Movement Disorders - 2021 - Kaasinen - Dopamine Receptors in Parkinson S Disease A Meta Analysis of Imaging Studies

REVIEW
Dopamine Receptors in Parkinson’s Disease: A Meta-Analysis

of Imaging Studies
Valtteri Kaasinen, MD,1,2* Tero Vahlberg, MSc,3 A. Jon Stoessl, MD,4 Antonio P. Strafella, MD,5,6,7
and Angelo Antonini, MD8
1
Clinical Neurosciences, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
2
Neurocenter, Turku University Hospital, Turku, Finland
3
Biostatistics, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland
4
Pacific Parkinson’s Research Centre, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia,
Vancouver, British Columbia, Canada
5
Division of Brain, Imaging and Behaviour-Systems Neuroscience, Krembil Research Institute, UHN, University of Toronto,
Toronto, Ontario, Canada
6
Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto,
Toronto, Ontario, Canada
7
Morton and Gloria Shulman Movement Disorder Unit and E.J. Safra Parkinson Disease Program, Neurology Division, Department of Medicine,
Toronto Western Hospital, UHN, University of Toronto, Toronto, Ontario, Canada
8
Parkinson and Movement Disorders Unit, Department of Neuroscience, University of Padua, Padua, Italy
A B S T R A C T : Dopamine receptors are abundant along the the striatum contralateral to the predominant motor symp-
central nigrostriatal tract and are expressed as 5 subtypes in toms. PSP and MSA-P patients had lower striatal D2R bind-
two receptor families. In PD, compensatory changes in dopa- ing than PD patients (14.2% and 21.8%, respectively). There
mine receptors emerge as a consequence of the loss of is initial upregulation of striatal D2Rs in PD, which down-
dopamine nerve terminals or dopaminergic pharmacotherapy. regulate on average 4 years after motor symptom onset, pos-
We performed a systematic review and meta-analysis of the sibly because of agonist-induced effects. The consistent
available PET and single-photon emission computed tomog- upregulation of D2Rs in the PD striatum contralateral to the
raphy studies that have investigated dopamine receptors in predominant motor symptoms indicates that receptor
PD, PSP and MSA. The inclusion criteria were studies includ- changes are driven by neurodegeneration and loss of
ing human PET or single-photon emission computed tomog- striatal neuropil. Both PSP and MSA patients have
raphy imaging; dopamine receptor tracers (D1-like or D2-like) clearly lower striatal D2R binding values than PD
and idiopathic PD, PSP, or MSA patients compared with patients, which offers an opportunity for differential
healthy controls. The 67 included D2-like studies had 1925 diagnostics. © 2021 The Authors. Movement Disorders
patients. Data were insufficient for an analysis of D1-like stud- published by Wiley Periodicals LLC on behalf of Inter-
ies. PD patients had higher striatal binding early in the dis- national Parkinson and Movement Disorder Society
ease, but after a disease duration of 4.36 years, PD patients
had lower binding values than healthy controls. Striatal D2R Key Words: Parkinson’s disease; neuroimaging; dopa-
binding was highest in unmedicated early PD patients and in mine receptors; PSP; MSA
-This
- - - is- -an- - open
- - - - -access
- - - - - - article
- - - - - under
- - - - - -the- - terms
- - - - - of- - the
- - - Creative
---------------
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly Endogenous dopamine and most antiparkinsonian
cited. drugs exert their actions via postsynaptic dopamine
*Correspondence to: Dr. Valtteri Kaasinen, Neurocenter, Turku Univer- receptors. The two dopamine receptor families (D1-
sity Hospital, POB 52, 20521 Turku, Finland; E-mail: valtteri.
kaasinen@tyks.fi and D2-like) and 5 dopamine receptor subtypes (D1R–
Relevant conflicts of interest/financial discolosures: Nothing to report.
D5R) are encoded in humans by 5 genes (DRD1–
DRD5).1 In Parkinson’s disease (PD), the therapeutic
Funding agency: None
use of dopamine receptor agonists bypasses degenerated
Received: 29 December 2020; Revised: 15 March 2021; Accepted: 13
April 2021 mesencephalic dopamine production, but the clinical
benefits of agonists are generally less than those with
Published online 6 May 2021 in Wiley Online Library levodopa, and their use can be complicated by various
(wileyonlinelibrary.com). DOI: 10.1002/mds.28632
Movement Disorders, Vol. 36, No. 8, 2021 1781

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K A A S I N E N E T A L
side effects ranging from fibrotic heart disease with Search Strategy
ergoline derivatives to impulsive/compulsive disor- PubMed was searched with specific headings alone
ders.2,3 There are also results to suggest that long-term and in combination with key words for longitudinal
and intermittent administration of dopaminergic drugs progression studies from database inception until
may cause dopamine receptor downregulation in March 6, 2020 (Fig. 1). The references of retrieved arti-
advanced PD, when response to levodopa is suboptimal cles and review articles were also manually searched for
and characterized by fluctuations and dyskinesias.4 missed studies.
Dopamine receptor upregulation in PD was first dem-
onstrated in the striatum of postmortem brains of PD Specific Aims for the Meta-Analysis
patients.5 The effect was assumed to be a consequence
This meta-analysis aimed to systematically investigate
of dopaminergic denervation. Later postmortem studies
changes in striatal dopamine receptor binding in PD
and in vivo imaging have provided mixed results of this
patients compared with healthy controls and patients
upregulation in relation to temporal associations during
with PSP and MSA. The primary outcome was the
PD progression. Although many studies have suggested
mean difference in striatal subregions in relation to
that there is detectable upregulation in striatal dopa-
potential effect size moderators such as age, disease
mine receptors in early PD, advanced PD patients
duration, and motor symptom severity measures.
appear to show downregulation (eg, references 6–9). A
critical question is whether the dynamic changes in
dopamine receptor availability represent disease or Selection Criteria
treatment effects and whether receptor downregulation All titles and abstracts from searches were
is a factor that reduces the efficacy of dopaminergic reviewed, and studies were excluded if the title and/or
drug treatment. abstract were not appropriate for the aim of the
From a diagnostic point of view, it is possible that review. Full texts were obtained for eligible studies or
patients with progressive supranuclear palsy (PSP) and when the relevance of an article was uncertain. The
multiple system atrophy (MSA) lack the initial inclusion criteria for the selected studies were:
upregulation phase of dopamine receptor binding, (1) study involved human PET or single-photon emis-
which would support the use of combined pre- and sion computed tomography (SPECT) imaging;
postsynaptic dopaminergic imaging in patients with (2) binding of a dopamine receptor tracer (D1-like or
clinically uncertain parkinsonian syndromes.10,11 How- D2-like) was assessed; (3) idiopathic PD, PSP, or
ever, small sample size is a major limitation of most MSA patients were compared with healthy controls
functional neuroimaging studies, which complicates the (unmedicated or medicated, patients with deep brain
interpretation of individual studies. Meta-analysis stimulation [DBS] or thalamotomy excluded in group
increases the power to detect differences while making comparisons); and (4) binding was reported as the
it possible to study potential moderating variables and mean SD in at least one striatal region. If more
biases associated with single studies. than one population was reported in a study (eg,
The present meta-analysis aimed to investigate dopa- early and advanced PD patients), those populations
mine receptor changes in PD patients using pooled publi- were included as separate samples with the same con-
shed PET and single-photon emission computed trol sample.
tomography data. We specifically aimed to answer:
(1) whether there is dopamine receptor upregulation in Risk of Bias in Included Studies
early PD or downregulation in advanced PD, (2) when The presence of publication bias was explored by
the possible upregulation turns to downregulation and funnel plots and Egger’s tests for asymmetry, together
how this is associated with drug treatments, (3) if with the trim-and-fill method with imputed data
there are clinically relevant interhemispheric differ- points. The quality of studies was evaluated with a
ences in dopamine receptor binding, and (4) if dopa- modified Newcastle-Ottawa scale.1
mine receptor binding characteristics could be used to
help in the differential diagnosis of PD versus atypical
Data Extraction
parkinsonian syndromes.
The variables extracted were study year, first author’s
family name, study site (city, state, country), method
for binding uptake calculation, number of subjects in
Methods each group, mean SD age (years), sex of participants,
mean SD disease duration (years), mean SD
The study was carried out in accordance with the Pre- Unified Parkinson’s Disease Rating Scale (UPDRS)
ferred Reporting Items for Systematic Reviews and motor score, mean SD Hoehn and Yahr stage score,
Meta-Analyses (PRISMA) guidelines.12 scanner type, mean injected dose (MBq), scan duration
1782 Movement Disorders, Vol. 36, No. 8, 2021

D O P A M I N E R E C E P T O R S I N P D
FIG. 1. Flowchart of study inclusion and exclusion.
(minutes), and mean SD uptake data (for each group SAS System for Windows, version 9.4 (SAS Institute
and brain region; if the study did not report mean Inc., Cary, NC). The normality assumptions of the resid-
striatal values, they were generated using means of cau- uals were examined with histograms. The homoscedas-
date and putamen values). ticity was checked with scatterplots between predicted
values and residuals. Both the normality and homosce-
dasticity assumptions were met.
Statistical Analysis Subgroup analyses between medicated and unmedi-
Brain regional group comparisons were conducted cated PD patients and between PET and SPECT studies
using Meta-Essentials (version 1.0; Erasmus University, were performed using random effects for between-
Rotterdam, The Netherlands).13 The effect sizes were subgroup weighting and random effects (tau separate
measured with Hedges’ g values as standardized mean for subgroups) for within-subject weighting. Differences
differences using a random-effects model. Heterogeneity in the combined effect sizes of the subgroups were
of the effect sizes was examined using I2 statistics. If sub- tested with an analysis of variance based on sums of
stantial heterogeneity with I2 > 50% was observed, the squares.14 Interhemispheric correlation coefficients were
influence of effect moderators, including age, disease calculated from 4 studies that reported individual hemi-
duration, UPDRS motor score, and HY scale, on tracer spheric values.15–18 The weighted mean r of 0.913 was
uptake was analyzed using meta-regression analyses with used for the remaining studies in the meta-analysis of

dependent effect sizes. Percent differences were (β = 0.13; CI, 0.06–0.21; P < 0.001; Fig. 4). A similar
expressed as weighted relative differences (weighting moderator effect was observed for Hoehn and Yahr
according to sample size). Statistical significance was stage, as striatal D2R binding was elevated in patients
set at two-tailed P < 0.05. with a Hoehn and Yahr stage score below 2.1 and
reduced in motorically more severely affected patients
(β = 0.52; CI, 0.17–0.86; P = 0.002) and for motor
Results UPDRS score (β = 0.04; CI, 0.00–0.08; P = 0.031) but
Study Characteristics not for age of PD patients (β = 0.02; CI, 0.02 to
0.06; P = 0.28).
The demographic and clinical characteristics of the
patient samples included in the 67 D2R studies are
PSP and MSA
presented in Table 1 and in Tables S1–S3. Data were
insufficient for analyses of D1R studies, as only 5 D1R PSP patients had 26.5% lower striatal D2R binding
studies reported PET or SPECT results in PD, MSA, or (g = 1.59; CI, 1.19–1.99; n = 6/89, I2 = 0%, P < 0.0001),
PSP patients. The 67 included D2R studies had 75 indi- and MSA-P patients had 32.6% lower striatal D2R bind-
vidual patient samples involving 1925 patients (Fig. 1, ing than healthy controls (g = 2.08; CI, 0.03–4.13; n = 4/
Table S1). Because MSA-C samples were reported only 75, I2 = 75.6%, P = 0.001). PSP patients had 14.2%
in two studies, they were excluded from the analysis, lower striatal D2R binding (g = 0.99; CI, 1.65 to
and the included MSA samples had patients with 0.34; n = 11/204, I2 = 62.5%, P = 0.001), and MSA-P
MSA-P or unspecified MSA. patients had 21.8% lower striatal D2R binding
(g = 1.32; CI, 0.71 to 2.95; n = 12/221,
I2 = 63.1%, P < 0.001) than PD patients. There were no
Parkinson’s Disease
differences in striatal (g = 0.10; CI, 0.52 to 0.33;
D2R binding in the caudate nucleus was 9.8% lower n = 8/122, I2 = 0%, P = 0.59), caudate (g = 0.07;
in PD patients (medicated and unmedicated combined) CI, 1.67 to 1.53; n = 4/55, I2 = 67.7%, P = 0.89), or
than in healthy controls (g = 0.67; CI, 0.34–1.01; n putamen (g = 0.16; CI, 0.88 to 0.56; n = 4/55,
[samples/patients], 29/680; I2 = 71.6%, P < 0.0001), I2 = 0%, P = 0.49) D2R binding between PSP and
but there were no differences in the putamen (g = 0.32; MSA-P patients (Fig. S1).
CI, 0.73 to 0.10; n = 29/680, I2 = 79.6%, P = 0.12) or
the striatum (g = 0.16; CI, 0.06 to 0.39; n = 50/1292, Data Quality
I2 = 65.3%, P = 0.13; Fig. 2).
In subgroup analyses of unmedicated de novo PD Twelve studies scored 1–2 of 6 stars on the
patients compared with healthy controls, there were no Newcastle-Ottawa scale (Table S4). When these studies
differences in the mean striatal binding (g = 0.18; were excluded from the analysis, the results remained
CI. 0.43 to 0.07; I2 = 19.8%; Fig. 2), caudate nucleus essentially the same except for the striatal D2R differ-
binding (g = 0.43; CI, 0.06 to 0.92; I2 = 67.0%) or ence between unmedicated PD patients and healthy
putamen binding (g = 0.46; CI = 1.45 to 0.52, controls, which became significant (higher binding in
I2 = 88.9%). The mean striatal binding was 2.7% PD; g = 0.34; CI, 0.59 to 0.09). There were no
lower in medicated PD patients than in healthy controls differences in mean striatal effect sizes between PET
(g = 0.30; CI, 0.03–0.58; I2 = 68.6%; Fig. 2), and the (25 studies, 27 samples) and SPECT (19 studies, 23
caudate nucleus binding was 10.0% lower (g = 0.80; samples) studies (P = 0.27). Funnel plots with imputed
CI, 0.38–1.23; I2 = 73.8%), whereas there was no dif- data points for the striatum in PD and PSP samples
ference in the putamen (g = 0.23; CI, 0.58 to 0.13; suggested no significant publication bias with 0–1 nega-
I2 = 65.8%). The effect sizes for D2R binding differed tive studies missing (PD: Egger intercept P = 0.55).
between unmedicated and medicated patients in mean One negative study was missing in MSA versus HC and
striatal binding (P = 0.007). MSA versus PD analyses (Egger intercept P < 0.05), but
Binding in the striatum contralateral to the predomi- trim-and-fill–adjusted effect sizes remained essentially
nant motor symptoms of PD was 2.8% higher than that the same, suggesting minimal impact of
in the ipsilateral side (g = 0.19; CI, 0.26 to 0.11; publication bias.
n = 27/475, I2 = 69.7%, P < 0.0001; Fig. 3). Twenty-
three of 27 samples showed higher binding values on Discussion
the contralateral side.
PD disease duration was an effect moderator for There are three primary results in this meta-analysis.
striatal D2R binding. PD patients had higher binding First, the pooled results demonstrate that there was ini-
early in the disease, but the regression line crossed zero tial upregulation of striatal D2Rs in PD patients, which
at a disease duration of 4.36 years, after which PD was reversed to downregulation on average 4.4 years
patients had lower binding values than healthy controls after motor symptom onset. Second, there was

TABLE 1 Summary of included studies

Study Sitea Method Tracer Patients Scannerb
Baron 198619 PAR PET [76Br]bromospiperone PSP LETI prototype

20 11
Hägglund, 1987 UPP PET [ C]NMSP PD Scanditronix PC 382-3B
Rutgers, 1987 15
GRO PET 11
[ C]NMSP PD —
21 123
Brücke, 1991 VIE SPECT [ I]IBZM PD Siemens Dual Rota ZLC37
22 123
Tatsch, 1991 MUN SPECT [ I]IBZM PD Siemens Rota II
6 11
Brooks, 1992 LON PET [ C]raclopride PDP, PSP, MSA CTI 931/08/12
23 11
Sawle, 1993 LON PET [ C]raclopride PD CTI 931/12/8
24 11
Shinotoh, 1993 CHI PET [ C]NMSP PD, MSA Three-ring PET system
25 123
Brücke, 1993 VIE SPECT [ I]IBZM PD Siemens Dual Rota ZLC37
26 123
Cordes, 1993 BER SPECT [ I]IBZM PD APEX 409, Elscint
Pizzolato, 1993 27
PAD SPECT [ 123
I]IBZM PD —
28 123
Laulumaa, 1993 KUO SPECT [ I]IBZM PD Siemens Orbiter
29 123
van Royen, 1993 AMS SPECT [ I]IBZM PSP, MSA Strichman 810
30 123
Giobbe, 1993 TUR SPECT [ I]IBZM PD GE 400 T
31 11
Schwarz, 1994 MUN PET [ C]raclopride PD CTI 933/04–16
32 123
Hublin, 1994 HEL SPECT [ I]IBZM PD Picker DDC4096
7 11
Antonini, 1994 VIL PET [ C]raclopride PD CTI 933/04–16
33 123
Schulz 1994 TÜB SPECT [ I]IBZM PD, MSA Picker Digital Dyna
34 11
35 123
Buck, 1995 ZÜR SPECT [ I]IBZM PD, PSP Picker Prism 3000
16 123
Knable, 1995 BET SPECT [ I]IBZM PD Ceraspect
36 123
Nadeau, 1995 GAI SPECT [ I]IBZM PD Triad 88
37 11
Rinne, 1995 TKU PET [ C]raclopride PD ECAT 931/08–12
38 123
Pizzolato, 1995 PAD SPECT [ I]IBZM PD GE Starcam 400 AC
Cordes, 1996 39
BER SPECT [ 123
I]lisuride PD —
40 11
8 123
Staffen, 1997 SAL SPECT [ I]IBZM PD Picker Prism 3000
41 11
Turjanski, 1997 LON PET [ C]raclopride PD CTI 931/ 08/12
Pirker, 1997 42
VIE SPECT [ 123
I]epidepride PD, MSA —
43 123
Schwarz, 1997 MUN SPECT [ I]IBZM PD Rota II Siemens
44 11
Antonini, 1997 VIL PET [ C]raclopride PD, MSA CTI 933/04–16
17 123
Wenning, 1998 INN SPECT [ I]IBZM PD Siemens Orbiter Digitrac ZLC
45 123
Hierholzer, 1998 BER SPECT [ I]IBZM PD, PSP, MSA Apex 409
46 123
Ichise, 1998 TOR SPECT [ I]IBF PD Prism 3000XP, Picker
47 11
Dentresangle, 1999 LYO PET [ C]raclopride PD TTV03 LETI
9 11
Samii, 1999 VAN PET [ C]raclopride PD ECAT 953B
Nagabeppu, 1999 KAG SPECT [123
I]IBF PD, PSP, MSA —
18 11
Kaasinen, 2000 TKU PET [ C]raclopride PD ECAT 931/08–12
(Continues)

TABLE 1 Continued
Study Sitea Method Tracer Patients Scannerb
Hilker, 200148 COL PET [11C]raclopride PD ECAT EXACT HR
49 123
Prunier, 2001 TOU SPECT [ I]lisuride PD, PSP, MSA Helix Elscint
11 123
Kim, 2002 TOR SPECT [ I]IBF PD, PSP, MSA Prism 3000XP, Picker
50 123
Arnold, 2002 MUN SPECT [ I]IBZM PSP Siemens Rota II
51 11
Ghaemi, 2002 COL PET [ C]raclopride PD ECAT EXACT/ECAT EXACT HR
52 123
Oyanagi, 2002 KYO SPECT [ I]IBF PD, PSP Prism 3000 Picker
53 11
Hilker, 2003 COL PET [ C]raclopride PD ECAT EXACT HR
54 18
Schreckenberger, 2004 MAI PET [ F]fallypride PD ECAT EXACT
55 11
Scherfler, 2004 LON PET [ C]raclopride PD ECAT EXACT HR++
56 123
Seppi, 2004 INN SPECT [ I]IBZM PD, MSA ADAC VertexPlus
10 123
Plotkin, 2005 BER SPECT [ I]IBZM PD, PSP Multispect 3
57 11
Mishina, 2005 CHI PET [ C]raclopride PD HEADTOME V
58 11
Nakagawa, 2005 FUK PET [ C]raclopride PD, PSP, MSA ECAT EXACT HR+
59 11
Strafella, 2005 MON PET [ C]raclopride PD CTI-Siemens HR+
60 123
Hesse, 2006 LEI SPECT [ I]IBZM PD Ceraspect
61 11
Strafella, 2006 MON PET [ C]raclopride PD CTI/Siemens HR+
62 123
Verstappen, 2007 NIJ SPECT [ I]IBZM PD Multispect 2
63 11
Ribeiro, 2009 ORS PET [ C]raclopride PD ECAT EXACT HR+
64 11
Ishibashi, 2010 TOK PET [ C]raclopride PD SET-2400 W
65 123
Pifarre, 2010 BAR SPECT [ I]IBZM PD, PSP, MSA Siemens E-CAM
66 123
Lin, 2010 TAO SPECT [ I]IBZM PD, PSP Siemens E.CAM
67 123
Südmeyer, 2011 DÜS SPECT [ I]IBZM PD Prism 2000
68 123
Hellwig, 2012 FRE SPECT [ I]IBZM PD, PSP, MSA Siemens E.CAM
69 123
Hammesfahr, 2016 DÜS SPECT [ I]IBZM PD Prism 2000
70 11
Akamatsu, 2017 KOB PET [ C]raclopride PD Discovery 690 PET/CT
71 11
Mishina, 2017 KAN PET [ C]raclopride PD SET-2400 W
72 11
Politis, 2017 LON PET [ C]raclopride PD ECAT HR+
73 18
Stark, 2018 NAS PET [ F]fallypride PD GE Discovery STE PET/CT
74 11
Sacheli, 2018 VAN PET [ C]raclopride PD HRRT
[11C]NMSP, 3-N-[11C]methylspiperone; [123I]IBZM, [123I]-(S-)-2-hydroxy-3-iodo-6-methoxy-N([l-ethyl-2-pyrrolidyl]methyl)-benzamide.
a
AMS, Amsterdam, The Netherlands; BAR, Barcelona, Spain; BER, Berlin, Germany; BET, Bethesda, MD USA; CHI, Chiba, Japan; COL, Cologne, Germany; DÜS,
Düsseldorf, Germany; FRE, Freiburg, Germany; FUK, Fukuoka, Japan; GAI, Gainesville, FL, USA; GRO, Groningen, The Netherlands; HEL, Helsinki, Finland; INN, Inns-
brück, Austria; LON, London, UK; LYO, Lyon, France; KAG, Kagoshima, Japan; KAN, Kanawaga, Japan; KOB, Kobe, Japan; KUO, Kuopio, Finland; KYO, Kyoto, Japan;
LEI, Leipzig, Germany; MAI, Mainz, Germany; MON, Montreal, QC, Canada; MUN, Munich, Germany; NAS, Nashville, TN, USA; NIJ, Nijmegen, The Netherlands;
ORS, Orsay, France; PAD, Padova, Italy; PAR, Paris, France; SAL, Salzburg, Austria; TAO, Taoyuan, Taiwan; TKU, Turku, Finland; TOK, Tokyo, Japan; TOR, Toronto,
ON, Canada; TOU, Tours, France; TUR, Turin, Italy; TÜB, Tübingen, Germany; UPP, Uppsala, Sweden; VAN, Vancouver, BC, Canada; VIE, Vienna, Austria; VIL,
Villigen, Switzerland; ZÜR, Zürich, Switzerland.
b
Scanner models written as they were reported in the original articles.
consistent upregulation of D2Rs in the striatum contra- terminals, which is potentially important for
lateral to the predominant motor symptoms in PD neuroimaging-based differential diagnostics.
patients. Third, both PSP and MSA patients clearly had A critical question is whether the downregulation of
lower striatal D2R binding than PD patients despite striatal D2Rs seen in advanced PD patients was because
similar or even more profound loss of dopamine nerve of disease progression or dopaminergic medication.

FIG. 2. Forest plot of differences in striatal dopamine D2 receptor binding between PD patients and healthy controls. Red, samples with PD patients
treated with antiparkinsonian medications, mixed samples (medicated and unmedicated), or medication not reported; blue, samples with unmedicated
PD patients.
There are neuroimaging results in DBS-treated patients binding in PD patients. Because there are practically no
that support the hypothesis that receptor down- unmedicated PD patients with disease duration longer
regulation is a consequence of drug treatment, as the than 4 years, it is not possible to determine if the down-
downregulation seems to disappear in patients whose regulation in advanced patients was from disease pro-
medications are withdrawn after DBS implantation.4 gression. Given that agonist-induced downregulation of
There is also evidence indicating that changes in D1 receptors has been described in a number of other cen-
versus D2 dopamine receptor density contribute to the tral neurotransmitter systems, such as 5-HT receptors,76
development of dyskinesia.75 Indeed, in the present muscarinic acetylcholine receptors,77 AMPA receptors,78
meta-analysis, both longer disease duration and phar- and opioid receptors,79 the agonist-induced mechanism
macotherapy were associated with lower D2 receptor seems likely in PD, a view that is supported by studies

FIG. 3. Forest plot of D2R interhemispheric differences in PD patients. The analysis was carried out with studies that reported separate values for
striatal D2R binding in hemispheres contra- and ipsilateral to the predominant motor symptoms of PD. Note the higher contralateral binding in all but
4 samples. Red, samples with PD patients treated with antiparkinsonian medications, mixed samples (medicated and unmedicated), or medication not
reported; blue, samples with unmedicated PD patients.
downregulation may be secondary to therapy, the consis-

tently higher D2R binding in the hemisphere contralateral
to the predominant symptoms of PD points to a regionally
specific mechanism and indicates that the increase in D2R
binding is associated with a decrease in presynaptic dopa-
mine function. This is a strong indicator of pathology-
driven changes in dopamine receptor density. As the
increase in contralateral binding does not seem to be
directly related to synaptic dopamine levels,18 it is possible
that the upregulation is a consequence of the loss of striatal
neuropil in PD.
Another aspect is the subregional differences in dopa-
mine receptor-binding characteristics in PD patients.
When the caudate nucleus and putamen were studied
separately in the present meta-analysis, PD patients
(early and advanced combined) showed lower binding
FIG. 4. Association between effect size (Hedges’ g) and disease dura- in the caudate than healthy subjects with no difference
tion in PD patients. Negative effect sizes indicate receptor upregulation observed in the putamen. This suggests relatively more
in relation to healthy controls. The initial upregulation becomes down-
regulation 4.36 years after disease onset. Blue, unmedicated patient pronounced receptor loss in the caudate over the dis-
samples; red, medicated patient samples. Circle size denotes ease course of PD. It is of high importance to note that
sample size. executive cognitive deficits in early patients with PD
appear to be particularly associated with deficits in dor-
with rodents demonstrating a reduction in D2Rs after con- sal caudate dopaminergic function.81 Although associa-
tinuous treatment with dopamine receptor agonists,80 as tions between dopamine and cognitive measures should
well as findings in advanced PD patients withdrawn from be considered in the context of frontostriatothalamic
all medication following STN DBS.4 Although the circuitry, caudate D2R activity seems to be especially

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Dopamine Receptors in Parkinson’s Disease: A Meta-Analysis

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FIG. 1. Flowchart of study inclusion and exclusion.

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TABLE 1 Summary of included studies

Baron 198619 PAR PET [76Br]bromospiperone PSP LETI prototype

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downregulation may be secondary to therapy, the consis-

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