Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer’s Disease

Article type: Research Article

Authors: Scherr, Martin^{a; b; 1; *} | Pasquini, Lorenzo^{c; 1} | Benson, Gloria^d | Nuttall, Rachel^{e; f; g} | Gruber, Martin^h | Neitzel, Julia^{g; h} | Brandl, Felix^{f; h} | Sorg, Christian^{b; f; h} | for the Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Department of Neurology, Paracelsus Medical University Salzburg, and Christian Doppler Medical Centre, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria | [b] Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Munich, Germany | [c] Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA | [d] Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany | [e] Department of Psychology, University of Salzburg, Salzburg, Austria | [f] TUM Neuroimaging Center (TUM-NIC), Klinikum rechts der Isar, Technische Universität München, Munich, Germany | [g] General and Experimental Psychology, Department of Psychology, Ludwig-Maximilians-Universität München, Munich, Germany | [h] Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Correspondence: [*] Correspondence to: Martin Scherr, MD, Department of Neurology, Paracelsus Medical University Salzburg and Christian Doppler Medical Centre, Salzburg, Austria; Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria. Tel.: +43 5 7255 56040; E-mail: m.scherr@salk.at.

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

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer’s disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region’s sensitivity to afferent input from other regions, i.e., FC. Objective:We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ). Methods:Healthy adults (n=20) and Aβ+patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation. Results:RLMA/FC decreased with disease severity (F=20.09, p<0.001). This decrease was specifically associated with pDMN Aβ (r=−0.273, p=0.029) but not global Aβ (r=−0.112, p=0.378) and with the impact of Aβ on FC (i.e., rAβ/FC, r=−0.339; p=0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively. Conclusion:Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline.

Keywords: Alzheimer’s disease, amyloid-β, default mode network, functional connectivity, local metabolic activity

DOI: 10.3233/JAD-180022

Journal: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 405-415, 2018