High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

dc.contributor.authorHendrickson, Ronald C.en
dc.contributor.authorLee, Anita Y.H.en
dc.contributor.authorSong, Qinghuaen
dc.contributor.authorLiaw, Andyen
dc.contributor.authorWiner, Matten
dc.contributor.authorPaweletz, Cloud P.en
dc.contributor.authorSeeburger, Jeffrey L.en
dc.contributor.authorLi, Jennyen
dc.contributor.authorMeng, Fanyuen
dc.contributor.authorDeyanova, Ekaterina G.en
dc.contributor.authorMazur, Matthew T.en
dc.contributor.authorSettlage, Robert E.en
dc.contributor.authorZhao, Xuemeien
dc.contributor.authorSouthwick, Katieen
dc.contributor.authorDu, Yien
dc.contributor.authorHolder, Danen
dc.contributor.authorSachs, Jeffrey R.en
dc.contributor.authorLaterza, Omar F.en
dc.contributor.authorDallob, Aimeeen
dc.contributor.authorChappell, Derek L.en
dc.contributor.authorSnyder, Karenen
dc.contributor.authorModur, Vijayen
dc.contributor.authorKing, Elizabethen
dc.contributor.authorJoachim, Catharineen
dc.contributor.authorBondarenko, Andrey Y.en
dc.contributor.authorShearman, Marken
dc.contributor.authorSoper, Keith A.en
dc.contributor.authorSmith, A. Daviden
dc.contributor.authorPotter, William Z.en
dc.contributor.authorKoblan, Ken S.en
dc.contributor.authorSachs, Alan B.en
dc.contributor.authorYates, Nathan A.en
dc.description.abstractDisease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.en
dc.description.sponsorshipThis discovery proteomics and analysis work was supported by Merck & Co.en
dc.rightsIn Copyrighten
dc.titleHigh Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluiden
dc.title.serialPLoS ONEen
dc.typeArticle - Refereeden


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