Cerebrospinal Fluid ?-synuclein As A Novel Biomarker For Alzheimer's Disease:A Prospective Cohort Analysis

Background and objective Accumulating reports suggest that ?-synuclein(SNCA)is involved in Alzheimer disease(AD)pathogenesis.More than 50% AD patients exhibit abundant brain accum?lation of SNCA-positive Lewy bodies,partic?larly in the amygdala.The presence of SNCA does not appear to be innocuous,as these patients demonstrate an accelerated cognitive decline than subjects with AD alone.Previous studies indicated that SNCA co?ld be secreted into the surrounding media in the brain and then to the cerebrospinal fluid(CSF).Studying CSF co?ld provide clues to the mechanism of SNCA metabolism in brain.We aim to use the Alzheimer's neural initiative database(ADNI)and the samples collected from the Qingdao municipal hospital affiliated to Qingdao university and the Daping hospital affiliated to the army medical university for detection CSF SNCA levels.To test 1)whether CSF SNCA is altered in AD and different AD pathophysiological profiles based on “ATN” classifications 2)whether CSF SNCA is associated with other AD biomarkers,cognitive decline and imaging evidence of neurodegeneration.This provides evidence for how SNCA is involved in the pathogenesis of AD.Subjects and Methods The research object and its related clinical data are from Qingdao municipal hospital,army medical university affiliated Daping hospital and ADNI database.The ADNI database is a large m?lti-center neuroimaging database with longitudinal data initiated in 2003.We include data on their cognitive function(Mini-Mental State Examination(MMSE),Alzheimer's disease assessment scale(ADAS-cog)and Clinical Dementia Rating sum of boxes(CDRSB))and brain structure(hippocampus volume and entorhinal thickness)for six years of follow up.Data on the level of amyloid protein(?-amyloid,A?42),total tau protein(t-tau)and phosphorylated tau protein(p-au)in the brain.And follow-up data on glucose metabolism in the brain for four years.The samples from Qingdao municipal hospital affiliated to Qingdao university were from outpatient and inpatient hospitals.Luminex x MAP technique was used to determine the contents of A?42,t-tau and p-tau181 p in cerebrospinal fluid.The determination method was strictly in accordance with the instructions of the kit.Samples from outpatients and inpatients in the army medical university affiliated daping hospital were collected.The content of A?42,T-tau and Ptau181 p in CSF was determined by enzyme-linked immunosorbent assay.General demographic data(including age,gender,hospital number,contact information,etc.)and clinical data(including admission diagnosis,previous history,family history,laboratory examination,imaging examination,etc.)were collected through the hospital medical record management system.Genomic DNA was extracted with whole blood DNA extraction kit and divided into different packages.Genotyping was conducted using Multiplex SNa Pshot.Correlation analysis of CSF SNCA with baseline data was performed using a m?ltivariate linear regression model.Correlation analysis of CSF SNCA with longitudinal data was performed using a mixed effect model.We used age,sex,education,APOE ?4 carries and baseline diagnosis as covariates.We evaluated the incidence and progression of AD using the ROC curve and the AUC prediction model for CSF SNCA and its association with other CSF biomarkers.For all the statistical operations,we use R software.Res?lts A total of 222 non-dementia elderly patients were included in the alzheimer's disease biomarker database of Qingdao municipal hospital affiliated to Qingdao university,and 361 non-dementia elderly patients were included in the alzheimer's disease biomarker database of daping hospital affiliated to the army medical university.In ADNI database,we included 382 subjects: 109 cognitively healthy controls,117 patients with stable mild cognitive impairment(s MCI),66 patients with progressive mild cognitive impairment(p MCI)and 90 patients with AD dementia from the ADNI database.According to the new “ATN” scheme,258 A?-positive patients [220 A?-positive tau-positive(A+T+)] and 124 A?-negative controls [96 A?-negative tau-negative(A-T-)] were included.In Qingdao municipal hospital,daping hospital and ADNI database,higher CSF SNCA level was associated with higher CSF total tau and phosphorylated tau levels in the whole cohort,but not with CSF A? level.In ADNI databse,CSF SNCA concentrations were significantly higher in the AD and p MCI groups compared with the cognitively normal group(P<0.0001 and P < 0.001respectively)and with the s MCI group(P = 0.02 and P= 0.04 respectively).CSF SNCA had high diagnostic accuracy for patients with the diagnosis of AD based on the “ATN” system(A+T+)vs controls(A-T-)(area under the receiver operating characteristic curve,0.84,which is comparable to established CSF biomarkers).Longitudinal analysis showed significant associations of higher CSF SNCA with poor cognition(Mini-Mental State Examination scores: ?=-0.1473,P < 0.001)and AD-related brain atrophy(hippocampus: ?=-0.1016,P < 0.001 and entorhinal: ?=-0.2448,P < 0.001)in the whole cohort during follow-up.Conclusion CSF SNCA predicts neurodegeneration and clinical progression in nondemented elderly adults and it is expected to be a potential biomarker for AD.