The Role of
Norepinephrine in the
The behavioral and psychological symptoms of de-
mentia (BPSD) are common serious problems that
are a major contributor to caregiver burden. De-
spite their significance, the underlying neurobiol-
ogy of these disturbances is still unclear. This re-
view examines the role of norepinephrine (NE) on
BPSD, including depression, aggression, agitation
and psychosis. A number of lines of evidence sug-
gest that NE dysfunction leading to BPSD may
result from increased NE activity and/or hyper-
sensitive adrenoreceptors compensating for loss of
NE neurons with progression of Alzheimer’s dis-
ease (AD). With greater appreciation of the un-
derlying neurobiology of behavioral and psycho-
logical symptoms of dementia (BPSD) more
effective, rational, targeted pharmacotherapy will
hopefully emerge.
(The Journal of Neuropsychiatry and Clinical
Neurosciences 2004; 16:261–276)
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004
Behavioral and
Psychological Symptoms
of Dementia
Nathan Herrmann, M.D., F.R.C.P.C.
Krista L. Lanctôt, Ph.D.
Lyla R. Khan, Hon.B.Sc.
A notable source of morbidity and mortality, de-
mentia accounts for an excess of health care costs.1
The total economic cost of the disorder, including direct
and indirect medical costs, has been estimated to be $100
billion per year (in U.S. dollars).2 Alzheimer’s disease
(AD) is a progressive and incurable disease character-
ized by cognitive and behavioral abnormalities and is
the most common cause of dementia in North America.1
The estimated prevalence of AD among individuals
above 65 years of age in the United States is 10.3%.3
The behavioral abnormalities associated with AD fre-
quently disrupt patient care and present a management
problem to the caregiver. Behavioral and psychological
symptoms of dementia (BPSD) that complicate AD in-
clude behaviors with psychotic features (e.g., delusions
and hallucinations) as well as those without (e.g., de-
pression, anxiety, agitation, wandering, hostility, and
uncooperativeness).4 Disruptive agitated behaviors are
common and occur in 40% to 90% of patients with AD
at some point during the course of their illnesses.5,6 Evi-
dence suggests that BPSD have a detrimental impact on
Received August 1, 2002; revised October 29, 2002; accepted Novem-
ber 18, 2002. From the Division of Geriatric Psychiatry, Sunnybrook
and Women’s College Health Sciences Centre, Geriatric Psychiatry,
Department of Psychiatry, University of Toronto; HOPE Research Cen-
tre, Sunnybrook and Women’s College Health Sciences Centre, De-
partments of Psychiatry and Pharmacology, University of Toronto.
Address correspondence to Dr. Herrmann, Division of Geriatric Psy-
chiatry, Sunnybrook and Women’s College Health Sciences Centre,
2075 Bayview Avenue, Room FG05, Toronto, ON M4N 3M5, Canada;
Nathan.Herrmann@sw.ca (E-mail).
Copyright 䉷 2004 American Psychiatric Publishing, Inc.
261
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA
both patients7 and caregivers.8 Aggression occurs in 18%
to 65% of patients9–11 and is the behavioral disturbance
that causes the greatest impact. Behaviors such as agi-
tation and aggression complicate management12,13 and
contribute to caregiver burden14 and the institutionali-
zation of demented patients.15–18
The treatment of behavioral disorders in AD has em-
phasized the use of psychotropic medications.19–21
Studies in nursing homes,22–24 hospitals,25 and the com-
munity18 have shown that psychotropic medications
are frequently used in elderly patients. Guidelines out-
lining the appropriate use of psychotropics in elderly
institutionalized patients have been created in re-
sponse to persistent psychotropic use.26 The Omnibus
Budget Reconciliation Act of 1987 was enacted to cur-
tail inappropriate and overuse of psychoactive medi-
cations in long-term care facilities, which often resulted
in high incidence of adverse events.27,28 For example,
antipsychotic medications, the most commonly used
psychotropic for BPSD, can produce serious extrapyra-
midal side effects. Extrapyramidal symptoms such as
rigidity, tremors, and parkinsonian gait29are common
with antipsychotic drug administration and may limit
treatment in the elderly demented population and lead
to discontinuation of medication. Psychotropics have
also been found to induce agitation, confusion, and cog-
nitive impairment in elderly demented patients,30 fur-
ther contributing to BPSD. Novel therapies targeting
specific neurotransmitters are believed to underlie be-
havioral dysfunction in AD are being studied as alter-
natives to the modestly efficacious antipsychotics.31,32
The idea here is that we can rationalize treatment by
studying the neurotransmitters involved. This has been
demonstrated with serotonin, one of the best examined
neurotransmitters.33,34
METHOD
Neuropathological and neurochemical disruptions in
the central noradrenergic system have been established
as important factors in the etiology of AD and BPSD.
Evidence supporting these neurobiological alterations
as well as the putative links between the noradrenergic
system and behavior, including BPSD, are reviewed.
Noradrenergic pharmacotherapies are also examined to
assess the clinical significance they may have in AD and
BPSD. Sources used to obtain articles included electronic
databases (MEDLINE, EMBASE) and manual cross-ref-
262
erences from bibliographies of relevant literature. The
following keywords were used: norepinephrine, nor-
adrenergic, Alzheimer’s disease, dementia, behavior,
behavioral disorders, aggression, agitation, psychosis,
depression, and noncognitive.
NOREPINEPHRINE SYSTEM
The central noradrenergic system is known to have two
different projections: 1) neurons originating from the
ventrolateral tegmental noradrenergic cells—involved
in sexual and feeding behaviors35—that flow to the fore-
brain, an area commonly involved in traumatic brain
injury and associated with violent behavior and reduc-
tion in rage control,36 and 2) neurons originating from
the locus coeruleus (LC), which line the bottom of the
fourth ventricle in the rostral pons37 and are associated
with cognitive functions.38 Noradrenergic neurons give
rise to diffuse axonal projections that innervate large ar-
eas of the brain, including the cerebellum, thalamus, hy-
pothalamus, and midbrain,35 and thus can be expected
to influence many different functions.
Norepinephrine (NE) and epinephrine are catechol-
amines and are formed from the amino acid L-tyrosine
which is actively transported from the blood. L-Tyrosine
is converted to L-dihydroxyphenylacetic acid (L-dopa)
through tyrosine hydroxylase, which is the rate limiting
enzyme of the metabolic pathway. L-dihydroxypheny-
lacetic acid is then transformed to dopamine (DA), the
immediate precursor of NE, by dopa-decarboxylase and
transported into storage vesicles. Storage vesicles con-
taining DA beta hydroxylase (DBH), found in NE-spe-
cific neurons, convert the stored DA to NE through b-
hydroxylation. Dopamine producing neurons have
storage vesicles without DBH.
Norepinephrine is the primary neurotransmitter of
the sympathetic nervous system in the periphery but is
also prevalent in the brain. Epinephrine is an analog of
NE and is formed by N-methylation. It is released prin-
cipally from the adrenal medulla; however, its function
in the CNS has not been fully elucidated. Norepineph-
rine is released from the vesicles into the synaptic cleft
at the occurrence of an action potential. Norepinephrine
transporters on the synaptic terminals take up NE into
storage vesicles. Monoamine oxidase (MAO) deami-
nates and, hence, deactivates free NE in the cytosol that
has not been taken up into the vesicles, leading to the
formation of the metabolite, 3,4-dihydroxyphenylglycol
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

(DHPG). Dihydroxyphenylglycol is then converted to 3-
methoxy-4-hydroxyphenylglycol (MHPG) by catechol
O-methyltransferase (COMT). Residual NE in the syn-
apse is first metabolized by COMT and then MAO to
form MHPG and other metabolites.
Noradrenergic receptors are divided into ␣-adrener-
gic and b-adrenergic subtypes, each of which has further
subtypes: ␣1, ␣2, b1, b2 and b3. The postsynaptic b-ad-
renergic receptors activate Gs type G proteins to stimu-
late adenylyl cyclase, leading to a physiological re-
sponse. The ␣2 adrenergic receptors decrease adenylyl
cyclase activity or activate specific KⳭ channels through
coupling to Gi and/or Go,39 and are located both pre-
and postsynaptically. The ␣1 adrenergic receptor stim-
ulates the action of phospholipase C through Gx. and it
is located on the postsynaptic terminals. Only ␣2 and b2
adrenoreceptors are located on both presynaptic and
postsynaptic terminals. Norepinephrine and epineph-
rine stimulate both the ␣- and b-adrenergic receptors in
the periphery and CNS with the effects, depending on
the balance between the ␣- and b-receptors that are pres-
ent and have been activated. Presynaptic ␣2 adrenore-
ceptors modulate the negative feedback of NE release
and are pharmacologically different from postsynaptic
␣2 adrenergic receptors. Norepinephrine release can be
enhanced by the stimulation of b2 adrenoreceptors. Epi-
nephrine is more potent than norepinephrine on the b2
adrenoreceptor.
Norepinephrine mediates and is modulated by other
neurochemicals in the brain, many known to affect be-
havior. A loss or alteration in any one neurotransmitter
is likely to affect other neurotransmitters and potentially
lead to deviations in behavior. The noradrenergic sys-
tem interacts with acetylcholine,40–43 serotonin,44–46
DA47–49 and c-aminobutyric acid.50 Other neurotrophic
factors that interact with and modulate the noradren-
ergic system include a corticotropin releasing hor-
mone,51 ,52 somatostatin,53 and neuropeptide Y.54 Many
of these neurotrophic factors have been associated with
behaviors such as aggression, anxiety, and depression in
nondemented populations55 and thus alterations in par-
ticular neuropeptides may play a role in aggravating
already disrupted neurotransmitter systems. Since mul-
tiple neurochemical systems are known to be compro-
mised in AD,56 they may magnify behavioral distur-
bances.
NOREPINEPHRINE AND ALZHEIMER’S DISEASE
Alzheimer’s disease is associated with multiple neuro-
transmitter system dysfunction. The most well studied
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004
HERRMANN et al.
neuronal system dysfunction is the cholinergic system.
However, evidence supporting noradrenergic, seroto-
nergic, dopaminergic, corticotropin-releasing factor, and
somatostatin system dysfunction has also accumu-
lated,56–58 and mounting evidence supports the presence
of significant abnormalities in the noradrenergic system
in AD.58–78
Norepinephrine Concentrations
Postmortem studies have consistently shown noradren-
ergic system involvement in the AD disease process
with decreased NE levels being recognized in many
brain areas.58,59,61,62,64–67,71,72,74–78 The majority of studies
indicate significantly decreased cortical and subcortical
NE levels in the frontal medial gyrus, temporal superior
gyrus, cingulate gyrus, hippocampus, amygdala, thala-
mus, hypothalamus, caudate, putamen as well as the
LC.58,59,62,64,66,67,71,75,76 However, some studies did not
replicate these results due to possible confounders such
as postmortem delay.
Loss of Noradrenergic Neurons
A loss of noradrenergic neurons in the LC, the major
noradrenergic source in the brain, has been well estab-
lished in patients with AD,59,68–70,73–75,79,80 and has not
been found in other types of dementia such as vascular
dementia.59 These changes in the LC may account for a
deficiency in the noradrenergic system in the pathogen-
esis of AD.
However, NE concentrations in tissue may not di-
rectly correlate with functional noradrenergic transmis-
sion. Rather, noradrenergic turnover and neuronal ac-
tivity deduced through measurements of relative
concentrations of NE and its predominant intraneuronal
metabolite, MHPG, provide a more accurate represen-
tation of actual noradrenergic function. In postmortem
studies, when both NE and MHPG were quantified to-
gether, although brain NE was often decreased, MHPG
was found to be unchanged or high in AD patients com-
pared to control subjects.58,62,65,67,71,72,81 These findings
suggest that neuronal loss may lead to subsequent in-
creased NE metabolism and hence increased noradren-
ergic activity, possibly as a compensatory mechanism
for LC NE loss. Hoogendijk et al.62 demonstrated a sig-
nificant inverse correlation between the MHPG/NE ra-
tio and the number of remaining pigmented LC neurons
in AD patients, inferring an overactivity or activation of
the remaining LC neurons to counterbalance cerebral
263
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA
NE losses. It remains unclear whether this compensa-
tory activity occurs in the noradrenergic neuron termi-
nals in the projection areas, in the LC cell bodies or in
both.62
Galanin (GAL), a major inhibitory modulator of cho-
linergic and noradrenergic transmission, has been
shown to be hyperinnervated in the basal forebrain and
cortex of AD patients. Galanin fibers are thought to
originate in the LC. Miller et al.73 explored the possibil-
ity that GAL expression is increased in the LC of patients
with AD. Although the authors observed a significant
reduction in the amount of neuromelanin-pigmented,
which identifies NE presence, neurons in the LC of AD
patients, when investigated alongside age- and sex-
matched control subjects, there was no significant dif-
ference found between the number of both the pig-
mented and nonpigmented GAL mRNA expressing
neurons in either demented patients or control subjects.
This resulted in a significant increase in the percentage
of neuromelanin-pigmented GAL co-expressing cells in
patients with AD compared to control subjects, hence,
suggesting preservation or sparing of noradrenergic
neurons co-expressing GAL mRNA in a brain area oth-
erwise diminished of noradrenergic neurons. These re-
sults indicate a possible neuroprotective feature of GAL,
safeguarding the GAL co-localized group of noradren-
ergic neurons from damage resulting from the disease
process.73 The possibility that augmented GAL fiber in-
nervation may be due to the enhanced expression of
GAL within the remaining neurons in the LC region re-
mains to be investigated further.
Link With Severity
There is a well-established link between AD severity
and loss of noradrenergic neurons.69 Bondareff et al.69
compared total neuronal counts of 19 AD patients com-
pared to 10 nondemented subjects and found the group
of AD patients could be further divided into two distinct
groups according to LC neuronal cell counts, which also
correlated with severity of dementia. The authors re-
ported an 81% decrease in nucleus LC neurons in the
group of demented patients with more severe dementia,
when compared to control subjects. The group of pa-
tients with less severe dementia showed a 20% decrease
in LC neuronal loss. NE levels in the brain have also
been found to have an inverse relationship with cogni-
tive impairment.61,78 Lawlor et al.82 noted a significant
positive relationship between basal plasma MHPG lev-
els and cognitive impairment, further corroborating pre-
264
vious suppositions that increased MHPG from height-
ened NE turnover, as a result of losses of NE, is
correlated with increased cognitive dysfunction.
Dopamine Beta Hydroxylase (DBH)
Studies of DBH may further substantiate evidence of
noradrenergic dysfunction in AD. Both postmortem and
antemortem studies have shown DBH, a noradrenergic
biological marker, to be reduced in the hippocampus
and frontal and temporal cortices of AD patients when
compared to controls74,83,84 and patients with vascular
dementia.83,84 However, these results must still be inter-
preted with caution as the extent to which DBH activity
is associated with LC neuronal degeneration is still un-
clear.84
Cerebral Spinal Fluid (CSF)
Resting cerebral spinal fluid NE is thought to be gen-
erally increased with age, particularly in patients with
advanced AD, and has been shown to be higher in AD
patients when compared to control subjects.63,85 This is
consistent with the proposed compensatory action of
noradrenergic neurons. It is essential to note that the
major method of NE clearance from the CSF is through
NE reuptake by presynaptic noradrenergic terminals.86
Therefore, it is possible that AD related noradrenergic
circuit degeneration may lead to impairment of NE
reuptake resulting in increased CSF NE levels.87 Hence,
measuring CSF NE concentrations may not allow a di-
rect evaluation of CNS noradrenergic dynamics. It is
more important to measure NE precursors and metab-
olites as well CSF NE levels for a comprehensive anal-
ysis of NE activity.88 Moreover, MHPG, unlike NE,
crosses the blood-brain barrier freely, hence CSF MHPG
can provide an indication of neuronal NE metabolism
and dispersion of circulating MHPG into CSF. Therefore,
it is imperative that plasma MHPG levels are accounted
for in order to accurately interpret CNS noradrenergic
activity.63 Raskind et al.87 compared levels of NE, its me-
tabolite DHPG, and precursor dopa in both CSF and
plasma following administration of yohimbine (a selec-
tive ␣2 adrenergic receptor blocker), clonidine (a selec-
tive ␣2 agonist), and placebo in older subjects with AD,
older subjects without AD and younger subjects. The
results suggested that the increase in CSF NE subse-
quent to yohimbine administration in both older sub-
jects and AD subjects is not likely due to a reduction in
NE clearance but rather mechanisms that compensate
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

for NE neuron loss through augmented NE biosynthe-
sis.
Cerebral spinal fluid NE response to manipulation of
the ␣2 adrenergic receptor by the administration of yo-
himbine and clonidine has been studied to evaluate nor-
adrenergic tone, yet a very limited amount of evidence
is available regarding noradrenergic dysfunction. A
general increase in CSF NE has been seen in response to
yohimbine in both AD and older control subjects (with
a greater increase in the AD subjects), when compared
to younger control subjects.87,89 Results of studies of the
CSF NE response to clonidine have been inconsistent,
with insignificant results predominating. Further re-
search into this area is needed to elucidate the value and
capacity of CSF catechols as an index of neuronal neu-
rotransmission function.
Compensating for lost neurons results in the tonic ac-
tivation of the noradrenergic system leading to an in-
creased noradrenergic response. Mechanisms that may
account for this include the following: 1) Neuronal plas-
ticity38,89—resulting in the hyperinnervation of certain
brain regions. This may be a result of regenerating neu-
rons and has been observed in rats.38,89 2) Increased NE
synthetic capacity and firing rate in damaged LC neu-
rons.38,89 3) Decreased ability of presynaptic ␣2 receptors
to inhibit noradrenergic activity.38,89 Studies have indi-
cated a loss of ␣2 receptor inhibition in AD, leading to
the tonically activated state of the noradrenergic system
and increased CSF NE levels.87,89 This increase in com-
pensatory activity is usually accompanied by compen-
satory activity in other neurotransmitter systems as
well.
Both postmortem and antemortem evidence supports
a consistent link between noradrenergic dysfunction
and AD (Tables 1 and 2). Postmortem studies provide
the strongest evidence of noradrenergic degeneration in
AD. Although postmortem evidence may provide a de-
scriptive representation of the loss of noradrenergic neu-
rons, postmortem results may not directly reflect the an-
temortem state. Nonetheless, much of the evidence
reviewed reveals decreased levels of both NE and nor-
adrenergic neurons, while MHPG levels have been
found to be increased, suggesting increased NE metab-
olism and, hence, activity. The fact that this correlates
positively with increased AD severity, further validates
these findings.
NOREPINEPHRINE AND BEHAVIOR
The LC is sensitive to both variations in the body’s in-
ternal homeostasis and external environmental stimuli,
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004
HERRMANN et al.
which can activate not only the central noradrenergic
system and sympathoadrenal system but may result in
behavioral manifestations as well. The LC is involved in
regulation of levels of arousal, flight-and- fight re-
sponses,89,90 agitation, anxiety,89 sleep-wake cycle, and
levels of vigilance and emotion70,91,92 as well as aggres-
sive behaviors.93–95 Noradrenergic projections from the
LC also modulate sympathetic nervous system re-
sponse, including blood pressure, pulse rate and danger
signals. Hence, the noradrenergic system, directly or in-
directly, has the potential to modify a variety of behav-
iors through actions in both the cortical and subcortical
regions. A disruption of such an integrated system
could potentially lead to abnormal behavioral responses
to otherwise ordinary stimuli. LC damage has been de-
termined in several neurologic disorders that are char-
acterized by altered behavior including Parkinson’s dis-
ease, schizophrenia and depression.70,92
The link between NE disruption and behavior has
been studied in a variety of psychiatric disturbances in-
cluding depression, anxiety, agitation and aggression. In
depression there is evidence of ␣2 receptor dysfunction
including postsynaptic ␣2 receptor downregulation,96–98
increased presynaptic ␣2 receptor sensitivity,99 and in-
creased ␣2 receptor density in the LC.100,101 Decreased
noradrenergic receptor sensitivity and increased nor-
adrenergic turnover have been noted in patients with
anxiety,102 generalized anxiety disorder,103 and posttrau-
matic stress disorder.104 High levels of NE release have
been associated with aggression in animals, healthy
adults93,105,106 and patients with depression and ma-
nia.107,108 In animal models, NE enhances aggressive be-
haviors106,109 and b-adrenoreceptor blockers have been
shown to decrease aggression.106 Finally NE and NE me-
tabolite levels are positively correlated with aggressive
behaviors in patients with personality disorders.110–112
In summary, there is significant evidence of noradren-
ergic system involvement in a variety of psychiatric and
behavioral disorders from animals and nondemented
human studies.
NOREPINEPHRINE AND BEHAVIOR IN
DEMENTIA (BPSD)
As previously mentioned, behavioral problems, particu-
larly agitation and aggression are prevalent in AD. This
has been consistently shown in various studies.113–116 A
prospective, 10-year, longitudinal study on the change
in aggressive behavior throughout the course of demen-
265
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA

tia by Keene et al.117 measured physical aggression, ag-
gressive resistance, physical threats, verbal aggression,
refusing to speak, destructive behavior and general ir-
ritability. The authors reported 96% of the 99 subjects
with AD/vascular dementia showed profound or con-
tinuing aggressive behavior of at least one type during
the dementia disease process, with verbal aggression as
the most common behavioral disturbance. As the nor-
adrenergic system has been implicated in the disorder
of behavior in animals as well as other psychiatric ail-
ments, it has been suggested that NE may likely play a
role in the noncognitive behavioral disturbances asso-
ciated with AD.118 Agitation, particularly aggression
and akathisia, has been linked with increased norepi-
nephrine activity.119 Noradrenergic system components
have been associated with behaviors associated with de-

TABLE 1. Summary of Literature Concerning Changes in NE Neurons and Levels in Patients with AD
Measures and References Finding Comments
NE neurons postmortem
Mann et al. 198259 f neurons (vagus nucleus, LC) 19 patients with AD, eight with MID, versus 21 control
subjects
79
Förstl et al. 1992 f neurons (LC), depressed AD ⬍ nondepressed AD 52 patients with AD; depressed AD (n⳱14); no control
subjects
Bondareff et al. 198269 f neurons (LC) 20 patients with AD versus 10 control subjects
Mann et al. 198468 f neurons (LC, nucleus basalis) 22 patients with AD versus control subjects; AD severity
varied from moderate to severe
Hoogendijk et al. 199570 f neurons (in large neurons), f neurons (in small Five patients with AD, five with Parkinson’s disease, five
neurons) with amyotrophic lateral sclerosis, versus five control
subjects; control subjects concomitant with viral
encephalitis and AIDS, cerebral infarctions without
dementia; diabetes II and liver cirrhosis from chronic
non-A non-B hepatitis
Miller et al. 199973 f neurons (rostral, caudal LC) Six patients with AD versus control subjects
Perry et al. 198180 f neurons (LC) Patients with AD, unipolar depressed, versus control
subjects
Iversen et al. 198374 f neurons (LC) Six patients with AD versus six control subjects
Moll et al. 199075 f neurons (LC) Seven patients with AD versus seven control subjects
Matthews et al. 200278 f neurons (rostral LC, mid LC) 36 patients with AD, 10 with mixed/other dementia, 33
control subjects; concurrently on antidepressant (n⳱1),
sedative hypnotics (n⳱10), neuroleptics (n⳱13) in AD
group; concurrently on antidepressant (n⳱2), sedative
hypnotics (n⳱5), neuroleptics (n⳱3) in mixed/other
dementia group
NE levels postmortem
Mann et al. 198259 f NE (hypothalamus, caudate) 19 patients with AD, eight patients with MID versus 21
control subjects
Adolfsson et al. 1979 f NE (putamen, cortex gyrus frontalis)
61
19 patients with AD versus control subjects
Hoogendijk et al. 199962 f NE (frontal medial gyrus, temporal superior gyrus, 16 patients with AD (depressed n⳱6, transiently
amygdala, thalamus, LC) depressed n⳱5, nondepressed n⳱5) versus control
subjects; comorbid hallucinations (n⳱3), anxiety
(n⳱2), agitation (n⳱4), compulsive eating (n⳱1),
delirium (n⳱2), apathy (n⳱1), chronic psychosis
(n⳱1); clinical assessment by NINCDS-ADRDA, DSM-
III-R, Cornell scale
Arai 198464 f NE (cingulate gyrus, substantia innominata, Four patients with AD versus nine control subjects;
hypothalamus, putamen, medial nucleus of thalamus, concurrent sulpiride (n⳱1), estazolam (n⳱1)
raphe)
Francis et al. 198565 f NE (early and late onset) 48 patients with AD (early onset n⳱19, older onset
n⳱29) versus 34 control subjects
Nazarali et al. 199266 f NE (temporal cortex, amygdala) 13 patients with AD versus 22 control subjects (non-AD
dementia n⳱12, normal n⳱10)
Storga et al. 199667 f NE (amygdala, caudate, substantia nigra, cingulate Eight patients with AD versus six control subjects;
gyri) concurrent neuroleptic use (n⳱6)
Gottfries et al. 198371 f NE (hypothalamus, caudate, hippocampus, cortex of 14 patients with AD versus 16 control subjects;
the cingulate gyrus) comorbidity in AD with mild Parkinson’s disease and
treated with l dopa (n⳱1)
a
NE⳱norepinephrine; LC⳱locus caeruleus; AD⳱Alzheimer’s disease; MID⳱multi-infarct dementia; NINCDS-ADRDA⳱National Institute
of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria.

266 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

 TABLE 2. Summary of Literature Concerning Changes in NE Metabolites in Patients with ADa
Measures and References
MHPG
Postmortem
Bierer et al. 199558
Hoogendijk et al. 199962
Francis et al. 198565
67
Storga et al. 1996
Gottfries et al. 198371
Herregodts et al. 198972
Finding
F MHPG
} MHPG (frontal medial gyrus, superior temporal gyrus,
LC, hippocampus, amygdala, thalamus)
F MHPG (early onset), F MHPG (late onset)
F MHPG (globus pallidus, raphe putamen, amygdala,
caudate, substantia nigra, cingulate gyrus)
F MHPG (caudate, cortex of the cingulate gyrus,
hippocampus)
F MHPG (cortical, subcortical)
Comments
47 patients with AD versus 10 control subjects, clinical assessment by
CERAD, Khachaturian criteria, control group included patients with
MID (n⳱5); concurrent antibiotic treatment, diuretic, antiarrhythmics
or antianginal treatment, and neuroleptic use
16 patients with AD (depressed n⳱6, transiently depressed n⳱5,
nondepressed n⳱5) versus control subjects; comorbid hallucinations
(n⳱3), anxiety (n⳱2), agitation (n⳱4), compulsive eating (n⳱1),
delirium (n⳱2), apathy (n⳱1), chronic psychosis (n⳱1); clinical
assessment by NINCDS-ADRDA, DSM-III-R, Cornell Scale
48 patients with AD (early onset n⳱19, older onset n⳱29) versus 34
control subjects
Eight patients with AD versus six control subjects; concurrent neuroleptic
use (n⳱6)
14 patients with AD versus 16 control subjects; comorbidity in patients
with AD with mild Parkinson’s disease and treated with l-dopa (n⳱1)
Eight patients with AD (early-onset n⳱4, late-onset n⳱4) versus six

J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

Antemortem
Palmer et al. 198760
CSF
Raskind et al. 198463
Tohgi et al. 1992(81
Plasma
Raskind et al. 198463
Lawlor et al. 199582
MHPG/NE ratio
Postmortem
Hoogendijk et al. 199962
Antemortem
Palmer et al. 198760
DHPG
CSF (in response to yohimbine challenge)
Raskind et al. 199987
Plasma (in response to yohimbine
challenge)
Raskind et al. 199987
control subjects
} MHPG (temporal lobe) Patients with AD versus control subjects; clinical assessment by WAIS,
the Token Test, a continuous Visual Reaction Time task; duration of
onset not reported.
F MHPG (in advanced AD) 16 patients with AD (advanced n⳱9, moderate n⳱7) versus control
subjects; concurrent sympathetic nervous system medication (n⳱4),
low dose antipsychotic use (n⳱2), low dose tricyclic antidepressant use
(n⳱2); tricyclic antidepressant effect on MHPG level
F MHPG 11 patients with AD/SDAT, 17 patients with VDBT, and 15 control
subjects
F MHPG (in advanced AD) 16 patients with AD (advanced n⳱9, moderate n⳱7) versus control
subjects. See above for further information
F MHPG (in AD with respect to decline of cognition) 23 patients with AD; results controlled for age, age at onset, sex, and
interval between plasma MHPG determination and cognitive testing
F MHPG/NE ratio (LC, frontal medial gyrus, superior 16 patients with AD (depressed n⳱6, transiently depressed n⳱5,
temporal gyrus, hippocampus, thalamus) nondepressed n⳱5) versus control subjects. See above for further
information.
F MHPG/NE ratio Patients with AD versus control subjects. See above for further
information.
} DBH 10 patients with AD versus 21 control subjects (young n⳱11, old n⳱10);
behavior rating nurses were not blinded; behavior assessment with
BPRS
} DBH 10 patients with AD versus 21 control subjects (young n⳱11, old n⳱10).
See preceding page for further information.
HERRMANN et al.

267
continued
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA

12 patients with AD, five patients with MID, nine with depression versus
mentia (Table 3). The role of norepinephrine in the fa-

control subjects; clinical assessment with Hachinski’s ischemic score,

31 patients with AD and 31 patients with MID versus 46 age-matched

31 patients with AD and 31 patients with MID versus 46 age-matched

MHPG⳱3-methoxy-4-hydroxyphenylglycol; CERAD⳱Consortium to Establish a Registry for Alzheimer’s Disease; AD⳱Alzheimer’s disease; MID⳱multi-infarct dementia;
computerized tomography, Hasegawa’s Dementia Rating Scale
cilitation of BPSD in AD is reviewed below.

LC⳱locus caeruleus; NINCDS-ADRDA⳱National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders
16 control subjects; subject background not reported

control subjects. See above for further information.

Association criteria; SDAT⳱senile dementia of the Alzheimer type; PD⳱Parkinson’s disease; VDBT⳱vascular dementia of the Binswanger type; NE⳱norepinephrine;
Depression
Six patients with AD versus six control subjects

Depression may complicate AD and has been found to

be most common among people with mild severity of
dementia.120 Both AD and depression share similar
signs and symptoms, including loss of interest and ap-
petite, apathy, and sleep disturbances.4 Studies have
found that AD patients suffering from comorbid
depression have significantly more LC neuron degen-
eration when compared to nondepressed AD pa-
tients.79,121,122 However, contradictory evidence exists.
Hoogendijk et al.123 also compared LC neuronal cell
counts between depressed and nondepressed AD pa-
tients but found no significant differences in LC degen-
DHPG⳱3,4-dihydroxyphenylglycol; DBH⳱dopamine-beta-hydroxylase enzyme; BPRS⳱Brief Psychiatric Rating Scale.

eration between depressed and nondepressed AD pa-

tients. This may be due to methodological differences
Summary of Literature Concerning Changes in NE Metabolites in Patients with ADa (continued)

between the studies such as confounding by level of se-

verity of both dementia121 and depression,121,122 LC sam-
ple section size and location of analysis.79,122 A reduction
in NE has also been observed in cortex of depressed AD
patients124 further supporting the role altered noradren-
ergic function may play in influencing depressive symp-
f DBH activity (frontal, temporal cortex, hippocampus)

f DBH (especially with severe dementia and/or severe

toms. Thus, the literature currently supports an associ-

ation between NE and depression in AD.

Aggression and Agitation

Russo-Neustadt and Cotman125 observed a small but
brain atrophy)

significant increase in total b-adrenoreceptor concentra-

f DBH (LC)

tion in the cerebella of aggressive AD patients when

f DBH

compared to nonaggressive AD patients and healthy

control subjects. This finding suggests a possible link
between aggression/agitation and b-adrenergic receptor
binding.
Since presynaptic ␣2 receptors regulate the negative
feedback of NE and postsynaptic receptors are thought
to regulate postsynaptic neuronal function, the differ-
ential location of the ␣2 adrenoreceptor may play a role
in modulating aggression.106 Activation of the ␣2 adre-
noreceptor by an agonist may lead to differing results
depending on whether the post- or presynaptic recep-
Iversen et al. 198374

tors were stimulated or, possibly, depending on the ratio

Miyata et al. 198483

Miyata et al. 198483

Cross et al. 198184

of the activated receptors. A postmortem study125 of the

frontal cortex, hypothalamus and cerebellum (areas in-
Postmortem

nervated by LC neurons) of agitated AD patients, non-

TABLE 2.

agitated AD subjects and healthy elderly control sub-

Serum

jects revealed a significantly elevated level of ␣2

CSF
DBH

receptors in the cerebellum of aggressive subjects, 70%

268 J Neuropsychiatry Clin Neurosci 16:3, Summer 2004


higher than the nonagitated AD subjects. The levels of
␣2 receptors found in the nonagitated AD patients were
slightly but not significantly higher than the levels
found in the healthy elderly control subjects. Measure-
ments of the ␣2 receptors in the frontal cortex and hy-
pothalamus were not found to vary significantly.
There is some evidence that supports an association
between motor restlessness and increased MHPG levels.
MHPG levels have been found to be correlated with
restlessness in AD patients.126
In vivo studies have also been performed to address
the link between BPSD and NE. Yohimbine has been
reported to lead to increased release of NE and succes-
sive activation of the postsynaptic ␣1 adrenoreceptors.127
It has been shown that AD patients are more sensitive
to administration of yohimbine, compared to other el-
derly patients and younger subjects,87,128 and exhibit
more agitated behaviors. This may be due to increased
postsynaptic noradrenergic sensitivity in AD.87,89 This is
plausible, as postsynaptic b-receptors have been re-
ported to be up-regulated in the prefrontal cortex and
hippocampus of AD patients,89 consistent with the pos-
tulated increase in sensitivity to noradrenergic stimu-
lation.87 As a result of noradrenergic overactivation, AD
patients would no longer be able to focus attention and
their mechanisms of coping with stressful stimuli would
be compromised. Even in the absence of stressful stim-
uli, the noradrenergic system would be active. This may
account for the aggression displayed in many AD pa-
tients.38,62 These findings further consolidate the prob-
ability of an adrenergic dysfunction contributing to the
pathophysiology of agitated behaviors in AD.
TABLE 3. Summary of Studies Linking Noradrenergic System Components With BPSDa
Noradrenergic System Finding
Component
␣1—post — —
␣2 (not specified if pre or post) F cerebellum, } frontal cortex,
hypothalamus
b1—post F cerebellum
b2—post F cerebellum
3-Methoxy-4- F CSF MHPG
hydroxyphenylglycol (MHPG)
levels
LC cell counts F degeneration
F degeneration
} degeneration
} degeneration, f degeneration
a
F⳱increased; }⳱no change.
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004
HERRMANN et al.
Psychosis
Psychosis is a cluster of clinically disruptive behaviors
often observed in AD patients. Psychotic behaviors in-
volve delusions and hallucinations and can aggravate
aggression.129 Both evidence supporting the association
between psychotic behaviors and noradrenergic pres-
ervation,130 and evidence showing no association be-
tween psychosis and NE121,131 have been published. Zu-
benko and associates130 found higher NE concentrations
in the substantia nigra of psychotic AD patients when
compared to nonpsychotic AD patients. Förstl et al.131
found that AD patients with auditory hallucinations or
delusions had significantly higher neuron counts in the
parahippocampal gyrus and a trend towards lower dor-
sal raphe nucleus neuron counts compared to AD pa-
tients without psychosis; however, this was not ob-
served in the LC. The link between the noradrenergic
system and psychotic behaviors is still unclear and fur-
ther investigation is necessary.
In summary, evidence from both animal and human
studies supports a link between noradrenergic dysfunc-
tion and behavior, particularly aggressive behavior. De-
pressed patients, patients suffering from anxiety disor-
ders and AD patients all show blunted growth hormone
(GH) responses to clonidine, strongly suggesting a dis-
ruption in noradrenergic control. Intensified noradren-
ergic activity and/or hypersensitive adrenoreceptors are
thought to mediate this NE dysfunction in aggression
associated both with and without AD as well as anxiety
and depression. It is believed that compensation for the
loss of the noradrenergic neurons that occurs during the
progression of AD leads to an increase in the number of
Behavior Reference
—
Aggression Russo-Neustadt et al. 1997125
Aggression Russo-Neustadt et al. 1997125
Aggression Russo-Neustadt et al. 1997125
Restlessness Brane et al. 1989126
Aggression Matthews et al. 200278
Depression Förstl et al. 199279, Zubenko et al.
1988122, Zweig et al. 1988121
Depression Hoogendijk et al. 1999
Psychosis Zweig et al. 1988121, Förstl et al. 1994131,
Zubenko et al. 1991130
269
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA
noradrenergic receptors and/or increased activity of re-
maining noradrenergic neurons, the potential source of
aggressive behavior. This is credible as b1, b2 and ␣2 re-
ceptor upregulation has been shown in aggressive AD
patients when compared to nonaggressive AD patients.
The clinical expression of aggression likely is also de-
pendent on other neurotransmitters. In summary, it has
been shown that both ␣ and b-adrenoreceptors are in-
volved in the modulation of aggression. However, the
exact role each receptor plays is still uncertain and fur-
ther research is needed to clearly assess the link with NE
and behavior, particularly BPSD.
NORADRENERGIC PHARMACOTHERAPY
The probability that the noradrenergic system contrib-
utes to the pathophysiology of BPSD associated with
AD has led to potential therapeutic interventions. Phar-
macological manipulation of the CNS noradrenergic
system through the blockade of the beta adrenergic re-
ceptors has been studied as a treatment for a variety of
neuropsychiatric disorders.132 As it is believed norepi-
nephrine is involved in the modulation of behavior, nor-
adrenergic agents have much pharmacological potential
for the amelioration of behavioral disturbances. Study-
ing the effects of noradrenergic agents on the various
behavioral disturbances associated with dementia can
also lead to a better understanding of their neurochem-
ical etiology in the way neuroleptic response led to an
understanding of the role of DA in schizophrenia.
Beta Blockers
Previous studies have indicated propanolol, a long-act-
ing b-blocker, to be an effective treatment for aggression
and agitation in patients with dementia who have been
unsuccessfully treated with conventional therapies.133–137
In a randomized double-blind crossover placebo-con-
trolled study, Greendyke et al.133 evaluated the efficacy
of propanolol for an 11-week period at a maintenance
dosage of 520 mg/day, in assaultive patients with or-
ganic brain impairment. The authors reported signifi-
cantly fewer assaults and attempted assaults by the nine
patients who completed the study, during the active
treatment phase when compared to the placebo phase.
Five patients showed marked improvement, two
showed moderate improvement and two showed little
or no improvement of violent behavior. A similar study
was repeated by Greendyke and Kanter138 using pin-
dolol, another b1 blocking agent, rather than propanolol.
270
Pindolol wields a partial agonist effect thereby exerting
similar therapeutic benefits as propanolol but with less
cardiovascular side effects such as hypotension, brady-
cardia and decreased cardiac output. Patients were
maintained on an individualized optimum dosage be-
tween 40–60 mg/day for a minimum of 10 days. Signifi-
cant reductions in assaultiveness, hostility, lack of com-
munication, uncooperativeness and repetitive behaviors
were noted. Shankle et al.135 observed a 71% response
rate in patients with either AD or vascular dementia
(VaD) with both agitated and aggressive behaviors who
were treated with propanolol. The 12 patients received
20 mg propanolol per day which was increased to an
efficacious maximum that ranged between 30 and 80 mg
per day. One patient suffered an adverse event (brady-
cardia), which was resolved by lowering the dose. A
case series by Weiler et al.137 also demonstrated success
in relieving treatment refractory disruptive behavior in
4 patients with AD and 2 patients with VaD. The pro-
panolol doses ranged from 80 mg/day to 520 mg/day
and no adverse events were noted. These studies indi-
cate that the modulation of the b-adrenoreceptors
through the use of b-blockers has been useful in the re-
duction of aggressive behaviors. However, many of
these studies involved patients with varying dementia
etiologies. A randomized controlled trial with AD pa-
tients treated for BPSD using b-blockers is necessary be-
fore one can accurately judge effectiveness. Important
clinical considerations must be recognized when using
b-blockers in elderly patients. b- Blockers may exacer-
bate various concomitant illnesses such as chronic ob-
structive pulmonary disease, diabetes mellitus and pe-
ripheral vascular disease. Additionally, beta-blockers
have been shown to increase plasma concentrations of
some antipsychotics, including chlorpromazine and
thioridazine.139
Antidepressants
Imipramine, a tricyclic antidepressant, inhibits the reup-
take of noradrenaline and has been shown to prevent
upregulation of b-adrenoreceptors induced by stress140
and may hinder the induction of tyrosine hydroxylase
in the LC following cold stress,51 suggesting a lessening
of stress-induced norepinephrine release. Reifler et al.141
compared the use of imipramine with placebo in 61 AD
patients, of those, 28 had a diagnosis of depression and
33 did not. The authors found that the depressed pa-
tients scored significantly higher than the nondepressed
patients on the Hamilton Depression Rating Scale and
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004

though all patients improved significantly during the
study, the depressed patients improved significantly
more than the patients without depression. Although
clinical recommendations have been made about avoid-
ing the use of tertiary amines in the elderly demented
population,142 imipramine was found to be extremely
well tolerated in Reifler’s study, as no significant differ-
ences in adverse events were noted in the imipramine-
treated group compared to the placebo-treated group.
Mirtazapine is a noradrenergic and specific seroto-
nergic antidepressant that directly blocks the pre- and
postsynaptic ␣2 receptors and antagonizes the 5-hydrox-
ytryptamine (5-HT)2 and 5-HT3 receptors with high af-
finity and 5-HT1 receptors with low affinity.143 Mirta-
zapine has been used with favorable results in a case
series by Raji and Brady144 in AD patients suffering from
depression as well as anxiety, weight loss and insomnia.
Three patients were given a trial of mirtazapine. Two
patients were started at 7.5 mg and titrated up over 2
weeks to 15 mg. One of those patients was further ti-
trated up over 2 more weeks to 30 mg. The third patient
was started at 15 mg and was increased to 30 mg after
2 weeks. No changes were noted in cognition; however,
improvement in appetite and sleep was documented
within 2–4 weeks and cessation of anxiety and depres-
sion was noted at 2 months. None of the patients suf-
fered any adverse effects. This case series suggests that
mirtazapine may be an effective therapy for depressed
AD patients with comorbid insomnia, anxiety and ap-
petite loss. However, there is a lack of randomized con-
trolled trials using mirtazapine, and therefore the extent
of the usefulness of mirtazapine pharmacotherapy is
still unknown and remains to be explored.
Other antidepressants with putative effects on the NE
system include venlafaxine, bupropion, and reboxetine,
though none of these agents have been tested for BPSD.
Psychostimulants
Psychostimulants, such as methylphenidate (MPD),
have been used in the past to treat affective disorders,
particularly depression. MPD is believed to block both
norepinephrine and DA uptake and promote catechol-
amine release.145 Few controlled studies have evaluated
the efficacy of psychostimulants in the treatment BPSD.
A case series by Maletta and Winegarden145 examined
three severely demented patients, suffering from apathy
and anorexia resulting in weight loss, using methyl-
phenidate therapy. Two patients were started on 5 mg
bid and one patient was started on 5 mg once daily.
J Neuropsychiatry Clin Neurosci 16:3, Summer 2004
HERRMANN et al.
Doses were increased up to the maintenance dose of 10
mg bid. Appetite was found to increase within 3–7 days
of initiating therapy, and complete resolution of an-
orexia, leading to weight gain, was observed within a
few weeks. Improvement in social interaction and hence
a decrease in apathy was also noted by the nurses. The
patients were maintained on methylphenidate for 9, 16
and 24 months, respectively, and were eventually ta-
pered off successfully. No adverse effects were noted
and no other psychotropic was used during the period
of treatment. Kaufmann et al.146 also found favorable
results with one dementia patient who was treated suc-
cessfully for depressive symptoms including appetite
loss and apathy, using methylphenidate.
Branconnier and Cole147 also conducted a placebo-
controlled study in demented, apathetic patients using
20–30 mg MPD and found an improvement in apathy
that correlated with a lessening of depressive symp-
toms. Galynker et al.148 treated 12 AD patients and 15
VaD patients using methylphenidate and found a sig-
nificant improvement in negative symptoms.
Although the benefits of methylphenidate therapy in
the elderly have been reported for the last 50 years, the
results are limited by poor designs and lack of stan-
dardized assessments for behavior and even diagnoses.
Methylphenidate appears to be useful in alleviating de-
pressive symptoms including appetite loss and apathy;
however, more research is needed to explore the value
of; MPD in the pharmacotherapy of other behavioral
disturbances associated with AD. Furthermore, as noted
previously, psychostimulants have effects on other neu-
rotransmitters, and it is not clear whether their beneficial
effects for BPSD are due to their actions on NE or other
systems.
It is difficult to treat BPSD pharmacologically as some
patients may be very sensitive to first-line therapy with
antipsychotic medications. Treatment emergent side ef-
fects may be intolerable resulting in the discontinuation
of the drug. Hence, prescribing medication for BPSD of-
ten involves trying a series of medications on each pa-
tient. The use of b adrenergic antagonists for BPSD such
as agitation and aggression may be clinically advanta-
geous due to the absence of the extrapyramidal symp-
toms and sedation commonly seen with antipsychotics.
Other adrenergic agents have been studied for the alle-
viation of other behavioral symptoms frequently asso-
ciated with dementia, however, the vast majority of nor-
adrenergic agents prescribed are for depression.
Although the pharmacological management of depres-
271
NOREPINEPHRINE IN SYMPTOMS OF DEMENTIA
sion with noradrenergic drugs has been shown to be
successful, there is a great need for further research to
elucidate the role of noradrenergic pharmacotherapy in
the treatment of depression associated with AD. Given
the modest efficacy of antipsychotics and the variable
responses to antidepressants, randomized controlled tri-
als of noradrenergic agents for BPSD are urgently
needed.
CONCLUSIONS
The bulk of neuropathological studies in AD show nor-
adrenergic neuron degeneration, decreased NE levels
and increased NE metabolites. This evidence strongly
and consistently suggests enhanced NE turnover. The
vast majority of studies; however, have been done post-
mortem, and consequently caution is necessary in their
interpretation. As altered behavior may be a result of
“state” rather than “trait” phenomenon, it is important
that the behavior being examined is manifested at the
time of death, so as to accurately measure the neurolog-
ical changes believed to be responsible. Postmortem de-
lay is a confounding variable in neurophysiological
analysis as postmortem results may not correctly rep-
resent the antemortem state. The consequences of delay
in freezing brain tissue after death and prolonged pres-
ervation of brain tissue prior to catecholamine analysis
have not yet been fully accounted for and may limit the
usefulness of postmortem studies.
Norepinephrine is involved in the sympathetic
“flight-or-fight” response and thus is sensitive to envi-
ronmental challenges and can modulate behavior ac-
cordingly. The noradrenergic system has been shown to
mediate behavior, particularly aggression, in animals as
well as in psychiatric illnesses. Although there is sub-
stantial evidence correlating NE with aggression, a di-
rect link between NE function and aggression associated
with dementia needs to be examined further. More re-
search into identifying the role of the noradrenergic re-
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