Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314-1322

Article (PDF Available)inBrain 128(Pt 6):1314-22 · July 2005with642 Reads
DOI: 10.1093/brain/awh445 · Source: PubMed
Abstract
The reason for the high frequency of depression and anxiety in Parkinson's disease is poorly understood. Degeneration of neurotransmitter systems other than dopamine might play a specific role in the occurrence of these affective disorders. We used [11C]RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, to localize differences between depressed and non-depressed patients. We studied eight and 12 Parkinson's disease patients with and without a history of depression matched for age, disease duration and doses of antiparkinsonian medication. The depressed Parkinson's disease cohort had lower [11C]RTI-32 binding than non-depressed Parkinson's disease cases in the locus coeruleus and in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum. Exploratory analyses revealed that the severity of anxiety in the Parkinson's disease patients was inversely correlated with the [11C]RTI-32 binding in most of these regions and apathy was inversely correlated with [11C]RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.
doi:10.1093/brain/awh445 Brain (2005), 128, 1314–1322
Depression in Parkinson’s disease: loss of
dopamine and noradrenaline innervation in the
limbic system
Philippe Remy,
1,2
Miroslava Doder,
2
Andrew Lees,
3
Nora Turjanski
2
and David Brooks
2
Correspondence to: Philippe Remy , CNRS-CEA URA2210,
Service Hospitalier Fre
´
de
´
ric Joliot, 4, place du Ge
´
ne
´
ral
Leclerc, 91401 Orsay cedex, France.
E-mail: remy@shfj.cea.fr
1
CNRS-CEA URA2210, Service Hospitalier Fre
´
de
´
ric Joliot,
CHU Henri Mondor et Faculte
´
de Me
´
decine Paris 12,
France
2
Faculty of Medicine, Hammersmith Hospital,
Imperial College-MRC Clinical Sciences Centre and
Division of Neuroscience and
3
Institute of Neurology,
Queen Square, London, UK
Summary
The reason for the high frequency of depression and
anxiety in Parkinson’s disease is poorly understood.
Degeneration of neurotransmitter systems other than
dopamine might play a specific role in the occurrence of
these affective disorders. We used [
11
C]RTI-32 PET, an
in vivo marker of both dopamine and noradrenaline trans-
porter binding, to localize differences between depressed
and non-depressed patients. We studied eight and 12
Parkinson’s disease patients with and without a history
of depression matched for age, disease duration and
doses of antiparkinsonian medication. The depressed
Parkinson’s disease cohort had lower [
11
C]RTI-32 binding
than non-depressed Parkinson’s disease cases in the locus
coeruleus and in several regions of the limbic system
including the anterior cingulate cortex, the thalamus,
the amygdala and the ventral striatum. Exploratory
analyses revealed that the severity of anxiety in the
Parkinson’s disease patients was inversely correlated
with the [
11
C]RTI-32 binding in most of these regions
and apathy was inversely correlated with [
11
C]RTI-32
binding in the ventral striatum. These results suggest
that depression and anxiety in Parkinson’s disease might
be associated with a specific loss of dopamine and norad-
renaline innervation in the limbic system.
Keywords: PET imaging; Parkinson’s disease; depression; limbic system; catecholamines
Abbreviations: ADD = additional integrated image; BDI = Beck Depression Inventory; BP = binding potential;
CingA = anterior cingulate cortex; DAT = dopamine transporter; NAT = noradrenaline transporter; ROI = region of interest;
SPM = statistical parametric mapping; UPDRS = Unified Parkinson’s Disease Rating Scale
Received November 4, 2004. Revised January 13, 2005. Accepted January 18, 2005. Advance Access publication
February 16, 2005
Introduction
The frequency of depression in Parkinson’s disease is 40%
(Brown and Jahanshahi, 1995; Cummings and Masterman,
1999). The rate of severe depression is twice that seen in other
equivalently disabled patients (Rodin and Voshart, 1986).
The natural history of depression in Parkinson’s disease
does not parallel the progression of physical symptoms, sug-
gesting that it is an independent process that might affect
vulnerable patients (Brown and Jahanshahi, 1995). However,
the pathophysiology of depression in Parkinson’s disease
remains obscure. Some authors constructed models including
multiple factors (Brown and Jahanshahi, 1995), whereas
others postulate that neurochemical abnormalities may
explain depression in Parkinson’s disease (Cummings and
Masterman, 1999). While widespread dopamine deficiency
is the main feature of Parkinson’s disease, other neuro-
transmitter systems degenerate or are altered by the degen-
erative process, such as the noradrenergic and serotoninergic
brainstem nuclei (Halliday et al., 1990). Several studies have
suggested the involvement of these neurotransmitters in the
pathogenesis of depression in Parkinson’s disease, but no
clear pattern has emerged (Brown and Jahanshahi, 1995;
Tom and Cummings, 1998).
We used [
11
C]RTI-32 PET to study the role of catechola-
minergic neurotransmission in the pathophysiology of
depression in Parkinson’s disease. [
11
C]RTI-32 binds with
similar nanomolar affinities to the dopamine (DAT) and
#
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noradrenaline (NAT) membrane transporters but with far lower
affinity to the serotonin transporter (Carroll et al., 1995). We
compared the binding of this tracer in depressed and non-
depressed Parkinson’s disease patients who had similar age,
disease severity and doses of antiparkinsonian medication.
Subjects and methods
Subjects
Twenty patients aged 58.5 6 7.9 years were recruited from
Movement Disorders clinics in London (Table 1). All fulfilled the
UK PDS Brain Bank criteria for prospective diagnosis of idiopathic
Parkinson’s disease (Hughes et al., 1992). Disease duration ranged
from 0.5 to 9.0 years and the Hoehn and Yahr stage was between
1 and 3.5. The patients were divided into two groups according to the
presence (n = 8) or absence (n = 12) of episodes of major depression
based on DSM-IV criteria. Parkinson’s disease patients having a
personal history of major depression that occurred before the begin-
ning of Parkinson’s disease or a Mini-Mental Parkinson score of <24
(Mahieux et al., 1995), were excluded. All subjects gave informed
written consent and the study was approved by the Research
Ethics Committees of the Imperial College School of Medicine
(Hammersmith) and the Institute of Neurology. Permission to
administer radiotracers was obtained from the Administration of
Radioactive Substances Advisory Committee (UK).
All examinations took place while the depressed patients had been
antidepressant free for at least 3 months. On the day of the PET
study, neuropsychiatric evaluations were conducted on all patients.
The Beck Depression Inventory (BDI) was used to quantify the
severity of depression (Beck et al., 1961). Scores of apathy and
anxiety were measured using the Apathy Evaluation Scale (Marin
et al., 1991) and the State Trait Anxiety Inventory (Spielberger et al.,
1970), respectively.
The depressed and non-depressed groups of Parkinson’s disease
patients were matched for age and disease severity measured using
the Unified Parkinson’s Disease Rating Scale (UPDRS)-3 score ‘off’
medication (Table 1). We also examined seven healthy subjects,
age-matched to the patients (55.8 6 13.6 years). None of these con-
trols had any sign or history of neurological disorder or depression.
Image acquisition
PET was performed with an ECAT966 HR ++ tomograph
(CTI-Siemens, Knoxville) with measured attenuation and scatter
correction [resolution: 4 mm FWHM (full width at half-maximum)].
Patients withdrew all dopaminergic medication the day before the
PET study to limit interactions between dopaminergic drugs and
tracer uptake. An average of 222.7 6 20.6 MBq of [
11
C]RTI-32
with a specific radioactivity of 24 419.2 6 6806.2 MBq/mmol was
injected intravenously in the subjects and a 90 min acquisition in
3D mode was performed. Each subject underwent an MRI using
a Picker 1 T system including a T1-weighted 3D volumetric acquisi-
tion to allow co-registration.
Image analysis
The kinetics of [
11
C]RTI-32 brain time activity curves were mod-
elled using a simplified reference tissue compartmental approach to
Table 1 Parkinson’s disease patient characteristics
Patient/sex Age Disease duration UPDRS-3 BDI Apathy Anxiety L-Dopa eq. (mg) Other medications
1/M 54 5.0 15.0 12 19 28 400.0
2/F 65 2.0 48.0 29 46 41 830.0
3/M 70 2.0 30.0 20 29 60 300.0
4/F 50 3.5 20.0 19 44 46 500.0
5/M 41 0.5 18.0 15 21 52 0
6/M 61 1.5 19.0 16 13 72 0
7/M 57 5.0 29.0 30 22 71 1780.0 Cabergoline 5 mg,
entacapone 600 mg
8/F 54 5.0 15.0 12 37 32 400.0
Mean
(SD)
56.5
(9.0)
3.1
(1.8)
24.3
(11.2)
19.1
(7.0)
18.8
(7.3)
50.3
(16.6)
526.3
(573.4)
9/M 67 3.0 29.5 7 10 37 400.0
10/M 64 8.0 28.0 4 5 21 610.0 Entacapone 600 mg
11/F 61 6.0 14.0 3 8 32 300.0
12/M 57 4.0 15.0 6 12 51 300.0
13/M 68 2.0 22.0 3 9 30 350.0 Cabergoline 3 mg
14/F 55 4.0 21.0 10 9 30 240.0
15/M 52 7.0 36.0 4 8 28 500.0
16/M 58 2.5 24.0 3 6 34 700.0 Cabergoline 1 mg
17/M 58 9.0 26.5 9 10 27 350.0
18/M 70 8.0 26.0 3 25 27 1180.0 Entacapone 800 mg
19/F 45 3.0 15.0 6 22 25 400.0
20/M 63 2.0 22.0 8 5 46 400.0
Mean
(SD)
59.8
(7.2)
4.9
(2.6)
23.3
(6.7)
5.5
(2.5)
5.2
(2.7)
32.3
(8.7)
477.5
(257.8)
Patients 1–8 were those with and patients 12–20 those without episodes of major depression based on DSM-IV criteria. Disease duration is
in years.
L-Dopa eq. is the daily dose of all antiparkinsonian medication taken by the patient converted into L-Dopa equivalents (mg).
When patients had drugs other than
L-Dopa, these are listed in the last column. UPDRS-3 (motor) score was measured in patients
‘off’ medication. BDI = score given by the Beck Depression Inventory; apathy and anxiety were measured using the Apathy Evaluation
Scale and the State Trait Anxiety Inventory, respectively (see Subjects and methods).
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obtain a parametric image of the binding potential (BP) (Gunn et al.,
1997). Radioactivity in the cerebellum was used as the non-specific
tissue reference input (Guttman et al., 1997; Meyer et al., 2001).
In addition, an integrated (ADD) image was created by summing the
time series of [
11
C]RTI-32 uptake scans collected 0–90 min after
tracer administration.
We performed two image analyses, one using a priori placed
regions of interest (ROIs) and the other using voxel-based statistical
parametric mapping (SPM99, Wellcome Department of Cognitive
Neurology, London).
ROIs
The MRI of each subject was co-registred with the corresponding
ADD image (Woods et al., 1993). ROIs were traced on each MRI
and transferred onto the [
11
C]RTI-32 BP image. The regions were:
caudate, putamen, substantia nigra, thalamus, amygdala, anterior
cingulate cortex (CingA, Brodmann areas 24–32), orbitofrontal cor-
tex (OF, areas 11/47) and dorsolateral prefrontal cortex (DLPF, areas
10/45/46). These regions were chosen because they receive abundant
monoaminergic projections or because of their implication in
depression (Drevets, 1998; Mayberg et al., 1990; Ring et al., 1994).
SPM99 analysis
The ADD image of each subject was transformed into standard
stereotaxic space using a dedicated template. The BP images
were transformed by applying the transformation parameters used
for the corresponding ADD images. These normalized BP images
were used for voxel-by-voxel comparisons.
Statistical analyses
We compared clinical scores between depressed and non-depressed
Parkinson’s disease using the Student’s unpaired t test. BP values
obtained from the different ROIs in the controls, depressed and
non-depressed Parkinson’s disease patients were averaged over both
hemispheres and compared using a two-way analysis of variance
(ANOVA; Fisher’s PLSD post hoc test). In addition, we performed
an SPM99 voxel-by-voxel comparison between controls and all
Parkinson’s disease patients and between depressed and non-
depressed Parkinson’s disease patients. These comparisons were
based on a two-tailed unpaired t test and a priori restricted to a
volume of interest which included the striatum, the thalamus and
amygdala in both hemispheres and the midbrain. This masking
(small volume correction; Worsley et al., 1996) drastically reduces
the number of voxel-by-voxel statistical comparisons, and a thres-
hold of P < 0.01 (cluster-corrected at P < 0.05) was selected for
considering statistical significance. Finally, we used SPM99 to
explore the relationships between clinical scores of depression,
apathy and anxiety and BP values in the Parkinson’s disease patients
(n = 20). A voxel-by-voxel correlation analysis between the indi-
vidual scores and BP images was performed, this analysis being
restricted to the volume mentioned above. These correlations
were exploratory, with a statistical threshold for significance set at
P < 0.05.
Results
Clinical data
There was no statistical difference between the depressed and
non-depressed Parkinson’s disease groups regarding age, dis-
ease duration, doses of anti-parkinsonian medication (
L-Dopa
equivalents) and UPDRS-3 ‘off’ scores. The depressed cohort
of patients had higher scores than the non-depressed patients
for the BDI [t(18) = 6.21, P < 0.0001], apathy [t(18) = 4.37,
P = 0.0004] and anxiety [t(18) = 3.17, P = 0.005].
PET: ROI analysis
The ANOVA performed on BP values revealed a significant
effect of both the group [controls, depressed Parkinson’s dis-
ease and non-depressed Parkinson’s disease, F(2,26) = 18.6,
P < 0.0001] and the ROI [F(9,26) = 409.1, P < 0.0001] and an
interaction between group and ROI (F = 15.7, P < 0.0001)
(Table 2). Post hoc analyses showed that controls had higher
BP values than both groups of Parkinson’s disease patients in
the caudate, putamen, ventral striatum and substantia nigra
(Table 2). In addition, controls had higher values than
depressed Parkinson’s disease in the CingA and thalamus,
and non-depressed Parkinson’s disease had higher BP values
than depressed Parkinson’s disease in the thalamus, CingA,
amygdala and locus coeruleus (Table 2).
Table 2 Results obtained with the regions of interest analysis
Region Volume
(mm
3
)
Controls Parkinson’s
disease
depressed
Parkinson’s
disease
non-depressed
Post hoc Fisher’s PLSD
Controls/
depressed
Controls/
non-depressed
Depressed/
non-depressed
Caudate 3468 2.42 (0.47) 1.65 (0.37) 1.66 (0.39) 0.001 <0.001
Putamen 5744 2.79 (0.49) 1.33 (0.22) 1.49 (0.37) <0.001 <0.001
Ventral striatum 2040 2.05 (0.38) 1.12 (0.37) 1.37 (0.37) <0.001 <0.001
SN 1476 0.56 (0.11) 0.29 (0.18) 0.35 (0.21) 0.006 0.02
Midbrain 1440 0.12 (0.07) 0.09 (0.14) 0.20 (0.12)
Coeruleus 512 0.22 (0.09) 0.11 (0.16) 0.24 (0.11) 0.04
Thalamus 4492 0.46 (0.07) 0.25 (0.17) 0.37 (0.09) 0.002 0.04
Amygdala 1696 0.26 (0.07) 0.15 (0.18) 0.28 (0.10) 0.03
CingA 12 292 0.18 (0.07) 0.01 (0.12) 0.15 (0.10) 0.002 0.005
OF 6596 0.02 (0.03) –0.03 (0.12) 0.07 (0.10)
DLPF 5876 0.05 (0.07) 0.09 (0.16) 0.06 (0.11)
SN = substantia nigra; OF = orbito-frontal cortex; DLPF = dorsolateral prefrontal cortex.
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PET: SPM99 analysis
Controls versus Parkinson’s disease
The controls had higher BP values than the whole Parkinson’s
disease group in the putamen, caudate, ventral striatum and
substantia nigra, bilaterally (Fig. 1, Table 3).
Non-depressed versus depressed Parkinson’s
disease
The non-depressed Parkinson’s disease had significantly
(P < 0.01, cluster-corrected at P < 0.05) higher BP values
than depressed Parkinson’s disease in the following regions:
locus coeruleus bilaterally, mediodorsal thalamus bilaterally,
inferior thalamus bilaterally, left ventral striatum and right
amygdala (Fig. 2, Table 4).
Relationships between depression scores and
BP values in Parkinson’s disease patients
We found a negative correlation between the BDI score and
the BP in the left ventral striatum (Z = 3.12, P = 0.001, uncor-
rected, x = –18, y = 10, z = 4). The apathy score was negatively
correlated with BP values in the ventral striatum, bilaterally
(Table 5, Fig. 3). The anxiety score was negatively correlated
with the BP values in the left ventral striatum, left caudate,
left locus coeruleus, left inferior thalamic region, and bilater-
ally in the amygdala and medial thalamus (Table 6, Fig. 4).
Discussion
Depression in Parkinson’s disease patients is associated with
a reduction of [
11
C]RTI-32 binding in several limbic regions.
In addition, there is an inverse relationship between the
binding of [
11
C]RTI-32 in these regions and the severity of
anxiety and mood disorders in these patients.
These abnormalities seem specific for depression in
Parkinson’s disease since we matched depressed and non-
depressed Parkinson’s disease patients for demography and
locomotor disability, including age, disease duration,
UPDRS-motor ‘off’ score and doses of antiparkinsonian
medication. Accordingly, we found no difference between
the two groups of patients for [
11
C]RTI-32 uptake in the
striatum or the substantia nigra.
Differences between depressed and non-depressed
Parkinson’s disease were observed using both an ROI ana-
lysis and voxel-based SPM. The slight differences between
the results obtained using these approaches are explained by
methodological considerations. For example, the CingA was
not included in the masked SPM comparison in order to
restrict the analysis to subcortical and brainstem areas and
gain statistical power.
The decrease of [
11
C]RTI-32 BP reflects a loss of
catecholaminergic innervation in the corresponding regions
of the brain. [
11
C]RTI-32 binds mainly to DAT in the striatum
(Carroll et al., 1995; Wilson et al., 1996), and the binding of
this tracer is markedly reduced in the putamen of patients
with Parkinson’s disease (Guttman et al., 1997). We also
found a reduction of [
11
C]RTI-32 binding in the substantia
nigra of Parkinson’s disease patients. Thus, it is possible to
demonstrate loss of dopaminergic cell function directly in the
substantia nigra (Rakshi et al., 1999), since DAT is present on
Fig. 1 Regions with reduced [
11
C] RTI-32 binding in the whole
group of PD patients compared to controls (P < 0.001, corrected
at (P < 0.05). Up: the glass view obtained with SPM99. Down:
overlay on a MRI showing the loss of binding bilaterally in
the striatum and susbtantia nigra of the patients.
Table 3 SPM99: controls versus Parkinson’s disease
patients
Region Coordinates (x, y, z) Z-score Voxels (n)
Putamen R 28, 6, 12 7.08 1104
Putamen L 26, 8, 10 6.56 1135
Caudate R 14, 12, 20 4.12 803
Caudate L 10, 20, 4 4.71 953
Ventral striatum R 20, 14, 0 4.37 100
Ventral striatum L 20, 12, 0 4.40 181
Substantia nigra R 8, 16, 0 6.30 107
Substantia nigra L 6, 16, 0 4.83 100
Regions where BP values are higher (P < 0.001, cluster-corrected
at P < 0.05) in controls (n = 7) than in the Parkinson’s disease
patients (n = 20). R, L = right, left. The coordinates (in mm) refer
to the Talairach and Tournoux atlas (1988). The last column
indicates the cluster size (number of voxels in each statistical
peak, with one voxel = 8 mm
3
).
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the dendrites of dopaminergic neurons (Nirenberg et al.,
1996).
[
11
C]RTI-32 has nanomolar affinity for the NAT, whereas
it has a low affinity for the serotonin transporter (Carroll et al.,
1995). Therefore, part of the decrease of [
11
C]RTI-32 binding
observed in depressed Parkinson’s disease patients could be
related to loss of noradrenergic terminals. This is supported
by the finding that [
11
C]RTI-32 binding was reduced in
the locus coeruleus and in the thalamus. In addition, the
locus coeruleus sends noradrenergic projections to the
frontal cortex, the amygdala and the ventral striatum (Ressler
and Nemeroff, 1999). Altogether, this suggests that the
decrease of [
11
C]RTI-32 binding observed in the depressed
Parkinson’s disease patients corresponds to the loss of both
dopamine and noradrenaline projections. Alternatively,
the downregulation of DAT and NAT binding might be
secondary to reduced release of endogenous ligand in
these synapses (Metzger et al., 2002). Nevertheless, in
Parkinson’s disease patients, we suspect that loss of cat-
echolaminergic terminals (Paulus and Jellinger, 1991)
plays a much more dominant role in the reduction of
[
11
C]RTI-32 binding observed in this study than any
Fig. 2 Regions where there is a significant reduction (P < 0.01) of [
11
C]RTI-32 binding in the depressed compared to non-depressed PD
patients. The regions seen in the glass view are shown overlayed on a MRI: (A) locus ceruleus; (B) medial thalamus; (C) left ventral
striatum; (D) right amygdala.
Table 5 Regions in which BP is negatively correlated with
apathy
Region Coordinates
(x,y,z)
Z-score P-value Voxels (n)
Ventral striatum L 20, 6, 4 2.37 0.009 96
Ventral striatum R 16, 14, 0 2.02 0.022 50
Exploratory analysis with P < 0.05, uncorrected. R, L = right, left.
The coordinates (in mm) refer to the Talairach and Tournoux atlas
(1988).
Table 4 SPM99: non-depressed versus depressed
Parkinson’s disease
Region Coordinates (x, y, z) Z-score Voxels (n)
Locus coeruleus L 6, 32, 28 3.50 267
Locus coeruleus R 6, 34, 30 3.10 191
Thalamus R 16, 12, 16 3.10 532
Thalamus L 16, 22, 14 2.68 454
Ventral striatum L 16, 10, 2 2.68 480
Amygdala R 30, 6, 24 2.60 229
Regions where BP values are higher (P < 0.005, corrected at
P < 0.05 at the cluster level) in non-depressed (n = 12) than in
depressed (n = 8) Parkinson’s disease patients. R, L = right, left.
The coordinates (in mm) refer to the Talairach and Tournoux atlas
(1988).
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pharmacodynamic regulation of the transporter density on the
remaining membranes.
Dopamine interactions with the limbic system are probably
involved in stress and depression (Cabib and Puglisi-Allegra,
1996). In Parkinson’s disease, pessimism measured using
the harm-avoidance personality score was reported to be
correlated with [
18
F]Dopa uptake in the right caudate nucleus
(Kaasinen et al., 2001). Mood fluctuations can occur inde-
pendently from motor fluctuations (Maricle et al., 1995),
implicating involvement of ventral rather than dorsal brain
circuitary, and are often improved by antiparkinsonian
medication (Czernecki et al., 2002). Parkinsonian patients
with major depression do not feel euphoria following admin-
istration of the dopamine-releasing agent methylphenidate.
This has been attributed to degeneration of the dopaminergic
innervation of the limbic system (Cantello et al., 1989).
The role of noradrenaline in affective disorders is widely
documented (Ressler and Nemeroff, 1999; Sullivan et al.,
1999). A loss of pigmented neurons has been found in the
locus coeruleus of suicide victims (Arango et al., 1996),
and the level of NAT is reduced post-mortem in the locus
coeruleus of patients with major depression (Klimek et al.,
1997). The degeneration of the locus coeruleus occurring in
Parkinson’s disease (Paulus and Jellinger, 1991) might play a
role in mood changes in these patients (Zweig et al., 1993).
This is supported here by the lower [
11
C]RTI-32 binding found
in the locus coeruleus of depressed compared with non-
depressed patients. In addition, the negative correlation
found between locus coeruleus [
11
C]RTI-32 binding and
severity of anxiety in Parkinson’s disease supports a direct
role for noradrenaline in the pathophysiology of anxiety in
Parkinson’s disease.
It is striking that the reduction of catecholaminergic
innervation in depressed Parkinson’s disease patients occurs
in regions thought to comprise the emotional circuits of the
brain. Indeed, the amygdala, mediodorsal thalamus, ventral
striatum and CingA belong to the limbic system and have
been implicated as dysfunctional regions in mood disorders
(Drevets, 1998).
The amygdala is a key structure for emotional processing
in humans (LeDoux, 2000). Functional abnormalities in the
amygdala correlate with severity of endogenous depression
(Drevets, 1998), and the amygdala mediates fear processing
and anxiety (LeDoux, 2000). The amygdala connects with
locus coeruleus and receives a noradrenergic and dopamin-
ergic innervation (Fallon et al., 1978; Fudge and Emiliano,
2003) which is reduced in Parkinson’s disease (Moore, 2003).
In addition, it has been reported in a post-mortem study that
Parkinson’s disease patients have up to a 20% reduction of
amygdala volume and that this structure contains Lewy bod-
ies (Harding et al., 2002). In our study, [
11
C]RTI-32 binding
was significantly reduced in the right amygdala of depressed
Parkinson’s disease patients and the anxiety score was
negatively correlated with bilateral amygdala [
11
C]RTI-32
binding. The loss of noradrenaline and dopamine in the
Fig. 3 The [
11
C]RTI-32 binding in the ventral striatum is inversely correlated (P < 0.05) with apathy in the whole group of patients.
Table 6 Regions in which BP is negatively correlated
with anxiety
Region Coordinates
(x, y, z)
Z-score P-value Voxels (n)
Ventral striatum L 18, 10, 8 2.72 0.003 292
Caudate L 12, 14, 14 2.34 0.010 55
Locus coeruleus L 6, 30, 18 2.70 0.003 131
Thalamus R 16, 10, 16 2.55 0.005 365
Thalamus L 6, 8, 12 2.38 0.009 292
Amygdala R 22, 0, 10 2.10 0.018 34
Amygdala L 24, 4, 14 2.06 0.020 47
See footnotes of Table 5.
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amygdala is likely to play a role in generating affective
symptoms in Parkinson’s disease.
The amygdala has connections with the CingA (LeDoux,
2000) where, with an ROI analysis, we found a reduction of
[
11
C]RTI-32 binding in the depressed compared with the
non-depressed Parkinson’s disease patients. The CingA is part
of the limbic system and involved in many cognitive and
emotional processes (Paus et al., 1993; Drevets, 1998). In
addition, the CingA receives a strong dopaminergic and
noradrenergic innervation (Williams and Goldman-Rakic,
1993). Two PET studies have revealed CingA hypometabol-
ism associated with depression in Parkinson’s disease (Ring
et al., 1994; Mentis et al., 2002). Our results suggest that such
dysfunction of CingA in depressed Parkinson’s disease might
be related to a specific loss of catecholaminergic projections.
Noradrenergic projections to the thalamus target the medial
and intralaminar subnuclei (Oke et al., 1997), where we found
a significant loss of [
11
C]RTI-32 binding in depressed com-
pared with non-depressed Parkinson’s disease patients. The
role of the thalamus in depression is unclear. However, a
recent study showed that depression and anxiety induced
by a-methylparatyrosine, a tyrosine hydroxylase inhibitor,
was associated with a marked reduction of glucose metabol-
ism in the thalamus (Bremner et al., 2003). The role of the
thalamus in affective disorders might be related to its involve-
ment in arousal. Indeed, anxiety is associated with changes in
vigilance that implicate the same thalamo-cortical inter-
actions which are under the control of the noradrenergic
innervation originating in the locus coeruleus (Ressler and
Nemeroff, 1999; David Johnson, 2003). Accordingly, the
correlation between anxiety and [
11
C]RTI-32 binding
in the thalamus in these patients suggests that impaired
noradrenergic modulation of thalamic activity plays a role
in the generation of anxiety in Parkinson’s disease.
Finally, depressed Parkinson’s disease patients showed
a relative reduction of [
11
C]RTI-32 binding in the ventral
striatum, which is involved in emotional processing via its
connections with frontal limbic regions (Nakano, 2000). The
dopaminergic system is less affected in the ventral striatum
than more dorsal regions in Parkinson’s disease (Kish et al.,
1988), but receives most of the noradrenergic afferents of the
striatum (Nicola and Malenka, 1998). In non-parkinsonian
depressed patients, a single photon emission computed tomo-
graphy (SPECT) study using [
123
I]b-CIT reported an increase
of tracer uptake in the striatum compared with controls
(Laasonen-Balk et al., 1999). However, [
123
I]b-CIT also
binds to the serotonin transporter (Carroll et al., 1995) and
increased uptake may reflect serotonin transporter upregula-
tion in depression. Conversely, a recent study reported a
decrease of [
11
C]RTI-32 binding in the ventral striatum of
depressed subjects (Meyer et al., 2001). In line with this
result, we found a reduction of the [
11
C]RTI-32 binding in
the left ventral striatum of the depressed Parkinson’s disease
patients. Interestingly, we found that [
11
C]RTI-32 binding in
the ventral striatum was inversely correlated with the degree
of apathy and the intensity of depression in the patients.
It seems that the dopaminergic and noradrenergic innervation
of the ventral striatum is involved in both endogenous and
Parkinson’s disease depression, and, might specifically play a
role in apathy which is a major feature of depression. Inter-
estingly,
L-Dopa treatment might improve motivation in some
patients with Parkinson’s disease (Czernecki et al., 2002).
In conclusion, our results suggest that depression in
Parkinson’s disease is associated with a specific loss of
Fig. 4 Regions in which anxiety is inversely correlated (P < 0.05) with [
11
C]RTI-32 binding. Left: SPM99 glassview. Right: overlay on a
MRI showing the locus ceruleus (sagittal view), the left ventral striatum and left and right amygdala (coronal view) and the medial thalamus
bilaterally and left ventral striatum (axial view).
1320 P. Remy et al.
by guest on June 4, 2013http://brain.oxfordjournals.org/Downloaded from
dopamine and noradrenaline innervation of cortical and sub-
cortical components of the limbic system. These results might
help in understanding the functional anatomy of depression in
Parkinson’s disease and have therapeutic implications.
These results might be replaced in the more general
context of the relationships between ageing, depression and
catecholamines. Briefly, the reduction of catecholaminergic
innervation that occurs in the cortical limbic structures might
participate in the loss of cognitive abilities such as flexibility,
attention or executive functions that is known to occur with
ageing (Nieoullon, 2002). On the same lines, it is considered
that increased anxiety found in elderly people might be rela-
ted to the loss of dopaminergic and noradrenergic innerva-
tion, especially in the amygdala (Gareri et al., 2002).
Therefore, some authors have suggested that pre-depressive
and pre-dementia states that are sometimes observed with
ageing have underlying pathophysiology in common with
Parkinson’s disease (Gareri et al., 2002).
Acknowledgements
P.R. was supported by grants from the Fondation pour la
Recherche Me
´
dicale and the Association France-Parkinson.
M.D. was supported by the Parkinson’s Disease Society, UK.
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    • "Indeed, we did not analyse here the contribution of other neurotransmission systems, such as the noradrenergic or the cholinergic ones that are also involved in the pathogenesis of the Parkinson's disease-related neuropsychiatric symptoms. Some neuroimaging studies have, for instance, reported the involvement of norepinephrine in the pathogenesis of several non-motor signs, such as depression or anxiety (Remy et al., 2005). Similarly, the role of the cholinergic system dysfunction as a possible pathophysiological mechanism in apathy has been suggested , notably by some pharmacological studies having demonstrated an improvement of apathy following anticholinesterasic drug intake (Devos et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Apathy, which can occur separately or in combination with depression and anxiety, is one of the most frequently encountered neuropsychiatric symptoms in Parkinson’s disease. Pathophysiological evidence suggests that parkinsonian apathy is primarily due to a mesolimbic dopaminergic denervation, but the role of the serotonergic alteration has never been examined, despite its well-known involvement in the pathogenesis of depression and anxiety. To fill this gap, we address here the pure model of de novo Parkinson’s disease, without the confounding effects of antiparkinsonian treatment. Fifteen apathetic (Lille Apathy Rating Scale scores ≥ −21) and 15 non-apathetic (−36 ≤ Lille Apathy Rating Scale scores ≤ −22) drug-naïve de novo parkinsonian patients were enrolled in the present study and underwent detailed clinical assessment and positron emission tomography imaging, using both dopaminergic [¹¹C-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane (PE2I)] (n = 29) and serotonergic [¹¹C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine (DASB)] (n = 27) presynaptic transporter radioligands. Apathetic parkinsonian patients presented higher depression (P = 0.0004) and anxiety (P = 0.004) scores – as assessed using the Beck Depression Inventory and the part B of the State-Trait Anxiety Inventory, respectively – compared to the non-apathetic ones – who were not different from the age-matched healthy subjects (n = 15). Relative to the controls, the non-apathetic parkinsonian patients mainly showed dopaminergic denervation (n = 14) within the right caudate nucleus, bilateral putamen, thalamus and pallidum, while serotonergic innervation (n = 15) was fairly preserved. Apathetic parkinsonian patients exhibited, compared to controls, combined and widespread dopaminergic (n = 15) and serotonergic (n = 12) degeneration within the bilateral caudate nuclei, putamen, ventral striatum, pallidum and thalamus, but also a specific bilateral dopaminergic disruption within the substantia nigra–ventral tegmental area complex, as well as a specific serotonergic alteration within the insula, the orbitofrontal and the subgenual anterior cingulate cortices. When comparing the two parkinsonian groups, the apathetic patients mainly displayed greater serotonergic alteration in the ventral striatum, the dorsal and the subgenual parts of the anterior cingulate cortices, bilaterally, as well as in the right-sided caudate nucleus and the right-sided orbitofrontal cortex. Regression analyses also revealed that the severity of apathy was moreover mainly related to specific serotonergic lesions within the right-sided anterior caudate nucleus and the orbitofrontal cortex, while the degree of both depression and anxiety was primarily linked to serotonergic disruption within the bilateral subgenual parts and/or the right dorsal part of the anterior cingulate cortex, without prominent role of the dopaminergic degeneration in the pathogenesis of these three non-motor signs. Altogether, these findings highlight a prominent role of the serotonergic degeneration in the expression of the neuropsychiatric symptoms occurring at the onset of Parkinson’s disease.
    Full-text · Article · Aug 2016
    • "Anxiety has been postulated to be a prodromal symptom of PD [30], resulting from damage to the brainstem nuclei (e.g. locus coeruleus), striatum and amygdala [31][32][33][34][35][36]. Furthermore, FOG has been suggested to manifest in instances where the dopamine-depleted striatum is unable to process the competing yet concurrent inputs from the cognitive-, motor-and limbic- loops [13,14]. "
    [Show abstract] [Hide abstract] ABSTRACT: Previous research has shown that anxiety in Parkinson’s disease (PD) is associated with freezing of gait (FOG), and may even contribute to the underlying mechanism. However, limited research has investigated whether PD patients with FOG (PD + FOG) have higher anxiety levels when compared directly to non-freezing PD patients (PD-NF) and moreover, how anxiety might contribute to FOG. The current study evaluated whether: (i) PD + FOG have greater anxiety compared to PD-NF, and (ii) anxiety in PD is related to attentional set-shifting, in order to better understand how anxiety might be contributing to FOG. In addition, we explored whether anxiety levels differed between those PD patients with mild FOG (PD + MildFOG) compared to PD-NF. Four hundred and sixty-one patients with PD (231 PD-NF, 180 PD + FOG, 50 PD + MildFOG) were assessed using the Freezing of Gait Questionnaire item 3 (FOG-Q3), Hospital Anxiety and Depression Scale (HADS), Digit Span Test, Logical Memory Retention Test and Trail Making Tests. Compared to PD-NF, PD + FOG had significantly greater anxiety (p < 0.001). PD + MildFOG, however, demonstrated similar levels of anxiety as the PD + FOG. In all patients, the severity of anxiety symptoms was significantly correlated to their degree of self-reported FOG on FOG-Q3 (p < 0.001) and TMT B-A (p = 0.039). Similar results were found for depression. In conclusion, these results confirm the key role played by anxiety in FOG and also suggest that anxiety might be a promising biomarker for FOG. Future research should consider whether treating anxiety with pharmacological and/or cognitive behavioural therapies at early stages of gait impairment in PD may alleviate troublesome FOG.
    Full-text · Article · Aug 2016
    • "Although one cannot dismiss psychosocial factors, like receiving the diagnosis of a chronic disabling disease, and disability caused by the dementia and/or motor symptoms, or even side effects of anti-choreic drugs, like tetrabenazine (used by HD patients) (Huntington Study, 2006), they should not be solely accounted for the depression. In fact, depressive symptoms in neurodegenerative disorders can be due to several factors: impairment in the serotonergic and noradrenergic systems (Caraceni et al., 1977; Kish et al., 2008; Reinikainen et al., 1990; Remy et al., 2005; Richards et al., 2011), hypothalamic-pituitary-adrenal (HPA) axis dysfunction (Charlett et al., 1998; Davis et al., 1986; Gurevich et al., 1990; Heuser et al., 1991; Politis et al., 2008; Shirbin et al., 2013), alterations in neurogenesis and in neurotrophic factor expression (reviewed in (Groves, 2007)) or neuroinflammation (Frommberger et al., 1997; Nair and Bonneau, 2006; Pike and Irwin, 2006). Probably, all these factors act together promoting the depressive symptoms observed in neurodegenerative disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases.
    Article · Jul 2016
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