Cerebrospinal Fluid Osteopontin Is A Potential Early Biomarker Of Alzheimer’s Disease

Background:Alzheimer’s disease is a chronic neurodegenerative disease characterized by changes in cerebrospinal fluid proteins and cognitive impairment.At present,there are no specific therapeutic drugs in the medical and health field,and these can not prevent or reverse the progression of AD.In recent years,many clinical trials on modified drugs for AD disease have ended in failure,which may be due to the fact that most of the subjects involved in the trial are in the middle and late stages of the AD process,and these patients have long missed the best opportunity to benefit from drug intervention.At the same time,more and more epidemiological studies have shown that AD is preventable,and we can reduce the incidence of disease through effective control of risk factors and rational use of protective factors.Therefore,more research should be devoted to the early diagnosis of dementia and the prediction of the occurrence and development of the disease,so as to do a good job in the prevention and treatment of AD.Previous studies have found that osteopontin（OPN）plays an important role in the occurrence and development of AD in both animals and humans.The purpose of this study was to evaluate whether OPN can be used as an early biomarker of Alzheimer’s disease.Methods:Subjects of this study are people in the Alzheimer’s Disease Neuroimaging Initiative.After rigorous screening,305 samples containing Cerebrospinal fluid（CSF）OPN data（including 91 controls,149 MCI patients and 65 AD patients）,350 samples containing plasma OPN data（including 58 controls,194 MCI patients and 98 AD patients）and 199 samples containing neuroimaging data（including 82 controls and 117 MCI patients）were included in this study.We combined the clinical diagnosis of AD with biomarker diagnosis and divided them into AD,MCI Aβ+,CN Aβ+,and CN Aβ-groups.Chi-square test was used to compare the classified data between groups.For the inter-group comparison of continuous variables,we use one-way analysis of variance or Kruskal-Wallis test.We used covariance analysis to analyze the differences of OPN levels among diagnostic groups by adjusting for age,sex,APOEε4 gene carrier and education level.We first examined the correlation between OPN and Aβ42,t-tau,p-tau and hippocampal volume by Spearman’s correlation analysis,and then performed multiple linear regression analysis to further examine the relationship between OPN and Aβ42,t-tau,p-tau and hippocampal volume in baseline CSF.In the regression analysis,the continuous response variable should first pass the Kolmogorov-Smirnov test whether it is normal or not.When the normality is not satisfied,the approximate normality will be satisfied by Box-Cox transform.We used a linear mixed model to calculate the longitudinal change rates of cerebrospinal fluid Aβ₄₂,t-tau,p-tau and hippocampal volume,and further analyzed the Spearman’s correlation with OPN.We use R software（R,version 3.5.3 position R Foundation）to make a statistical analysis of the data,and draw graphs to explain the relevant research results.Results:There was no significant difference in age（χ2=1.7861,p=0.7750）,sex（χ2=9.487,p=0.0500）and education level（F=0.839,p=0.501）among CN Aβ-,CN Aβ+,MCI Aβ+,AD and MCI Aβ-groups.The number of APOEε4 carriers in CN Aβ-group was significantly lower than that in MCI Aβ+group and AD group（p<0.001）.There were significant differences in CSF OPN concentration among groups.The CSF OPN of AD（F=12.329,p=0.0006）and MCI Aβ+group（F=12.291,p=0.0006）was higher than that of CN Aβ-group,but there was no significant difference between CN Aβ-group and MCI Aβ-group（F=1.974,p=0.164）.In the cross-sectional study,CSF OPN was negatively correlated with CSF Aβ₄₂ levels in non-demented people(r=-0.2651,p=1.086×10^-6),and positively correlated with total tau of CSF(t-tau:r=0.5274,p=2.2×10^-16)and phosphorylated tau(p-tau:r=0.3086,p=1.086×10^-6).We also got similar results in each subgroup analysis.In the longitudinal study,the level of CSF OPN in non-dementia population was correlated with the change rates of CSF Aβ42（r=-0.1285,p=0.0370）,CSF t-tau(r=0.3146,p=6.511×10^-7),CSF p-tau(r=0.2714,p=2.011×10^-5)and hippocampal volume（r=-0.151,p=0.0337）.Similarly,we get similar results in the subgroup analysis.However,no significant correlation was found between plasma OPN and the above-mentioned AD-related biomarkers.Conclusion:CSF OPN increases in the early stage of AD and is related to the early pathological changes of AD,so our study further proves that CSF OPN is a potential early biomarker of AD.These findings support the potential of CSF OPN to monitor the pathological progress and improve the prognosis of AD.The biomarker may play a certain role in clinical research,drug development and other clinical practice.