Proteomes of Paired Human Cerebrospinal Fluid and Plasma: Relation to Blood−Brain Barrier Permeability in Older Adults Loïc Dayon,* ,† Ornella Cominetti, † Je ́ rô me Wojcik, ‡ Antonio Nú ñ ez Galindo, † Aikaterini Oikonomidi, § Hugues Henry, ∥ Eugenia Migliavacca, † Martin Kussmann, †,¶ Gene L. Bowman, †,# and Julius Popp §,⊥ † Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland ‡ Precision for Medicine, 1202 Geneva, Switzerland § Old Age Psychiatry, Department of Psychiatry, CHUV, 1011 Lausanne, Switzerland ∥ Department of Laboratories, CHUV, 1011 Lausanne, Switzerland ⊥ Geriatric Psychiatry, Department of Mental Health and Psychiatry, HUG, 1226 Geneva, Switzerland * S Supporting Information ABSTRACT: The systems-level relationship between the pro- teomes of cerebrospinal fluid (CSF) and plasma has not been comprehensively described so far. Recently developed shotgun proteomic workflows allow for deeper characterization of the proteomes from body fluids in much larger sample size. We deployed state-of-the-art mass spectrometry-based proteomics in paired CSF and plasma samples volunteered by 120 elders with and without cognitive impairment to comprehensively characterize and examine compartmental proteome differences and relationships between both body fluids. We further assessed the influence of blood−brain barrier (BBB) integrity and tested the hypothesis that BBB breakdown can be identified from CSF and plasma proteome alterations in nondemented elders. We quantified 790 proteins in CSF and 422 proteins in plasma, and 255 of the proteins were identified in both compartments. Pearson’s statistics determined 28 proteins with associated levels between CSF and plasma. BBB integrity as defined with the CSF/serum albumin index influenced 76 CSF/plasma protein ratios. In least absolute shrinkage and selection operator models, CSF and plasma proteins improved identification of BBB impairment. In conclusion, we provide here a first comprehensive draft map of interacting human CSF and plasma proteomes, in view of their complex and dynamic compositions, and influence of the BBB. KEYWORDS: BBB, blood, brain, cerebrospinal fluid, circulation, clinical proteomics, CSF, mass spectrometry, nervous system, serum/plasma ■ INTRODUCTION Cerebrospinal fluid (CSF) is a fluid proximal to the central nervous system (CNS), including the brain and spinal cord. The CSF offers a protective cushion against mechanical forces and a sink for byproducts that reflect brain metabolism. Maintenance of CSF is due primarily to the ultrafiltration of arterial blood at the choroid plexus, and at any time about 20− 30% of CSF proteins are thought to be derived from the brain specifically. 1,2 CSF protein analysis is used in the diagnosis of tumors, bleeding, inflammation, and injury. 3 CSF peptides and proteins (i.e., total tau (tau), hyperphosphorylated tau (P-tau), and β-amyloid 1−42 (Aβ1−42)) can complement clinical examination by the objective evidence to improve the diagnosis of Alzheimer’s disease (AD). 4,5 In 2010, Schutzer et al. established an initial database including 2630 proteins contained in “normal” human CSF. 6 A few years later, Guldbrandsen et al. released the CSF Proteome Resource composed of 3081 proteins, also making a proteome coverage comparison of CSF and plasma. 7 Zhang et al. also contributed to the CSF protein map by reporting 2513 proteins in normal CSF, 8 and Macron et al. recently reported in-depth character- izations of the human CSF proteome. 9,10 Blood is more easily accessible than CSF regarding sampling. Blood sampling can be more often repeated, and material amounts are less limited. Therefore, many efforts have been made to discover blood-based biomarkers for neurological disorders, in particular proteins. 11−14 Protein biomarker candidates from the circulating blood are likely to prove useful for the diagnosis and prognosis of CNS disorders as well as for Received: October 12, 2018 Published: January 31, 2019 Article pubs.acs.org/jpr Cite This: J. Proteome Res. 2019, 18, 1162-1174 © 2019 American Chemical Society 1162 DOI: 10.1021/acs.jproteome.8b00809 J. Proteome Res. 2019, 18, 1162−1174 Downloaded via COPYRIGHT CLEARANCE CTR DCMT DLVRY on September 6, 2019 at 12:50:16 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.