An in vivo 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:10.1016/j.neuroimage.2020.117487

Cited by 63 publications

(108 citation statements)

References 67 publications

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Section: Methodsmentioning

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 and Ye 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: Methodsmentioning

confidence: 99%

“…That is, they report disease-related differences in MR-indexed LC integrity (Dordevic et al, 2017; Takahashi et al, 2015) without exploring potential topographical patterns therein, precluding direct comparisons (but see Betts, Cardenas-Blanco, et al, 2019). 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 %; cf.…”

Section: Introductionmentioning

confidence: 99%

“…However, estimates of locus coeruleus’ dimensions and localizations show a sizeable variance across publications (range of agreement: 48–94 %; 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. Second, we aimed at determining whether MR-indexed LC integrity can serve as marker for noradrenergic degeneration in early-onset Alzheimer’s disease.…”

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

David

Malhotra

2022

Ann Clin Transl Neurol

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There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

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The role of the arousal system in age‐related differences in cortical functional network architecture

Guardia

Geerligs

Tsvetanov

et al. 2021

Human Brain Mapping

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A common finding in the aging literature is that of the brain's decreased within‐ and increased between‐network functional connectivity. However, it remains unclear what is causing this shift in network organization with age. Given the essential role of the ascending arousal system (ARAS) in cortical activation and previous findings of disrupted ARAS functioning with age, it is possible that age differences in ARAS functioning contribute to disrupted cortical connectivity. We test this possibility here using resting state fMRI data from over 500 individuals across the lifespan from the Cambridge Center for Aging and Neuroscience (Cam‐CAN) population‐based cohort. Our results show that ARAS‐cortical connectivity declines with age and, consistent with our expectations, significantly mediates some age‐related differences in connectivity within and between association networks (specifically, within the default mode and between the default mode and salience networks). Additionally, connectivity between the ARAS and association networks predicted cognitive performance across several tasks over and above the effects of age and connectivity within the cortical networks themselves. These findings suggest that age differences in cortical connectivity may be driven, at least in part, by altered arousal signals from the brainstem and that ARAS–cortical connectivity relates to cognitive performance with age.

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An in vivo probabilistic atlas of the human locus coeruleus at ultra-high field

Cited by 63 publications

References 67 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

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

The role of the arousal system in age‐related differences in cortical functional network architecture

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