Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events

Hämmerer, Dorothea; Callaghan, Martina F.; Hopkins, Alexandra; Kosciessa, Julian Q.; Betts, Matthew J.; Cárdenas-Blanco, Arturo; Kanowski, Martin; Weiskopf, Nikolaus; Dayan, Peter; Dolan, Raymond J.; Düzel, Emrah

doi:10.1073/pnas.1712268115

Cited by 131 publications

(155 citation statements)

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“…Animal and post-mortem human studies suggest a link between memory performance in aging and the integrity of the central noradrenergic system 7,10 . So far, in vivo research on humans, however, has been stymied by methodological difficulties in the reliable assessment of LC integrity 26,40,41 (but see Hämmerer and colleagues 11 ). Here, we took advantage of the paramagnetic properties of neuromelanin, a byproduct of NE synthesis, in T 1 -weighted MRI to image the LC in vivo 46,48 .…”

Section: Discussionmentioning

confidence: 99%

“…However, direct in vivo evidence relating LC integrity to interindividual differences in general memory abilities is scarce. While there is an initial indication of a selective role of LC integrity, as indexed magnetic resonance imaging (MRI; see below), in the encoding of negative emotional events 11 , the relation of LC integrity to memory performance in general is still an open question. Given LC's pivotal role in age-related memory disorders like Alzheimer's disease 8,9,12 , this relationship, however, is of high clinical and scientific importance.…”

Section: Introductionmentioning

confidence: 99%

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

Dahl

Mather

Düzel

et al. 2018

Preprint

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For decades, the search for drivers of memory decline in human cognitive aging 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 non-invasive monitoring of LC integrity have hindered the study of LC-cognition associations in humans so far. 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 large samples of younger (n = 66), and older adults (n = 233). Moreover, we observed spatially confined and functionally relevant age differences in rostral LC. Older adults who showed 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 human aging and extend our knowledge about the role of the LC norepinephrine system in senescent decline in human cognition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Dahl

Mather

Düzel

et al. 2018

Preprint

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“…Neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) can detect NM, a by‐product of noradrenaline metabolism, in the LC in vivo . Using NM‐MRI, recent studies have reported that LC integrity in old age is selectively related to memory and that LC signal intensity is associated with verbal intelligence in older adults . The neuromelanin of LC is significantly lower in MCI and Alzheimer's disease (AD) patients, compared with healthy controls .…”

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confidence: 99%

Mild cognitive impairment in de novo Parkinson's disease: A neuromelanin MRI study in locus coeruleus

Wang

et al. 2019

Movement Disorders

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Background We aimed to investigate neuromelanin‐sensitive magnetic resonance imaging (NM‐MRI) features in the locus coeruleus of de novo Parkinson's disease patients with different cognitive states and to determine whether these features are associated with cognitive impairment. Methods Three groups of subjects were recruited in this study, including patients with de novo PD with mild cognitive impairment (n = 23), patients with de novo PD without cognitive impairment (n = 48), and control subjects (n = 32). All subjects underwent clinical evaluations, as well as MRI scanning. The contrast‐to‐noise ratio of the locus coeruleus in the neuromelanin‐sensitive MRI images and cortical thickness were measured. Results The contrast‐to‐noise ratio of the locus coeruleus in PD patients with mild cognitive impairment was significantly lower than that of controls (P = 0.016). The contrast‐to‐noise ratio of the locus coeruleus for PD patients without cognitive impairment was intermediate between that of controls and PD patients with mild cognitive impairment. Furthermore, multiple linear regression analysis showed that the contrast‐to‐noise ratio of the locus coeruleus was negatively associated with performance on the Trail Making Test B in all PD patients, controlling for age, sex, years of education, the Unified Parkinson's Disease Rating Scale motor scores from right upper limb, Geriatric Depression Rating Scales scores, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores, and cortical thickness. Conclusions Dysfunction of the locus coeruleus neurons may partly contribute to the decline in executive function in early de novo PD. In the future, the locus coeruleus‐norepinephrine system might be targeted for early‐intervention strategies in PD patients. © 2019 International Parkinson and Movement Disorder Society

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“…The contrast to noise ratio (CNR) estimated from in vivo imaging has been widely used as a marker of LC structural integrity for disease stratification, differential diagnosis (Ohtsuka et al, 2013, Takahashi et al, 2015, Ohtsuka et al, 2014, Matsuura et al, 2013), or to explain variance in cognitive performance (Clewett et al, 2018, Dahl et al, 2019, Hammerer et al, 2018). Previous 3T imaging studies typically employed 2D sequences with large slice thickness to improve the signal-to-noise ratio (SNR) and reduce the scan duration.…”

Section: Introductionmentioning

confidence: 99%

“…The application of LC CNR as an imaging biomarker in clinical studies relies on an adequate and unbiased estimation of the signal in disease groups where the neuronal loss relates to volumetric reduction (Theofilas et al, 2017). Manual segmentation is often used for extracting the LC signal, but this method relies on subjective estimations that only have fair to good intra-rater reliability (Tona et al, 2017, Hammerer et al, 2018). The manual segmentation approach becomes more unreliable when the signal-to-noise is reduced by pathological changes and when the signal is more dispersed by anisotropic resolution.…”

Section: Introductionmentioning

confidence: 99%

Anin vivoProbabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

Rua

O’Callaghan

et al. 2020

Preprint

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Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson’s disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (resolution 0.4×0.4×0.5 mm, duration seven minutes). Magnetisation transfer images from 53 healthy older volunteers (52-84 years) revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults, appropriate for clinical research. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance differences of the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset is available for researchers, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

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Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events

Cited by 131 publications

References 56 publications

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

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

Mild cognitive impairment in de novo Parkinson's disease: A neuromelanin MRI study in locus coeruleus

Anin vivoProbabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

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