Pre- and post-synaptic dopamine imaging and its relation with
frontostriatal cognitive function in Parkinson disease: PET studies
with [11C]NNC 112 and [18F]FDOPA
Vanessa L. Cropleya,e,⁎, Masahiro Fujitaa, William Bara-Jimenezb, Amira K. Browna,
Xiang-Yang Zhanga, Janet Sangarea, Peter Herscovitchc, Victor W. Pikea, Mark Hallettb,
Pradeep J. Nathand, Robert B. Innisa,⁎
aMolecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA
bHuman Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
cPET Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
dSchool of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton, Victoria, Australia
eBrain Sciences Institute, Swinburne University of Technology, Hawthorn, Victoria, Australia
Received 15 August 2007; received in revised form 12 November 2007; accepted 14 November 2007
Frontostriatal cognitive dysfunction is common in Parkinson disease (PD), but the explanation for its heterogeneous expressions
remains unclear. This study examined the dopamine system within the frontostriatal circuitry with positron emission tomography
(PET) to investigate pre- and post-synaptic dopamine function in relation to the executive processes in PD. Fifteen non-demented
PD patients and 14 healthy controls underwent [18F]FDOPA (for dopamine synthesis) and [11C]NNC 112 (for D1receptors) PET
scans and cognitive testing. Parametric images of [18F]FDOPA uptake (Ki) and [11C]NNC 112 binding potential (BPND) were
calculated using reference tissue models. Group differences in Kiand BPNDwere assessed with both volume of interest and
statistical parametric mapping, and were correlated with cognitive tests. Measurement of [18F]FDOPA uptake in cerebral cortex
was questionable because of higher Kivalues in white than adjacent gray matter. These paradoxical results were likely to be caused
by violations of the reference tissue model assumption rendering interpretation of cortical [18F]FDOPA uptake in PD difficult. We
found no regional differences in D1receptor density between controls and PD, and no overall differences in frontostriatal
performance. Although D1receptor density did not relate to frontostriatal cognition, Kidecreases in the putamen predicted
performance on the Wisconsin Card Sorting Test in PD only. These results suggest that striatal dopamine denervation may
contribute to some frontostriatal cognitive impairment in moderate stage PD.
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: [18F]FDOPA; [11C]NNC 112; PET; Parkinson disease; Frontostriatal cognition; Dopamine
Cognitive impairment is frequently observed in
patients with Parkinson disease (PD), most commonly
Available online at www.sciencedirect.com
Psychiatry Research: Neuroimaging 163 (2008) 171–182
⁎Corresponding authors. National Institute of Mental Health,
National Institutes of Health, Bldg. 31, Rm. B2-B37, 1 Center
Drive, MSC 0135, Bethesda, MD 20892-0135, USA. Tel.: +301 594
1368; fax: +301 480 3610.
E-mail addresses: firstname.lastname@example.org
(V.L. Cropley), email@example.com (R.B. Innis).
0925-4927/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
in tests of executive functioning such as working me-
mory, planning, strategies, attentional set-shifting and
concept formation (for review, see Cools, 2006). Alter-
ation of the neuronal loops connecting the frontal cortex,
thalamus, and basal ganglia (commonly termed fronto-
striatal circuitry) are suggested to play a role in the
executive dysfunction of PD (Owen, 2004). This notion
is largely based on the concept of basal ganglia
organization, of which frontostriatal circuits are structu-
rally and functionally segregated into “motor”, “limbic”
and “associative” (including prefrontal) domains (Alex-
ander et al., 1986; Alexander et al., 1990).
The neurochemical basis of frontostriatal and cog-
nitive dysfunction in PD (particularly in the early stages)
is hypothesized to be linked predominately to dopami-
nergicdysfunctionwithinneuralnetworks linking dorsal
striatum (i.e. dorsolateral putamen and dorsal caudate
nucleus) to dorsolateral prefrontal cortex (Owen, 2004;
Cools, 2006). In PD, tests sensitive to dorsal fronto-
striatal dysfunction (so-called executive processes) such
as planning and set-shifting were impaired following L-
dopa (L-3,4-dihydroxyphenylalanine) withdrawal (Lange
et al., 1992; Hayes et al., 1998; Cools et al., 2003) and
improved with L-dopa treatment (Bowen et al., 1975;
Lange et al., 1993), suggesting a primarily dopaminergic
substrate. Further, a cerebral blood flow study in PD pa-
tients demonstrated dopaminergic modulation of fronto-
striatal networks during planning (Cools et al., 2002).
While together these studies provide strong evidence
linking dopamine with frontostriatal executive processes,
the findings do not directly address the locus of the mo-
lecular pathology and its relationship to the cognitive
Positron emission tomography (PET) allows direct in
vivo assessment of pre- and post-synaptic dopaminergic
function in PD. Pre-synaptic markers of dopamine
neurons include [18F]FDOPA and dopamine transporter
ligands, which are consistently lower in the striatum of
PD patients (Heiss and Hilker, 2004). Several PET and
SPECT studies have correlated striatal, especially cau-
date nucleus, dopamine loss with cognitive disturbance
in PD (Holthoff-Detto et al., 1997; Marie et al., 1999;
Müller et al., 2000; Rinne et al., 2000; Bruck et al.,
2001). Recently, [18F]FDOPA has also been assessed in
the cortex of PD patients and was reduced in the frontal
cortex (Rinne et al., 2000) and in the anterior cingulate
(Ito et al., 2002). Reductions of frontal cortical [18F]
FDOPA uptake in PD were also associated with impair-
ments in working memory, verbal fluency and sup-
pressed attention (Rinne et al., 2000; Bruck et al., 2005).
These findings indicate involvement of both striatal and
cortical dopamine depletion in the executive impairment
of PD, although the precise relationship with fronto-
striatal tasks such as planning and set-shifting remains
Work from experimental animals suggests a critical
role for post-synaptic dopamine D1receptors within the
prefrontal cortex in modulating executive processes
(Arnsten, 1997, 1998). In humans, examination of D1
receptors in executive processes is limited owing to the
lack of selective D1compounds for human use. Whether
D1receptors are altered in PD is largely unknown. Two
PET studies have not shown changes in D1receptor
density in striatum and orbitofrontal cortex of PD pa-
tients (Shinotohet al.,1993;Ouchietal.,1999),butboth
studies used the D1ligand [11C]SCH 23390 (KD=~0.4–
0.14 nM), which has low specific-to-nonspecific ratios
(Karlsson et al., 1997). The D1ligand [11C]NNC 112
also displays high affinity for the D1 receptor
(KD=0.18 nM) but shows greater specific-to-non-
specific binding than [11C]SCH 23390 (Halldin et al.,
1998). Increases in [11C]NNC 112 binding in the pre-
frontal cortex were associated with impairments of
working memory in schizophrenia (Abi-Dargham et al.,
2002). Whether D1receptors are associated with front-
ostriatal cognitive processes in PD is not known.
The purpose of the current study was to investigate
the relationship between pre- and post-synaptic dopa-
mine markers within the frontostriatal circuitry and
executive function in PD. Specifically, the role of striatal
and cortical dopamine function on frontostriatal execu-
tive processes in non-demented PD was assessed with
[18F]FDOPA (a measure of pre-synaptic dopamine syn-
thesis), [11C]NNC 112 (a marker of post-synaptic D1
receptors), and two frontostriatal cognitive tests (the
Stockings of Cambridge planning task and the Wiscon-
sin Card Sorting Test).
2.1. Study population
Fifteen non-demented, moderately impaired patients
with idiopathic PD (nine males, six females) and 14 age-
matched healthy volunteers (eight males, six fe-
males) participated in the study (Table 1). Patients
were non-smokers and were free of current medical and
neurological disorder not related to PD. No patient met
current criteria for major depressive disorder, as
assessed with the Structured Clinical Interview for
DSM-IV Disorders. Controls were non-smokers, medi-
cally and neurologically healthy, and free of current
psychiatric illness according to DSM-IVAxis I criteria.
All but one patient was being treated for PD with L-dopa
172V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
pramipexole and one with amantadine. All patients had
their medication stopped at least 12 h before the [18F]
FDOPA PETscan and were clinically assessed using part
III (motor examination) of the Unified Parkinson's
Disease Rating Scale on the morning of the PET scan.
Patients were at clinical stage 1.5–4 using Hoehn and
Yahr (1967) classification system. The Radiation Safety
Committee of the National Institutes of Health and the
Institutional Review Board of the National Institute of
Mental Health approved the study. All participants gave
written informed consent.
2.2. Radiopharmaceutical preparation
The (+)-desmethyl-NNC 112 (1.0 mg per radiolabel-
ing) was obtained from Professor Christer Halldin of the
Karolinska Institutet. [11C]NNC 112 was synthesized
from [11C]methyl iodide (Halldin et al., 1998) via a
captive solvent method using a commercially available
radiochemistry ‘loop’ module. The radiochemical pu-
rities of all [11C]NNC 112 batches were greater than
99%. [18F]FDOPA was produced using the method of
Adam and Jivan (1998) with slight modifications to the
purification steps. The radiochemical purities of all [18F]
FDOPA batches were greater than 90%.
2.3. Scanning protocol
PET scans were performed on a GE Advance tomo-
an 8-min transmission scan for attenuation correction of
the brain was performed with a68Ge rotating pin source.
Dynamic emission scans were acquired following an
intravenous bolus injection of 379–601 MBq of [18F]
FDOPA and 391–766 MBq of [11C]NNC 112 for a total
scan time of 90 min (6×30 s, 3×1 min, 2×2 min,
16×5 min). Scans were reconstructed with the filtered-
back projection algorithm which resulted in a final image
resolution of 7.5 mm full width half maximum. For the
[18F]FDOPA scan, all subjects received an oral dose of
200 mg carbidopa, a peripheral inhibitor of aromatic-L-
amino-acid decarboxylase (AADC), 1 h before scanning.
Administration of L-dopa medication was resumed after
did not complete the [18F]FDOPA scan due to transient
high blood pressure after discontinuing L-dopa medica-
tion. For the [11C]NNC 112 scans, PD patients continued
their normal medication regime. Approximately half of
the subjects in each group underwent the [18F]FDOPA
scanfirst.The average intervalbetween [18F]FDOPA and
[11C]NNC 112scans was 18days. All subjectsreceiveda
1.5 T MRI scan for coregistration and segmentation pur-
poses. Inversion recovery fast gradient recalled-echo (IR-
FGRE; TR~12 ms, TE~5 ms, flip angle 20°, voxel size:
0.86×0.86×1.2 mm), fast spin echo (FSE) T2-weighted
(TR~3700 ms, TE~101 ms, flip angle 90°, voxel size:
0.43×0.43×5 mm) and fluid attenuated inversion
recovery (FLAIR; TR~10,002 ms, TE~140 ms, flip
angle 90°, voxel size: 0.86×0.86×5 mm) images were
2.4. Neuropsychological tests
All subjects were administered the Mini-Mental State
Examination (Folstein et al., 1975). We included
patients with a score of 24 or greater. The Dementia
Rating Scale-2 (Jurica et al., 2001), with a cut-off score
of ≥123, was additionally administered to PD patients
to evaluate the overall cognitive performance and rule
out dementia. Depressive symptoms were evaluated
with the Beck Depression Inventory fast screen (Beck
Participant demographics and clinical measures
Education15.3±2.8 1.40 0.174
Mini-Mental State Exama
Beck Depression Inventorya
Dementia Rating Scale Total
Motor Unified Parkinson
Disease Rating Scale
Hoehn & Yahr classification
Disease duration (yrs)
[11C]NNC Injected Activity
[11C]NNC Specific Activity
[18F]FDOPA Injected Activity
[18F]FDOPA Specific Activity
Wisconsin Card Sorting Test
Wisconsin Card Sorting Test
Stockings of Cambridge initial
think time 5 movesa(s)
Stockings of Cambridge perfect
Data are mean±standard deviation. Group comparisons performed
with an independent samples t-test.aGroup comparison performed
with Mann–Whitney U non-parametric test.
value. P-values are two-tailed.
173V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
et al., 2000). To examine the frontostriatal functioning,
subjects were administered a computerized version of
the Wisconsin Card Sorting Test (Heaton and Goldin,
2003) and the Stockings of Cambridge task from the
Cambridge Automated Neuropsychological Test Battery
(Cambridge Cognition, UK), which is a computerized
form of the Tower of London test of planning (Shallice,
1982). These tests reveal impairment in some non-
demented, medicated PD patients (Taylor et al., 1986;
manipulation (Cropley et al., 2006). The Wisconsin test
requires subjects to match multi-dimensional test cards
to reference cards according to the color, shape or
number of the card stimuli. Subjects are not told how to
match the cards but must deduce the correct rule of
classification. After a fixed number of correct matches,
the classification rule changes, requiring subjects to shift
their response set to a new stimulus dimension.
Performance on the Wisconsin test was based on the
number of categories achieved (0–6) and the number of
perseverative responses. The Stockings of Cambridge
task consists of two arrangements of three colored balls,
one in the top half of the screen and the other in the
bottom half. Subjects are required to rearrange the balls
in the bottom display to match the ‘goal’ arrangement in
the top display in the minimal number of moves. For this
task, initial thinking time for the most difficult (5-move)
problems and number of perfect solutions (across all
neuropsychological tasks in an “on-state,” defined as
30–60 min after medication and the patient's subjective
dopamine replacement therapy to minimize the effect of
motor impairment on test scores and because deficits in
these tasks have been observed in medicated patients.
One PD patient and one healthy control didnot complete
the Stockings of Cambridge task due to time constraints
and technical problems, respectively.
2.5. Statistical analysis
Group comparisons (two-tailed) of demographic,
clinical and PET variables were performed using the
independent sample t-test for parametric data and the
Mann–Whitney U test for non-parametric data. Non-
parametric variables were determined by the Shapiro–
Wilk normality test. Correlations between neuro-
psychological measures and frontostriatal regions were
performed with Spearman's rank correlation or Pear-
son's correlation coefficient, as appropriate. Multiple
comparisons were controlled for with a false discovery
rate correction (Benjamini and Hochberg, 1995). This
modified Bonferroni procedure involves ordering the P
values (P(i)s) for the number of comparisons made from
highest to lowest. Controlling the false discovery rate at
0.05, each P(i)is compared sequentially with 0.05 i/m,
down procedure is continued until a P value satisfies the
constraint, and subsequently all hypotheses below this P
value are also rejected. All statistical analyses, except
voxel-based comparisons, were performed using SPSS
for Windows (SPSS Inc., 1989–2004, Release 13.0).
2.6. Image analysis
2.6.1. Preprocessing and parametric imaging
To correct for head movement during the scan, PET
frames of both [11C]NNC 112 and [18F]FDOPA were
realigned to a standard frame using the FLIRT algorithm
(Jenkinson and Smith, 2001) and MRI (IR, T2 and
FLAIR) was coregistered to an average image of initial
frames of each of [11C]NNC 112 and [18F]FDOPA using
Statistical Parametric Mapping (SPM2, The Wellcome
Departmentof Cognitive Neurology, London, UK).Para-
metric images of PET data were calculated using PMOD
2.65 (pixel-wise modeling computer software; PMOD
Technologies Ltd, Adliswil, Switzerland). For [18F]
FDOPA PET scans, parametric images in which each
pixel represents the influx constant Ki(min−1) of [18F]
(Patlak and Blasberg, 1985). For each subject, putamen
(target) and occipital cortex (reference) volumes of in-
terest were obtained in the Montreal Neurological In-
curve in putamen was used to determine the start time of
the linear segment (t⁎) of the graph. This same t⁎was
used for pixel-wise calculations ofKiin all target regions.
The slope of the linear segment equals the influx constant
Ki, and represents the uptake rate constant of [18F]
FDOPA. For [11C]NNC 112 scans, parametric images of
binding potential (BPND) and K1/K1' relative ligand
delivery (R1) were generated using the Multilinear Re-
ference Tissue Model 2 (Ichise et al., 2003). BPNDrefers
to the ratio at equilibrium of the specifically bound radio-
ligand to that of the nondisplaceable radioligand in tissue
(see Innis et al., 2007), while R1is a measure of radio-
ligand delivery to tissue relative to the reference region.
Putamen and cerebellum volumes of interest (obtained in
Montreal Neurological Institute space) were used as re-
ceptor-rich and reference regions, respectively. All data
points were used in the fitting for [11C]NNC 112, since
Logan plots were fairly linear from early time points in a
previous study (Abi-Dargham et al., 2000). Parametric
images of [18F]FDOPA Kiwere coregistered to [11C]
174V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
NNC 112 space, and subsequentlyboth [18F]FDOPA and
[11C]NNC 112 parametric images were spatially normal-
15 PD and 13 control subjects' [11C]NNC 112 R1para-
2.6.2. Partial volume correction
Because the thickness of cortical gray matter is only a
matter. We applied partial volume correction to [18F]
FDOPA PET to minimize the white matter influence on
partial volume correction for purposes of comparison.
Partial volume correction was performed using three seg-
ments (gray matter, white matter, and cerebrospinal fluid)
and FLAIR images using SPM2 and coregistered to PET
in of activity from white matter. To do this, white matter
activity was subtracted from the uncorrected image and
divided by the smoothed gray matter image. Pure white
matter activity was estimated by extrapolating with linear
membership greater than 99% (Giovacchini et al., 2004).
To eliminate noisy voxels, the resulting corrected image
the pixel to belong to gray matter. PMOD was used to
perform partial volume correction. Parametric images of
corrected [18F]FDOPA Kiand [11C]NNC 112 BPNDwere
created as described above.
2.6.3. Volume of interest analysis
Volumes of interest within the frontostriatal circuitry
bilaterally on the caudate nucleus and putamen of a mean
image of the study sample's spatially normalized MRI.
Extrastriatal volumes were taken from the anatomical
labeling template (Tzourio-Mazoyer et al., 2002) and were
defined on the superior, middle and inferior (triangular)
lateral frontal gyri and thalamus. Independent sample t-
tests were performed to compare average Kiand BPNDof
patients and controls. Correlations between neuropsycho-
logical variables and Kiand BPNDwere assessed with
Spearman's or Pearson's correlation.
2.6.4. SPM analysis
Voxel-based statistical analysis of parametric Kiand
BPNDimages were performed using SPM2. An isotropic
10-mm Gaussian kernel was used to smooth normalized
parametric images. As Kiand BPNDvalues are quan-
titative, all SPM analyses were performed without glo-
bal normalization. Between-group comparisons of Ki
and BPNDat the voxel level were performed using a
two-sample t-test. Analyses testing the correlation
between neuropsychological score and Ki or BPND
values were performed with a regression analysis. A
false discovery rate of P less than 0.05 (voxel-level) was
considered significant. Because [18F]FDOPA data in
extrastriatal areas are contaminated by white matter (see
below), Ki analyses were done using small-volume
correction, i.e. restricted to the striatum. The striatal
mask was created from the average [18F]FDOPA
parametric image of healthy subjects. Covariate ana-
lyses of BPNDwere made on the whole brain parametric
images to explore possible correlations outside the
frontostriatal network. Voxel-wise analysis was not
performed on partial volume corrected data.
3.1. Demographic and neuropsychological data
PD patients did not significantly differ from controls
in age, education or Mini-Mental State Examination
score (Table 1). Although PD patients reported sig-
nificantly more symptoms of depression on the Beck
Depression Inventory fast screen, the mean score indi-
cated mild depressive symptoms, and no patients were
clinically depressed. Furthermore, there were no sig-
nificant correlations (Spearman's, two-tailed) between
the Beck Depression Inventory and PET and cognitive
measures in PD patients. Patients did not significantly
differ in performance from controls on any of the neuro-
psychological measures, although they did not complete
as many Wisconsin categories as controls (Table 1).
Cognitive performance of PD patients was variable,
consisting of both high- and low-performing indivi-
duals. Six PD patients (40%) were identified as being
cognitively impaired (defined as falling within the 5th
percentile of the cognitive test based on normative data)
on at least one neuropsychological measure.
3.2. [18F]FDOPA uptake
3.2.1. Striatal [18F]FDOPA uptake
The mean Kiin putamen and caudate was signifi-
cantly decreased in PD patients compared with controls
(Table 2) with both SPM and volume of interest ana-
lysis. In patients, the putamen showed lower Kivalues
than the caudate nucleus. The [18F]FDOPA influx
175 V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
constant was reduced in PD patients by 70% in the
putamen (S.D.=0.04, range: 64–80%) and by 36% in
the caudate nucleus (S.D.=0.11, range: 19–56%). PD
patients showed lateralized differences in striatal Ki,
which was significantly lower (paired t-test, t=3.7,
df=13, P=0.003,) in striata (putamen and caudate)
contralateral to the side of the body with the initial pre-
sentation of symptoms in all but two patients.
3.2.2. [18F]FDOPA uptake in extrastriatal regions
[18F]FDOPA Kivalues in extrastriatal regions were
considerably lower than in striatum. Kivalues were un-
expectedly higher in cerebral white matter than adjacent
gray matter regions (Fig. 1). Values were approximately
two- to three-fold higher in white matter than in frontal
gyrus regions. Unlike the asymmetry in striata, Kiin
body showing initial symptoms.
3.2.3. Partial volume correction of [18F]FDOPA PET
Minimizing the influence of white matter data by
partial volume correction decreased Kiand increased
inter-subject variability in all frontal cortical regions
studied. Partial volume correction decreased Kiby ap-
proximately 45% and increased COV (S.D./mean) by 45
to 115% in PD patients (Table 3), and decreased Kiby a
similar amount (42%) and increased COV by 12 to 55%
in controls. Partial volume correction typically increases
gray matter PET values,because the signal or variable of
interest is typically higher in gray than in white matter.
Partial volume correction decreased gray matter Kival-
ues because of greater Kiin white matter. Because of the
unreasonably high Kivalues in white matter and small
and variable Kivalues with partial volume correction,
[18F]FDOPA analyses were only conducted in the
3.3. [11C]NNC 112 binding
Between-group SPM and volume of interest analysis
showed no significant differences or trends in regional
Striatal [18F]FDOPA influx constant in PD patients compared with
RegionParkinson disease ControlstP
Mean±S.D. [18F]FDOPA influx constant (Ki×10−3min−1).
Group comparison performed with an independent sample t-test.
Fig. 1. (a) Mean parametric image of [18F]FDOPA Kiof healthy subjects superimposed onto MRI template. Kivalues are greater in cortical white
matter than adjacent gray matter regions (b). The kinetics of white matter ( ) uptake and washout from a representative healthy subject is
significantly different from reference region occipital cortex ( ) (c).
176 V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
[11C]NNC 112 BPNDbetween PD patients and controls
(Table 4). Patients showed only a weak trend of lower
BPND values with the smallest false discovery rate-
corrected P value of 0.16 in the right median cingulate.
Striatal BPNDwas approximately seven-fold higher than
that in frontal regions, which is consistent with the
known distribution of D1receptors in brain (De Keyser
et al., 1988; Hall et al., 1994). A mean parametric image
of [11C]NNC 112 BPNDin healthy subjects illustrates
markedly higher BPNDin striatal than in extrastriatal
regions (Fig. 2). Patients did not show marked asym-
metry of BPNDin striatum. BPNDvalues in striata and in
frontal cortex of patients were not related to the side of
body showing initial symptoms. Partial volume cor-
rection of [11C]NNC 112 increased BPNDvalues 2.5
fold and decreased inter-subject variability (COV) by
50%. [11C]NNC 112 BPNDvalues were markedly lower
across brain regions in our subjects than in control
subjects of a previous PET study using [11C]NNC 112
(Abi-Dargham et al., 2002).
3.4. Correlational analyses
For [11C]NNC 112, there were no significant cor-
relations between neurocognitive scores and BPNDin
PD and controls with volume of interest and SPM ana-
lysis. For D1receptors, the maximum correlation was
observed between BPNDin the caudate of healthy con-
trols and Stockings of Cambridge perfect solutions
(Pearson's r=0.67, P=0.013), although this did not
survive multiple comparison correction. For [18F]
FDOPA, correlations were restricted to only the stria-
tum. With volume of interest analysis, PD patients
showed a significant positive correlation between Kiin
the putamen and number of categories achieved on the
Wisconsin Card Sorting Test (Spearman's rho=0.69,
P=0.006) (Fig. 3). SPM with small-volume correction
which would have been missed in the VOI analysis. The
SPM analysis did not show significant correlations. No
other correlations were found with other neuropsycho-
logical measures or in the caudate. Disease severity
indices and age were not related to neuropsychological
measures in PD, and partial correlations with age as the
Effect of partial volume correction on frontal [18F]FDOPA influx
constants in Parkinson disease patients
Superior frontal gyrus
Middle frontal gyrus
Inferior frontal gyrus
Mean±S.D. [18F]FDOPA influx constant (Ki×10−3min−1) in PD
patients before and after partial volume correction (PVC). COV=S.D./
[11C]NNC 112 binding potential from volume of interest analysis
Region Parkinson diseaseControls
Superior frontal gyrus
Middle frontal gyrus
Inferior frontal gyrus
No significant differences in any region.
Fig. 2. Mean parametric image of [11C]NNC 112 BPNDof healthy
subjects. Binding potential values are clearly higher in striatum than in
extrastriatal areas such as frontal cortex, which is consistent with the
known distribution of D1receptors in human brain. In contrast to [18F]
FDOPA, BPNDvalues are greater in gray than white regions.
Fig. 3. Wisconsin Card Sorting test categories achieved score versus
[18F]FDOPA uptake (Ki) in the putamen of PD patients (Spearman
rho=0.69, P=0.006, two-tailed).
177V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
control variable produced almost identical statistical re-
sults. Volume of interest and SPM analysis showed no
significant correlations between striatal Kiand neuro-
cognitive scores in healthy controls.
In this sample of non-demented PD patients, we
found no differences in dopamine D1receptor density in
fronto–striatal–thalamic regions and no overall differ-
ence in frontostriatal cognitive performance. Variability
in performance in PD patients on a task reliant on the
integrity of the frontostriatal circuitry was associated
with dopamine loss in the putamen. D1receptor density
did not significantly correlate with cognitive perfor-
in white matter were erroneously higher than those in
gray matter, which casts significant doubt on the validity
of cortical dopamine synthesis measurements with [18F]
4.1. Pre-synaptic dopamine synthesis and questionable
measurement of cortical [18F]FDOPA
Consistent with over two decades of research, our PD
patients showed reduced Kiin striatum, with greater loss
in the putamen than in the caudate nucleus. Unexpect-
edly however, we found higher [18F]FDOPA Kiin white
than in adjacent gray matter, which is unreasonable
since aromatic amino-acid decarboxylase (AADC) is
minimally present in white matter. Over a decade of
published [18F]FDOPA studies using Patlak parametric
modeling with a reference tissue input have not, to our
knowledge, reported this phenomenon. One article has
shown an [18F]FDOPA parametric image with appar-
ently greater Kiin white matter (Nagano et al., 2000),
although this was not mentioned. This error in quan-
tification of the cortical [18F]FDOPA signal was possi-
bly caused by slower washout of radioactivity from
white than gray matter. The reference region (occipital
cortex) contains both gray and white matter, and its
kinetics would be different from that of either frontal
gray or white matter. Such a discrepancy with the
reference region would violate an assumption of the
Patlak and Blasberg (1985) model that the ratio of
activity in nondisplaceable compartments in target com-
pared with reference regions should be constant after t⁎.
We found that the time-activity curves were markedly
different between white matter and occipital cortex,
which violated this assumption and caused Kivalues to
be erroneously greater in white matter. Removal of
white matter from PET images with partial volume
correction to circumvent this model violation actually
reduced gray matter Kiand increased intersubject var-
iability. Instead of increasing the specific signal in gray
matter, as occurred with [11C]NNC 112, the signal be-
came considerably smaller and noisier after partial
volume correction, making it vulnerable to statistical
noise. Therefore, [18F]FDOPA Kivalues in extrastriatal
regions are unreliable and did not undergo further
between-group and correlational analyses.
Our finding of greater Kiin white than adjacent gray
matter places significant doubt on the validity and in-
terpretation of cortical [18F]FDOPAwith reference input
models. Six studies have reportedly measured cortical
[18F]FDOPA uptake in PD patients (Rakshi et al., 1999;
Rinne et al., 2000; Kaasinen et al., 2001; Ito et al., 2002;
Bruck et al., 2005) or normal elderly controls (Nagano
et al., 2000) using cerebellum or occipital cortex as re-
ference regions. Such studies have reported increases
(Rakshi et al., 1999; Kaasinen et al., 2001; Bruck et al.,
2005) and decreases (Rinne et al., 2000; Ito et al., 2002)
in Kiin cortex, which has been interpreted as reflecting
either increased or decreased dopamine synthesis. Al-
though parametric images were analyzed, most of these
studies presented [18F]FDOPA images by summing up
data obtained during the entire scan. Please note that
such images do not reflect Kibecause images at early
time points reflect mainly blood flow. Since early im-
ages have greater activity than late images, a large por-
tion of the summed up images reflect merely blood flow
but not the metabolism of [18F]FDOPA to [18F]F-
dopamine. We question whether [18F]FDOPA gives a
specific PET signal and is meaningful in cortex for the
following reasons: (1) Comparisons of Kiin gray and
white matter are unreasonable and may be due to a
model violation. (2) DOPA decarboxylase activity is
very low in frontal cortex of human brain tissue and
activity ratio of cortex/caudate is 1% (Mackay et al.,
1978). Our ratio of frontal cortex/caudate Kiafter partial
volume correction in healthy controls was high, with a
value of 4%. Previous studies without partial volume
correction have shown unrealistically high cortex/cau-
date ratios of Kiin controls, ranging between 10 and
30% (Rakshi et al., 1999; Nagano et al., 2000; Rinne
et al., 2000; Kaasinen et al., 2001; Ito et al., 2002; Bruck
et al., 2005), suggesting that [18F]FDOPA measure-
ments are not specific to DOPA decarboxylase activity.
By not applying partial volume correction, in other
words, leaving greater influence from white matter data,
frontal cortex/caudate Kiin the current study became
8%, which is close to the ratios reported in previous
studies. (3) Tyrosine hydroxylase, the first step
dopamine-synthesizing enzyme, and AADC do not
178 V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
coexist in neurons in human cingulate cortex (Ikemoto
et al., 1999), suggesting that AADC-only neurons in at
least the cingulate are not specific to dopamine. As such,
the scientific community should be aware that the
cortical [18F]FDOPA signal has serious deficiencies.
4.2. Post-synaptic dopamine D1receptors in Parkinson
Lack of alteration of dopamine D1receptors in our
PD sample is consistent with previous studies showing
no regional differences in [11C]SCH 23390 binding in
PD (Shinotoh et al., 1993; Ouchi et al., 1999). Ouchi
et al. (1999) studied only early (Hoehn and Yahr stages 1
and 2) PD patients while Shinotoh et al. (1993) ex-
amined a heterogeneous sample consisting of patients in
Hoehn and Yahr stages 1–4 and with disease duration of
6 months to 10 years. Our study found no changes in D1
receptors in PD patients with moderate symptom seve-
rity using a different radioligand for measuring D1re-
ceptors in low-density cortical regions. Taken together,
these studies suggest that post-synaptic dopamine D1
receptors are not altered in PD, at least in early to
moderate stage patients. A problem with these ligands,
however, is their affinity to cortical 5-HT2Areceptors. A
very recent study has shown that about 20 to 30% of
cortical [11C]NNC 112 uptake in humans is to 5-HT2A
receptors (Slifstein et al., 2007), making [11C]NNC 112
almost equivalent to [11C]SCH 23390 with regard to D1
receptor selectivity (Ekelund et al., 2007). Development
of more selective ligands for D1receptors is therefore
needed to adequately assess changes in cortical D1re-
ceptor expression in PD.
Due to feasibility issues, PD patients remained on
their normal dopaminergic medications for the [11C]
NNC 112 PETscan. This included L-dopa and dopamine
D2/D3agonists such as pramipexole and amantadine.
Although these medications are not known to directly
interact with D1receptors, it is possible that the indirect
increases in extracellular dopamine generated by L-dopa
may lead to changes in D1receptors. However, evidence
to date suggests that such changes are unlikely. For
example, no changes in D1receptors have been found in
untreated or drug-naive PD patients (Shinotoh et al.,
1993; Ouchi et al., 1999), and treated patients (Shinotoh
et al., 1993), suggesting that dopaminergic medication
has little effect on D1receptor PET measurement. Fur-
thermore, [11C]NNC 112 binding was unaltered follow-
ing acute administration of the dopamine agonist,
amphetamine, in monkeys (Chou et al., 1999). While
long-term L-dopa exposure is likely to downregulate D1
receptors (Turjanski et al., 1997), no evidence of this
was noted. Nevertheless, such medication-induced in-
teractions as a potential confound on [11C]NNC 112
binding cannot be ruled out and requires clarification by
measuring D1receptor availability on and off L-dopa
Binding potential of [11C]NNC 112 was about 65–
75% lower in our study compared with values reported
by Abi-Dargham et al. (2002) in their healthy cohort.
This discrepancy was possibly due to differences in the
methods for obtaining volume of interest data and age-
related decline of D1receptors in human brain (Suhara
et al., 1991; Wang et al., 1998), as our subjects were
approximately 30 years older than those in the Abi-
4.3. Frontostriatal cognitive functionin Parkinson disease
and association with pre- and post-synaptic dopamine
Our sample of moderately severe PD patients did not
show overall frontostriatalcognitive impairment in com-
parison with elderly controls. Previous studies have
reported impairments on the Wisconsin Card Sorting
Test (Bowen et al., 1975; Taylor et al., 1986; Brown and
Marsden, 1988; Canavan et al., 1989; Paolo et al., 1995)
and Tower of London type planning tasks (Owen et al.,
1992; Dubois and Pillon, 1997) in medicated, non-
demented PD patients, and in patients with a moderate
relative to their medication effectiveness because some
tests are affected by motor function. Thus, the admin-
istration of dopaminergic medication may have had a
facilitating or normalizing effect on their executive pro-
cesses and contributed to the lack of overall cognitive
impairment. Testing patients both on and off dopamine
medication would help determine the effect of dopamine
treatment on cognitive processes.
Although PD patients showed no overall cognitive
impairment, they did show large variability in fronto-
striatal cognitive performance. Such variability was not
associated with D1receptors in any region. This con-
trasts with several PET studies reporting associations
between executive processes and D1receptor density in
prefrontal cortex and striatum in disorders associated
with dopamine dysfunction, such as schizophrenia and
Huntington's disease (Okubo et al., 1997; Lawrence
et al., 1998; Abi-Dargham et al., 2002). Although D1
receptors are proposed to play a critical role in cognitive
stability of prefrontal neural networks (Durstewitz et al.,
2000; Bilder et al., 2004), as required in maintenance
tasks or sustained attention, they may not be critical for
179 V.L. Cropley et al. / Psychiatry Research: Neuroimaging 163 (2008) 171–182
‘plasticity’ or cognitive flexibility, processes which were
largely required in the current study. Whether D2re-
ceptors, which may be more important for ‘resetting/
updating’ or behavioral switching functions (see Bilder
et al., 2004; Cools, 2006), are associated with planning
and set-shifting performance in PD patients remains to
In contrast, impairment in a measure of executive
function (Wisconsin categories achieved) in PD patients
was associated with pre-synaptic dopamine loss in the
putamen but not the caudate nucleus, a relationship not
due to age or disease severity. This relationship was
observed even after correction of the false discovery rate
(Benjamini and Hochberg, 1995), which is notable as
many previous studies reporting similar relationships
have not adequately controlled for multiple compar-
isons. Such an association between putamen Kiand
Wisconsin performance is consistent with several PET
and SPECT studies showing associations between
striatal (particularly caudate nucleus but also putamen)
dopamine loss and memory, attention and executive
impairment in PD (Holthoff-Detto et al., 1997; Marie
e al., 1999; Müller et al., 2000; Rinne et al., 2000; Bruck
et al., 2001; Duchesne et al., 2002), suggesting that
striatal dopamine depletion in PD may contribute to
frontostriatal cognitive impairment. Given the assertion
that a “cognitive” loop connects areas of the dorsal
prefrontal cortex to the dorsal striatum (including the
dorsal caudate and dorsolateral putamen) (Alexander
et al., 1986; Alexander et al., 1990), it is surprising that
dopamine synthesis in the caudate nucleus was not as-
sociated with performance on the Wisconsin Card
Sorting Test. While the observed relationship with the
findings are contrary to several animal and human
1994; Marie et al., 1999). Nevertheless, the Wisconsin
test reflects executive processes other than attentional
set-shifting. A recent functional imaging study suggests
that the putamen may play a critical role in the execution
stage of a set-shift (Monchi et al., 2006). While it is
possible that dopamine synthesis in the putamen may
also be associated specifically with the execution stage
of the card sorting task, our study does not allow us to
delineate specific components of the Wisconsin test that
may be modulated by putaminal dopamine synthesis.
We thank Jeih-San Liow, Ph.D., for image proces-
sing; Hiroto Kuwabara, M.D., Ph.D., and Karen
Berman, M.D., for discussion of [18F]FDOPA measure-
ment; PMOD Technologies for providing its image
analysis and modeling software; and Robert Gladding,
CNMT, and the staff of the PET Department for the
successful completion of the study. This research was
supported in part by the Intramural Program of NIMH
(project number Z01-MH-002852-01).
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