Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlyi...Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.展开更多
Although the development of covID-19 vaccines has been a remarkable success,the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict.In this study,blood samples were...Although the development of covID-19 vaccines has been a remarkable success,the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict.In this study,blood samples were collected from 163 participants who next received two doses of an inactivated COvVID-19 vaccine(CoronaVac)at a 28-day interval.Using TMT-based proteomics,we identified 1,715 serum and 7,342 peripheral blood mononuclear cells(PBMCs)proteins.We proposed two sets of potential biomarkers(seven from serum,five from PBMCs)at baseline using machine learning,and predicted the individual seropositivity 57 days after vaccination(AUC=0.87).Based on the four PBMC's potential biomarkers,we predicted the antibody persistence until 180 days after vaccination(AUC=0.79).Our data highlighted characteristic hematological host responses,including altered lymphocyte migration regulation,neutrophil degranulation,and humoral immune response.This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after coVID-19 vaccination,shedding light on immunization mechanisms and individual booster shot planning.展开更多
基金This work was supported by grants from the Key Research and Development project of Zhejiang Province(2019C03039)the National Natural Science Foundation of China(81970998)+1 种基金the Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Projects(nos.2021ZD0201103 and 2021ZD0201803)the Integrative Traditional Chinese and Western Medicine Innovation Team for Neurodegenerative Diseases of Zhejiang Province.
文摘Amyloid-b,tau pathology,and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease(AD).However,these proteins represent only a fraction of the complex biological processes underlying AD,and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers.More ADspecific early diagnostic and disease staging biomarkers are needed.In this study,we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid(CSF)and serum samples in a discovery cohort comprising 98 participants.Candidate biomarkers were validated by parallel reaction monitoring–based targeted proteomic assays in an independent multicenter cohort comprising 288 participants.We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort,identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers,respectively.In the validation cohort,58 and 21 CSF proteins,as well as 12 and 18 serum proteins,were verified as early diagnostic and staging biomarkers,respectively.Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment(MCI)due to AD from normal cognition with areas under the curve of 0.984 and 0.881,respectively.The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases.Moreover,we identified 21 CSF and 18 serum stage-associated proteins re-flecting AD stages.Our findings provide a foundation for developing bloodbased tests for AD screening and staging in clinical practice.
基金supported by the National Natural Science Foundation of China(32200763)Key medical disciplines of Hangzhou,the Medical Health Science and Technology Project of Hangzhou municipal Health Commission(A20210205)+1 种基金the National Key R&D Program of China(2020YFE0202200)Funding for Clinical Trials from the Affiliated Drum Tower Hospital,Medical School of Nanjing University(2022-LCYJ-MS-08).
文摘Although the development of covID-19 vaccines has been a remarkable success,the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict.In this study,blood samples were collected from 163 participants who next received two doses of an inactivated COvVID-19 vaccine(CoronaVac)at a 28-day interval.Using TMT-based proteomics,we identified 1,715 serum and 7,342 peripheral blood mononuclear cells(PBMCs)proteins.We proposed two sets of potential biomarkers(seven from serum,five from PBMCs)at baseline using machine learning,and predicted the individual seropositivity 57 days after vaccination(AUC=0.87).Based on the four PBMC's potential biomarkers,we predicted the antibody persistence until 180 days after vaccination(AUC=0.79).Our data highlighted characteristic hematological host responses,including altered lymphocyte migration regulation,neutrophil degranulation,and humoral immune response.This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after coVID-19 vaccination,shedding light on immunization mechanisms and individual booster shot planning.
