[en] Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.
Disciplines :
Neurology
Author, co-author :
Baumeister, Hannah ; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
Vogel, Jacob W ; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden
Insel, Philip S ; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
Kleineidam, Luca; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Wolfsgruber, Steffen; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Stark, Melina; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Gellersen, Helena M; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
Yakupov, Renat ; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany
Schmid, Matthias C; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Institute for Medical Biometry, University Hospital Bonn, 53127 Bonn, Germany
Lüsebrink, Falk; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Ziegler, Gabriel; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany
Freiesleben, Silka D; German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany ; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Preis, Lukas; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Schneider, Luisa-Sophie; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany ; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Altenstein, Slawek; German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany ; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Lohse, Andrea; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Fliessbach, Klaus; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Vogt, Ina R; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Bartels, Claudia; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany
Schott, Björn H ; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany ; Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
Rostamzadeh, Ayda; Department of Psychiatry, Medical Faculty, University of Cologne, 50937 Cologne, Germany
Glanz, Wenzel; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
Incesoy, Enise I; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany ; Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, 39120 Magdeburg, Germany
Butryn, Michaela; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
Janowitz, Daniel; Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-Universität, 81377 Munich, Germany
Rauchmann, Boris-Stephan; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität, 80336 Munich, Germany ; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK ; Department of Neuroradiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany
Kilimann, Ingo; German Center for Neurodegenerative Diseases (DZNE), 18147 Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, 18147 Rostock, Germany
Goerss, Doreen; German Center for Neurodegenerative Diseases (DZNE), 18147 Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, 18147 Rostock, Germany
Munk, Matthias H; German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany ; Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany
Hetzer, Stefan; Berlin Center for Advanced Neuroimaging, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
Dechent, Peter; MR-Research in Neurosciences, Department of Cognitive Neurology, Georg-August-University Göttingen, 37075 Göttingen, Germany
Ewers, Michael ; Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-Universität, 81377 Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
Scheffler, Klaus; Department for Biomedical Magnetic Resonance, University of Tübingen, 72076 Tübingen, Germany
Wuestefeld, Anika; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden
Strandberg, Olof; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden
van Westen, Danielle ; Diagnostic Radiology, Institution of Clinical Sciences Lund, Lund University, 211 84 Lund, Sweden ; Image and Function, Skåne University Hospital, 211 84 Lund, Sweden
Mattsson-Carlgren, Niklas ; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden ; Department of Neurology, Skåne University Hospital, Lund University, 211 84 Lund, Sweden ; Wallenberg Center for Molecular Medicine, Lund University, 22184 Lund, Sweden
Janelidze, Shorena; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden
Stomrud, Erik; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden ; Memory Clinic, Skåne University Hospital, 205 02 Malmö, Sweden
Palmqvist, Sebastian ; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden ; Memory Clinic, Skåne University Hospital, 205 02 Malmö, Sweden
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Laske, Christoph; German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany ; Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany ; Section for Dementia Research, Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany
Teipel, Stefan ; German Center for Neurodegenerative Diseases (DZNE), 18147 Rostock, Germany ; Department of Psychosomatic Medicine, Rostock University Medical Center, 18147 Rostock, Germany
Perneczky, Robert; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität, 80336 Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany ; Ageing Epidemiology Research Unit (AGE), School of Public Health, Imperial College London, London SW7 2AZ, UK
Buerger, Katharina; Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-Universität, 81377 Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany
Schneider, Anja; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany ; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany ; Department of Psychiatry and Psychotherapy, Technical University of Munich, 81675 Munich, Germany ; Centre for Clinical Brain Sciences, University of Edinburgh and UK DRI, Edinburgh EH16 4SB, UK
Peters, Oliver; German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany ; Department of Psychiatry and Neurosciences, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Ramirez, Alfredo ; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, 50931 Cologne, Germany ; Department of Psychiatry & Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, The University of Texas at San Antonio, San Antonio, TX 78229, USA
Wiltfang, Jens; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany ; Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Wagner, Michael; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn Medical Center, 53127 Bonn, Germany
Düzel, Emrah ; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany ; Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany ; Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany ; Department of Psychiatry, Medical Faculty, University of Cologne, 50937 Cologne, Germany ; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Hansson, Oskar ; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden ; Memory Clinic, Skåne University Hospital, 205 02 Malmö, Sweden
Berron, David ; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany ; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 222 42 Lund, Sweden ; Center for Behavioral Brain Sciences (CBBS), Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany
The authors thank all DELCODE and BioFINDER-2 participants along with their relatives and caregivers for their valuable contributions. The study was funded by the German Center for Neurodegenerative Diseases (Deutsches Zentrum f\u00FCr Neurodegenerative Erkrankungen; DZNE), reference number BN01. Work within the Swedish BioFINDER-2 study was supported by the Alzheimer s Association (SG-23-1061717), Swedish Research Council (2022-00775, 2018-02052, 2021-02219), ERA PerMed (ERAPERMED 2021-184), the Knut and Alice Wallenberg foundation (2017-0383), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson s disease) at Lund University, the Swedish Alzheimer Foundation (AF-980907, AF-981132, AF-994229), the Swedish Brain Foundation (FO2021-0293, FO2022-0204 and FO2023-0163), the EU Joint Programme Neurodegenerative Disease Research (2019-03401), the WASP and DDLS Joint call for research projects (WASP/DDLS22-066), the R\u00F6nstr\u00F6m Family Foundation (FRS-0003), the Parkinson Foundation of Sweden (1412/22), the Cure Alzheimer s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Sk\u00E5ne University Hospital Foundation (2020-O000028), Regionalt Forskningsst\u00F6d (2022-1259) and the Swedish Federal Government under the ALF agreement (2022-Projekt0080, 2022-Projekt0107).The study was funded by the German Center for Neurodegenerative Diseases (Deutsches Zentrum f\u00FCr Neurodegenerative Erkrankungen; DZNE), reference number BN01. Work within the Swedish BioFINDER-2 study was supported by the Alzheimer\u2019s Association (SG-23-1061717), Swedish Research Council (2022-00775, 2018-02052, 2021-02219), ERA PerMed (ERAPERMED2021-184), the Knut and Alice Wallenberg foundation (2017-0383), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson\u2019s disease) at Lund University, the Swedish Alzheimer Foundation (AF-980907, AF-981132, AF-994229), the Swedish Brain Foundation (FO2021-0293, FO2022-0204 and FO2023-0163), the EU Joint Programme \u2013 Neurodegenerative Disease Research (2019-03401), the WASP and DDLS Joint call for research projects (WASP/DDLS22-066), the R\u00F6nstr\u00F6m Family Foundation (FRS-0003), the Parkinson Foundation of Sweden (1412/22), the Cure Alzheimer\u2019s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Sk\u00E5ne University Hospital Foundation (2020-O000028), Regionalt Forskningsst\u00F6d (2022-1259) and the Swedish Federal Government under the ALF agreement (2022-Projekt0080, 2022-Projekt0107).
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