[en] Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
Disciplines :
Neurology
Author, co-author :
Franzmeier, Nicolai; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Düzel, Emrah; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924 Cologne, Germany
Buerger, Katharina; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
Levin, Johannes; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
Duering, Marco; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Dichgans, Martin; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Haass, Christian; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Suárez-Calvet, Marc; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Fagan, Anne M; Department of Radiology, Washington University in St Louis, St Louis, Missouri, USA ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA
Paumier, Katrina; Department of Radiology, Washington University in St Louis, St Louis, Missouri, USA
Benzinger, Tammie; Department of Radiology, Washington University in St Louis, St Louis, Missouri, USA ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA
Masters, Colin L; The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia
Morris, John C; Department of Radiology, Washington University in St Louis, St Louis, Missouri, USA ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA
Perneczky, Robert; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nußbaumstr. 7, 80336 Munich, Germany ; Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, Exhibition Road, SW7 2AZ London, UK ; West London Mental Health Trust, 13 Uxbridge Road, UB1 3EU London, UK
Janowitz, Daniel; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Catak, Cihan; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Wolfsgruber, Steffen; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Wagner, Michael; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Teipel, Stefan; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany ; Department of Psychosomatic, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
Kilimann, Ingo; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
Ramirez, Alfredo; Department of Psychiatry, University of Cologne, Medical Faculty, Kerpener Strasse 62, 50924 Cologne, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany ; Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany
Rossor, Martin; Dementia Research Centre, University College London, Queen Square, London, UK
Jucker, Mathias; Hertie Institute for Clinical Brain Research, Tübingen, Germany and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Chhatwal, Jasmeer; Departments of Neurology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129, USA ; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129, USA
Spottke, Annika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Boecker, Henning; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Radiology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Falkai, Peter; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nußbaumstr. 7, 80336 Munich, Germany
Fliessbach, Klaus; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Laske, Christoph; Dementia Research Centre, University College London, Queen Square, London, UK ; Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
Nestor, Peter; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Queensland Brain Institute, University of Queensland, Brisbane, Australia
Peters, Oliver; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Hindenburgdamm 30, 12203 Berlin, Germany
Fuentes, Manuel; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
Menne, Felix; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Psychiatry and Psychotherapy, Charité, Hindenburgdamm 30, 12203 Berlin, Germany
Priller, Josef; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charite - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Spruth, Eike J; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charite - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Franke, Christiana; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany ; Department of Neuropsychiatry, Charite - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Schneider, Anja; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Kofler, Barbara; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Westerteicher, Christine; German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Speck, Oliver; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany ; Leibniz Institute for Neurobiology, Magdeburg, Germany ; Center for Behavioral Brain Sciences, Magdeburg, Germany ; Department of Biomedical Magnetic Resonance, Leipziger Str. 44, 39120 Magdeburg, Germany
Wiltfang, Jens; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany ; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Von-Siebold-Str. 5, 37075 Goettingen, Germany ; iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal
Bartels, Claudia; Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Von-Siebold-Str. 5, 37075 Goettingen, Germany
Araque Caballero, Miguel Ángel; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Metzger, Coraline; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Bittner, Daniel; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
Weiner, Michael; University of California at San Francisco, 505 Parnassus Ave, San Francisco, CA94143, USA
Lee, Jae-Hong; Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
Salloway, Stephen; Department of Neurology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
Danek, Adrian; German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany ; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
Goate, Alison; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA ; Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Schofield, Peter R; Neuroscience Research Australia, Barker Street Randwick, Sydney 2031, Australia ; School of Medical Sciences, University of New South Wales, Sydney 2052, Australia
Bateman, Randall J; Department of Radiology, Washington University in St Louis, St Louis, Missouri, USA ; Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA ; Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, USA
Ewers, Michael; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen Straße 17, 81377 Munich, Germany
Alzheimer Forschung Initiative National Institute on Aging German Center for Neurodegenerative Diseases German Center for Neurodegenerative Diseases
Funding text :
The study was funded by an ERC career integration grant (PCIG12-GA-2012-334259 to M. E.), LMUexcellent (to M.E.) and Alzheimer Forschung Initiative (to M.E.), and the the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1 to M.R.). Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer’s Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA) and the German Center for Neurodegenerative Diseases (DZNE, to J.L. and M.J.). The DELCODE study was funded by the German Center for Neurodegenerative Diseases (DZNE), Study-ID: BN012DZNE.The study was funded by an ERC career integration grant (PCIG12-GA-2012-334259 to M. E.), LMUexcellent (to M.E.) and Alzheimer Forschung Initiative (to M.E.), and the the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1 to M.R.). Data collection and sharing for this project was supported by The Dominantly Inherited Alzheimer?s Network (DIAN, U19AG032438) funded by the National Institute on Aging (NIA) and the German Center for Neurodegenerative Diseases (DZNE, to J.L. and M.J.). The DELCODE study was funded by the German Center for Neurodegenerative Diseases (DZNE), Study-ID: BN012DZNE.
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