A Residual Marker of Cognitive Reserve Is Associated with Resting-State Intrinsic Functional Connectivity Along the Alzheimer’s Disease Continuum

Article type: Research Article

Authors: Ersoezlue, Ersin^{a; b; 1} | Perneczky, Robert^{a; c; d; e; f; 1; *} | Tato, Maia^a | Utecht, Julia^a | Kurz, Carolin^a | Häckert, Jan^a | Guersel, Selim^a | Burow, Lena^a | Koller, Gabriele^a | Stoecklein, Sophiaⁱⁱ | Keeser, Daniel^a | Papazov, Borisⁱⁱ | Totzke, Marie^a | Ballarini, Tommaso^g | Brosseron, Frederic^g | Buerger, Katharina^{i; j} | Dechent, Peter^k | Dobisch, Laura^{l; m} | Ewers, Michael^{i; j} | Fliessbach, Klaus^{g; h} | Glanz, Wenzel^l | Haynes, John Dylanⁿ | Heneka, Michael T.^{g; h} | Janowitz, Daniel^j | Kilimann, Ingo^{o; p} | Kleineidam, Luca^g | Laske, Christoph^{q; r} | Maier, Franziska^s | Munk, Matthias H.^{q; r} | Peters, Oliver^{t; u} | Priller, Josef^{v; w; x} | Ramirez, Alfredo^{g; h; y; z} | Roeske, Sandra^g | Roy, Nina^g | Scheffler, Klaus^aa | Schneider, Anja^{g; h} | Schott, Björn H.^{bb; cc; gg} | Spottke, Annika^{g; dd} | Spruth, Eike J.^{u; v} | Teipel, Stefan^{o; p} | Unterfeld, Chantal^t | Wagner, Michael^{g; h} | Wang, Xiao^t | Wiltfang, Jens^{bb; cc; ee} | Wolfsgruber, Steffen^{g; h} | Yakupov, Renat^l | Duezel, Emrah^{l; m} | Jessen, Frank^{g; s; ff} | Rauchmann, Boris-Stephan^{a; c; f; hh; *} | for the DELCODE study group

Affiliations: [a] Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany | [b] Department of Gerontopsychiatry and Developmental Disorders, kbo-Isar-Amper-Klinikum Haar, University Teaching Hospital of LMU Munich, Germany | [c] German Center for Neurodegenerative Diseases (DZNE) Munich, Germany | [d] Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College, London, UK | [e] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany | [f] Sheffield Institute for Translational Neurology (SITraN), University of Sheffield, Sheffield, UK | [g] German Center for Neurodegenerative Diseases (DZNE) Bonn, Germany | [h] Medical Center of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Germany | [i] German Center for Neurodegenerative Diseases (DZNE Munich), Munich, Germany | [j] Institute for Stroke and Dementia Research (ISD), University Hospital LMU Munich, Germany | [k] MR-Research in Neurosciences Department of Cognitive Neurology, Georg-August-University Goettingen, Germany | [l] German Center for Neurodegenerative Diseases (DZNE) Magdeburg, Germany | [m] Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University Magdeburg, Germany | [n] Bernstein Center for Computational Neuroscience Charité — Universitätsmedizin Berlin, Germany | [o] German Center for Neurodegenerative Diseases (DZNE) Rostock, Germany | [p] Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany | [q] German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany | [r] Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Germany | [s] Department of Psychiatry, Medical Faculty of University of Cologne, Germany | [t] Department of Psychiatry, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany | [u] German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany | [v] Department of Psychiatry and Psychotherapy, Charité Berlin, Germany | [w] Department of Psychiatry and Psychotherapy, School of Medicine Technical University of Munich, Germany | [x] University of Edinburgh and UK DRI Edinburgh, UK | [y] Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, Germany | [z] Department of Psychiatry & Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA | [aa] Department for Biomedical Magnetic Resonance, University of Tübingen, Germany | [bb] German Center for Neurodegenerative Diseases (DZNE) Goettingen, Germany | [cc] Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Germany | [dd] Department of Neurology, University of Bonn, Germany | [ee] Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Portugal | [ff] Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Germany | [gg] Leibniz Institute for Neurobiology, Magdeburg, Germany | [hh] Department of Neuroradiology, University Hospital, LMU Munich, Germany | [ii] Department of Radiology, University Hospital, LMU Munich, Germany

Correspondence: [*] Correspondence to: Dr. Boris-Stephan Rauchmann and Prof. Dr. Robert Perneczky, Division of Mental Health of Older Adults, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nussbaumstr. 7, 80336 Munich, Germany. Tel.: +49 89 4400 53439; Fax: +49 89 4400 53413; E-mails: [email protected] and [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Cognitive reserve (CR) explains inter-individual differences in the impact of the neurodegenerative burden on cognitive functioning. A residual model was proposed to estimate CR more accurately than previous measures. However, associations between residual CR markers (CRM) and functional connectivity (FC) remain unexplored. Objective:To explore the associations between the CRM and intrinsic network connectivity (INC) in resting-state networks along the neuropathological-continuum of Alzheimer’s disease (ADN). Methods:Three hundred eighteen participants from the DELCODE cohort were stratified using cerebrospinal fluid biomarkers according to the A(myloid-β)/T(au)/N(eurodegeneration) classification. CRM was calculated utilizing residuals obtained from a multilinear regression model predicting cognition from markers of disease burden. Using an independent component analysis in resting-state fMRI data, we measured INC of resting-state networks, i.e., default mode network (DMN), frontoparietal network (FPN), salience network (SAL), and dorsal attention network. The associations of INC with a composite memory score and CRM and the associations of CRM with the seed-to-voxel functional connectivity of memory-related were tested in general linear models. Results:CRM was positively associated with INC in the DMN in the entire cohort. The A+T+N+ group revealed an anti-correlation between the SAL and the DMN. Furthermore, CRM was positively associated with anti-correlation between memory-related regions in FPN and DMN in ADN and A+T/N+. Conclusion:Our results provide evidence that INC is associated with CRM in ADN defined as participants with amyloid pathology with or without cognitive symptoms, suggesting that the neural correlates of CR are mirrored in network FC in resting-state.

Keywords: Alzheimer’s disease, cognition, cognitive reserve, functional MRI, intrinsic network connectivity, resting-state functional connectivity

DOI: 10.3233/JAD-220464

Journal: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 925-940, 2023