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.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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 (email@example.com). 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).
The custom code used for these analyses is available from the corresponding authors upon request.
Nyberg, L., Lövdén, M., Riklund, K., Lindenberger, U. & Bäckman, L. Memory aging and brain maintenance. Trends Cogn. Sci. 16, 292–305 (2012).
Crook, T. et al. Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change—report of a National Institute of Mental Health work group. Dev. Neuropsychol. 2, 261–276 (1986).
Prince, M. J. et al. World Alzheimer Report 2015 – The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends (Alzheimer’s Disease International, 2015).
Nyberg, L. et al. Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory. Proc. Natl Acad. Sci. USA 113, 7918–7923 (2016).
Fandakova, Y., Lindenberger, U. & Shing, Y. L. Deficits in process-specific prefrontal and hippocampal activations contribute to adult age differences in episodic memory interference. Cereb. Cortex 24, 1832–1844 (2014).
Lindenberger, U. Human cognitive aging: corriger la fortune? Science 346, 572–578 (2014).
Leslie, F. M. et al. Noradrenergic changes and memory loss in aged mice. Brain Res. 359, 292–299 (1985).
Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).
Marien, M. R., Colpaert, F. C. & Rosenquist, A. C. Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res. Rev. 45, 38–78 (2004).
Wilson, R. S. et al. Neural reserve, neuronal density in the locus coeruleus, and cognitive decline. Neurology 80, 1202–1208 (2013).
Mather, M. & Harley, C. W. The locus coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn. Sci. 20, 214–226 (2016).
Mei, Y. et al. Aging-associated formaldehyde-induced norepinephrine deficiency contributes to age-related memory decline. Aging Cell 19, 659–668 (2015).
Luo, Y. et al. Reversal of aging-related emotional memory deficits by norepinephrine via regulating the stability of surface AMPA receptors. Aging Cell 14, 170–179 (2015).
Arnsten, A. F. T. & Goldman-Rakic, P. S. Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230, 1273–1276 (1985).
Hämmerer, D. et al. Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events. Proc. Natl Acad. Sci. USA 115, 2228–2233 (2018).
Theofilas, P. et al. Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 13, 236–246 (2017).
Szabadi, E. Functional neuroanatomy of the central noradrenergic system. J. Psychopharmacol. 27, 659–693 (2013).
Fernandes, P., Regala, J., Correia, F. & Gonçalves-Ferreira, A. J. The human locus coeruleus 3-D stereotactic anatomy. Surg. Radiol. Anat. 34, 879–885 (2012).
German, D. C. et al. The human locus coeruleus: computer reconstruction of cellular distribution. J. Neurosci. 8, 1776–1788 (1988).
Aston-Jones, G. & Waterhouse, B. Locus coeruleus: from global projection system to adaptive regulation of behavior. Brain Res. 1645, 75–78 (2016).
Berridge, C. W. & Waterhouse, B. D. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res. Rev. 42, 33–84 (2003).
Manaye, K. F., McIntire, D. D., Mann, D. M. A. & German, D. C. Locus coeruleus cell loss in the aging human brain: a non-random process. J. Comp. Neurol. 358, 79–87 (1995).
Schwarz, L. A. & Luo, L. Organization of the locus coeruleus-norepinephrine system. Curr. Biol. 25, R1051–R1056 (2015).
Waterhouse, B. D. & Chandler, D. J. Heterogeneous organization and function of the central noradrenergic system. Brain Res. 1641, v–x (2016).
Ordway, G. A., Schwartz, M. A. & Frazer, A. Brain Norepinephrine: Neurobiology and Therapeutics (Cambridge Univ. Press, 2007).
Arnsten, A. F. T. & Li, B. M. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol. Psychiatry 57, 1377–1384 (2005).
Aston-Jones, G. & Cohen, J. D. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu. Rev. Neurosci. 28, 403–450 (2005).
Bouret, S. & Sara, S. J. Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci. 28, 574–582 (2005).
Mather, M., Clewett, D., Sakaki, M. & Harley, C. W. Norepinephrine ignites local hotspots of neuronal excitation: how arousal amplifies selectivity in perception and memory. Behav. Brain Sci. 39, e200 (2016).
Nieuwenhuis, S. & Jepma, M. Investigating the role of the noradrenergic system in human cognition. in Decision Making, Affect, and Learning: Attention and Performance XXIII (eds Delgado, M., et al.) 367–386 (Oxford Univ. Press, 2011).
Sara, S. J. Locus coeruleus in time with the making of memories. Curr. Opin. Neurobiol. 35, 87–94 (2015).
Sara, S. J. The locus coeruleus and noradrenergic modulation of cognition. Nat. Rev. Neurosci. 10, 211–223 (2009).
Hansen, N. The longevity of hippocampus-dependent memory is orchestrated by the locus coeruleus-noradrenergic system. Neural Plast. 2017, 2727602 (2017).
O’Dell, T. J., Connor, S. A., Guglietta, R. & Nguyen, P. V. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn. Mem. 22, 461–471 (2015).
Bray, N. Learning and memory: you only learn once. Nat. Rev. Neurosci. 19, 59 (2018).
McNamara, C. G. & Dupret, D. Two sources of dopamine for the hippocampus. Trends Neurosci. 40, 383–384 (2017).
Takeuchi, T. et al. Locus coeruleus and dopaminergic consolidation of everyday memory. Nature 537, 357–362 (2016).
Ohm, T. G., Busch, C. & Bohl, J. Unbiased estimation of neuronal numbers in the human nucleus coeruleus during aging. Neurobiol. Aging 18, 393–399 (1997).
Mouton, P. R., Pakkenberg, B., Gundersen, H. J. G. & Price, D. L. Absolute number and size of pigmented locus coeruleus neurons in young and aged individuals. J. Chem. Neuroanat. 7, 185–190 (1994).
Astafiev, S. V., Snyder, A. Z., Shulman, G. L. & Corbetta, M. Comment on ‘Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI’ and ‘Jomeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area’. Science 328, 309 (2010).
Keren, N. I., Lozar, C. T., Harris, K. C., Morgan, P. S. & Eckert, M. A. In vivo mapping of the human locus coeruleus. Neuroimage 47, 1261–1267 (2009).
Zecca, L. et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc. Natl Acad. Sci. USA 101, 9843–9848 (2004).
Mann, D. M. A. & Yates, P. O. Lipoprotein pigments–their relationship to ageing in the human nervous system. II. The melanin content of pigmented nerve cells. Brain 97, 489–498 (1974).
Marcyniuk, B., Mann, D. M. A. & Yates, P. O. The topography of nerve cell loss from the locus caeruleus in elderly persons. Neurobiol. Aging 10, 5–9 (1989).
Sasaki, M., Shibata, E., Kudo, K. & Tohyama, K. Neuromelanin-sensitive MRI: basics, technique, and clinical applications. Clin. Neuroradiol. 18, 147–153 (2008).
Sasaki, M. et al. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson’s disease. Neuroreport 17, 1215–1218 (2006).
Liu, K. Y. et al. Magnetic resonance imaging of the human locus coeruleus: a systematic review. Neurosci. Biobehav. Rev. 83, 325–355 (2017).
Keren, N. I. et al. Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. Neuroimage 113, 235–245 (2015).
Albert, M. S., Moss, M. B., Tanzi, R. & Jones, K. Preclinical prediction of AD using neuropsychological tests. J. Int. Neuropsychol. Soc. 7, 631–639 (2001).
Belleville, S., Fouquet, C., Hudon, C., Zomahoun, H. T. V. & Croteau, J. Neuropsychological measures that predict progression from mild cognitive impairment to Alzheimer’s type dementia in older adults: a systematic review and meta-analysis. Neuropsychol. Rev. 27, 328–353 (2017).
Moradi, E., Hallikainen, I., Hänninen, T. & Tohka, J. Rey’s auditory verbal learning test scores can be predicted from whole brain MRI in Alzheimer’s disease. NeuroImage Clin. 13, 415–427 (2017).
Schoenberg, M. R. et al. Test performance and classification statistics for the Rey auditory verbal learning test in selected clinical samples. Arch. Clin. Neuropsychol. 21, 693–703 (2006).
Zimprich, D., Rast, P. & Martin, M. Individual differences in verbal learning in old age. in Handbook of Cognitive Aging: Interdisciplinary Perspectives (eds Hofer, S. & Alwin, D.) 224–243 (SAGE Publications, 2008).
Jones, R. N. et al. A growth curve model of learning acquisition among cognitively normal older adults. Exp. Aging Res. 31, 291–312 (2005).
Zimprich, D. & Rast, P. Verbal learning changes in older adults across 18 months. Neuropsychol. Dev. Cogn. B 16, 461–484 (2009).
McArdle, J. J. Dynamic but structural equation modeling of repeated measures data. in Handbook of Multivariate Experimental Psychology (eds Nesselroade, J. R. & Cattell, R. B.) 561–614 (Springer, 1988).
Curran, P. J., Obeidat, K. & Losardo, D. Twelve frequently asked questions about growth curve modeling. J. Cogn. Dev. 11, 121–136 (2010).
Kievit, R. A. et al. Developmental cognitive neuroscience using latent change score models: a tutorial and applications. Dev. Cogn. Neurosci. 33, 99–117 (2018).
Brown, T. A. Confirmatory Factor Analysis for Applied Research. (Guilford Press, 2006).
Eid, M., Gollwitzer, M. & Schmitt, M. Statistik und Forschungsmethoden: Lehrbuch. Grundlagen Psychologie (Beltz, 2015).
Betts, M. J., Cardenas-Blanco, A., Kanowski, M., Jessen, F. & Düzel, E. In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults. Neuroimage 163, 150–159 (2017).
Maris, E. & Oostenveld, R. Nonparametric statistical testing of EEG- and MEG-data. J. Neurosci. Methods 164, 177–190 (2007).
Steiger, J. H. Beyond the F test: effect size confidence intervals and tests of close fit in the analysis of variance and contrast analysis. Psychol. Methods 9, 164–182 (2004).
Steiger, J. H. Tests for comparing elements of a correlation matrix. Psychol. Bull. 87, 245–251 (1980).
Schmidt, M. Rey Auditory Verbal Learning Test: A Handbook (Western Psychological Services, 2004).
Gifford, K. A. et al. Associations between verbal learning slope and neuroimaging markers across the cognitive aging spectrum. J. Int. Neuropsychol. Soc. 21, 455–467 (2015).
Priovoulos, N. et al. High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage 168, 127–136 (2017).
Chen, X. et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magn. Reson. Imaging 32, 1301–1306 (2014).
Langley, J., Huddleston, D. E., Liu, C. J. & Hu, X. Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. Magn. Reson. Mater. Phys. Biol. Med. 30, 121–125 (2017).
Tona, K. D. et al. In vivo visualization of the locus coeruleus in humans: quantifying the test–retest reliability. Brain Struct. Funct. 222, 4203–4217 (2017).
Weinshenker, D. Long road to ruin: noradrenergic dysfunction in neurodegenerative disease. Trends Neurosci. 41, 211–223 (2018).
Chalermpalanupap, T., Weinshenker, D. & Rorabaugh, J. M. Down but not out: the consequences of pretangle tau in the locus coeruleus. Neural Plast. https://doi.org/10.1155/2017/7829507 (2017).
Jagust, W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19, 687–700 (2018).
Robertson, I. H. A noradrenergic theory of cognitive reserve: implications for Alzheimer’s disease. Neurobiol. Aging 34, 298–308 (2013).
Shibata, E. et al. Age-related changes in locus coeruleus on neuromelanin magnetic resonance imaging at 3 Tesla. Magn. Reson. Med. Sci. 5, 197–200 (2006).
Clewett, D. V. et al. Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiol. Aging 37, 117–126 (2016).
Bouret, S. & Sara, S. J. Locus coeruleus activation modulates firing rate and temporal organization of odour-induced single-cell responses in rat piriform cortex. Eur. J. Neurosci. 16, 2371–2382 (2002).
Fries, P. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends Cogn. Sci. 9, 474–480 (2005).
Li, S.-C., Lindenberger, U. & Sikstrom, S. Aging cognition: from neuromodulation to representation. Trends Cogn. Sci. 5, 479–486 (2001).
Shing, Y. L. et al. Episodic memory across the lifespan: the contributions of associative and strategic components. Neurosci. Biobehav. Rev. 34, 1080–1091 (2010).
Ehrenberg, A. J. et al. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 43, 393–408 (2017).
Kaufman, S. K., Del Tredici, K., Thomas, T. L., Braak, H. & Diamond, M. I. Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. Acta Neuropathol. 136, 57 (2018).
Heinsen, H. & Grinberg, L. T. On the origin of tau seeding activity in Alzheimer’s disease. Acta Neuropathol. 136, 815–817 (2018).
Grinberg, L. T. & Heinsen, H. Light at the beginning of the tunnel? Investigating early mechanistic changes in Alzheimer’s disease. Brain 140, 2770–2773 (2017).
Zarow, C., Lyness, S. A., Mortimer, J. A. & Chui, H. C. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch. Neurol. 60, 337 (2003).
Chalermpalanupap, T. et al. Locus coeruleus ablation exacerbates cognitive deficits, neuropathology, and lethality in P301S tau transgenic mice. J. Neurosci. 38, 74–92 (2018).
Betts, M. J., Ehrenberg, A. J., Hämmerer, D. & Düzel, E. Commentary: locus coeruleus ablation exacerbates cognitive deficits, neuropathology, and lethality in P301S tau transgenic mice. Front. Neurosci. 12, 401 (2018).
Rorabaugh, J. M. et al. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease. Brain 140, 3023–3038 (2017).
Folstein, M. F., Folstein, S. E. & McHugh, P. R. Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198 (1975).
Delius, J. A. M., Düzel, S., Gerstorf, D. & Lindenberger, U. Berlin Aging Studies (BASE and BASE-II). in Encyclopedia of Geropsychology (ed. Pachana, N. A.) 386–395 (Springer, 2015).
Gerstorf, D. et al. The Berlin Aging Study II – an overview. Gerontology 62, 311–315 (2016).
Bertram, L. et al. Cohort profile: the Berlin Aging Study II (BASE-II). Int. J. Epidemiol. 43, 703–712 (2014).
Düzel, S. et al. Supplementary material for: the Subjective Health Horizon Questionnaire (SHH-Q): assessing future time perspectives for facets of an active lifestyle. Gerontology 62, 345–353 (2016).
von Oertzen, T., Brandmaier, A. M. & Tsang, S. Structural equation modeling with Ωnyx. Struct. Equ. Modeling 22, 148–161 (2015).
Avants, B. B. et al. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage 54, 2033–2044 (2011).
Avants, B. B., Tustison, N. & Song, G. Advanced normalization tools: V1.0. Insight J. 2, 1–35 (2009).
Klein, A. et al. Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. Neuroimage 46, 786–802 (2009).
Friston, K. J. Experimental design and Statistical Parametric Mapping. in Human Brain Function (eds Frackowiak, R. S. J. et al.) 599–632 (Academic Press, 2004).
Dahl, M. J., Ilg, L., Li, S.-C., Passow, S. & Werkle-Bergner, M. Diminished pre-stimulus alpha-lateralization suggests compromised self-initiated attentional control of auditory processing in old age. Neuroimage 197, 414–424 (2019).
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.
The authors declare no competing interests.
Peer Review Information: Primary Handling Editor: Marike Schiffer
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Journal of Alzheimer's Disease (2020)
Optimizing neuromelanin contrast in the substantia nigra and locus coeruleus using a magnetization transfer contrast prepared 3D gradient recalled echo sequence