title: Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes.
abstract: Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Linda J C
authors.initials: LJ
authors.lastname: van Waalwijk van Doorn
authors.affiliation: Barcelona Beta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain.|Pompeu Fabra University, Barcelona, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Gispert
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: H Bea
authors.initials: HB
authors.lastname: Kuiperij
authors.affiliation: Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jurgen A H R
authors.initials: JA
authors.lastname: Claassen
authors.affiliation: University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arighi
authors.affiliation: Center for Neuroscience and Cell Biology (CNC.IBILI), Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Baldeiras
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bozzali
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) and ICNAS (Institute for Nuclear Sciences Applied to Health), University of Coimbra, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Castelo-Branco
authors.affiliation: AXA Research Fund and UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital, F-75013, Paris, France.
authors.forename: Enrica
authors.initials: E
authors.lastname: Cavedo
authors.affiliation: Department of Psychology, The Faculty of Arts, Department of Neurosciences, The Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey.
authors.forename: Derya D
authors.initials: DD
authors.lastname: Emek-Savaş
authors.affiliation: Izmir Biomedicine and Genome Institute, Department of Neurosciences, The Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey.
authors.forename: Erden
authors.initials: E
authors.lastname: Eren
authors.affiliation: Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Eusebi
authors.affiliation: Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Farotti
authors.affiliation: University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Juan Fortea
authors.initials: JF
authors.lastname: Ormaechea
authors.affiliation: Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.|Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Freund-Levi
authors.affiliation: Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy.|University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.affiliation: University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Izmir Biomedicine and Genome Institute, Department of Neurosciences, The Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey.
authors.forename: Sermin
authors.initials: S
authors.lastname: Genc
authors.affiliation: Proteomics and Metabolomics Unit, IRCCS-Fondazione Santa Lucia, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Greco
authors.affiliation: AXA Research Fund and UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM), Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Salpêtrière, Boulevard de l'hôpital, F-75013, Paris, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Yawu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.affiliation: Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Flavio M
authors.initials: FM
authors.lastname: Nobili
authors.affiliation: Hacettepe University, Faculty of Medicine, Department of Neurology, Sihhiye, Ankara, Turkey.
authors.forename: Kader K
authors.initials: KK
authors.lastname: Oguz
authors.affiliation: Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Parnetti
authors.affiliation: Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: João
authors.initials: J
authors.lastname: Pereira
authors.affiliation: Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Picco
authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pikkarainen
authors.affiliation: Center for Neuroscience and Cell Biology (CNC.IBILI), Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Catarina Resende
authors.initials: CR
authors.lastname: de Oliveira
authors.affiliation: Hacettepe University, Faculty of Medicine, Department of Neurology, Sihhiye, Ankara, Turkey.
authors.forename: Esen
authors.initials: E
authors.lastname: Saka
authors.affiliation: Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Salvadori
authors.affiliation: Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Valle
authors.affiliation: Center for Neuroscience and Cell Biology (CNC.IBILI), Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.affiliation: University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Alzheimer center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.|Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tarducci
authors.affiliation: Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Teunissen
authors.affiliation: Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, "G Papanicolaou" General Hospital, Thessaloniki, Greece.
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Proteomics and Metabolomics Unit, IRCCS-Fondazione Santa Lucia, Rome, Italy.|Istituto di Biochimica e Biochimica Clinica, Universitá Cattolica, Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.affiliation: Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Vilaplana
authors.affiliation: Alzheimer center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.|Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.|Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands.
authors.forename: Pieter Jelle
authors.initials: PJ
authors.lastname: Visser
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: Asa K
authors.initials: AK
authors.lastname: Wallin
authors.affiliation: Department of Neurology, Medical School Izmir, Biomedicine and Genome Institute, Brain Dynamics Multidisciplinary Research Center, Dokuz Eylül University, Izmir, Turkey.
authors.forename: Görsev
authors.initials: G
authors.lastname: Yener
authors.affiliation: Barcelona Beta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain.|Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Olga
authors.initials: O
authors.lastname: Meulenbroek
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
mesh_terms: D000368:Aged; D000465:Algorithms; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D019540:Area Under Curve; D001284:Atrophy; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002552:Cerebral Ventricles / Q000000981:diagnostic imaging*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging*; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D010363:Pattern Recognition, Automated; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D012372:ROC Curve; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; amyloid biomarkers; cerebrospinal fluid; lateral ventricles; tau protein