Norepinephrine in Neurodegeneration: A Coerulean Target
Elena M Vazey1, Vanessa K Hinson2,3, Ann-Charlotte Granholm1, Mark A Eckert4 and Gary Aston-Jones1*
1Department of Neurosciences - Research, Medical University of South Carolina, Charleston, SC, USA
2Department of Neurosciences - Neurology, Medical University of South Carolina, Charleston, SC, USA
3Ralph H Johnson VA Medical Center, Charleston, SC, USA
4Department of Otolaryngology, Medical University of South Carolina, Charelston, SC, USA
- Corresponding Author:
- Gary Aston-Jones
Department of Neurosciences
Medical University of South Carolina
173 Ashley Avenue, BSB 403, Charleston
SC, 29425, USA
E-mail: [email protected]
Received date: April 21, 2012; Accepted date: April 23, 2012; Published date: April 25, 2012
Citation: Vazey EM, Hinson VK, Granholm AC, Eckert MA, Jones GA (2012) Norepinephrine in Neurodegeneration: A Coerulean Target. J Alzheimers Dis Parkinsonism 2:e114. doi:10.4172/2161-0460.1000e114
Copyright: © 2012 Vazey EM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Alzheimer’s (AD) and Parkinson’s (PD) diseases are the two
most common neurodegenerative disorders in older adults. Currently
over 6 million Americans have been diagnosed with AD or PD, and
this incidence is expected to increase dramatically in the near future
[1,2]. Many recent advances in medicine have increased lifespan, and
consequently an aging population has contributed to the burgeoning
load of persons suffering from AD and PD. Both disorders are in the
top 15 leading causes of death in the United States , and have no
effective cures nor treatments that alter their progression. Since clinical diagnosis often occurs many years after the onset of neurodegeneration,
early detection of neuropathological features and potentially overlooked
prodromal symptoms may benefit future treatment strategies.
AD and PD patients both exhibit pathology and loss of locus
coeruleus (LC) norepinephrine (NE) neurons prior to current clinical
diagnostic criteria [4,5]. Novel assays or biomarkers could be used as
early identifiers and directives for early treatments in AD or PD. This
will be important for applying treatments that could reduce symptoms,
increase productive lifespan, and alter disease progression. Below
we briefly highlight evidence for the brain nucleus LC as a candidate
early biomarker for these neurodegenerative disorders. We also point
to certain functions of the LC-NE system primarily in the cognitive
domain, as early intervention targets for both AD and PD treatments.
LC is the sole source of NE throughout cerebral cortex. These
neurons project to parietal, temporal and frontal lobes [6,7], all of
which are areas prominently involved in cognitive functions and
susceptible to pathology in neurodegenerative disorders. Within the
CNS, there is a caudorostral progression of degeneration in both AD
and PD; pathology and loss of LC-NE neurons occurs very early (e.g.,
preceding loss of dopamine neurons in PD) [5,8,9]. Patients with AD
and PD show depleted cortical NE [10,11]. Compensatory responses to
LC loss by residual NE neurons or alterations in NE receptor expression
in target regions may also disrupt network functions modulated by
NE and affect behavior. NE has well known neuromodulatory effects
in cortical targets, loss of which may disrupt network functions in
relatively intact circuits and increase susceptibility of target neural
populations to subsequent insult.
LC-NE neurons innervate both substantia nigra dopamine (DA)
neurons and nucleus basalis (nbM) cholinergic (Ach) populations,
which are critically susceptible to neurodegeneration in PD and AD,
respectively . The loss of excitatory NE input to nbM ACh and ventral
tegmental area DA neurons by LC-NE projections may contribute to
decreased cortical Ach and DA levels in these disorders [11,13-15]. In
animal models of PD, loss of NE-LC innervation increases toxic injury
and substantia nigra DA neuron cell death . In addition, NE loss
may exacerbate effects of DA loss, e.g., LC-NE lesions increase motor
dysfunction and dyskinesias in models of PD . Finally, in animal
models of AD, LC loss exacerbates amyloid load, cholinergic cell loss,
and memory impairment, whereas supplementing NE levels modulates
neuroinflammatory processes to reduce amyloid load, presumably
by altering expression of pro-inflammatory cytokines regulated by
adrenergic receptors on microglial cells [18-20]. In humans LC-NE pathology is posited to begin many years, if not decades, before clinical
diagnosis. LC degeneration in AD and PD is present in prodromal
phases and during early symptoms [5,21], making identification of LC
loss an attractive potential early biomarker for diagnosis, monitoring
and interventional strategies. LC-NE degeneration may contribute to
many features common to these disorders including mood, sleep and
cognitive dysfunction seen early in AD and PD [4,22,23].
We propose LC-NE loss in AD and PD may significantly
contribute to cognitive deficits that characterize these disorders, as LCNE
is a critical ascending modulatory system that regulates prefrontal
executive function. The cortical NE (from LC-NE pathway) is a core
element in regulation of behavioral flexibility and executive functions
[7,24-26]. Cortical executive dysfunction is a symptom often present in
prodromal stages of both AD and PD, leading us to propose that such
executive dysfunctions in early stages of these diseases are due, at least
in part, to LC-NE degeneration that occurs early in these disorders. The
predicted role of LC in cognitive sequelae of AD and PD is grounded in
a comprehensive theory of LC function developed from basic research
findings . Work from our lab and others have identified two modes
of LC-NE firing (phasic and tonic) that differentially regulate behaviors
in cognitive tasks [27-31]. Specifically, a host of basic neuroscience
indicates a role for LC-NE neurons in cognitive flexibility. Several
studies find that depleted NE in PFC results in executive dysfunction,
common to mild cognitive impairment, early AD and early PD .
Preclinically, such impairment can be resolved by manipulations that
increase NE transmission, suggesting a possible pharmacological
target [33-35]. Therefore we predict that loss of LC-NE neurons would
cause deficits in cognitive flexibility, as is observed in PD [23,36]. Of
course, other executive dysfunction may also be caused or exacerbated
by LC-NE loss. Importantly, cognitive deficits in these disorders have
significant impact on quality of life, life expectancy and caregiver stress
, but are not treated by current PD medications, leaving cognitive
impairment an unmet need for this severe and common disorder.
Integrating studies on LC-NE cognitive function with pathology of
model systems may identify novel insights for early diagnosis and early
interventions to improve current therapeutic strategies. Together,
these links for AD and PD with LC neurodegeneration indicate that
early interventional strategies targeting LC-NE transmission may alter
disease progression in addition to direct benefits on NE mediated symptoms. Indeed, NE has the potential to limit declines through its
neuroprotective effects [16,38].
Using neuroimaging to identify the structural integrity of LC
would significantly advance the study and treatment of both AD and
PD. We therefore propose that LC-NE degeneration could be used
as a biomarker for suspected AD or PD, allowing early, targeted NEbased
interventions where appropriate. The LC has been observed in
humans using an MRI protocol that has been thought to be sensitive to
neuromelanin because the sequence reveals signal hyper-intensities in
the LC and the substantia nigra , two regions where neuromelanin
accumulates. The same sequence was used to demonstrate reduced
ability to visualize the LC in PD patients . Neuromelanin containing
LC neurons are fewer in number, have smaller neuromelanin granules,
and are less densely packed in PD post-mortem brains compared to
controls . These results indicate that the LC-MRI signal may be driven
by the number of LC cells, possibly by the amount of neuromelanin,
and could be used as a biomarker for AD and PD. The importance of
an LC biomarker for tracking cognitive changes is underscored by the
linkage of LC neuron loss to disease progression [41-46]. For example,
PD patients with significant executive function impairment exhibited
reduced post-mortem LC neuron counts compared to PD patients
without significant cognitive impairment . These findings strongly
indicate that an LC biomarker can characterize the risk for cognitive
decline. As LC neurons degenerate early, an LC biomarker could track
the severity of LC decline and/or treatment effects.
NE modulation is a viable therapeutic target due to the proven safety
and efficacy of NE modulators in other disorders, early involvement of
LC in the neuropathology, opportunity for efficacy in other concurrent
symptoms like mood and inflammation as well as potential impact on
disease progression [48-50]. In terms of effectiveness of NE enhancers
for cognitive dysfunction, very few trials have been undertaken in a
small number of patients, with positive results that suggest more
comprehensive testing in the future is warranted. For PD, the specific
NE reuptake inhibitor atomoxetine recently led to improvements in
clinical global impression scales of cognition in two separate studies
[51,52]. Cognitive flexibility was not examined in these studies, but
the findings are consistent with preclinical studies where atomoxetine
improved cognitive flexibility deficits produced by specific LC-NE
lesions in PFC . In AD, increasing NE transmission increases
electrophysiological correlates of attentional processing , which
may provide benefits for cognitive dysfunctions. Evidence from 1) in
vivo lesions in the LC-NE system and 2) preclinical studies highlights a
role for LC-NE neuromodulation in early cognitive dysfunction, which
points towards the use of NE modulation as a means for enhancing
cognitive processing in both AD and PD patients.
Evidence is increasing for an important role of LC in AD and PD
neurodegeneration [50,55,56]. We, and others, have argued that LC has
a number of functions besides its roles in cognitive processing, including
regulation of sleep, mood and neuroinflammation, all of which may
benefit from NE-based therapies [19,57-59]. The pathological relation
between progressive LC-NE loss and cognitive symptom profiles
in AD and PD degeneration make the LC-NE neurons a promising
candidate biomarker to assist early diagnosis and drug development.
Addressing NE signaling dysfunction, particularly in early stages
of neurodegenerative disorders, may enhance the opportunity for
intervention strategies that could not only manage cognitive symptoms
but may have disease–modifying effects on subsequent pathology.
Authors are supported by PHS grant 1R01MH092868 (GAJ), Parkinson’s Disease Foundation (EMV), Charles and Diane Barmore Fund, and TEVA
Neuroscience (A-Ch. G).
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