In vivo assessment of the noradrenergic nucleus locus coeruleus in Alzheimer’s disease and other types of dementia

AbstractAbnormally 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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The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.045511 ◽

2020 ◽

Vol 16 (S4) ◽

Author(s):

Seraphina K. Solders ◽

Alexandra L. Clark ◽

Alexandra J. Weigand ◽

Scott F. Sorg ◽

Vitaly Galinsky ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

At Risk ◽

Locus Coeruleus ◽

In Vivo Characterization ◽

With Memory

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The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging Review

Journal of Alzheimer s Disease ◽

10.3233/jad-210191 ◽

2021 ◽

pp. 1-18

Author(s):

Rebecca Beardmore ◽

Ruihua Hou ◽

Angela Darekar ◽

Clive Holmes ◽

Delphine Boche

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Locus Coeruleus ◽

Current Knowledge ◽

Imaging Techniques ◽

Experimental Studies ◽

Disease Process ◽

Neuronal Loss

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer’s disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

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In Vivo Assessment of Retinal Biomarkers by Hyperspectral Imaging: Early Detection of Alzheimer’s Disease

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00331 ◽

2019 ◽

Vol 10 (11) ◽

pp. 4492-4501 ◽

Cited By ~ 8

Author(s):

Swati S. More ◽

James M. Beach ◽

Collin McClelland ◽

Ali Mokhtarzadeh ◽

Robert Vince

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Detection ◽

Hyperspectral Imaging ◽

In Vivo Assessment

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P1-311: In Vivo Assessment of Hippocampal Subfield Metabolism, Perfusion and Diffusion Changes in MCI and Alzheimer's Disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.1061 ◽

2016 ◽

Vol 12 ◽

pp. P541-P542

Author(s):

Maged Goubran ◽

Audrey Fan ◽

Praveen Gualaka ◽

David Douglas ◽

Steven Chao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

And Diffusion ◽

In Vivo Assessment

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In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline

Science Translational Medicine ◽

10.1126/scitranslmed.abj2511 ◽

2021 ◽

Vol 13 (612) ◽

Author(s):

Heidi I. L. Jacobs ◽

John A. Becker ◽

Kenneth Kwong ◽

Nina Engels-Domínguez ◽

Prokopis C. Prokopiou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Locus Coeruleus ◽

Data Support

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Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer’s disease plasma biomarkers: a 7T MRI study

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00902-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Maxime Van Egroo ◽

Roy W. E. van Hooren ◽

Heidi I. L. Jacobs

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Locus Coeruleus ◽

Structural Integrity ◽

Critical Role ◽

7 Tesla ◽

Older Individuals ◽

Plasma Biomarkers ◽

Total Tau

Abstract Background The brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer’s disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals. Methods Seventy-two cognitively unimpaired older individuals aged 50–85 years (mean age = 65.2 ± 8.2 years, 37 women, 21 APOE ε4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau181, Aβ40, and Aβ42 were measured using single-molecule array technology. Results Intensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t70 = −5.12, p < 0.0001). After correction for age, sex, depression, and APOE status, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F1,63 = 6.73, pFDR = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F1,61 = 4.26, p = 0.04). Conclusion Our findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions.

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