Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer’s Disease Spectrum

Article type: Research Article

Authors: Teipel, Stefan J.^{a; b; *} | Dyrba, Martin^a | Ballarini, Tommaso^c | Brosseron, Frederic^{c; d} | Bruno, Davide^e | Buerger, Katharina^{f; g} | Cosma, Nicoleta-Carmen^h | Dechent, Peterⁱ | Dobisch, Laura^j | Düzel, Emrah^{j; k} | Ewers, Michael^{f; g} | Fliessbach, Klaus^{c; d} | Haynes, John D.^l | Janowitz, Daniel^g | Kilimann, Ingo^{a; b} | Laske, Christoph^{m; n; o} | Maier, Franziska^p | Metzger, Coraline D.^{j; k; q} | Munk, Matthias H.^{m; o; r} | Peters, Oliver^{h; s} | Pomara, Nunzio^{t; u} | Preis, Lukas^h | Priller, Josef^{s; v; w} | Ramírez, Alfredo^{c; d; x; y; ff} | Roy, Nina^c | Scheffler, Klaus^z | Schneider, Anja^{c; d} | Schott, Björn H.^{aa; bb; cc} | Spottke, Annika^{c; dd} | Spruth, Eike J.^{s; v} | Wagner, Michael^{c; d} | Wiltfang, Jens^{aa; bb; ee} | Jessen, Frank^{c; p; ff} | Heneka, Michael T.^{c; d}

Affiliations: [a] German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany | [b] Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany | [c] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany | [d] Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany | [e] School of Psychology, Liverpool John Moores University, Liverpool, UK | [f] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany | [g] Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University, Munich, Germany | [h] Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany | [i] Department of Cognitive Neurology, MR-Research in Neurosciences, Georg-August-University, Goettingen, Germany | [j] German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany | [k] Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany | [l] Bernstein Center for Computational Neuroscience, Berlin, Germany | [m] German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany | [n] Section for Dementia Research, Hertie Institute for Clinical Brain Research, Tuebingen, Germany | [o] Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany | [p] Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany | [q] Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany | [r] Department of Biology, Systems Neurophysiology, Darmstadt University of Technology, Darmstadt, Germany | [s] German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany | [t] Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA | [u] Department of Psychiatry, School of Medicine, New York University, New York City, NY, USA | [v] Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany | [w] Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University Munich, Munich, Germany | [x] Department of Psychiatry and Psychotherapy, Division of Neurogenetics and Molecular Psychiatry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany | [y] Department of Psychiatry & Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA | [z] Department for Biomedical Magnetic Resonance, University of Tuebingen, Tuebingen, Germany | [aa] German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany | [bb] Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany | [cc] Leibniz Institute for Neurobiology, Magdeburg, Germany | [dd] Department of Neurology, University Hospital Bonn, Bonn, Germany | [ee] Neurosciences and Signaling Group, Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal | [ff] Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

Correspondence: [*] Correspondence to: Stefan J. Teipel, MD, Department of Psy-chosomatic Medicine, University of Rostock, and DZNE Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany. Tel.: +01149 381 494 9470; Fax: +01149 381 494 9472; E-mail: [email protected].

Abstract: Background:Inflammation has been described as a key pathogenic event in Alzheimer’s disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. Objective:To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. Methods:We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. Results:We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aβ42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. Conclusion:Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aβ42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

Keywords: Alzheimer’s disease, cerebrospinal fluid, cholinergic system, neuroinflammation, MRI, plasma, sTREM2

DOI: 10.3233/JAD-215196

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1267-1282, 2022