Insights from Functional MRI: Understanding the Mechanisms underlying Reserve and Brain Maintenance

Abstract Background Cognitive reserve (CR) and Brain Maintenance (BR) are constructs defined at a theoretical level (Stern et al., Neurobiol Aging, 2021 Apr, 124:100‐103). Our aim was to propose a reproducible procedure to compare CR‐like of BR‐like mechanisms underlying interindividual differences in memory stability. Method Leveraging data from the Lifebrain consortia (Walhovd et al. Eur Psychiatry. 2018 Jan;47:76‐87) we gathered information regarding 1) episodic memory (EM) stability, defined as those subjects showing no negative memory changes across two time point assessments (i.e., change ≥0), 2) brain structure and 3) brain functionality (resting‐state functional magnetic resonance imaging [MRI]) changes). We designed a unified approach where at each step an analysis between EM and multimodal MRI‐based measures provides a general metric, referring to either associations between EM and hippocampal (HC) volume changes, or to EM and fMRI connectivity changes (see Figure). This aimed to distinguish a ‘BM – Pathway 1’ identifying those subjects presenting a correspondence between both stability of EM and of HC volumes (i.e x≥0 & y≥0 quadrants of the upper left scatterplot) and a, ‘BM ‐ pathway 2’ reflecting a correspondence between stability of EM and HPC fMRI functionality (i.e x≥0 & y≥0 quadrants of the bottom right scatterplot). Finally, a CR ‐ pathway (‘deviant cases’ in Figure) was defined for subjects where a discrepancy between EM stability and their neural substrates was found (i.e. x>0 and y<0 quadrants in both scatterplots). Result Findings obtained from N = 532 participants (67.8 years at baseline, 294 women) revealed that N = 275 exhibited memory stability over time. Present analyses show that from those, N = 166 (60%) could be classified as BM ‐pathway 1 at the first step, whereas N = 109 (40%) cases were classified as CR ‐ pathway. Further results from a subsample, indicate that CR ‐ pathway cases exhibited a positive change in EM and negative in HC volumes, evidencing reductions in functional connectivity between HC and the Medial Prefrontal node from the dorsal Default Mode Network. Conclusion The present approach combining structural and functional MRI to study CR and BM constructs shall provide new relevant empirical data helping to clarify the conceptual boundaries between these categories.