Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer’s Disease Patients and Controls after Correction for Ventricular Volumes

Article type: Research Article

Authors: van Waalwijk van Doorn, Linda J.C.^{a; b; 1} | Gispert, Juan D.^{c; d; e; 1} | Kuiperij, H. Bea^{a; b} | Claassen, Jurgen A.H.R.^f | Arighi, Andrea^g | Baldeiras, Inês^h | Blennow, Kaj^{i; j} | Bozzali, Marco^k | Castelo-Branco, Miguel^l | Cavedo, Enricaⁿ | Emek-Savaş, Derya D.^o | Eren, Erden^p | Eusebi, Paolo^q | Farotti, Lucia^q | Fenoglio, Chiara^g | Ormaechea, Juan Fortea^r | Freund-Levi, Yvonne^{s; t} | Frisoni, Giovanni B.^{m; u} | Galimberti, Daniela^g | Genc, Sermin^p | Greco, Viviana^v | Hampel, Haraldⁿ | Herukka, Sanna-Kaisa^w | Liu, Yawu^w | Lladó, Albert^x | Lleó, Alberto^r | Nobili, Flavio M.^y | Oguz, Kader K.^z | Parnetti, Lucilla^q | Pereira, João^k | Picco, Agnese^y | Pikkarainen, Maria^w | de Oliveira, Catarina Resende^h | Saka, Esen^z | Salvadori, Nicola^q | Sanchez-Valle, Raquel^x | Santana, Isabel^h | Scarpini, Elio^g | Scheltens, Philip^{aa; ab} | Soininen, Hilkka^w | Tarducci, Roberto^q | Teunissen, Charlotte^ac | Tsolaki, Magda^ad | Urbani, Andrea^{v; ae} | Vilaplana, Eduard^r | Visser, Pieter Jelle^{aa; ab; af} | Wallin, Asa K.^ag | Yener, Görsev^ah | Molinuevo, José L.^{c; ai} | Meulenbroek, Olga^f | Verbeek, Marcel M.^{a; b; *}

Affiliations: [a] Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands | [b] Department of Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands | [c] Barcelona Beta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain | [d] Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain | [e] Pompeu Fabra University, Barcelona, Spain | [f] Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands | [g] University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy | [h] Center for Neuroscience and Cell Biology (CNC.IBILI), Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal | [i] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [j] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [k] Neuroimaging Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy | [l] Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) and ICNAS (Institute for Nuclear Sciences Applied to Health), University of Coimbra, Portugal | [m] Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [n] 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 | [o] Department of Psychology, The Faculty of Arts, Department of Neurosciences, The Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey | [p] Izmir Biomedicine and Genome Institute, Department of Neurosciences, The Health Sciences Institute, Dokuz Eylül University, Izmir, Turkey | [q] Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy | [r] Neurology Department, Hospital de Sant Pau, Barcelona, Spain | [s] Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden | [t] Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden | [u] University Hospitals and University of Geneva, Geneva, Switzerland | [v] Proteomics and Metabolomics Unit, IRCCS-Fondazione Santa Lucia, Rome, Italy | [w] Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland | [x] Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS, Barcelona, Spain | [y] Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy | [z] Hacettepe University, Faculty of Medicine, Department of Neurology, Sihhiye, Ankara, Turkey | [aa] Alzheimer center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands | [ab] Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands | [ac] Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands | [ad] Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, “G Papanicolaou” General Hospital, Thessaloniki, Greece | [ae] Istituto di Biochimica e Biochimica Clinica, Universitá Cattolica, Roma, Italy | [af] Department of Psychiatry and Neuropsychology, Maastricht University, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht, the Netherlands | [ag] Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden | [ah] Department of Neurology, Medical School Izmir, Biomedicine and Genome Institute, Brain Dynamics Multidisciplinary Research Center, Dokuz Eylül University, Izmir, Turkey | [ai] Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, IDIBAPS, Barcelona, Spain

Correspondence: [*] Correspondence to: Dr. Marcel M. Verbeek, TML, r.830, Department of Neurology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 243614567; Fax: +31 2436 68754; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, amyloid biomarkers, cerebrospinal fluid, lateral ventricles, tau protein

DOI: 10.3233/JAD-160668

Journal: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 543-555, 2017