doi:10.1093/brain/awh445Brain (2005), 128, 1314–1322
Depression in Parkinson’s disease: loss of
dopamine and noradrenaline innervation in the
Philippe Remy,1,2Miroslava Doder,2Andrew Lees,3Nora Turjanski2and David Brooks2
Correspondence to: Philippe Remy, CNRS-CEA URA2210,
Service Hospitalier Fre ´de ´ric Joliot, 4, place du Ge ´ne ´ral
Leclerc, 91401 Orsay cedex, France.
1CNRS-CEA URA2210, Service Hospitalier Fre ´de ´ric Joliot,
CHU Henri Mondor et Faculte ´ de Me ´decine Paris 12,
France2Faculty of Medicine, Hammersmith Hospital,
Imperial College-MRC Clinical Sciences Centre and
Division of Neuroscience and3Institute of Neurology,
Queen Square, London, UK
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 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’sdisease cohorthadlower [11C]RTI-32binding
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 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
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 [11C]RTI-32 PET to study the role of catechola-
minergic neurotransmission in the pathophysiology of
depression in Parkinson’s disease. [11C]RTI-32 binds with
similar nanomolar affinities to the dopamine (DAT) and
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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
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).
Allexaminations tookplace 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.,
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.
PET was performed with an ECAT966 HR++
(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 [11C]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.
The kinetics of [11C]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 durationUPDRS-3BDI Apathy Anxiety
L-Dopa eq. (mg) Other medications
1780.0Cabergoline 5 mg,
entacapone 600 mg
Entacapone 600 mg
Cabergoline 3 mg
Cabergoline 1 mg
Entacapone 800 mg
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).
Depression in Parkinson’s disease1315
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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 [11C]RTI-32 uptake scans collected 0–90 min after
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
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 [11C]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).
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.
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.
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
Post hoc Fisher’s PLSD
SN = substantia nigra; OF = orbito-frontal cortex; DLPF = dorsolateral prefrontal cortex.
P. Remy et al.
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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
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).Theapathyscorewas 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).
Depression in Parkinson’s disease patients is associated with
a reduction of [11C]RTI-32 binding in several limbic regions.
In addition, there is an inverse relationship between the
binding of [11C]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
UPDRS-motor ‘off’ score and doses of antiparkinsonian
medication. Accordingly, we found no difference between
the two groups of patients for [11C]RTI-32 uptake in the
striatum or the substantia nigra.
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 [11C]RTI-32 BP reflects a loss of
catecholaminergic innervation in the corresponding regions
of the brain. [11C]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 [11C]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 [11C] 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
RegionCoordinates (x, y, z)Z-score Voxels (n)
Ventral striatum R
Ventral striatum L
Substantia nigra R
Substantia nigra L
28, ?6, 12
?26, ?8, 10
14, 12, 20
?10, 20, 4
20, 14, 0
?20, 12, 0
8, ?16, 0
?6, ?16, 0
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 mm3).
Depression in Parkinson’s disease1317
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the dendrites of dopaminergic neurons (Nirenberg et al.,
[11C]RTI-32 has nanomolar affinity for the NAT, whereas
ithasalow affinity forthe serotonintransporter(Carrolletal.,
1995). Therefore, part of the decrease of [11C]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 [11C]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 [11C]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
[11C]RTI-32 binding observed in this study than any
Fig. 2 Regions where there is a significant reduction (P < 0.01) of [11C]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
(x, y, z)
Z-scoreP-value Voxels (n)
Ventral striatum L
Ventral striatum R
?20, 6, 4
16, 14, 0
Exploratory analysis withP < 0.05, uncorrected.R, L =right, left.
Table 4 SPM99:
Region Coordinates (x, y, z)Z-score Voxels (n)
Locus coeruleus L
Locus coeruleus R
Ventral striatum L
?6, ?32, ?28
6, ?34, ?30
16, ?12, 16
?16, ?22, 14
?16, 10, 2
30, ?6, ?24
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.
P. Remy et al.
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pharmacodynamic regulation of the transporter density on the
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 [18F]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).
in the locus coeruleus of depressed compared with non-
depressed patients. In addition, the negative correlation
found between locus coeruleus [11C]RTI-32 binding and
severity of anxiety in Parkinson’s disease supports a direct
role for noradrenaline in the pathophysiology of anxiety in
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
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, [11C]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 [11C]RTI-32
binding. The loss of noradrenaline and dopamine in the
Fig. 3 The [11C]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
(x, y, z)
Z-score P-value Voxels (n)
Ventral striatum L ?18, 10, 8
Locus coeruleus L ?6, ?30, ?18 2.70
Thalamus R 16, ?10, 16
?6, ?8, 12
?22, 0, ?10
?24, 4, ?14
See footnotes of Table 5.
?12, 14, 14
Depression in Parkinson’s disease 1319
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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
[11C]RTI-32 binding in the depressed compared with the
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 etal.,1997), wherewe found
a significant loss of [11C]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 [11C]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 [11C]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 [123I]b-CIT reported an increase
of tracer uptake in the striatum compared with controls
(Laasonen-Balk et al., 1999). However, [123I]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 [11C]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 [11C]RTI-32 binding in
the left ventral striatum of the depressed Parkinson’s disease
patients. Interestingly, we found that [11C]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 [11C]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).
P. Remy et al.
by guest on June 4, 2013
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).
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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