An<i>in vivo</i>Probabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

Ye, Rong; Rua, Catarina; O’Callaghan, Claire; Jones, P. Simon; Hezemans, Frank H.; Kaalund, Sanne S; Tsvetanov, Kamen A.; Rodgers, Christopher T.; Williams, Guy B.; Passamonti, Luca; Rowe, James B.

doi:10.1101/2020.02.03.932087

Cited by 22 publications

(26 citation statements)

References 65 publications

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Section: Aggregating Across Published Locus Coeruleus Maps To Derive mentioning

confidence: 99%

“…Previous mapping studies used a variety of LC-sensitive MRI sequences (Turbo Spin Echo [TSE; Dahl et al, 2019;Keren et al, 2009;Tona et al, 2017]; Magnetization Transfer [MT;Liu et al, 2019;Ye et al, 2020]; Fast Low Angle Shot [FLASH;Betts et al, 2017]) at different field strength (7 Tesla: Ye et al, 2020;3 Tesla: all other studies) to visualize the nucleus. Most investigations were conducted across younger and older adults or even within lifespan samples (but see Tona et al, 2017 andYe et al, 2020 for studies in younger and older adults, respectively). After data collection, individual brainstem scans were transformed into a group or standard space in which a manual (Betts et al, 2017;Liu et al, 2019;Tona et al, 2017) or semi-automatic (Dahl et al, 2019;Keren et al, 2009;Ye et al, 2020) approach was taken to segment the LC from surrounding tissue.…”

Section: Aggregating Across Published Locus Coeruleus Maps To Derive mentioning

confidence: 99%

“…Investigations in healthy participants successfully applied LC MRI to map the spatial extent of the central noradrenergic nucleus in standard space (Betts et al, 2017;Dahl et al, 2019;Keren et al, 2009;Liu et al, 2019;Tona et al, 2017;Ye et al, 2020), paving the way for topographical cross-study comparisons. However, estimates of locus coeruleus' dimensions and localizations show a sizeable variance across publications (range of agreement: 48-94 %;…”

Section: Introductionmentioning

confidence: 99%

“…cf. Dahl et al, 2019;Liu et al, 2019;Ye et al, 2020; or even 1-40 % using a different methodology, Mäki-Marttunen & Espeseth, 2020). Such lack of consensus considerably limits the replicability of findings and impedes scientific progress.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the present study pursued two main goals: First, we aimed at improving the reliability and validity of MR-based LC detection. Leveraging a meta-analytical approach, we aggregated across previously published maps of the LC (Betts et al, 2017;Dahl et al, 2019;Keren et al, 2009;Liu et al, 2019;Tona et al, 2017;Ye et al, 2020) to derive a biologically plausible volume of interest (meta mask) that shows high agreement across investigations.…”

Section: Introductionmentioning

confidence: 99%

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Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Dahl

Mather

Werkle‐Bergner

et al. 2020

Preprint

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Abnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

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Section: Aggregating Across Published Locus Coeruleus Maps To Derive mentioning

confidence: 99%

Section: Aggregating Across Published Locus Coeruleus Maps To Derive mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Dahl

Mather

Werkle‐Bergner

et al. 2020

Preprint

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Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson’s disease using neuromelanin-sensitive MRI

Dünnwald

Ernst²,

Düzel

et al. 2021

Int J CARS

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Purpose Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Methods We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson’s disease subjects. Results The localization and segmentation pipeline demonstrated sufficient performance as measured by Euclidean distance (on average around 1.3mm on healthy aging subjects and 2.2mm in Parkinson’s disease subjects) and Dice similarity coefficient (overall around $$71\%$$ 71 % on healthy aging subjects and $$60\%$$ 60 % for subjects with Parkinson’s disease) as well as promising agreement with respect to contrast ratios in terms of intraclass correlation coefficient of $$\ge 0.80$$ ≥ 0.80 for healthy aging subjects compared to a manual segmentation procedure. Lower values ($$\ge 0.48$$ ≥ 0.48 ) for Parkinson’s disease subjects indicate the need for further investigation and tests before the application to clinical samples. Conclusion These promising results suggest the usability of the proposed algorithm for data of healthy aging subjects and pave the way for further investigations using this approach on different clinical datasets to validate its practical usability more conclusively.

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Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science

et al. 2021

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Aim In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. Methods To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. Results We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. Conclusion In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a “virtuous cycle,” leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.

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

Cited by 22 publications

References 65 publications

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson’s disease using neuromelanin-sensitive MRI

Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science

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