[en] [en] BACKGROUND: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD.
METHODS: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39).
RESULTS: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021).
CONCLUSION: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies.
TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 - retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .
Disciplines :
Neurology
Author, co-author :
Menze, Inga; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany. inga.menze@dzne.de ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany. inga.menze@dzne.de
Bernal, Jose; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany ; Centre for Clinical Brain Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK ; UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh Bioquarter, 49 Little France Crescent, Edinburgh Bioquarter, Edinburgh, EH16 4SB, UK
Kaya, Pinar; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Aki, Çağla; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Pfister, Malte; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Geisendörfer, Jonas; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Yakupov, Renat; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
Coello, Roberto Duarte; Centre for Clinical Brain Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK ; UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh Bioquarter, 49 Little France Crescent, Edinburgh Bioquarter, Edinburgh, EH16 4SB, UK
Valdés-Hernández, Maria D C; Centre for Clinical Brain Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK ; UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh Bioquarter, 49 Little France Crescent, Edinburgh Bioquarter, Edinburgh, EH16 4SB, UK
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Brosseron, Frederic; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany
Schmid, Matthias C; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Venusberg-Campus 1, Bonn, 53127, Germany
Glanz, Wenzel; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
Incesoy, Enise I; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany ; Department of Psychiatry and Psychotherapy, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
Butryn, Michaela; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
Rostamzadeh, Ayda; Department of Psychiatry, Medical Faculty, University of Cologne, Kerpener Strasse 62, Cologne, 50924, Germany
Meiberth, Dix; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Department of Psychiatry, Medical Faculty, University of Cologne, Kerpener Strasse 62, Cologne, 50924, Germany
Peters, Oliver; German Centre for Neurodegenerative Diseases (DZNE), Charitéplatz 1, Berlin, 10117, Germany ; Institute of Psychiatry and Psychotherapy, Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany
Preis, Lukas; Institute of Psychiatry and Psychotherapy, Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany
Lammerding, Dominik; Institute of Psychiatry and Psychotherapy, Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany
Gref, Daria; Institute of Psychiatry and Psychotherapy, Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany
Priller, Josef; UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh Bioquarter, 49 Little France Crescent, Edinburgh Bioquarter, Edinburgh, EH16 4SB, UK ; German Centre for Neurodegenerative Diseases (DZNE), Charitéplatz 1, Berlin, 10117, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany ; School of Medicine, Department of Psychiatry and Psychotherapy, Technical University of Munich, Ismaninger Str. 22, Munich, 81675, Germany
Spruth, Eike J; German Centre for Neurodegenerative Diseases (DZNE), Charitéplatz 1, Berlin, 10117, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany
Altenstein, Slawek; German Centre for Neurodegenerative Diseases (DZNE), Charitéplatz 1, Berlin, 10117, Germany ; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany
Lohse, Andrea; Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany
Hetzer, Stefan; Berlin Center for Advanced Neuroimaging, Charité, Charitéplatz 1, Berlin, 10117, Germany
Schneider, Anja; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, Bonn, 53127, Germany
Fliessbach, Klaus; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Venusberg-Campus 1, Bonn, 53127, Germany
Kimmich, Okka; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany
Vogt, Ina R; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany
Wiltfang, Jens; German Centre for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Von-Siebold-Str. 5, Goettingen, 37075, Germany ; Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Campus Universitário de Santiago, Aveiro, 3810-193, Portugal
Bartels, Claudia; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Von-Siebold-Str. 5, Goettingen, 37075, Germany
Schott, Björn H; German Centre for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Von-Siebold-Str. 5, Goettingen, 37075, Germany ; Leibniz Institute for Neurobiology, Brenneckestraße 6, Magdeburg, 39118, Germany
Hansen, Niels; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Von-Siebold-Str. 5, Goettingen, 37075, Germany
Dechent, Peter; Department of Cognitive Neurology, MR-Research in Neurosciences, Georg-August-University Goettingen, Robert-Koch-Straße 40, Göttingen, 37075, Germany
Buerger, Katharina; German Centre for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, Munich, 81377, Germany ; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Strasse 17, Munich, 81377, Germany
Janowitz, Daniel; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Feodor-Lynen-Strasse 17, Munich, 81377, Germany
Perneczky, Robert; German Centre for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, Munich, 81377, Germany ; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nußbaumstraße 7, Munich, München, 80336 , Germany ; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, Munich, 81377, Germany ; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, London, W6 8RP, UK
Rauchmann, Boris-Stephan; Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nußbaumstraße 7, Munich, München, 80336 , Germany ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Rd, Sheffield, Broomhall, Sheffield, S10 2HQ, UK ; Department of Neuroradiology, University Hospital LMU, Marchioninistr. 15, Munich, 81377, Germany
Teipel, Stefan; German Centre for Neurodegenerative Diseases (DZNE), Gehlsheimer Straße 20, Rostock, 18147, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Straße 20, Rostock, 18147, Germany
Kilimann, Ingo; German Centre for Neurodegenerative Diseases (DZNE), Gehlsheimer Straße 20, Rostock, 18147, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Straße 20, Rostock, 18147, Germany
Goerss, Doreen; German Centre for Neurodegenerative Diseases (DZNE), Gehlsheimer Straße 20, Rostock, 18147, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Straße 20, Rostock, 18147, Germany
Laske, Christoph; German Centre for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 23, Tübingen, 72076, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstraße 24, Tübingen, 72076, Germany
Munk, Matthias H; German Centre for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 23, Tübingen, 72076, Germany ; Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstraße 24, Tübingen, 72076 , Germany
Sanzenbacher, Carolin; German Centre for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 23, Tübingen, 72076, Germany
Hinderer, Petra; German Centre for Neurodegenerative Diseases (DZNE), Otfried-Müller-Straße 23, Tübingen, 72076, Germany
Scheffler, Klaus; Department for Biomedical Magnetic Resonance, University of Tübingen, Otfried-Müller-Straße 51, Tübingen, 72076, Germany
Spottke, Annika; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Department of Neurology, University of Bonn, Venusberg-Campus 1, Bonn, 53127, Germany
Roy-Kluth, Nina; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany
Lüsebrink, Falk; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany
Neumann, Katja; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Wardlaw, Joanna; Centre for Clinical Brain Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK ; UK Dementia Research Institute Centre at the University of Edinburgh, Edinburgh Bioquarter, 49 Little France Crescent, Edinburgh Bioquarter, Edinburgh, EH16 4SB, UK
Jessen, Frank; German Centre for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1, Bonn, 53127, Germany ; Department of Psychiatry, Medical Faculty, University of Cologne, Kerpener Strasse 62, Cologne, 50924, Germany ; Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne, 50931, Germany
Schreiber, Stefanie; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
Düzel, Emrah; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
Ziegler, Gabriel; German Centre for Neurodegenerative Diseases (DZNE), Leipziger Str. 44, Magdeburg, 39120, Germany ; Institute of Cognitive Neurology and Dementia Research, Otto-Von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany
We would like to express our gratitude to all DELCODE participants. We also thank the Max Delbr\u00FCck Centre for Molecular Medicine in the Helmholtz Association (MDC), Freie Universit\u00E4t Berlin Centre for Cognitive Neuroscience Berlin (CCNB), Bernstein Center f\u00FCr Computional Neuroscience Berlin, Universit\u00E4tsmedizin G\u00F6ttingen Core Facility MR-Research G\u00F6ttingen, Institut f\u00FCr Klinische Radiologie Klinikum der Universit\u00E4t M\u00FCnchen, and Universit\u00E4tsklinikum T\u00FCbingen MR-Forschungszentrum. We would like to thank Dr. Farshid Sepehrband for sharing his insights on PVS segmentation with us at the early stages of this project. ED and GZ are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) \u2013\u00A0Project-ID 425899996.Open Access funding enabled and organized by Projekt DEAL. This research was supported by the German Centre for Neurodegenerative Diseases (Deutsches Zentrum f\u00FCr Neurodegenerative Erkrankungen, DZNE; reference number BN012). The computational PVS quantification was supported by The Galen and Hilary Weston Foundation under the Novel Biomarkers 2019 scheme (ref UB190097) administered by the Weston Brain Institute and the Row Fogo Charitable Trust (ref no. BRO-D. FID3668413). The funding bodies played no role in the design of the study or collection, analysis, or interpretation of data or in writing the manuscript.We would like to thank Dr. Farshid Sepehrband for sharing his insights on PVS segmentation with us at the early stages of this project. ED and GZ are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) \u2013 Project-ID 425899996.
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