Tiny Brain Structure Plays Big Role in Memory
The humble locus coeruleus, a minute speck of tissue nestled deep in the brain stem, has received relatively scant attention in studies of cognitive decline. Now, data published September 9 in Nature Human Behavior add to a recent spate of findings suggesting the structure is important for memory. Martin Dahl and Markus Werkle-Bergner at the Max Planck Institute for Human Development, Berlin, and colleagues correlate age-related neurodegeneration in the frontal part of the locus coeruleus (LC) with worse memory performance. People who maintain a healthy LC into old age do better on cognitive tests, the scientists show. The study makes use of a relatively new MRI technique that images the structure, allowing it to be tracked over time.
- MRI suggests the rostral locus coeruleus degenerates with age.
- This correlated with poorer memory.
- The region is among the first to accumulate phosphorylated tau.
“This paper provides real-time correlations between LC density and memory performance in living subjects,” wrote Scott Counts, Michigan State University, Grand Rapids, to Alzforum. Counts was not involved in the study. “This not only validates and advances the concepts [arising] 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.”
At just 15 mm long and 1–3 mm wide, the cylindrical locus coeruleus serves as the brain’s primary source of the neurotransmitter norepinephrine. Neurons from the front, i.e., rostral, LC project to the hippocampus, while its back, i.e., caudal, region projects to the cerebellum and spinal cord. By releasing norepinephrine, LC neurons modulate attention, learning, memory via long-term potentiation, and depression of synaptic activity, which are important for network plasticity.
The locus coeruleus takes a hit both structurally and functionally in people with Alzheimer’s, Parkinson’s, or dementia with Lewy bodies (Jacobs et al., 2019; Weinshenker 2018). In AD, the LC is one of the earliest regions to accumulate hyperphosphorylated tau (Braak et al., 2011). It’s unclear how toxic tau species affect LC neurons, but some studies suggest that damage to the LC and the resulting loss of norepinephrine speeds up AD pathology (see Dec 2010 Alzforum webinar). This may be related to decline in density of the rostral region with age (for a review, see Manaye et al., 1995). This decline appears to correlate with age-related cognitive impairment, according to postmortem human data (Wilson et al., 2013).
While the LC’s small size and location deep in the brain obscure it to traditional MRI, scientists try to use its natural pigmentation to see it on a scan (Sasaki et al., 2006). Neuromelanin, the dark byproduct of norepinephrine production, builds up in the LC over time, peaking at around age 50 to 60, after which it plateaus or declines. Turbo-spin echo (TSE) MRI takes advantage of neuromelanin’s paramagnetic properties to visualize the structure of the LC.
In the current study, Dahl and colleagues used TSE to correlate the integrity of the LC with memory performance in cognitively healthy participants from the Berlin Aging Study II (Gerstorf et al., 2016). The authors tested 66 people with an average age of 33, and 228 older people, average age 72. Each had a TSE scan and took the Rey Auditory Verbal Learning Test (RAVLT), which asks participants to memorize a list of 15 words and freely recall them in five successive trials.
As expected, the younger volunteers recalled more words than did the older ones, and those with a smaller rostral LC recalled even fewer (see image below). Other memory tasks showed a similar correlation. A denser rostral LC meant people could better recognize faces, remember the locations of pictures on a grid, and memorize pictures of indoor/outdoor scenes. “This indicates a stable link between LC integrity and general memory performance,” Dahl said.
Age Differences. Over five successive trials, the number of recalled words (y-axis) increases for most individuals (thin lines). In general, younger people (left) recall more words than older people (right). Among the latter, those with an LC signal below the median (thick black band) remember fewer words than those with a higher-than-average signal (red). [Courtesy of Dahl et al., 2019.]
The results are in line with recent data implicating neurodegeneration in the LC in age-related cognitive decline (Clewett et al., 2016; Hämmerer et al., 2018). “The study by Dahl et al. shows that it is the rostral part of the LC which is particularly predictive for cognitive decline,” wrote Dorothea Hämmerer, Emrah Düzel, and Matthew Betts of Otto-von-Guericke-University Magdeburg, Germany, to Alzforum.
All three were co-authors on a September 1 consensus statement from the first European Locus Coeruleus Imaging meeting, held in Magdeburg in 2018. The statement discusses how to noninvasively measure locus coeruleus integrity in vivo and use this information for clinical research in neurodegenerative diseases (Betts et al., 2019). Among the challenges is spatial post-processing of imaging data for such a small structure, they told Alzforum. “Together with the advent of other big data samples, including a variety of physiological and imaging data, we are inching our way forward in understanding this enigmatic nucleus in the brainstem,” they wrote.—Gwyneth Dickey Zakaib
- 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.
- Weinshenker D. Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease. Trends Neurosci. 2018 Apr;41(4):211-223. Epub 2018 Feb 20 PubMed.
- Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.
- Manaye KF, McIntire DD, Mann DM, German DC. Locus coeruleus cell loss in the aging human brain: a non-random process. J Comp Neurol. 1995 Jul 17;358(1):79-87. PubMed.
- Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA. Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology. 2013 Mar 26;80(13):1202-8. PubMed.
- Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, Takahashi S, Ehara S, Terayama Y, Sakai A. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease. Neuroreport. 2006 Jul 31;17(11):1215-8. PubMed.
- Gerstorf D, Bertram L, Lindenberger U, Pawelec G, Demuth I, Steinhagen-Thiessen E, Wagner GG. Editorial. Gerontology. 2016;62(3):311-5. Epub 2016 Jan 29 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.
- 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.
- 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.
- Betts MJ, 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. 2017 Dec;163:150-159. Epub 2017 Sep 22 PubMed.
- 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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Rush University Medical Center
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.
Laboratory of Neurochemistry and Behavior
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.
University College London, German Centre for Neurodegenerative Diseases
University of Magdeburg, German center for neurodeg. diseases (DZNE), ICN/UCL
Deutsches Zentrum für Neurodegenerative Erkrankungen
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.
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.
Liu KY, Acosta-Cabronero J, Cardenas-Blanco A, Loane C, Berry AJ, Betts MJ, Kievit RA, Henson RN, Düzel E, Cam-CAN, Howard R, Hämmerer D. In vivo visualization of age-related differences in the locus coeruleus. Neurobiol Aging. 2019 Feb;74:101-111. Epub 2018 Oct 20 PubMed. Correction.
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.
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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.
Watanabe T, Wang X, Tan Z, Frahm J. Magnetic resonance imaging of brain cell water. Sci Rep. 2019 Mar 25;9(1):5084. PubMed.
Watanabe T, Wang X, Tan Z, Frahm J. Magnetic resonance imaging of brain cell water. Sci Rep. 2019 Mar 25;9(1):5084. PubMed.
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