Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort

Min Kim; Stuart Snowden; Tommi Suvitaival; Ashfaq Ali; David J Merkler; Tahmina Ahmad; Sarah Westwood; Alison Baird; Petroula Proitsi; Alejo Nevado-Holgado; Abdul Hye; Isabelle Bos; Stephanie Vos; Rik Vandenberghe; Charlotte Teunissen; Mara Ten Kate; Philip Scheltens; Silvy Gabel; Karen Meersmans; Olivier Blin; Jill Richardson; Ellen De Roeck; Kristel Sleegers; Régis Bordet; Lorena Rami; Petronella Kettunen; Magda Tsolaki; Frans Verhey; Isabel Sala; Alberto Lléo; Gwendoline Peyratout; Mikel Tainta; Peter Johannsen; Yvonne Freund-Levi; Lutz Frölich; Valerija Dobricic; Sebastiaan Engelborghs; Giovanni B Frisoni; José L Molinuevo; Anders Wallin; Julius Popp; Pablo Martinez-Lage; Lars Bertram; Frederik Barkhof; Nicholas Ashton; Kaj Blennow; Henrik Zetterberg; Johannes Streffer; Pieter J Visser; Simon Lovestone; Cristina Legido-Quigley

doi:10.1016/j.jalz.2019.03.004

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort

Alzheimers Dement. 2019 Jun;15(6):817-827. doi: 10.1016/j.jalz.2019.03.004. Epub 2019 May 8.

Authors

Min Kim¹, Stuart Snowden², Tommi Suvitaival³, Ashfaq Ali³, David J Merkler⁴, Tahmina Ahmad⁵, Sarah Westwood⁶, Alison Baird⁶, Petroula Proitsi⁷, Alejo Nevado-Holgado⁶, Abdul Hye³, Isabelle Bos⁸, Stephanie Vos⁸, Rik Vandenberghe⁹, Charlotte Teunissen¹⁰, Mara Ten Kate¹⁰, Philip Scheltens¹¹, Silvy Gabel¹², Karen Meersmans¹², Olivier Blin¹³, Jill Richardson¹⁴, Ellen De Roeck¹⁵, Kristel Sleegers¹⁶, Régis Bordet¹⁷, Lorena Rami¹⁸, Petronella Kettunen¹⁹, Magda Tsolaki²⁰, Frans Verhey⁸, Isabel Sala²¹, Alberto Lléo²¹, Gwendoline Peyratout²², Mikel Tainta²³, Peter Johannsen²⁴, Yvonne Freund-Levi²⁵, Lutz Frölich²⁶, Valerija Dobricic²⁷, Sebastiaan Engelborghs²⁸, Giovanni B Frisoni²⁹, José L Molinuevo³⁰, Anders Wallin³¹, Julius Popp³², Pablo Martinez-Lage²³, Lars Bertram³³, Frederik Barkhof¹⁰, Nicholas Ashton³⁴, Kaj Blennow³⁵, Henrik Zetterberg³⁶, Johannes Streffer³⁷, Pieter J Visser³⁸, Simon Lovestone⁶, Cristina Legido-Quigley³⁹

Affiliations

¹ Institute of Pharmaceutical Science, King's College London, London, UK; Steno Diabetes Center Copenhagen, Gentofte, Denmark.
² Institute of Pharmaceutical Science, King's College London, London, UK; Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge, UK.
³ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
⁴ Department of Chemistry, University of South Florida, Tampa, FL, USA.
⁵ Institute of Pharmaceutical Science, King's College London, London, UK.
⁶ Department of Psychiatry, University of Oxford, Oxford, UK.
⁷ Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.
⁸ Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
⁹ University Hospital Leuven, Leuven, Belgium.
¹⁰ Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, The Netherlands.
¹¹ Department of Neurology, Alzheimer Center, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
¹² University Hospital Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
¹³ Service de Pharmacologie Clinique et Pharmacovigilance, Institut de Neurosciences des Systèmes, Aix Marseille University, APHM, INSERM, Marseille, France.
¹⁴ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
¹⁵ Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹⁶ Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Flanders, Belgium.
¹⁷ University of Lille, INSERM, CHU, Degenerative and Vascular Cognitive Disorders, Lille, Lille, France.
¹⁸ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic-IDIBAPS, Barcelona, Spain.
¹⁹ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Memory Clinic at Department of Neuropsychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden; Nuffield Department of Clinical Neurosciences, University of Oxford, West Wing, John Radcliffe Hospital, Oxford, UK.
²⁰ First Department of Neurology, AHEPA University Hospital, Makedonia, Thessaloniki, Greece.
²¹ Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
²² University Hospital of Lausanne, Lausanne, Switzerland.
²³ CITA-Alzheimer Foundation, San Sebastian, Spain.
²⁴ Danish Dementia Research Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁵ 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.
²⁶ Department of Geriatric Psychiatry, Zentralinstitut für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany.
²⁷ Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Germany.
²⁸ Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Germany; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
²⁹ University of Geneva, Geneva, Switzerland.
³⁰ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic-IDIBAPS, Barcelona, Spain; Barcelona Beta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
³¹ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³² University Hospital of Lausanne, Lausanne, Switzerland; Geriatric Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Geneva, Switzerland.
³³ University of Lübeck, Lübeck, Germany.
³⁴ Steno Diabetes Center Copenhagen, Gentofte, Denmark; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
³⁵ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
³⁶ Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK.
³⁷ Experimental Medicine, Janssen Pharmaceutical Companies, Beerse, Belgium.
³⁸ Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands; Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, The Netherlands.
³⁹ Institute of Pharmaceutical Science, King's College London, London, UK; Steno Diabetes Center Copenhagen, Gentofte, Denmark. Electronic address: cristina.legido.quigley@regionh.dk.

Abstract

Introduction: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.

Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.

Results: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.

Discussion: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.

Keywords: Alzheimer's disease; Amyloid; Biomarkers; Brain volume measurements; CSF; Cognitive function measurements; Dementia; EMIF-AD; Metabolomics; Tau.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Amyloid beta-Peptides* / blood
Amyloid beta-Peptides* / cerebrospinal fluid
Amyloidosis / blood*
Amyloidosis / cerebrospinal fluid
Amyloidosis / metabolism
Biomarkers* / blood
Biomarkers* / cerebrospinal fluid
Brain / pathology
Cognitive Dysfunction / diagnosis
Cohort Studies
Female
Hippocampus* / metabolism
Humans
Magnetic Resonance Imaging
Male
Memory / physiology*
Metabolomics*
Middle Aged
Neuropsychological Tests
tau Proteins / blood
tau Proteins / cerebrospinal fluid

Substances

Amyloid beta-Peptides
Biomarkers
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding