Rostral locus coeruleus integrity is associated with better memory performance in older adults

Abstract

For decades, research into memory decline in human cognitive ageing has focused on neocortical regions, the hippocampus and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantification of LC integrity have hindered the study of LC–cognition associations in humans. Using high-resolution, neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in both younger (n = 66) and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more ‘youth-like’ rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in ageing and highlight the role of the LC norepinephrine system in the decline of cognition.

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Fig. 1: Schematic overview of the verbal learning and memory task.
Fig. 2: Pictorial rendition of the structural equation model probing associations between LC integrity and memory performance in younger and older adults on a latent level.
Fig. 3: Schematic overview of the semi-automatic analysis procedure used to extract individual LC intensity values across the rostrocaudal extent.
Fig. 4: Estimated learning and memory performance trajectories for younger and older adults.
Fig. 5: Topographical age differences in LC intensity ratios and their functional implications.

Data availability

The data on which our results are based are available from the BASE-II steering committee following approval of a research proposal (https://www.base2.mpg.de/en/project-information/data-documentation). For inquiries please contact L. Müller, BASE-II project coordinator (lmueller@mpib-berlin.mpg.de). To facilitate comparability of study results, we freely share the established LC probability map with the neuroscientific community (https://www.mpib-berlin.mpg.de/LC-Map).

Code availability

The custom code used for these analyses is available from the corresponding authors upon request.

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Acknowledgements

This article uses data from the Berlin Aging Study II (BASE-II), which was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) under grant nos. 16SV5536 K, 16SV5537, 16SV5538, 16SV5837, 01UW070 and 01UW0808. Additional contributions (for example, financial, equipment, logistics, personnel) were provided by each of the other participating sites—that is, the Max Planck Institute for Human Development, Max Planck Institute for Molecular Genetics, Charité-Universitätsmedizin, German Institute for Economic Research and Humboldt-Universität zu Berlin, all located in Berlin, Germany; and the Universities of Lübeck and Tübingen, Germany. For further information about the BASE-II project, see https://www.base2.mpg.de/en. M.W.-B. received support from the German Research Foundation (grant no. WE 4269/5-1) and the Jacobs Foundation (Early Career Research Fellowship 2017–2019). M.J.D. recieves support from a fellowship with the International Max Planck Research School on the Life Course (http://www.imprs-life.mpg.de/en/). M.J.D. is recipient of a stipend from the Sonnenfeld-Foundation (http://www.sonnenfeld-stiftung.de/en/). M.M. was supported by an Alexander von Humboldt fellowship and by National Institutes of Health (grant no. R01AG025340). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank A. Bender, M. Betts and M. Sander for valuable discussions and assistance. We are grateful to S. Bachman and D. Zorbek, who performed the manual tracing of the LC, as well as Y. Köhncke and Y. Fandakova for statistical advice and M. Krause for help with cluster computing.

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U.L. and S.K. designed the broader BASE-II study. M.J.D., M.W.-B., M.M., S.K. and N.C.B. designed the additional LC component. S.D. performed the experiments. M.J.D. and M.W.-B. analysed the data. M.J.D. and M.W.-B. wrote the manuscript. U.L., S.K., M.M., S.D. and N.C.B. gave conceptual advice. All authors revised the manuscript.

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Correspondence to Martin J. Dahl or Markus Werkle-Bergner.

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Supplementary Table 1, Supplementary Figs. 1 and 2, Supplementary Results (including Supplementary Tables 2–12 and Supplementary Figs. 3–16), Supplementary Discussion and Supplementary References.

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Dahl, M.J., Mather, M., Düzel, S. et al. Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nat Hum Behav 3, 1203–1214 (2019). https://doi.org/10.1038/s41562-019-0715-2

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