Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort studyResearch in context
Laia Montoliu-Gaya,
Daniel Alcolea,
Nicholas J. Ashton,
Jordi Pegueroles,
Johannes Levin,
Beatriz Bosch,
Juan Lantero-Rodriguez,
María Carmona-Iragui,
Olivia Wagemann,
Mircea Balasa,
Przemyslaw Radoslaw Kac,
Isabel Barroeta,
Albert Lladó,
Wagner S. Brum,
Laura Videla,
Fernando Gonzalez-Ortiz,
Bessy Benejam,
Javier José Arranz Martínez,
Thomas K. Karikari,
Georg Nübling,
Alexandre Bejanin,
Andrea L. Benedet,
Rafael Blesa,
Alberto Lleó,
Kaj Blennow,
Raquel Sánchez-Valle,
Henrik Zetterberg,
Juan Fortea
Affiliations
Laia Montoliu-Gaya
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
Daniel Alcolea
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Nicholas J. Ashton
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK; NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
Jordi Pegueroles
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Johannes Levin
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Beatriz Bosch
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Institut de Neurociències, Universitat de Barcelona, Spain
Juan Lantero-Rodriguez
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
María Carmona-Iragui
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain
Olivia Wagemann
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Mircea Balasa
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Institut de Neurociències, Universitat de Barcelona, Spain
Przemyslaw Radoslaw Kac
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
Isabel Barroeta
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Albert Lladó
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Institut de Neurociències, Universitat de Barcelona, Spain
Wagner S. Brum
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
Laura Videla
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain
Fernando Gonzalez-Ortiz
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
Bessy Benejam
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain
Javier José Arranz Martínez
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Thomas K. Karikari
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Georg Nübling
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Alexandre Bejanin
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Andrea L. Benedet
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
Rafael Blesa
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Alberto Lleó
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Kaj Blennow
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Raquel Sánchez-Valle
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Institut de Neurociències, Universitat de Barcelona, Spain
Henrik Zetterberg
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute, University College London, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
Juan Fortea
Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain; Center of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain; Corresponding author. Hospital de la Santa Creu i Sant Pau, Neurology Department, Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
Summary: Background: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. Methods: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. Findings: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9−0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8–33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Interpretation: Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit.
