068),with a sensitivity of 64.29%and specificity of 80.77%.Compared with all PSP patients,the PSP-RS patients showed a higher sensitivity.For PSP-RS patients,the AUC was 0.762(95%CI 0.603-0.881,P = 0.0007),with a sensitivity of 76.19%and specificity of 80.00%,where the best cut-off concentration of serum YKL-40 was 51.20ng/mL.ConclusionThe level of YKL-40 in the serum of PSP patients(especially PSP-RS patients)was significantly higher than that of normal healthy people.The serum YKL-40 level of PSP-RS patients was correlated to the severity of PSP.YKL-40 has certain value in the diagnosis of PSP,and may be a potential biomarker for PSP diagnosis. |
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