Dahl MJ, Mather M, Düzel S, Bodammer NC, Lindenberger U, Kühn S, Werkle-Bergner M. Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nat Hum Behav. 2019 Sep 9; PubMed.

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  1. Our group and others have shown that postmortem variables such as locus coeruleus neuron number, density, and volume are all associated with antemortem performance in multiple cognitive domains, including memory. If you think about the role of forebrain norepinephrine in helping us to focus on and process salient information into memory circuits, this is perhaps not too surprising. However, this paper provides us with real-time correlations between LC density and memory performance in living subjects. This not only validates and advances the concepts from clinical pathologic studies, but raises the exciting possibility of a new imaging biomarker tool for cognitive impairment, Alzheimer’s disease, and Lewy body dementias.

    View all comments by Scott Counts

  2. The work of Dahl and colleagues confirms the supposition that the locus coeruleus may be spatially organized in rostral and caudal segments, each projecting to particular target regions that exert various neurobehavioral functions, among them being memory performance. The novelty is that the authors included a diverse study group with participation of young and old adults, which allows for a more accurate estimation of the spatial involvement of the nucleus. Strikingly, they found spatially confined differences between both groups, with more caudal involvement in older than younger adults.

    Despite its small size of roughly 15,000–30,000 neurons, LC integrity is crucial for behavioral and cognitive well-being, as was evidenced by previous research and underlined by the authors. In Parkinson’s disease and Lewy body dementia in particular, the fragility of this nucleus becomes apparent, with very early destruction of catecholaminergic neurons by α-synuclein aggregates, even before the appearance of motor or cognitive symptoms, and, most likely, years beforehand. The Holy grail for biomarker research in Parkinson’s or other neurodegenerative diseases, therefore, may well be confined to determining noradrenaline or its metabolite in peripheral biofluids, or the refinement of neuroimaging techniques and radiotracers that could well visualize the locus, similar to the work here by Dahl and co-authors.

    In short, the neuroprotective properties of the widespread catecholaminergic network in the human brain may signify more for neurodegenerative disease processes than initially thought.

    View all comments by Yannick Vermeiren

  3. The noradrenergic locus coeruleus (LC) in the brainstem shows functional and structural decline in a number of the most frequent neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Lewy Body dementia (Jacobs et al., 2019; Weinshenker, 2018), and has also been shown to be reduced in cognitively normal older adults (Betts et al., 2017; Liu et al., 2019; Shibata et al., 2006). 

    As the locus coeruleus is a very small structure (about 15 mm long and 1–3mm wide) in the brain stem, it can be quite challenging to investigate using in vivo imaging tools such as magnetic resonance imaging (MRI). Indeed, the first imaging protocols have only recently emerged (Sasaki et al., 2008) and there are currently only a few dozen studies employing those in different ageing or clinical populations (for a review see Liu et al., 2017). It is therefore encouraging to see a consistent pattern of results emerging in the investigation of the locus coeruleus in cognitive ageing, which suggests a link between lower LC integrity and lower cognitive capacity in aging (Clewett et al., 2016; Hämmerer et al., 2018; Mather et al., 2017), as well as particular vulnerability of the rostral part in aging (Betts et al., 2017; Liu et al., 2019). The study by Dahl et al. is able to bring these lines of research nicely together by showing that it is the rostral part of the LC which is in particular predictive for cognitive decline. 

    However, a long list of challenges in LC (imaging) research remains, such as understanding better which biological markers in the LC actually allow us to visualize it in MRI (for an overview of the current discussion, see Betts, Kirilina, et al., 2019; Watanabe et al., 2019). Also, these biological markers in the LC likely increase linearly across the lifespan (Liu et al., 2019; Mann and Yates, 1974), which highlights the need for more age-continuous studies to understand the comparability of LC imaging measures in different age groups. Last but not least, spatial post-processing of LC imaging data has to be meticulous, as imprecisions in the millimeter range can be detrimental when investigating such a small structure. 

    Despite these challenges, we are constantly making progress in imaging methods and data processing approaches for LC imaging (Betts, Cardenas-Blanco, et al., 2019; Priovoulos et al., 2017; Watanabe et al., 2019). Together with the advent of big data samples including a variety of relevant cognitive, physiological, and imaging data, and longitudinal approaches, we are thus inching our way forward in understanding this powerful yet vulnerable, and still in many ways enigmatic, nucleus in our brain stem. 

    References:

    Jacobs HI, Riphagen JM, Ramakers IH, Verhey FR. Alzheimer's disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2019 May 28; PubMed.

    Betts MJ, Cardenas-Blanco A, Kanowski M, Spottke A, Teipel SJ, Kilimann I, Jessen F, Düzel E. Locus coeruleus MRI contrast is reduced in Alzheimer's disease dementia and correlates with CSF Aβ levels. Alzheimers Dement (Amst). 2019 Dec;11:281-285. Epub 2019 Mar 27 PubMed.

    Betts MJ, Kirilina E, Otaduy MC, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lüsebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maaß A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HI, Düzel E, Hämmerer D. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain. 2019 Sep 1;142(9):2558-2571. PubMed.

    Clewett DV, Lee TH, Greening S, Ponzio A, Margalit E, Mather M. Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiol Aging. 2016 Jan;37:117-26. Epub 2015 Oct 29 PubMed.

    Hämmerer D, Callaghan MF, Hopkins A, Kosciessa J, Betts M, Cardenas-Blanco A, Kanowski M, Weiskopf N, Dayan P, Dolan RJ, Düzel E. Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events. Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2228-2233. Epub 2018 Feb 12 PubMed.

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    Liu KY, Marijatta F, Hämmerer D, Acosta-Cabronero J, Düzel E, Howard RJ. Magnetic resonance imaging of the human locus coeruleus: A systematic review. Neurosci Biobehav Rev. 2017 Dec;83:325-355. Epub 2017 Oct 28 PubMed.

    Mann DM, Yates PO. Lipoprotein pigments--their relationship to ageing in the human nervous system. I. The lipofuscin content of nerve cells. Brain. 1974 Sep;97(3):481-8. PubMed.

    Mather M, Joo Yoo H, Clewett DV, Lee TH, Greening SG, Ponzio A, Min J, Thayer JF. Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart rate variability. Neuroimage. 2017 Apr 15;150:329-335. Epub 2017 Feb 17 PubMed.

    Priovoulos N, Jacobs HI, Ivanov D, Uludağ K, Verhey FR, Poser BA. High-resolution in vivo imaging of human locus coeruleus by magnetization transfer MRI at 3T and 7T. Neuroimage. 2018 Mar;168:427-436. Epub 2017 Jul 22 PubMed.

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    Shibata E, Sasaki M, Tohyama K, Kanbara Y, Otsuka K, Ehara S, Sakai A. Age-related changes in locus ceruleus on neuromelanin magnetic resonance imaging at 3 Tesla. Magn Reson Med Sci. 2006 Dec;5(4):197-200. PubMed.

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    View all comments by Matthew Betts

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