Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study

Alberto Lleó; Daniel Alcolea; Pablo Martínez-Lage; Philip Scheltens; Lucilla Parnetti; Judes Poirier; Anja H Simonsen; Marcel M Verbeek; Pedro Rosa-Neto; Rosalinde E R Slot; Mikel Tainta; Andrea Izaguirre; Babette L R Reijs; Lucia Farotti; Magda Tsolaki; Rik Vandenbergue; Yvonne Freund-Levi; Frans R J Verhey; Jordi Clarimón; Juan Fortea; Lutz Frolich; Isabel Santana; José Luis Molinuevo; Sylvain Lehmann; Pieter J Visser; Charlotte E Teunissen; Henrik Zetterberg; Kaj Blennow

doi:10.1016/j.jalz.2019.01.015

Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study

Alzheimers Dement. 2019 Jun;15(6):742-753. doi: 10.1016/j.jalz.2019.01.015. Epub 2019 Apr 6.

Authors

Alberto Lleó¹, Daniel Alcolea², Pablo Martínez-Lage³, Philip Scheltens⁴, Lucilla Parnetti⁵, Judes Poirier⁶, Anja H Simonsen⁷, Marcel M Verbeek⁸, Pedro Rosa-Neto⁶, Rosalinde E R Slot⁴, Mikel Tainta³, Andrea Izaguirre³, Babette L R Reijs⁹, Lucia Farotti⁵, Magda Tsolaki¹⁰, Rik Vandenbergue¹¹, Yvonne Freund-Levi¹², Frans R J Verhey⁹, Jordi Clarimón², Juan Fortea², Lutz Frolich¹³, Isabel Santana¹⁴, José Luis Molinuevo¹⁵, Sylvain Lehmann¹⁶, Pieter J Visser¹⁷, Charlotte E Teunissen⁴, Henrik Zetterberg¹⁸, Kaj Blennow¹⁹

Affiliations

¹ Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain. Electronic address: alleo@santpau.es.
² Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
³ Center for Research and Advanced Therapies, Fundación CITA-alzheimer Fundazioa, San Sebastian, Spain.
⁴ Amsterdam UMC, Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
⁵ Centre for Memory Disturbances, Section of Neurology, Lab of Clinical Neurochemistry, University of Perugia, Perugia, Italy.
⁶ Centre for the Studies on the Prevention of Alzheimer's Disease, Douglas Mental Health University Institute, Montréal, QC, Canada.
⁷ Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Nijmegen, the Netherlands; Department of Laboratory Medicine, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Nijmegen, the Netherlands.
⁹ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
¹⁰ 1st Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Makedonia, Greece; Alzheimer Hellas, Thessaloniki, Greece.
¹¹ University Hospital Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹² Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Center for Alzheimer Research, Division of Clinical Geriatrics, Huddinge and Department of Old Age Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹³ Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
¹⁴ Dementia Clinic, Centro Hospitalar e Universitário de Coimbra and Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.
¹⁵ ICN Hospital Clinic i Universitari, Barcelona, Spain.
¹⁶ Univ Montpellier, CHU Montpellier, Montpellier, France.
¹⁷ Amsterdam UMC, Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
¹⁸ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, University College London, Queen Square, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom.
¹⁹ Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

PMID: 30967340
DOI: 10.1016/j.jalz.2019.01.015

Abstract

Introduction: Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.

Methods: We included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.

Results: CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.

Discussion: All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.

Keywords: Alzheimer; Amyloid; CSF; Inflammation; Neurofilaments; Tau; YKL-40.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease* / cerebrospinal fluid
Alzheimer Disease* / diagnosis
Amyloid beta-Peptides / cerebrospinal fluid*
Apolipoproteins E / genetics
Biomarkers / cerebrospinal fluid*
Chitinase-3-Like Protein 1
Cognitive Dysfunction* / cerebrospinal fluid
Cognitive Dysfunction* / diagnosis
Female
Humans
Longitudinal Studies
Male
Middle Aged
Neurofilament Proteins / cerebrospinal fluid
Peptide Fragments
Phosphorylation
tau Proteins / cerebrospinal fluid*

Substances

Amyloid beta-Peptides
Apolipoproteins E
Biomarkers
CHI3L1 protein, human
Chitinase-3-Like Protein 1
Neurofilament Proteins
Peptide Fragments
amyloid beta-protein (1-42)
tau Proteins