Gray matter network properties show distinct associations with CSF p-tau 181 levels and amyloid status in individuals without dementia
Lorenzini Luigi,
Ingala Silvia,
Wottschel Viktor,
Alle Meije Wink,
Henk JMM Mutsaerts,
Haller Sven,
Blennow Kaj,
John T. O'Brien,
Frisoni B. Giovanni,
Chételat Gael,
Payoux Pierre,
Martinez-Lage Pablo,
Waldman Adam,
Wardlaw Joanna,
Ritchie Craig,
Juan Domingo Gispert,
Pieter Jelle Visser,
Scheltens Philip,
Barkhof Frederik,
Betty M. Tijms
Affiliations
Lorenzini Luigi
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands; Corresponding author at: Dep. of Radiology and Nuclear Medicine, PK -1, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
Ingala Silvia
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands
Wottschel Viktor
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands
Alle Meije Wink
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands
Henk JMM Mutsaerts
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands; Ghent Institute for Functional and Metabolic Imaging (GIfMI), Ghent University, Ghent, Belgium
Haller Sven
CIMC – Centre d’Imagerie Médicale de Cornavin, Place de Cornavin 18, 1201 Genève, Switzerland; Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, PR China
Blennow Kaj
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
John T. O'Brien
Department of Psychiatry, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Box 189, Cambridge CB2 0QQ, UK
Frisoni B. Giovanni
Laboratory Alzheimer’s Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; University Hospitals and University of Geneva, Geneva, Switzerland
Chételat Gael
Université de Normandie, Unicaen, Inserm, U1237, PhIND “Physiopathology and Imaging of Neurological Disorders”, Institut Blood-and-Brain @ Caen-Normandie, Cyceron, 14000 Caen, France
Payoux Pierre
Department of Nuclear Medicine, Toulouse CHU, Purpan University Hospital, Toulouse, France; Toulouse NeuroImaging Center, University of Toulouse, INSERM, UPS, Toulouse, France
Martinez-Lage Pablo
Centro de Investigación y Terapias Avanzadas, Neurología, CITA‐Alzheimer Foundation, San Sebastián, Spain
Waldman Adam
Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK; Department of Brain Sciences, Imperial College London, London, UK
Wardlaw Joanna
Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK; UK Dementia Research Institute Centre at the University of Edinburgh, University of Edinburgh, UK
Ritchie Craig
Centre for Dementia Prevention, The University of Edinburgh, Scotland, UK
Juan Domingo Gispert
Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain; CIBER Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona Spain; Universitat Pompeu Fabra, Barcelona, Spain
Pieter Jelle Visser
Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands; Alzheimer Center Limburg, Department of Psychiatry & Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
Scheltens Philip
Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands
Barkhof Frederik
Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Centre, Amsterdam Neuroscience, Amsterdam, the Netherlands; Institute of Neurology and Healthcare Engineering, University College London, London, UK
Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer’s Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network’s graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p < 0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p < 0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels.Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.
