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.

Keywords: Aging; Alzheimer’s disease; human; locus coeruleus; magnetic resonance imaging; neuromelanin.

Fig. 1

Schematic of noradrenaline synthesis in the locus coeruleus. Phenylalanine is converted to tyrosine (Tyr) by phenylalanine hydroxylase (PAH). This is then converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase (TH) which is in turn converted to dopamine (DA) by the enzyme dopamine decarboxylase (DDC). Dopamine is taken up into storage vesicles, some of which contain dopamine beta-hydroxylase (DBH) which converts dopamine to noradrenaline (NA). Noradrenaline is either taken back up to the synapse by noradrenaline transporter (NET) or degraded by monoamine oxidase (MAO). Excess cytosolic dopamine and noradrenaline is oxidized by iron catalysts into dopaquinones which are stored as neuromelanin contained within autophagic organelles.

Fig. 2

Hematoxylin and eosin staining of 6μm thick axial sections of pons to show locus coeruleus cells (denoted by ^*) of A) 87-year-old female with Alzheimer’s disease diagnosis at death, Braak stage 6 compared to control brain of B) 86-year-old female, Braak stage I. Far fewer LC cells are observed in A. Brown pigmented neuromelanin granules can be seen (blue arrows). Scale bar A, B = 500μm, scale bar a, b = 200μm.

Fig. 3

NM-MR axial image of a 69 year old female with no cognitive impairment obtained on 3Tesla Siemens Skyra MRI scanner at the level approximately 7mm below the inferior colliculi, in which the LC can be observed as two hyperintense areas (red arrows) [184].

Fig. 4

MR image to show how locus coeruleus (LC) signal intensity (SI) is typically calculated as a contrast ratio using the pons tegmentum as a reference are (blue circle). Regions of Interest are placed around the LC (green circles). The average SI of the mean right LC and mean left LC (LCSI) minus the mean signal of the pons tegmentum (SIPT) divided by the signal intensity of the pons tegmentum: (LCSI –SIPT)/SIPT provides the contrast ratio.