[en] Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.
Disciplines :
Neurology
Author, co-author :
Nemy, Milan ; Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University in Prague, Prague, Czech Republic ; Department of Biomedical Engineering and Assistive Technology, Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic ; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
Dyrba, Martin ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Buerger, Katharina; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
Dechent, Peter; MR-Research in Neurosciences, Department of Cognitive Neurology, Georg-August-University Goettingen, Goettingen, Germany
Dobisch, Laura; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Ewers, Michael ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
Fliessbach, Klaus; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Glanz, Wenzel; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Goerss, Doreen ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Hetzer, Stefan; Berlin Center for Advanced Neuroimaging, Charité-Universitätsmedizin Berlin, Berlin, Germany
Incesoy, Enise I; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany
Janowitz, Daniel; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
Kilimann, Ingo ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
Laske, Christoph; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Maier, Franziska; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany
Munk, Matthias H; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Perneczky, Robert; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany ; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London, UK ; Sheffield Institute for Translational Neurosciences (SITraN), University of Sheffield, Sheffield, UK
Peters, Oliver; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Preis, Lukas; Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany ; Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany ; Centre for Clinical Brain Sciences, University of Edinburgh and UK DRI, Edinburgh, UK
Rauchmann, Boris-Stephan; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
Röske, Sandra; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Roy, Nina; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Scheffler, Klaus; Department for Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
Schneider, Anja; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Schott, Björn H ; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany ; Leibniz Institute for Neurobiology, Magdeburg, Germany
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Neurology, University of Bonn, Bonn, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany
Wagner, Michael; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Wiltfang, Jens; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany ; Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
Yakupov, Renat ; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Eriksdotter, Maria ; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden ; Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
Westman, Eric ; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden ; Department of Neuroimaging, Centre for Neuroimaging Science, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK
Stepankova, Olga ; Department of Biomedical Engineering and Assistive Technology, Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic
Vyslouzilova, Lenka ; Department of Biomedical Engineering and Assistive Technology, Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic
Düzel, Emrah ; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University, Magdeburg, Germany
Jessen, Frank ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Teipel, Stefan J ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
Ferreira, Daniel ; Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
Swedish Research Council Stockholm County Council Karolinska Institutet Center for Innovative Medicine Swedish Alzheimer Foundation Swedish Brain Foundation Neuro Fonden Czech Alzheimer Foundation Demensfonden Czech Technical University in Prague Federal Ministry of Research
Funding text :
This study was supported by the Swedish Research Council (2020-02014); the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet; Center for Innovative Medicine (CIMED); the Swedish Alzheimer Foundation; the Swedish Brain Foundation; Neuro Fonden, the Czech Alzheimer Foundation; and Demensfonden. Research by M.N., O.S. and L.V. was partially supported by institutional resources of Czech Technical University in Prague. The work was further supported by a grant to S.J.T. within the CureDem funding of the Bundesministerium für Bildung und Forschung (BMBF), grant number 01KX2130. The funding sources did not have any involvement in the study design; collection, analysis and interpretation of data; writing of the report and the decision to submit the article for publication.
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