Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum

Isabelle Bos; Stephanie Vos; Frans Verhey; Philip Scheltens; Charlotte Teunissen; Sebastiaan Engelborghs; Kristel Sleegers; Giovanni Frisoni; Olivier Blin; Jill C Richardson; Régis Bordet; Magda Tsolaki; Julius Popp; Gwendoline Peyratout; Pablo Martinez-Lage; Mikel Tainta; Alberto Lleó; Peter Johannsen; Yvonne Freund-Levi; Lutz Frölich; Rik Vandenberghe; Sarah Westwood; Valerija Dobricic; Frederik Barkhof; Cristina Legido-Quigley; Lars Bertram; Simon Lovestone; Johannes Streffer; Ulf Andreasson; Kaj Blennow; Henrik Zetterberg; Pieter Jelle Visser

doi:10.1016/j.jalz.2019.01.004

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum

Alzheimers Dement. 2019 May;15(5):644-654. doi: 10.1016/j.jalz.2019.01.004. Epub 2019 Mar 8.

Authors

Isabelle Bos¹, Stephanie Vos², Frans Verhey², Philip Scheltens³, Charlotte Teunissen⁴, Sebastiaan Engelborghs⁵, Kristel Sleegers⁶, Giovanni Frisoni⁷, Olivier Blin⁸, Jill C Richardson⁹, Régis Bordet¹⁰, Magda Tsolaki¹¹, Julius Popp¹², Gwendoline Peyratout¹³, Pablo Martinez-Lage¹⁴, Mikel Tainta¹⁴, Alberto Lleó¹⁵, Peter Johannsen¹⁶, Yvonne Freund-Levi¹⁷, Lutz Frölich¹⁸, Rik Vandenberghe¹⁹, Sarah Westwood²⁰, Valerija Dobricic²¹, Frederik Barkhof²², Cristina Legido-Quigley²³, Lars Bertram²⁴, Simon Lovestone²⁰, Johannes Streffer²⁵, Ulf Andreasson²⁶, Kaj Blennow²⁶, Henrik Zetterberg²⁷, Pieter Jelle Visser²⁸

Affiliations

¹ Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands. Electronic address: [email protected].
² Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands.
³ Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.
⁴ Neurochemistry Lab and Biobank, Department of Clinical Chemistry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands.
⁵ Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium; Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
⁶ Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
⁷ University of Geneva, Geneva, Switzerland; IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
⁸ Mediterranean Institute of Cognitive Neuroscience, Aix Marseille University, Marseille, France.
⁹ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
¹⁰ University of Lille, Inserm, CHU Lille, Lille, France.
¹¹ 1st Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece.
¹² Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland; Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
¹³ Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain.
¹⁵ Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
¹⁶ Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁷ 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; Department of Psychiatry Norrtälje Hospital Tiohundra, Norrtäije, Sweden.
¹⁸ Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
¹⁹ University Hospital Leuven, Leuven, Belgium.
²⁰ University of Oxford, Oxford, United Kingdom.
²¹ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
²² Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
²³ Steno Diabetes Center, Copenhagen, Denmark; King's College London, London, UK.
²⁴ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany; School of Public Health, Imperial College London, London, UK; Department of Psychology, University of Oslo, Oslo, Norway.
²⁵ Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Early Clinial Neurology, UCB Biopharma SPRL, Braine-l'Alleud, Belgium.
²⁶ Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden.
²⁷ Clinical Neurochemistry Lab, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, University of Gothenburg, Institute of Neuroscience and Physiology, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; UK Dementia Research Institute, London, UK.
²⁸ Alzheimer Centrum Limburg, Maastricht University, Maastricht, the Netherlands; Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands.

PMID: 30853464
DOI: 10.1016/j.jalz.2019.01.004

Abstract

Introduction: We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).

Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ- vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.

Results: Ng and T-tau distinguished between Aβ+ from Aβ- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.

Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

Keywords: APOE; Alzheimer's disease; Amyloid-β; Cerebrospinal fluid; Cognition; Neurofilament light; Neurogranin; YKL-40.

Publication types

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

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / cerebrospinal fluid*
Alzheimer Disease / physiopathology
Amyloid beta-Peptides
Apolipoprotein E4 / genetics
Biomarkers / cerebrospinal fluid*
Cognitive Dysfunction / cerebrospinal fluid*
Cognitive Dysfunction / physiopathology
Female
Humans
Neurofilament Proteins / cerebrospinal fluid*
Neurogranin / cerebrospinal fluid*
tau Proteins / cerebrospinal fluid*

Substances

Amyloid beta-Peptides
Apolipoprotein E4
Biomarkers
Neurofilament Proteins
tau Proteins
Neurogranin