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Neuroscience and Biobehavioral Reviews 152 (2023) 105311
Available online 11 July 2023
0149-7634/© 2023 Published by Elsevier Ltd.
Noradrenergic neuromodulation in ageing and disease
F. Krohn
a
,
b
,
1
,
2
, E. Lancini
a
,
b
,
*
,
1
,
2
, M. Ludwig
b
,
d
,
2
, M. Leiman
a
,
b
,
2
, G. Guruprasath
a
,
b
,
2
,
L. Haag
b
,
2
, J. Panczyszyn
b
,
2
, E. Düzel
a
,
b
,
c
,
d
,
2
,
3
, D. H¨
ammerer
a
,
b
,
c
,
d
,
e
,
4
, M. Betts
a
,
b
,
d
,
2
a
German Center for Neurodegenerative Diseases (DZNE), Otto-von-Guericke University Magdeburg, Magdeburg, Germany
b
Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University Magdeburg, Magdeburg, Germany
c
Institute of Cognitive Neuroscience, University College London, London UK-WC1E 6BT, UK
d
CBBS Center for Behavioral Brain Sciences, University of Magdeburg, Magdeburg, Germany
e
Department of Psychology, University of Innsbruck, A-6020 Innsbruck, Austria
ARTICLE INFO
Keywords:
Noradrenaline
Noradrenergic neuromodulation
Locus coeruleus
ABSTRACT
The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of
noradrenaline (NA) in the brain. Via its phasic and tonic ring, it modulates cognition and autonomic functions
and is involved in the brain’s immune response. The extent of degeneration to the LC in healthy ageing remains
unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer’s (AD) and Par-
kinson’s disease (PD). Despite their differences in progression at later disease stages, the early involvement of the
LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric
symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie
LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration
of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant
to other neurodegenerative diseases.
1. Introduction
The locus coeruleus (LC), Latin for ’blue spot’, is a brainstem nucleus
rst described in 1786 by F´
elix Vicq-d’Azyr (Vicq-d’Azyr, 1786). Despite
its small size, the LC projects to and receives input from widespread
brain regions (Liebe et al., 2022; Szabadi, 2013) and is thus involved in
numerous functions related to cognition such as memory formation
(Amaral and Foss, 1975; Gibbs et al., 2010; Hansen, 2017; Kety, 1972;
Zornetzer and Gold, 1976), attention, sensory processing (Bouret and
Sara, 2002; Lecas, 2004), novelty (Vankov et al., 1995; Yamasaki and
Takeuchi, 2017) and emotional memory (H¨
ammerer et al., 2018). It is
involved in autonomic functions such as blood pressure (Sved and
Felsten, 1987), immune function (Lehnert et al., 1998; Rassnick et al.,
1994) and the sleep-wake cycle (for a review see Osorio-Forero et al.,
2022). Furthermore, it is involved in the ght or ight response by
modulating heart rate, blood pressure, salivation and pupil dilation
(Ross and Van Bockstaele, 2021; Samuels and Szabadi, 2008). Alter-
ations to the noradrenergic system occur as a result of degeneration, that
therefore may impair these functions. Indeed, in humans, the LC has
recently become increasingly relevant in healthy aging because several
cognitive functions supported by the noradrenergic system, such as
verbal intelligence (Clewett et al., 2016), response inhibition (Liu et al.,
2020; Tomassini et al., 2022), memory (Calarco et al., 2022; Dahl et al.,
2019; Langley et al., 2022; Liu et al., 2020), emotional memory
(H¨
ammerer et al., 2018; Sterpenich et al., 2006), attention and pro-
cessing speed (Calarco et al., 2022) decline in older age (Harada et al.,
2013).
In addition to ageing, degeneration and dysfunction of the LC
noradrenergic system (LC-NA) also occurs during the rst stages of
Alzheimer´s (AD) and Parkinson´s (PD) disease and may contribute to the
* Correspondence to: Institute of Cognitive Neurology and Dementia Research Otto-von-Guericke University IKND (Haus 64), Leipziger Str. 44, 39120 Magdeburg,
Germany.
E-mail address: elisa.lancini@dzne.de (E. Lancini).
1
Authors contributed equally to this work
2
Leipziger Str. 44/Haus 64, 39120 Magdeburg (Germany)
3
Leipziger Str. 44/Haus 64, 39120 Magdeburg (Germany), Institute of Cognitive Neuroscience, University College London, London, UK-WC1E 6BT, UK
4
Leipziger Str. 44/Haus 64, 39120 Magdeburg (Germany)
,
University College London, London, UK-WC1E 6BT, UK 3, Universit¨
atsstrasse 5–7, 6020 Innsbruck,
Austria
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
https://doi.org/10.1016/j.neubiorev.2023.105311
Received 29 April 2023; Received in revised form 29 June 2023; Accepted 7 July 2023
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
2
spread of pathology (see Section 4.). There is signicant loss in LC vol-
ume and MRI contrast in both AD and PD (Betts et al., 2019a; Jacobs
et al., 2021a; Madelung et al., 2022; Theolas et al., 2017; Zarow et al.,
2003). The LC-NA system is mainly linked to AD pathology through its
metabolites, whose levels increased and interact with tau and
amyloid-beta (Aß) pathology: a recent review and meta-analysis found
elevated cerebrospinal uid (CSF) MHPG levels in AD compared to
healthy controls, while noradrenaline (NA) levels were unchanged
(Lancini et al., 2023). Moreover, as the noradrenergic metabolite 3,
4-Dihydroxyphenyl Glycolaldehyde (DOPEGAL) interacts with tau, NA
has been suggested to indirectly accelerate the progression of AD disease
(Kang et al., 2022). In PD, the LC also shows structural degeneration
early in the disease, which might be linked to non-motor symptoms that
occur prior to substantia nigra (SN) degeneration such as anxiety (Lapiz
et al., 2001), depression (Remy et al., 2005) and REM sleep disturbances
(Ehrminger et al., 2016; García-Lorenzo et al., 2013).
Finally, given the link between LC integrity and symptoms of
neurodegenerative diseases and ageing, the LC presents as a natural
target for therapeutic interventions to ameliorate those symptoms. And
indeed, different therapeutic interventions, that increase noradrenergic
levels, have successfully been used to improve cognition in individuals
with PD and in individuals with mild cognitive impairment (MCI) and
AD.
In this review, we summarise the involvement of the LC-NA system in
healthy aging and in neurodegenerative disease. The aim of this review
is to summarise the latest research ndings and encourage further
research on the involvement of the noradrenergic system in both healthy
aging and in the aetiology of AD and PD.
2. The noradrenergic system
The LC is the main source of NA in the brain. The LC’s azure look
stems from high levels of neuromelanin (NM), a byproduct of NA syn-
thesis and NA metabolism that binds metal ions (Zucca et al., 2006) Due
to its exposed location next to the 4th ventricle, the LC is more vulner-
able to inammatory molecules and toxins (for a review see Evans et al.,
2022; Matchett et al., 2021). Moreover, LC axons are partially myelin-
ated therefore less cost-efcient, resulting in higher energy consump-
tion, which in turn leads to higher levels of highly reactive oxygen
species (ROS) (Lushchak et al., 2021). Thus, the LC is more vulnerable to
the effects of ROS (for a review see Evans et al., 2022).
The LC receives afferent connections from the neocortex (Cedarbaum
and Aghajanian, 1978; Luppi et al., 1995), prefrontal cortex (PFC)
(Arnsten and Goldman-Rakic, 1984; Sesack et al., 1989), amygdala
(Cedarbaum and Aghajanian, 1978; Charney et al., 1998), and ventral
tegmental area (VTA) (Deutch et al., 1986) among other structures.
Efferent projections have been grouped into three major noradren-
ergic pathways: 1) the cortical (or ascendant) pathway (Szabadi,
2013), which includes projections to the ventral tegmental area (VTA)
(Alvarado et al., 2023; Mejias-Aponte, 2016), SN (Mejias-Aponte, 2016;
Rommelfanger and Weinshenker, 2007), amygdala (McCall et al., 2017;
Uematsu et al., 2017), hippocampus (Haring and Davis, 1985; Jones and
Moore, 1977; Takeuchi et al., 2016), hypothalamus (Giorgi et al., 2021;
Schwarz and Luo, 2015), thalamus (Beas et al., 2018; Rodenkirch et al.,
2019), basal forebrain (Espa˜
na and Berridge, 2006), PFC and sensory
cortices (McBurney-Lin et al., 2019; Schwarz and Luo, 2015; Szabadi,
2013), 2) the spinal pathway (or descendent) which includes brain-
stem nuclei such as the nervus vagi (Nosaka et al., 1982), sympathetic
premotor nuclei (Head et al., 1998; Tavares et al., 1996) and the
oculomotor nucleus (Carpenter et al., 1992) as well as various spinal
nuclei via 3) cerebellar pathways (Fu et al., 2011), where it connects to
both cerebellar cortex and nuclei (Dietrichs, 1988) and potentiates
Purkinje cell spiking (Moises et al., 1981), for a comprehensive review
on LC connections see Szabadi and colleagues (Szabadi, 2013).
Via the cortical pathways, the LC-NA system has been shown to be
involved in various cognitive processes such as memory (Clewett et al.,
2016; Takeuchi et al., 2016), attention (Dahl et al., 2019; Unsworth and
Robison, 2017) and sleep (Van Egroo et al., 2022). Via these projections,
the LC plays a crucial role in modulating the dopaminergic system.
Notably, noradrenergic terminals in cortical regions and the hippo-
campus have been found to co-release dopamine (DA), indicating a
functional overlap (Devoto et al., 2020, 2008, 2005; Kempadoo et al.,
2016; Pozzi et al., 1994; Smith and Greene, 2012; Takeuchi et al., 2016).
Moreover, the LC projects to the ventral tegmental area (VTA), a key hub
of the dopaminergic pathway, and modulates dopamine release in the
nucleus accumbens (nACC) and prefrontal cortex (PFC) (Sara, 2009).
Additionally, the LC has direct projections to the PFC, which, in turn,
sends inhibitory relay signals to the VTA. Reciprocal connections exist
between the VTA, PFC, and LC, forming a complex network that allows
for bidirectional modulation (Sara, 2009). NA modulation is also
implicated in psychiatric disorders such as PTSD (Debiec and LeDoux,
2006), depression (Brunello et al., 2002; Kobayashi et al., 2022; Remy
et al., 2005), ADHD (del Campo et al., 2011), schizophrenia (Meisenzahl
et al., 2007; Toda and Abi-Dargham, 2007), and substance use disorders
(Downs and McElligott, 2022), where alterations in noradrenaline-
dopamine signalling play a role.
The descendent pathways have been linked to sympathetic functions
such as blood pressure (Anselmo-Franci et al., 1999) and muscle tonus
(Kiyashchenko et al., 2001) while the LC cerebellar pathways remain
understudied up to date.
Signalling between LC and the projecting areas occur via NA. NA
synthesis starts with the amino acid tyrosine, which is converted into
dihydroxyphenylalanine (DOPA) and then into DA by the enzymes
tyrosine hydroxylase (TH), and DOPA decarboxylase. After its synthesis,
DA is transported into noradrenergic neurons, which contain the
enzyme dopamine β-hydroxylase (DBH), that converts DA to NA
(Molinoff and Axelrod, 1971). The synthesised NA is then stored in
presynaptic vesicles and released into the synaptic cleft where it binds to
the G-coupled adrenergic receptors (Ars) type β,
α
1, and
α
2 with
respectively intermediate, higher, and lowest afnity (Molinoff, 1984).
The effect of NA depends on the type of receptors expressed on the
postsynaptic neurons. Binding to
α
1 or β adrenergic receptors produces
stimulatory effects while binding to
α
2 adrenergic receptors produces
inhibitory effects on cell signalling (Schwarz and Luo, 2015; Szabadi,
2013).
After exerting its modulatory effect, NA is removed from the synaptic
cleft by either reuptake via NA transporters or by degradation by the
enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase
(COMT) and aldehyde reductase (AR) into several metabolites.
NA is metabolised into normetanephrine (NMN) and 3-methoxy 4
hydroxyphenylglycol aldehyde (MOPEGAL) by COMT and MAO, or into
DOPEGAL, 3,4-dihydroxyphenylglycol (DHPG) and subsequently 3-
Methoxy-4-hydroxyphenylglycol (MHPG) by MAO, AR and COMT.
MHPG, considered as the major metabolite of NA in the brain (Schan-
berg et al., 1968), is further converted to MOPEGAL via alcohol dehy-
drogenase (ADH), and into vanillylmandelic acid through aldehyde
dehydrogenase (Eisenhofer et al., 2004; Kamal and Lappin, 2022;
Molinoff and Axelrod, 1971).
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
3
2.1. LC ring modalities
The LC has two ring modes: tonic (persistent) and phasic (short
bursts). Animal studies suggest that electric LC stimulation in rats leads
to higher NA release when the neurons are stimulated by phasic rather
than tonic stimulation (e.g., Florin-Lechner et al., 1996). By shifting the
balance between these two ring modes (Berridge and Waterhouse,
2003), the LC modulates arousal levels (Aston-Jones and Cohen, 2005;
Chen and Sara, 2007, see Section 2) and supports memory encoding
(Klukowski and Harley, 1994; Mather et al., 2016; Sara, 2015, 2009, see
Section 2). Thalamic alpha wave strength, which has been linked to
cortical inhibition and desynchronization as well as selective attention
(Jensen and Mazaheri, 2010), have also been linked to shifts between
phasic and tonic ring (McCormick, 1989).
Thus, the LC might facilitate information processing overall
(Rodenkirch et al., 2019) and in particular the processing of
high-priority stimuli over less-prioritised stimuli (Mather et al., 2016).
Although differences in LC ring have not yet been systematically
analysed in healthy aging and disease, a disturbance, such as increased
noradrenergic levels during the early stages of AD (Palmer et al., 1987)
and a decline in LC connectivity in healthy aging (Langley et al., 2022),
may impair the ability of the LC to modulate downstream targets and
functions such as corticothalamic waves and vice versa: As reviewed by
Chalermpalanupp and colleagues (Chalermpalanupap et al., 2017), re-
sults from a tau pathology rat mouse model suggested that increasing
noradrenergic levels later in the disease might alleviate tau-mediated
pathology.
2.2. Role in neuroinammation and neurovascular system
The locus coeruleus-noradrenergic (LC-NA) system plays a major
role in modulating neuroinammation (Evans et al., 2022) and the
neurovascular system (Giorgi et al., 2020).
NA released by LC neurons play a role in the inammatory responses
through adrenergic receptors (Feinstein et al., 2002) as it can regulate
the expression of proinammatory cytokines (Flierl et al., 2009; Li et al.,
2015), but it can also increase the peripheral inammatory response
(Grisanti et al., 2010; Kavelaars et al., 1997; Spengler et al., 1990). NA
also regulates the activity of T cells and microglia (Kahn et al., 1985;
O’Neill and Harkin, 2018; Tanaka et al., 2002).
LC-lesioned animal models show neuronal damage, increased
microglia and inammatory response (Bharani et al., 2017; Song et al.,
2019a, 2019b) and the anti-inammatory effects of LC-NA system play
also a role in neurodegenerative diseases: direct stimulation of the
LC-NA system via vagus nerve stimulation (VNS) reduced both inam-
matory activation and a-synuclein accumulation in LC-lesioned rats
(Farrand et al., 2017) and In the presence of amyloid pathology, lower
NA levels in the LC target areas might impair the microglia in those
areas, therefore precluding amyloid to be cleared or surrounded by it
(Heneka et al., 2010). Therefore, NA can be an endogenous
anti-inammatory agent (Feinstein et al., 2002) and a loss in LC neurons
and consequent alterations of NA signalling could further exacerbate the
inammatory component of AD (Kelly et al., 2019) and PD (Qin et al.,
2007). This modulation helps maintain a balanced immune environment
in the brain. Moreover, it inuences the cerebral blood ow (CBF) via
the modulation of the neurovascular unit (NVU), a group of cells that are
involved in the mechanism of coupling between energy demand and
cerebral blood ow (Iadecola, 2017): in the neurovascular system,
LC-NA induces vasoconstriction, resulting in a global reduction of ce-
rebral blood ow (CBF) and redistribution of blood primarily to acti-
vated brain regions (Bekar et al., 2012).
Furthermore, the LC-NA plays a signicant role in maintaining the
homeostasis of the blood-brain barrier (BBB) (Erd˝
o et al., 2017) as it
controls the expression of tight junctions (TJs) (Kalinin et al., 2006) and
consequently the permeability of the BBB to water and solutes (Thomsen
et al., 2017).
3. Cognitive functions
Recently, several reviews on noradrenergic involvement in cognitive
function have been published, most notably a review by Gina Poe and
colleagues providing a comprehensive overview of LC embryonal
development, anatomy and function (Poe et al., 2020). Here we provide
a brief overview of recent reviews on LC function and cognition The LC
is tightly linked to sleep architecture: Decreases in LC activity (Foote
et al., 1980) and noradrenergic levels (Kalen et al., 1989) are linked to
the transition from wakefulness to sleep where the LC is virtually silent
during REM sleep (Foote et al., 1980). Similarly, increases in LC activity
precede unprovoked rousing from sleep (Aston-Jones and Bloom, 1981).
Increasing noradrenergic levels pharmacologically shortens REM sleep
and prolongs wakefulness across species (De Sarro et al., 1987; Spiegel
and DeVos, 1980). Interestingly, LC activity during NREM sleep has also
been linked to memory consolidation and sleep spindle activity (Kjaerby
et al., 2022; Osorio-Forero et al., 2021). Several afferents to and effer-
ents from sleep promiting regions enable this tight involvement in sleep
(Lew et al., 2021; Samuels and Szabadi, 2008; Saper and Fuller, 2017).
For comprehensive reviews on the topic see Van Egroo et al. (2022) and
Osorio-Forero et al. (2021).
Through its links to the entire neocortex (Szabadi, 2013), the LC has
been tightly linked to arousal and attention. As described by the GANE
model, the LC is capable of increasing the neuronal activity required for
the processing of currently prioritized stimuli while suppressing
neuronal activity of other brain regions (Mather et al., 2016). The
complex activity of the LC acts to coordinate adaptive neural dynamics
as recently reviewed by (Wainstein et al., 2022). Another theory on the
LC’s involvement in attentional modulation proposes that the LC mod-
ulates the magnitude of the cortical alpha wave, which is a measure for
disengagement, through a thalamic gating mechanism. This allows for
optimal sensory processing (Dahl et al., 2022). Although it has been
shown in vitro that the LC is capable of inactivating about 90% of rat
midbrain cholinergic neurons (Williams and Reiner, 1993), which also
are essential to maintaining attention (Knudsen, 2011), the behavioural
consequence of such inactivation is currently unknown. In humans,
higher connectivity between the LC and nucleus basalis of Meinert has
been linked to more dynamic global shifts in cortical functional con-
nectivity states (Taylor et al., 2022). For a concise review on the
noradrenergic-cholinergic interaction see Slater et al. (2022).
Through its dopaminergic (Kempadoo et al., 2016; Takeuchi et al.,
2016) and noradrenergic (Guo and Li, 2007; O’Malley et al., 1998)
connections to the hippocampus, the LC is shown to be crucial for
memory consolidation (Duszkiewicz et al., 2019; Pintus et al., 2018;
Takeuchi et al., 2016; Titulaer et al., 2021) and for novelty (Takeuchi
et al., 2016). It has been hypothesized that while the LC is important for
the processing and consolidation of intense, rst-time novel experiences,
the VTA is involved in semantic novelty of objects of a known category
(Duszkiewicz et al., 2019). It has also suggested that the dopaminergic
and noradrenergic system are important for rule-shifting during cogni-
tive tasks (Pajkossy et al., 2018). For a comprehensive overview over
noradrenergic projections see Szabadi (2013).
4. Noradrenergic dysfunction in healthy ageing
From an early age on, the LC accumulates tau (Harley et al., 2021)
Mounting evidence has shown that high LC “integrity” correlates well
with cognitive performance in older age (Bachman et al., 2021; Dahl
et al., 2020; Parent et al., 2022), which is not surprising giving its vast
cortical connections (Szabadi, 2013), its crucial role in cognition (Poe
et al., 2020), and it its protective role against neuroinammation (Giorgi
et al., 2020; McNamee et al., 2010).
4.1. Age-related differences in functional and structural LC connectivity
The functional and structural connectivity of the NA system in aging
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
4
and AD has recently gained more interest as a means for understanding
the role of the LC-NA system in aging and age-related cognitive decline.
Liebe and colleagues (Liebe et al., 2022) investigated both the
structural and functional connectivity of the LC using 7 T MRI and found
that brain areas with higher structural connection to the LC also showed
increased resting state functional connectivity to the LC. These include
the thalamus, ventral diencephalon, basal ganglia, motor cortex, cere-
bellum, amygdala, nucleus accumbens, and temporal brain areas
including the EC, presubiculum, and hippocampus (Liebe et al., 2022).
However, this link diminishes with age. Interestingly, connectivity also
was linked to subjective anxiety and alertness (Liebe et al., 2022).
High-resolution diffusion tensor imaging-based tractography (DTI)
showed that compared to younger adults, older adults showed reduced
integrity of the central tegmental tract (CTT), which branches into the
thalamus and rostral LC (Langley et al., 2022). Reduced integrity of the
CTT also correlated with verbal memory delayed recall scores, measured
by Rey- Auditory Verbal Learning Test (RAVLT). Porat and colleagues
(Porat et al., 2022) also found decreased FA in the ascending norad-
renergic bundle in older adults compared to younger adults (Porat et al.,
2022). It should be emphasised that both studies found an increase in LC
FA in older compared with younger adults (Langley et al., 2022; Porat
et al., 2022). These results suggest that the integrity of the LC and its
projections measured using DTI, are independently affected by ageing.
Cross-sectional differences in high-resolution resting state functional
connectivity (rfMRI) in a cohort of 19–74 years of age followed a
nonlinear correlation between left LC and most areas of frontal, tem-
poral, parietal regions and the nucleus basalis of Meyner (MBN) (Jacobs
et al., 2018): they showed an increase in connectivity until 25 years of
age followed by a continuous decrease until 60 years of age and a sub-
sequent increase at old ages (Jacobs et al., 2018). In contrast to this,
Song and colleagues (Song et al., 2021) showed an inverted U-shape
functional connectivity between the LC and visual, sensory and auditory
cortices and a U-shape correlation to frontal areas. The differences may
be explicable by a 10x larger sample size used in the Song study.
Moreover, it was shown that cross-sectionally, older adults showed
stronger functional connectivity between LC and visual processing re-
gions (Lee et al., 2020). Additionally, cross-sectionally, in older adults,
there is a decrease in LC-frontoparietal functional connectivity (Lee
et al., 2018) and a decrease in functional connectivity between the LC
and areas linked to the salience network (Lee et al., 2020) while the
functional activity between the salience and the frontoparietal network
increases (Lee et al., 2020). However, no differences in
LC-parahippocampal functional connectivity were found (Lee et al.,
2018). These results suggest that in older adults attentional selectivity,
which relies on frontoparietal regions is reduced, while stimuli
perception is intact.
It remains to be determined whether these differences underlie dif-
ferences in LC MRI signal, driven in part by age-related differences in LC
NM (Keren et al., 2015), and not accounting for additional physiological
measures, such as the extent of tau pathology or differential imaging
techniques and parameters across studies (Liu et al., 2017).
4.2. The role of tau and amyloid on LC function
Tau is a small soluble protein with a exible structure that helps with
microtubule stabilisation (Avila et al., 2016). Accumulation of misfolded
tau tangles, one hallmark feature of AD pathology, may occur in the LC
already at an early stage in life.
As reviewed by Harley and colleagues (Harley et al., 2021), even at
adolescence, most brains have pre-tangles, a precursor to tau tangles, in
the LC, that might spread to other regions such as the transentorhinal
(TEC) and/or entorhinal cortices (EC) (Harley et al., 2021). These
AT8-positive, misfolded pre-tangle tau seeds spreading from the LC
might be the origin of tau pathology in AD (Braak et al., 2011; Stratmann
et al., 2016).
This has also been shown in animals, where tau pathology in AD mice
models spread from LC to the forebrain and other regions affected by tau
pathology early in human AD thus potentially recapitulating tau human
pathology spread (Kang et al., 2019). However, another group has
theorised that tau pathology originates in the EC and then spreads to the
LC (Kaufman et al., 2018).
Memory symptoms typically appear when tau tangles reach the
hippocampus, temporal insular and association cortex at Braak stage III-
IV in AD (Therriault et al., 2022), which corresponds to tau spread at
very old age in healthy ageing.
Aß plaques are the other hallmark feature of AD. At nanomolar
concentration, Aß might regulate cellular activation (Turner et al.,
2003). However, when accumulated, Aß plaques hinder normal cell
functioning and cause hyperactivity (for review see Hector and Brouil-
lette, 2021). In the absence of Aβ, episodic-memory performance is best
explained by tau burden in the areas dened by Braak staging as I-III, the
TER/EC, suggesting a link between tau and cognitive decline (Maass
et al., 2018).
In a group composed of healthy older adults, patients with MCI and
AD patients, Jacobs and colleagues (Jacobs et al., 2021a) showed a
negative correlation between LC positron emission tomography (PET)
signal intensity, a measure of LC integrity and tau deposition in the EC as
well as the medial and lateral temporal regions and medial
parietal-frontal regions. For healthy participants, this correlation
remained only in the EC. In a subset with elevated Aβ levels, LC integrity
was associated with greater tau pathology outside the temporal lobe,
extra medial-temporal lobe, lateral temporal and medial-lateral parietal
and frontal regions. The autopsy data conrmed these results as LC tau
tangle density correlated with Braak stages and in the context of
elevated Aβ burden, also with steeper retrospective memory decline,
supporting the role of LC in tau pathology progression (Jacobs et al.,
2021a).
In the context of Aβ burden, Ciampa and colleagues (Ciampa et al.,
2022) showed that higher LC catecholamine synthesis capacity,
measured with PET in older adults, was related to lower tau in the
temporal lobe.
Moreover, adjusting for Aß status, catecholamine synthesis in the LC
but not in the raphe, midbrain, and striatum, was associated with lower
rates of tau accumulation over time and with better-than-expected
memory performance adjusting for individual’s tau burden (Ciampa
et al., 2022).
Low LC catecholamine synthesis is also related to vulnerability to
affective dysregulation, measured as high neuroticism and depression,
and tau PET burden in the amygdala (Parent et al., 2022). Interestingly,
low conscientiousness and high neuroticism are indirectly related to
increased tau burden in the amygdala, via their association with low LC
catecholamine synthesis capacity (Parent et al., 2022). Therefore LC
vulnerability could be involved in affective dysregulation and
neuroticism.
These results are strong indicators for the LC and the brainstem as
among the regions of earliest tau accumulation, if not the earliest,
showing a prevalent involvement of tau in LC dysregulation.
4.3. LC integrity is linked to cognitive performance in older age
As explained in Section 1, the LC contains high levels of NM, which
permits the visualisation of the LC using NM-sensitive MRI (for a review
see Betts et al., 2019b). Normalised NM-sensitive MRI contrast values
inside the LC have become a popular method to assess the “integrity” of
the LC in vivo (Betts et al., 2019b). It has been shown that LC MRI
contrast (consistent with an increase in neuromelanin) increases up until
about 60 years of age and then decreases thereafter (Liu et al., 2019;
Zecca et al., 2004). Several studies have also now shown, LC MRI
contrast is related to cognitive function. In older participants, a positive
association has been found between LC MRI contrast and episodic
memory performance (Dahl et al., 2022; H¨
ammerer et al., 2018), as well
as a delayed memory score (RAVLT) (Dahl et al., 2019). Overall LC
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5
integrity has been linked to a cognition score composed by education,
occupational attainment and verbal IQ, which was particularly pro-
nounced in the rostral subsection, and reading intelligence score (Cle-
wett et al., 2016). In particular, the rostral subsection has also been
linked to delayed memory performance (Dahl et al., 2019) and response
inhibition (Tomassini et al., 2022) as well as attention, delayed memory
performance and processing speed (Calarco et al., 2022). In addition, LC
integrity has also been associated with cortical thickness (Bachman
et al., 2021).
In older age, signicant variability in LC integrity has been observed
(Betts et al., 2019a) and age-related differences in LC have not been
consistently observed in cognitively intact older adults in the range of
60–80 (Betts et al., 2019b, 2017; Giorgi et al., 2021).
It remains to be determined whether these differences in the MRI
signal of the LCs are due in part to age-related differences in LC neu-
romelanin (Keren et al., 2015; Zucca et al., 2006), although additional
physiological measures such as the extent of tau pathology or different
imaging techniques and parameters are not considered in the various
studies (Liu et al., 2017).
4.4. The effect on neuroinammation and neurovascular system
Ageing and age-related disorders are characterized by elevated pro-
inammatory markers (Franceschi et al., 2000), which contribute to the
progression of neuropathology. Systemic inammation further exacer-
bates this process by triggering the activation of microglia, which
inltrate the brain through the blood-brain barrier (Bettcher and
Kramer, 2014; Heneka et al., 2015; Perry, 2010; Perry et al., 2007). The
presence of pro-inammatory cytokines in older adults has been asso-
ciated with cognitive impairment, highlighting the detrimental effects of
inammation on brain function (Cunningham et al., 2009; Cunningham
and Hennessy, 2015; Franceschi and Campisi, 2014; Holmes, 2013; Qin
et al., 2007; Simen et al., 2011).
Moreover, the degeneration of noradrenergic neurons in the LC and
the natural process compromise the integrity of the blood-brain barrier
(BBB) (Kalinin et al., 2006; Luissint et al., 2012). This compromised BBB
amplies the effects of systemic inammation, allowing inammatory
substances to inltrate the brain more easily. In aged rats with LC-NA
lesions, the inammatory response is intensied, and there are notable
alterations in brain-derived neurotrophic factor (BDNF) levels, showing
the role of the LC/NA system in modulating neuroinammation (Bhar-
ani et al., 2017).
Additionally, microglial dysfunction, combined with the compro-
mised BBB (Hussain et al., 2021) and reduced tissue perfusion in aging,
plays a signicant role in impairing synaptic plasticity (Erd˝
o et al.,
2017), that is an important mechanism for memory formation which
becomes impaired in aging and neurodegenerative diseases (Blau et al.,
2012).
5. The noradrenergic system and neurodegenerative diseases
5.1. Alzheimer’s disease
AD is a neurodegenerative disease which constitutes the vast ma-
jority of the cases of dementia in the older population (Evans et al.,
2022) with a prevalence in Europe of around 1%, an incidence that is
expected to triple by 2050 (Prince et al., 2015). AD can be considered a
proteinopathy as it is dened by the presence of amyloid plaques (Braak
and Braak, 1991) and tau aggregates called neurobrillary tangles
(NFTs) (Goedert, 1993).
NA plays a complex role in the pathogenesis and progression of AD,
encompassing both protective and contributory effects. NA exerts its
protective effect by destabilising Aβ protobril, impeding their assembly
into insoluble plaques (Zou et al., 2019). Moreover, it might have a
protective effect against oxidative stress caused by amyloid, by stimu-
lating CAMP production through b-adrenergic receptors, resulting in the
activation of the nerve growth factor (NGF) or brain-derived neuro-
trophic factor (BDNF) (Counts and Mufson, 2010) and regulates
inammation through microglia modulation (Mori et al., 2002; Sugama
and Kakinuma, 2021).
However, it might also be implicated in the further progression of AD
pathology as compensatory mechanism for LC neuronal loss during
aging and AD, like changes in the receptors and increased excitability of
remaining NA neurons might be implicated in the aetiology or further
progression of Aß pathology.
NA signalling is implicated in amyloid toxic effects through
α
2-
adrenergic receptors. Amyloid activated the glycogen synthase kinase
(GSK), enzyme responsible for tau phosphorylation, by binding on an
allosteric site of
α
2-adrenergic receptor, therefore redirecting NA sig-
nalling. The activation of GSK can be facilitated by concurrent binding
of amyloid on the allosteric site and NA on the main site of the receptor.
In fact, when this happens, amyloid can exert its effect at a concentration
as low as 1% of what is typically required for amyloid to exert the effect
alone.
The increase of NA turnover and thus the production of the toxic NA
metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) (Wein-
shenker, 2018), might play an important role in tau LC-derived toxicity
(Burke et al., 1999). DOPEGAL is the product of NA metabolism by the
enzyme monoamine oxidase A (MAO-A) (see Section 1. for an overview
on NA biosynthesis). It can be considered toxic as, in contrast to NE, it
promotes tau aggregation and propagation (Kang et al., 2022, 2019) and
induces tau-mediated neuronal cell apoptosis (Burke et al., 1998). Mice
lacking DBH, the protein that converts dopamine to NA, and therefore
the ability to produce NA, showed reduced tau pathology. Models in
which the asparagine endopeptidase (AEP), which is necessary for tau
cleavage, was knocked out, showed attenuated LC neuronal degenera-
tion in the presence of DOPEGAL (Kang et al., 2020). A further link
between AD and tau, mediated by DOPEGAL has been shown in mice
and AD brain tissue. Apoe4 allele induced DOPEGAL tau-mediated
toxicity, while Apoe3 prevents it by binding tau and blocking the
cleavage into misfolded tau (Kang et al., 2021). Tau neurotoxicity has
also been shown to lead to hippocampal atrophy and cognitive decits
(Kang et al., 2021). Together these studies show that NA, but specically
its metabolite DOPEGAL, have a toxic neuronal effect, which is mediated
by tau (for a review Kang et al., 2020). DOPEGAL is then processed to
MHPG, the major NA metabolites in the brain (Burke et al., 1999), which
has been also associated with compensatory mechanisms of LC surviving
neurons and AD progression (Hoogendijk et al., 1995; Nakamura and
Sakaguchi, 1990). Higher NA turnover (MHPG:NA ratio) inversely
correlated with LC neuronal cells (Hoogendijk et al., 1995). Higher CSF
levels of MHPG were also associated with greater tau and amyloid
concentration (Riphagen et al., 2021) in the CSF and with lower cortical
thickness in mild stages of AD (van Hooren et al., 2021). Finally, the
presence of MHPG facilitates tau spreading in AD mice model (Koppel
et al., 2019) suggesting a parallel with the DOPEGAL action of neuronal
apoptosis and pathology enhancement in the presence of tau pathology.
In the presence of amyloid pathology, lower NA levels in the LC
target areas might impair the microglia in those areas, therefore pre-
cluding amyloid to be cleared or surrounded by it (Heneka et al., 2010).
Therefore, NA can be an endogenous anti-inammatory agent (Feinstein
et al., 2002) and a loss in LC neurons and consequent alterations of NA
signalling could further exacerbate the inammatory component of AD
pathology (Kelly et al., 2019).
5.2. The LC-NA system in the context of AD
The loss of LC neurons in AD occurs at early stages (Betts et al.,
2019a, 2019b; Braak and Braak, 1991), is most pronounced in the rostral
and middle LC portion (Beardmore et al., 2021; Betts et al., 2019a;
Theolas et al., 2017; Tomlinson et al., 1981) and appears to correlate
with disease duration (Zarow et al., 2003) and disease severity (Cassidy
et al., 2022; Olivieri et al., 2019). In fact, a post-mortem analysis showed
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6
a decrease in LC volume by circa 8% for every Braak stage (Theolas
et al., 2017). Reduced LC volume during AD is also supported by in vivo
studies showing reduced LC MRI contrast in AD compared to healthy
controls (Betts et al., 2019a; Cassidy et al., 2022; Li et al., 2022; Olivieri
et al., 2019).
Animal studies suggest that the NA system might interact with Aβ
pathology. Catecholamines, including NA showed a dose-dependent
inhibitory effect on the aggregation of amyloid brils potentially by
destabilising amyloid protobrils in vitro (Huong et al., 2010). In rats,
the LC might protect against amyloid pathology as lesioning of the LC
led to an increase in amyloid and inammation compared to
non-lesioned controls (Kelly et al., 2019). Conversely, decreased NA
levels might impair amyloid clearance thus further propagating amyloid
accumulation (Dobarro et al., 2013; Ni et al., 2006).
As LC integrity and NA production are affected in AD, these results
support the idea that the loss of LC/NA-mediated protection in AD may
enhance the risk of amyloid aggregation in the brain, as the anti-amyloid
aggregatory and inammatory effect of NA might be impaired due to its
reduced levels.
The NA system might also link tau and amyloid pathology in AD:
Wang and colleagues demonstrated in vitro and in an AD mouse model
that amyloid binds hyperactive alpha 2 receptors on an allosteric site
activating a tau phosphorylation cascade (Wang, 2020).
Tau pathology is related to LC integrity and functioning: lower LC
neuron count is associated with higher plasma tau levels (Murray et al.,
2022) and LC integrity is shown to be decreased in tau-positive partic-
ipants (Cassidy et al., 2022) and inversely correlated to tau in the EC in
healthy participants (Jacobs et al., 2021a). As tau induces neuronal
hyperexcitability (Crimins et al., 2012; Rudy et al., 2015), this might
also be hypothesised to be the case for LC neurons (Weinshenker, 2018),
facilitating the spread of tau through its axonal pathways, as tau is
capable of trans-synaptic propagation (Kang et al., 2022, 2019). How-
ever, Liu and colleagues (Liu et al., 2021) did not observe an increase in
LC hyperactivity in AD compared to healthy controls with respect to
uorodeoxyglucose (FDG) PET, a tracer used to image metabolic activity
(Liu et al., 2021).
Increased activity of the remaining LC neurons has also been sug-
gested by studies reporting increased NA levels in AD, hypothesising this
increased activation as the cause of increased NA production and
therefore NA levels (Raskind, 1984; Raskind et al., 1997, 1999), how-
ever, this has not been seen consistently in the literature. In fact, a recent
meta-analysis focusing on NA and MHPG data in AD found a trend to-
wards lower levels of NA in CSF markers and signicantly increased
MHPG CSF markers in participants with AD dementia compared to
healthy controls (Lancini et al., 2023).
The discrepancies between studies on NA levels in participants with
AD may have several causes, such as the use of different diagnosis
criteria, methods of severity calculation, as well as small sample sizes
that may limit statistical power. Furthermore, although the meta-
analysis did not detect any differences between studies caused by con-
founding variables, inter- and intra-laboratory differences may have
played a role: differences in sample storage, handling and equipment
could have inuenced the results, despite the use of similar or identical
protocols.
As discussed by Lancini and colleagues (Lancini et al., 2023), in the
presence of amyloid and tau, NA metabolite MHPG seems to be a more
sensitive measure of AD symptoms characterisation, therefore altered
metabolism, more than production might play a substantial role in AD.
Higher CSF levels of MHPG, are associated with higher levels of p-tau
(Jacobs et al., 2021b; Riphagen et al., 2021) and higher amyloid-β 42
under high levels of inammation in CSF (Riphagen et al., 2021) and
lower cortical thickness in mild stages of AD (van Hooren et al., 2021) in
humans. Additionally, a structural equation model (SEM) analysis
showed a strong link between neuropsychiatric symptoms and MHPG
and p-tau, suggesting that noradrenergic dysfunction is coupled to AD
pathology and clinical symptoms (Jacobs et al., 2021b). Also, the
increase in the noradrenergic metabolite DOPEGAL has been shown to
promote tau aggregation and propagation in mice models (Kang et al.,
2022, 2019) and to induce tau-mediated neuronal cell apoptosis in AD
postmortem human brain tissue (Burke et al., 1999, 1998, 1997).
5.3. LC neurodegeneration and AD symptoms
In line with accumulating evidence of NA being intricately linked
with AD pathology, links between an LC-NA system and cognitive and
clinical symptoms of AD dementia are increasingly reported. General
cognition as measured by the Mini-Mental State Examination (MMSE)
and Montreal Cognitive Assessment (MoCA) and memory performance
has been shown to be positively correlated to LC integrity (Li et al.,
2022) and CSF noradrenergic levels (Elrod et al., 1997). Also, CSF MHPG
is correlated to memory decits in participants with Subjective cognitive
decline (SCD), MCI and AD (Jacobs et al., 2021b).
LC neuronal loss results in the dysregulation of circadian rhythms
early in the disease process (Van Egroo et al., 2019) and in fact sleep
impairment is another symptom that occurs early in AD and can also
precede cognitive symptoms (Ehrenberg et al., 2018; for a review see
Van Egroo et al., 2022). Critically, as studies in animal models showed
an intact sleep architecture is required to clear neurotoxic waste prod-
ucts from the brain, such as Aß (Xie et al., 2013), and that sleep loss
affected tau (Barth´
elemy et al., 2020), sleep disruption might accelerate
the propagation of AD pathology starting a vicious cycle (Tekieh et al.,
2022).
5.4. The effect on neuroinammation and neurovascular system
In AD, degeneration to the LC-NA may lead to the breakdown of the
blood-brain barrier (BBB) and microglia activation, impairing amyloid
clearance, exacerbating amyloid accumulation, promoting neuro-
inammation, and causing neuronal death. Decreased levels of NA
disrupt the regulation of pro-inammatory cytokines, leading to further
LC cell loss creating a negative feedback loop (I et al., 2014).
In-vivo, neuroinammation can be assessed with PET tracers that
bind mitochondrial translocator protein (TSPO), that is overexpressed in
cells with activated microglia (Werry et al., 2019). In AD participants,
TSPO tracer binding was found to be increased (Hamelin et al., 2016;
Kreisl et al., 2016), indicating inammation and microglial activation
(Werry et al., 2019) and to be correlated with amyloid pathology (Fan
et al., 2015) and severity of disease (Kreisl et al., 2013). Controls and
MCI did not show elevated TSPO showing that inammation occurs after
the conversion to MCI into AD (Kreisl et al., 2013). This nding suggests
that elevated TSPO expression may reect a more pronounced LC-NA
dysregulation and could therefore serve as possible marker of disease
progression in longitudinal studies, despite to this date no study corre-
lated TSPO measure with LC markers (Giorgi et al., 2020). In line with
the PET study from Fan and colleagues (Fan et al., 2015), postmortem
studies have also demonstrated the presence of activated microglia
surrounding amyloid plaques in AD brains (Taipa et al., 2018).
NA also plays a crucial role in clearing Aβ by microglia and sup-
pressing Aβ-induced cytokine production, where a reduction in NA
levels may contribute to insufcient suppression of pro-inammatory
mediators, contributing to AD progression (Heneka et al., 2010; Kali-
nin et al., 2007; Kong et al., 2010). Experiments in mice have demon-
strated that NA β-adrenergic stimulation protects cortical and LC cells
from Aβ-induced cell loss (Evans et al., 2020). Moreover, Both 5xFAD
mice (Kalinin et al., 2012) and P301S tau mice (Chalermpalanupap
et al., 2018) show microglial and astrocyte activation in the LC
compared to wild-type mice. In mice, NA maintains the clearance of Aβ
via microglia and suppresses Aβ-induced cytokine production as
β-adrenergic stimulation by NA protects cortical and LC cells from
Aβ-induced cell loss (Evans et al., 2020). These studies collectively
suggest that a reduction in NA levels may contribute to the progression
of AD and Aβ accumulation, making NA a potential target for
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7
pharmacological treatment.
5.5. Parkinson’s disease
PD - similar to AD - is one of the most common neurodegenerative
diseases worldwide, with an incidence rate for women and men of
respectively 37.55 and 61.21 per 100,000 person-years (Hirsch et al.,
2016). The main hallmark of the disease is a signicant reduction of
dopaminergic cells in the substantia nigra pars compacta (SNpc) and the
presence of
α
-synuclein aggregates, called Lewy Bodies (Dickson et al.,
2008). Recently, the role of NA in the development and progression of
idiopathic PD has drawn increased attention (Espay et al., 2014;
Paredes-Rodriguez et al., 2020).
Cellular accumulation of misfolded alpha-synuclein is one of the
hallmark features of PD (Atik et al., 2016). Spectroscopic and calori-
metric experiments suggest that NA stabilizes alpha-synuclein in inter-
mediate states into stable, cytotoxic species (Singh and Bhat, 2019) thus
possibly contributing to the generation of alpha-synuclein. Some the-
ories propose that alpha-synuclein misfolds in the gut and then spreads
to the brain (Berg et al., 2021; Braak et al., 2003; Engelender and
Isacson, 2017). A recent mouse model paper suggests a protective
noradrenergic mechanism against this spread: acute chemogenic
NA-depletion in PD Mouse models was linked to enteric inammation
and increased enteric alpha-synuclein levels 2 weeks later and Sub-
stantia Nigra neuronal degeneration as well as constipation and motor
decits 3–5 months later (Song et al., 2023). It has been suggested that
already in healthy elderly, higher LC neuronal density might be pro-
tective against deleterious effects of brainstem Lewy body numbers on
cognition (Wilson et al., 2013). Another PD mouse model suggests that
the noradrenergic system might also be protective against dopaminergic
neuronal depletion despite increasing alpha-synuclein aggregation and
microgliosis (Jovanovic et al., 2022).
In humans, the LC might be benecial against PD pathology even
before symptom onset: already in healthy subjects, higher LC neuronal
density diminishes the association between brainstem Lewy body
numbers (Wilson et al., 2013).
5.6. The LC-NA system in the context of PD
Comparative studies of subcortical nuclei found a high loss of LC
neurons in idiopathic PD, which is greater than the neuronal loss
observed in the nucleus basalis of Meynert and SNpc (Huynh et al.,
2021; Zarow et al., 2003). LC volume is found to be reduced (Hwang
et al., 2022), together with NA and MHPG CSF levels (Lancini et al.,
2023), and NM-sensitive MRI indicates subregion-specic degeneration
of the caudal and middle sub-portion of the LC (Doppler et al., 2021;
Madelung et al., 2022; Ye et al., 2022). Other studies showed an overall
decrease in LC MRI contrast (Schwarz et al., 2017; Wang et al., 2018). A
meta-analysis on white matter degeneration in PD found no change (Wei
et al., 2021; Zhang and Burock, 2020) or even improved white matter
integrity (Taylor et al., 2018) in LC tracts compared to healthy volun-
teers suggesting they may be unaffected in PD.
Several hypotheses such as the Braak model, and recently also the
brain-gut hypothesis (Borghammer and Van Den Berge, 2019; Horsager
et al., 2020) integrate the LC into early- to mid-stages of PD. However,
due to the heterogeneity of the disease (Farrow et al., 2022), a parsi-
monious model describing the whole breadth of variability is still
lacking.
As recently reviewed by Lancini and colleagues (Lancini et al., 2023),
NA transporter density, measured with PET NA transporter (NET) tracer,
is decreased in PD suggesting a functional decline to the noradrenergic
system including LC terminals (Doppler et al., 2021) besides structural
degeneration. Additionally, LC- specic
α
-synuclein expressing mouse
models showed degeneration of noradrenergic neurons (Henrich et al.,
2018), changes in the abundance and integrity of the immune system
(Butkovich et al., 2018; Henrich et al., 2018) and Parkinsonian
symptoms (Henrich et al., 2018).
Hyperactivation of remaining noradrenergic neurons in LC occurs in
rats after lesioning the nigrostriatal pathway (Wang et al., 2009), an
effect that was also in line with in vitro results and in a mouse model of
PD (Matschke et al., 2022). Interestingly, in mice stimulation of the
noradrenergic system protects against neuronal depletion but does not
prevent alpha-synuclein aggregation and immune system degeneration,
suggesting an immune system-independent mechanism (Jovanovic
et al., 2022). However, early LC degeneration is also linked to non-motor
symptoms such as anxiety and depression, that are typical in early stages
of the disease (Bremner et al., 1996; Remy et al., 2005). In LC-lesioned
animal models of PD, neuronal damage leads to increased microglia and
greater inammatory response to alpha-synuclein (Bharani et al., 2017;
Song et al., 2019b). Conversely, indirect stimulation of the LC-NA sys-
tem via invasive vagus nerve stimulation (iVNS) in rats, led to reduced
inammation as well as a-synuclein accumulation and increased loco-
motion in LC-lesioned rats (Farrand et al., 2020, 2017). Considering the
role that chronic inammation plays in the pathogenesis and further
progression of PD (Qin et al., 2007), these results indicate that LC-NA
system dysregulation may be involved in this process. To our knowl-
edge, in humans, there have been no correlations between noradren-
ergic levels in PD and inammation markers, which would be an
important step for future studies.
5.7. LC degeneration correlates with PD symptoms
NM-sensitive MRI correlates with a number of different PD symp-
toms. Rostral LC integrity has been linked to motor symptoms ipsilat-
erally (Ye et al., 2022) and lower LC contrast has also been linked to
self-evaluation of motor accuracy (Hezemans et al., 2022). Several
memory tests such as MoCA and Berlin model of intelligence structure
(BIS) scores (Ye et al., 2022), as well as short-term verbal and numerical
memory performance (Prasuhn et al., 2021), have been shown to be
associated with higher LC MRI contrast. LC integrity in PD is also related
to cognition: scores on episodic and short-term memory as well as lexical
uency (Prasuhn et al., 2021), response inhibition (Ye et al., 2021) and
trail-making test (TMT) results (Li et al., 2019) all correlate with LC
integrity. Additionally, left caudal and whole LC integrity have been
linked to orthostatic blood pressure (Madelung et al., 2022) and sleep
disruption (Doppler et al., 2021): sleep cyclic alternative patterns (CAP)
are diminished in PD and the rate of CAP was shown to be correlated
with noradrenergic PET binding only in patients but not in healthy
control participants while the duration of CAP subphases is altered in PD
patients as well. Finally, increased NA transporter binding and
decreased DA transporter binding in PD were linked to increased anxiety
(Carey et al., 2021).
5.8. The effect on neuroinammation and neurovascular system
In PD, LC-NA degeneration contributes to increased neuro-
inammation through reactive microglia and oxidative stress (Giorgi
et al., 2020). Animal studies have demonstrated that lesioning of the LC
leads to heightened activation of microglial cells (af Bjerk´
en et al., 2019)
and inammation in SN dopaminergic cells and when combined with
systemic inammation, LC degeneration exacerbates degeneration in
the nigrostriatal pathway, hippocampus, and motor cortex in PD models
(Bharani et al., 2017; Herrera et al., 2000; Song et al., 2019b, 2019a).
The presence of inammation in dopaminergic areas in PD has been
shown in vivo, as PET studies using tracers of microglia-activation
showed increased binding in basal ganglia, substantia nigra, and
fronto-temporal cortex in individuals with PD (Edison et al., 2013;
Gerhard et al., 2006; Iannaccone et al., 2013) and individuals diagnosed
with PD and dementia (PDD) displayed a signicantly more extensive
microglia activation pattern compared to individuals with PD (Edison
et al., 2013). This result provides further evidence for the involvement of
neuroinammatory responses in exacerbating the disease despite to this
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8
date no study correlated this measure with LC markers (Giorgi et al.,
2020).
In PD rat models, indirect stimulation of LC-NA activity through
vagus nerve stimulation has shown potential in reducing neuro-
inammation and protecting dopaminergic cells (Farrand et al., 2020),
whilst administration of NA in dopaminergic neurons reduces the pro-
duction of ROS and rate of neurodegeneration (Butkovich et al., 2018).
Animal studies using models of PD have provided further support for
the role of LC degeneration in neuroinammation and oxidative stress
(see Giorgi et al., 2020 for a review). The reverse inuence of inam-
mation has also been investigated: lipopolysaccharide-induced inam-
mation in DSP-4-induced LC lesion mice exacerbated degeneration to
the nigrostriatal pathway, hippocampus, and motor cortex and
increased microglial activation (Bharani et al., 2017; Song et al., 2019a,
2019b).
6. Methods to investigate the LC-NA system
The currently most established methods to investigate the structure
and function of the LC-NA system include structural and functional
magnetic resonance (sMRI and fMRI), PET, electroencephalography
(EEG) (for a review see Nieuwenhuis et al., 2011, 2005), and pupill-
ometry (for a review see Viglione et al., 2023).
Sasaki and colleagues demonstrated the possibility of measuring LC
cell density using a neuromelanin-sensitive MRI protocol (Sasaki et al.,
2006). In that study, brain images from healthy people and people with
PD were acquired with a T1-weighted Turbo Spin Echo (TSE) protocol, a
neuromelanin-sensitive sequence. In healthy adults, the contrast in-
tensity in the LC resulted in high signal intensity in areas that were
consistent with the anatomical location of the two NM-rich regions LC
and SN. The anatomical precision of this technique has been further
conrmed in postmortem tissue demonstrating colocalization between
MRI signal and NM-containing neurons (Cassidy et al., 2019; Keren
et al., 2015). Different neuromelanin-sensitive MRI sequences have
since then been used as a non-invasive ‘integrity’ measure for simulta-
neous assessment of the LC (for a review see Betts et al., 2019b; Galgani
et al., 2020; Liu et al., 2017; Sulzer et al., 2018) and SN (for a review see
Sulzer et al., 2018). However, to date, the mechanisms underlying MRI
contrast in the LC remain unclear (see Betts et al., 2019b for a
comprehensive review). LC tracts have been studied in vivo (Liebe et al.,
2022) using magnetic resonance tractography (Jbabdi and
Johansen-Berg, 2011), a method that investigates brain white matter
tracts and through which biologically accurate measures of bre con-
nectivity can be obtained (Smith et al., 2015). DTI can be signicantly
affected by several factors, namely low-resolution MRI, crossing-bres,
noise, and distortions. These inuences introduce complexities and po-
tential limitations, as they may impede the accurate delineation of the
LC. Furthermore, in the context of neurodegenerative disorders such as
AD and PD, the challenges associated with DTI LC measures become
more pronounced, due to the potential reduction in LC’s structural
integrity, which adds an additional layer of complexity to the assessment
process (Zhang et al., 2020; Zhang and Burock, 2020).
Changes in brain activation during tasks are approximated using
functional fMRI, a sequence that measures the changes in blood-oxygen
levels in the brain that occur in response to neuronal activity (Buxton
et al., 2004). These images are registered on structural MRI images to
allow a correct identication of the area that was active during the task,
which is especially important in the case of LC activity (Turker et al.,
2021). However, investigating LC activity with fMRI presents challenges
due to its size, location, and inter-individual variability.
The LC shows signicant inter-individual variability, particularly in
the context of aging (Liu et al., 2019), making it challenging to establish
a consistent region of interest (ROI) across individuals (Turker et al.,
2021). Moreover, limited resolution of standard MRI techniques can
lead to partial volume effects, where LC voxels contain non-LC tissue
(Cassidy et al., 2022). The proximity of the LC to large sources of
physiological noise, such as the CSF and the 4th ventricle, means that
spatial smoothing during preprocessing may introduce additional
physiological noise (Turker et al., 2021). Taken together, variations in
voxel size and smoothing kernel across studies contribute to
between-study variability, as evident from the heterogeneity of these
measures between studies (Liu et al., 2017). Recently, Yi and colleagues
proposed an optimised spatial transformation pipeline for the LC, along
with a method to quantify the precision of spatial transformations, that
could be of help to increase future comparability across studies (Yi et al.,
2023). Finally, the BOLD signal of the LC can be inuenced by physio-
logical noise, potentially attenuating the fMRI response (Liu et al.,
2017).
PET imaging uses radiotracers that specically bind to sites and
molecules of interest, thus allowing for an assessment of their spatial
distribution in the brain. Of particular interest for the LC-NA system is
the MeNER tracer (Schou et al., 2003), that was successfully used to
quantify NA transporters levels in healthy and PD (García-Lorenzo et al.,
2013; Sommerauer et al., 2018). Both AD and PD are multisystemic
diseases, therefore it is informative to also use PET tracers that allow
visualisation of brain pathology, neuroinammation, cholinergic and
monoamine neurotransmitter systems, synaptic density as well as
metabolism (for a review on AD see Bao et al., 2021; Guti´
errez et al.,
2022, for a review on PD see Prange et al., 2022). PET tau measures of
LC are currently not feasible as PET tau tracer binds to neuromelanin
rather than specically binding to tau protein leading (off-target bind-
ing) (Jacobs et al., 2021a; Lee et al., 2018; Marqui´
e et al., 2015).
The ring activity of the LC-NA system can be detected during wake
using EEG, as the event-related wave P3b, the parietal subcomponent of
the P3 reects phasic activity of the LC-NA system (Nieuwenhuis et al.,
2005; Polich, 2007). LC-NA modulation of sleep (Van Egroo et al., 2022)
can be assessed by concurrent polysomnography and PET Mener in
aging and disease, as sleep instability measured as cyclic alternating
pattern (CAP) had been shown to correlate with NA transporter density
in brainstem in PD (Doppler et al., 2021).
Pupillometry is also used as an indirect measure for LC activation
(Joshi et al., 2016; Szabadi, 2013) as the uctuations in the ring rate of
LC neurons closely parallel changes in pupil diameter (Aston-Jones and
Cohen, 2005; Gilzenrat et al., 2010; Joshi et al., 2016).
Levels of NA and its metabolites in blood (Katunina et al., 2023;
Teunissen et al., 2022) and CSF (David and Malhotra, 2022; Lotankar
et al., 2017) have also been used and are under constant development.
Despite being the closest measure to the central nervous system (CNS),
CSF biomarkers still require specic protocols and a deeper under-
standing of their dynamics in order to be considered reliable measure-
ments of central NA (Lancini et al., 2023).
7. The locus coeruleus as a therapeutic target
7.1. Drug interventions targeting the noradrenergic system
Numerous noradrenergic drugs have been tested to improve cogni-
tion in neurodegenerative diseases:
Methylphenidate is a noradrenergic and dopaminergic reuptake in-
hibitor that is mainly used to treat Attention decit hyperactivity dis-
order (ADHD). In a randomised trial, methylphenidate improved apathy
but not neuropsychiatric symptoms in participants with AD, compared
to placebo (Mintzer et al., 2021) while in participants with MCI, it
improved global cognitive scores and memory after 3 days of daily
intake (Press et al., 2021). In PD mouse models, methylphenidate
improved sleep and daily functioning (Oakes et al., 2021). A recent re-
view showed that methylphenidate improved cognition in a wide vari-
ety of conditions associated with elderly: it improved depressive
symptoms, accelerated post-stroke recovery and improved outcome
measures after stroke (Swartzwelder and Galanos, 2016).
Atomoxetine, a presynaptic NET inhibitor also used in ADHD treat-
ment, did not improve cognition in a 5-week trial with participants with
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
9
MCI but was associated with an increase in noradrenergic plasma and
CSF levels and a reduction in CSF tau and pTau 181 (Levey et al., 2022).
It is also associated with altered protein levels of pathophysiology
related to synaptic and metabolism, glial immunity and
inammation-related proteins as well as an increase in the
Brain-Derived Neurotrophic Factor (BDNF) (Levey et al., 2022). Finally,
atomoxetine as a treatment for MCI has been shown to be associated
with an increase in fMRI functional connectivity between the insula and
the hippocampus (Levey et al., 2022). In PD, atomoxetine plasma con-
centration correlated with uency in an animal category and letter
uency test (Borchert et al., 2019) and improved inhibition in a
stop-signal task (Borchert et al., 2019; O’Callaghan et al., 2021).
Clonidine, an alpha-2 receptor agonist commonly used against hy-
pertonia, has been shown in PD to improve movement initiation in a stop
signal task and to modulate the activity of the dorsomedial prefrontal
and anterior cingulate cortices, which are linked to the inhibitory
network (Criaud et al., 2022).
A meta-analysis of 19 randomised controlled trials that performed
interventions in AD patients using noradrenergic drugs found a positive
effect on the MMSE and apathy but no improvement on attention (David
et al., 2022).
As noradrenergic drugs have shown benecial effects in improving
LC-related affected functions in both healthy participants and partici-
pants with diseases, they are a promising tool for potential early or even
later-stage intervention.
7.2. Targeting the noradrenergic system via the vagus nerve
Transcutaneous vagus nerve stimulation (taVNS) offers the possi-
bility of electrical non-invasive stimulation of the cymba conchae of the
external ear, which has nerve bre connections to the vagus nerve
(Peuker and Filler, 2002) and is thought to stimulate the LC-NE system
via the nucleus tractus solitarius (NTS) (Butt et al., 2020; Ruffoli et al.,
2011). IVNS has already been shown to increase the ring rate of LC
neurons (Hulsey et al., 2017) to stimulus-specic cortical plasticity in
the motor cortex (Hulsey et al., 2019) and to a reduction in inamma-
tory markers (for a review see Ludwig et al., 2021). Additionally, iVNS
led to an increase in NA release in brain regions pathologically affected
early in AD and PD, such as the hippocampus, basolateral amygdala and
cortical target areas (Hassert et al., 2004; Hulsey et al., 2019; Manta
et al., 2013). This is consistent with the results of electrical tonic stim-
ulation of the LC, which resulted in higher NA release and increased
activation of the PFC (Florin-Lechner et al., 1996).
As taVNS is less invasive than iVNS, it is a more promising therapy
avenue: results combining taVNS and fMRI have demonstrated the ef-
cacy of taVNS to effectively increase activity in the NTS and LC as well
as in LC-NE projection areas such as the amygdala and hippocampus
(Sclocco et al., 2019; Yakunina et al., 2017). Meanwhile, taVNS is also
being investigated as a potential therapy to improve cognition in early
AD (for a review see Vargas-Caballero et al., 2022) as well as motor and
nonmotor symptoms in PD (Cakmak et al., 2017; Zaehle and Krauel,
2021). Further taVNS studies should take into account interindividual
differences in the integrity of the stimulated LC-NE system to accurately
validate the benet of taVNS for an individual (Ludwig et al., 2021).
7.3. Targeting the noradrenergic system via environmental enrichment
Environmental enrichment is the concept of providing a cognitively
or physically stimulating and challenging environment for humans and
animals, which improves cognition and overall brain health: it has been
shown that mice in an enriched environment display increased cortical
thickness in sensory areas (Engineer et al., 2004) and perform better in
cognitive tasks (Yuan et al., 2012). The number of years of education
(L¨
ovd´
en et al., 2020), a large social circle (Smith et al., 2018) and a
cognitively demanding occupation (Stebbins et al., 2022), all considered
to be an enriched environment, be benecial for cognitive performance
potentially from early childhood onwards (Schoentgen et al., 2020).
The LC seems to be an important link between environmental
enrichment and cognitive reserve: in mice, exposure to different odours
caused neuronal growth in murine olfactory bulbs (Veyrac et al., 2009).
However, this was blocked by the administration of ß-antagonists during
the environmental enrichment period (Veyrac et al., 2009). As moderate
LC activity is crucial for attention (Aston-Jones and Cohen, 2005) and as
LC activation also has been linked to anti-inammatory function
(McNamee et al., 2010) and BDNF secretion (Ivy et al., 2003), frequent
LC activation would conceptually be benecial for overall brain health
(for reviews on the importance of NA in healthy aging see Mather, 2021;
Mather and Harley, 2016). Results of the effect of cognitive training on
delaying dementia have been conicting (Sharp and Gatz, 2011; Wilson
et al., 2013) and more research is required in that eld.
An increasing number of studies have investigating whether physical
exercise can be benecial in aging and neurodegeneration.
In humans, it has been shown across age groups that exercise training
across a variety of tasks such as strength training (A˘
gg¨
on et al., 2020),
very light exercise (Kuwamizu et al., 2022), cycling and heavy running
(Strobel et al., 1997) can increase blood plasma noradrenergic levels
(A˘
gg¨
on et al., 2020; Strobel et al., 1997) and dilate pupil size, that is a
proxy of LC activity (Kuwamizu et al., 2022). The increase in norad-
renergic levels during physical exercise correlates with better cognitive
performance: during light cycling for 1 min, the increased level of the
noradrenergic metabolite MHPG of healthy young males from the rest to
exercise condition correlates with their faster response time in a mildly
mentally challenging 4-choice reaction time task (McMorris et al.,
2008). However, this effect could have also been explained by differ-
ences in exercise intensity (McMorris, 2003).
Recently, it has been shown in animal studies that exercise and
cognitive training through environmental enrichment can also increase
levels of NA (Naka et al., 2002) improve cognition (Bindra et al., 2021)
and may in part be mediated by ß-adrenergic receptors (Ebrahimi et al.,
2010). In Male Wistar rat model, it was shown that a pharmacological
decrease in hippocampal noradrenergic levels with timolol, β-adrenergic
receptor antagonist, decreased long-term object recognition memory
persistence while intrahippocampal NE injection had the opposite effect
(da Silva de Vargas et al., 2017). The same group furthermore showed
that in this rat model, object recognition memory consolidation was
accompanied by an increase in NE and BDNF (Mello-Carpes et al., 2016).
They furthermore showed that the increase in BDNF was eliminated if
the increase in NE was eliminated suggesting a causal relationship be-
tween both increases. Additionally, In Male Sprague-Dawley rats, the
benecial effects of exercise on cognition were shown to be partially
dependent on NA as giving the noradrenergic blocker propranolol
immediately after training abolished the increase in hippocampal BDNF
mRNA levels (Ivy et al., 2003).
Physical activity decreases the risk for dementia, although the type of
exercise and optimal frequency is still to be dened (for a review see
Iso-Markku et al., 2022; L´
opez-Ortiz et al., 2023). In mice, the benecial
effect of environmental enrichment on protection against AD has been
linked to the activation of ß-adrenergic receptors (Li et al., 2013).
8. Future outlook
It has been shown that LC degeneration is strongly linked to age and
pathology-related cognitive and physical decline, and may even precede
it. This might be expressed by a decline in LC-related functions such as
decreased muscle tonus, decreased working memory, sleeping problems
and hypertension.
As in healthy older adults, direct links between LC activity and task
performance are lacking, future human studies in both healthy young
and older adults should link differences in CSF NA levels or LC fMRI
activity tasks to differences in task performance to have a more direct
link between LC and other outcome measures such as task performance.
More emphasis should be put on LC tract integrity as it might drive
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
10
the link between LC integrity and cognition. However, this is more
challenging methodologically: the LC is a small structure, DTI requires
more advanced systems than structural MRI and LC white matter tracts
can be difcult to differentiate from surrounding tracts. Additionally, LC
tractography is not as well established as LC integrity measurements.
Therefore, future research is needed to rst establish standardised
methods for measuring LC tract integrity and to improve the accuracy
and reliability of this outcome measure.
The hypothesis that degeneration of the LC might accelerate the
progression of AD dementia, which in turn might further impair the LC,
is often complicated by the heterogeneity of data in cross-sectional de-
signs. However, longitudinal studies such as the DELCODE study (Jessen
et al., 2018), which collect structural measures and CSF data from the
same participants every year, or the longitudinal Harvard Aging Brain
Study (HABS) (Dagley et al., 2017), will allow matching changes in in-
dividual differences in LC integrity with individual changes in task
performance. Also studies that include longitudinal cognitive measures
and post-mortem data like the Religious Orders Study (ROS) and Aging
Project (MAP) (Bennett et al., 2018), allow to compare measures ob-
tained in vivo.
The LC-NA system can be targeted through exercise, pharmacologi-
cally and potentially via the vagus nerve in humans and has shown
promise as a target for healthy aging, AD and PD. However, large-scale
trials are lacking. Also, to maximise the effect, a combination of these
methods should be attempted.
Given the reciprocal relationship between degenerated LC and
inammation, more research should focus on the effects and combina-
tion of noradrenergic drugs with anti-inammatory agents. This bidi-
rectional interaction highlights the importance of targeting
inammation as a potential strategy to mitigate LC degeneration and
subsequently delay the aging process.
A viable yet often overlooked target for ADis MHPG, which is closely
related to tau, amyloid, inammation, cortical thickness (Jacobs et al.,
2021b; Riphagen et al., 2021; van Hooren et al., 2021) and, through its
link with p-tau, to neuropsychiatric symptoms (Jacobs et al., 2021b).
9. Conclusion
Recent developments in AD research have shown that the LC-NA
system might be exacerbating pathology in a vicious cycle with NA
metabolites promoting tau aggregation and tau promoting LC hyperac-
tivity causing higher levels of NE metabolites. Additionally, a decreased
protection from AD pathology due to decreased immune protection
caused by LC degeneration might further exacerbate the disease (Box
1a). However, NA also seems to be protective against amyloid aggre-
gation indicating a multifaceted LC involvement in AD.
In PD (Box 1b), the LC-NA system has been found to be involved in
early-to-mid stages, as it is linked to early non-motor symptoms such as
anxiety and depression, and its degeneration may accelerate PD
progression.
LC degeneration leads to neuroinammation in aging and neurode-
generative through shared increased microglia mechanisms but also
disease-specic mechanisms. In AD, LC degeneration contributes to
increased microglial reactivity and disruption of the BBB), thereby
accelerating the accumulation of Aß and tau proteins. On the other hand,
in PD, LC degeneration primarily leads to increased microglial reactivity
and oxidative damage. These mechanisms highlight the multifaceted
role of LC degeneration in promoting neuroinammation and the
pathological processes associated with AD and PD.
Finally, multiple noradrenergic drugs, vagus nerve stimulation and
physical exercise have all been shown to be promising therapeutic tar-
gets (Box 2) by potentially boosting noradrenergic function in aging and
neurodegenerative disease thus alleviating some of their debilitating
symptoms.
Box 1
Involvement of the LC-NA system in (A) AD and (B) PD.
.
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
11
Funding sources
F.K is supported by the German Federal Ministry of Education and
Research (BMBF, funding code 01ED2102B) under the aegis of the EU
Joint Programme – Neurodegenerative Disease Research (JPND).
E.L, J.P and L.H are supported by the Deutsche For-
schungsgemeinschaft (DFG, German Research Foundation) –
362321501/ Research Training Group (RTG) 2413 SynAGE.
M.Lu is supported by the federal state of Saxony-Anhalt and the
European Regional Development Fund (ERDF) in the Center for
Behavioral Brain Sciences (CBBS, ZS/2016/04/78113).
M.Le and G.G are supported by the Deutsche For-
schungsgemeinschaft (DFG, German Research Foundation) – Project-ID
425899994 – Sonderforschungsbereiche 1436 (SFB 1436).
E.D has received nancial support for his institution by Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation) – Project-
ID 425899994 – Sonderforschungsbereiche 1436 (SFB 1436), Human
Brain Project, Specic Grant Agreement 3 (SGA3), Deutsche For-
schungsgemeinschaft (DFG, German Research Foundation) – Sonder-
forschungsbereiche 1315 (SFB 1315).
M.J.B is supported by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) – Project-ID 425899994 – Sonderfor-
schungsbereiche 1436 (SFB 1436), Center for Behavioral Brain Sciences
(CBBS) NeuroNetzwerk 17, and by the German Federal Ministry of Ed-
ucation and Research (BMBF, funding code 01ED2102B) under the aegis
of the EU Joint Programme – Neurodegenerative Disease Research
(JPND).
D.H is supported by Sonderforschungsbereich 1315, Project B06,
Box 2
LC-NA as a therapeutic target.
.
F. Krohn et al.
Neuroscience and Biobehavioral Reviews 152 (2023) 105311
12
Sonderforschungsbereich 1436, Project A08, ARUK SRF2018B-004,
CBBS Neural Network (CBBS, ZS/2016/04/78113), and NIH
R01MH126971.
Competing interests
E.D has received payments for his role and works as consultant for
Roche, Biogen, RoxHealth and expert testimony for UCL Consultancy,
served at scientic advisory boards for EdoN Initiative and Ebsen Alz-
heimers Center (no payment) and Roche (personal nancial support),
and is a co-founder of the digital health start-up Neotiv.
F.K, E.L, M.Lu, M.Le, G.G, L.H, J.P, M.J.B and D.H have nothing to
disclose.
Data Availability
No data was used for the research described in the article.
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