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

Abstract

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.

Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks

“…These organize in small nuclei, and although most of them cannot be segmented by MRI (in our case we only considered the LC and Raphe nuclei), our model predicts they all are potentially highly relevant at connectivity level. Noradrenergic LC neurons establish connections that span the whole brain 27 , and both LC and trigeminal nuclei contribute to pathologies such as Alzheimer when are degenerated [28][29][30] .…”

Locus Coeruleus magnetic resonance imaging: a comparison between native-space and template-space approach

“…In the last decade, several studies have addressed the potential involvement of LC in the pathogenesis of neurodegenerative disorders (Gesi et al 2000 ; Kelly et al 2017 ). In particular, the development of MRI-based approaches aimed to visualize LC has allowed evaluating its integrity in vivo (see the reviews by Galgani et al 2020 ; Beardmore et al 2021 ). LC Magnetic Resonance Imaging (LC-MRI) has been already used to explore LC involvement in healthy aging (Dahl et al 2019 ; Liu et al 2020 ; Giorgi et al 2021 ), Alzheimer’s Disease (Betts et al 2019a ; Jacobs et al 2021 ), Parkinson’s Disease (Sommerauer et al 2018 ; Li et al 2019 ) and other pathological conditions (reviewed in Galgani et al 2020 ).…”

Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study

“…Norepinephrine dysfunction is common in MDD at any age ( Anand and Charney, 2000 , Cottingham and Wang, 2012 ) and is associated with deficits in cognitive flexibility, attention and memory ( Chamberlain and Robbins, 2013 ). The LC is among the first regions to show neuronal degeneration as a function of normal aging, and LC pathology is evident in several neurodegenerative conditions marked by cognitive impairment, including Alzheimer’s disease ( Beardmore et al, 2021 ). Additional postmortem studies, albeit in very small samples, suggest that age-dependent degenerative processes in the LC may be accelerated or accentuated in older individuals with chronic depression, even in the absence of dementia ( Chan-Palay and Asan, 1989 ).…”