A Dual-Tracer Study of Extrastriatal
6-[18F]fluoro-m-tyrosine and 6-[18F]-fluoro-
L-dopa Uptake in Parkinson’s Disease
CLARENCE T. LI,1,2MATTHEW PALOTTI,1,2JAMES E. HOLDEN,3JEN OH,4OZIOMA OKONKWO,4
BRADLEY T. CHRISTIAN,3,5BARBARA B. BENDLIN,4LAURA BUYAN-DENT,2
SANDRA J. HARDING,1,4CHARLES K. STONE,6ONOFRE T. DEJESUS,3
ROBERT J. NICKLES,3AND CATHERINE L. GALLAGHER1,2,4*
1William S. Middleton Veterans Hospital and Geriatric Research Education and Clinical Center, Madison, Wisconsin
2Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
3Department of Medical Physics, University of Wisconsin, Madison, Wisconsin
4Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
5Waisman Laboratory for Brain Imaging and Behavior, Madison, Wisconsin
6Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
adult; aged; humans; brain mapping; cerebral cortex/metabolism/
radionuclide imaging; dopamine agents/*diagnostic use/pharmacoki-
netics; dihydroxyphenylalanine/*analogs & derivatives/drug effects/
pharmacokinetics; tyrosine/*analogs & derivatives/diagnostic use;
imaging; research support; U.S. Gov’t; P.H.S.
for catecholamine synthesis, storage, and metabolism—its intense uptake in the stria-
tum, and fainter uptake in other brain regions, is correlated with the symptoms and
pathophysiology of Parkinson’s disease (PD). 6-[18F]fluoro-m-tyrosine (FMT), which
also targets L-amino acid decarboxylase, has potential advantages over FDOPA as a
radiotracer because it does not form catechol-O-methyltransferase (COMT) metabolites.
The purpose of the present study was to compare the regional distribution of these
radiotracers in the brains of PD patients. Fifteen Parkinson’s patients were studied
with FMT and FDOPA positron emission tomography (PET) as well as high-resolution
structural magnetic resonance imaging (MRI). MRI’s were automatically parcellated
nmr.mgh.harvard.edu); region-specific uptake rate constants (Kocc) were generated
from coregistered PET using a Patlak graphical approach. The essential findings were
as follows: (1) regional Koccwere highly correlated between the radiotracers and in
agreement with a previous FDOPA studies that used different ROI selection techniques;
(2) FMT Koccwere higher in extrastriatal regions of relatively large uptake such as
amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus,
whereas cortical Koccwere similar between radiotracers; (3) while subcortical uptake of
both radiotracers was related to disease duration and severity, cortical uptake was not.
These results suggest that FMT may have advantages for examining pathologic changes
within allocortical loop structures, which may contribute to cognitive and emotional
symptoms of PD. Synapse 68:325–331, 2014. V
6-[18F]-Fluoro-L-dopa (FDOPA) has been widely used as a biomarker
(ROIs) in Freesurfer(http://surfer.-
C2014 Wiley Periodicals, Inc.
6-[18F]-Fluoro-L-dopa (FDOPA) is a radiopharma-
ceutical that follows the metabolic pathway of L-dopa
(Brown et al., 1999b). In catecholaminergic neurons,
FDOPA is decarboxylated by aromatic L-amino acid
decarboxylase (AAAD) to fluorodopamine, which is
taken up into synaptic vesicles by vesicular monoa-
mine transporter type 2 (VMAT2) and cleared from
*Correspondence to: Catherine L. Gallagher; Department of Neurology, 7211
MFCB, 1685 Highland Ave., Madison, WI, 53705-2281, USA.
This paper was funded by primarily by a career development award from the
United States Department of Veterans Affairs Clinical Science Research and
Development Service and in addition by the University of Wisconsin Institute
for Clinical and Translational Research, [grant number 1UL1RR025011].
Received 24 October 2013; Accepted 3 April 2014
Published online 8 April 2014 in Wiley Online Library (wileyonlinelibrary.
? 2014 WILEY PERIODICALS, INC.
SYNAPSE 68:325–331 (2014)
the synaptic cleft by dopamine transporters (DAT;
Endres et al., 1997). Specific uptake of FDOPA in the
striatum as measured by positron emission tomogra-
phy (PET) has been correlated with pathophysiology,
duration, and functional status in Parkinson’s disease
(Nurmi et al., 2001). In addition to motor symptoms,
PD patients suffer from cognitive and emotional
symptoms that are not fully explained by nigrostria-
tal pathology. The ventral tegmental area (VTA) is
relatively preserved in PD and contributes dopami-
nergic projections to many brain regions outside the
striatum; several studies have related this extrastria-
tal uptake to non-motor symptoms (Bruck et al.,
2005; Rinne et al., 2000).
Quantitation of FDOPA uptake is limited by the
formation of catechol-O-methyltransferase (COMT)
(DeJesus, 2003). For extrastriatal tissue, this is espe-
cially problematic, as specific uptake in many of these
regions may be too low to be accurately measured by
PET (Brown et al., 1999b). 6-[18F]fluoro-m-tyrosine
(FMT), which also targets AAAD, has characteristics
that potentially increase its sensitivity as a radio-
tracer; it has a 10-fold greater affinity for AAAD and
is not a substrate for COMT. FMT and its metabolites
also have poor affinity for DAT and VMAT2 (DeJesus,
Few studies have compared FMT to FDOPA as
tools to study extrastriatal uptake; furthermore,
many studies of extrastriatal FDOPA uptake have
been done using normalized brain images. Since
these studies were done, Freesurfer (http://surfer.
nmr.mgh.harvard.edu) has been developed as a reli-
able tool for standard magnetic resonance imaging
(MRI)-based cortical parcellation in native space. The
goals of the present study were to compare the
uptakeprofiles of FMT
Freesurfer-defined regions of interest (ROIs), to rank
regional uptake values in comparison to previous
studies, and to relate regional uptake to disease
duration and severity of clinical symptoms.
MATERIALS AND METHODS
Fifteen subjects (mean age 60.3 years; SD, 6 years;
12 men) with Hoehn and Yahr stage 1–3 Idiopathic
Parkinson Disease (PD) by UK brain bank criteria
(Gibb and Lees, 1988), normal liver function, and
absence of other major disease, were recruited from
local movement disorders clinics. Of these subjects,
five were takingmonoamine
(MAOIs), seven were taking dopamine agonists (pra-
mipexole or ropinerole), and three were taking carbi-
dopa/levodopa (750–1200 mg of levodopa daily).
Procedures included brain FDOPA and FMT PET
imaging, magnetic resonance imaging (MRI), and
Unified Parkinson Disease Rating Scale (UPDRS;
Fahn et al., 1987) scoring by a movement disorders
specialist (CG). Subjects were off anti-Parkinson med-
ication for 18 hours prior to PET and UPDRS scoring.
The local institutional review board approved the
protocol, and informed consent was obtained from all
FDOPA and FMT were synthesized by electrophilic
fluorination of the appropriate stannylated precursors
stannyl)-l-phenylalanine ethyl ester (ABX, Radeberg,
Germany)] followed by flash chromatography over
alumina, hydrolysis in HBr, separation by semi-prep
HPLC andfinal workup
purity (Namavari et al., 1993; Nickles et al., 1984).
Subjects were pretreated with carbidopa, 2.5 mg/kg
orally prior to each PET scan, and 200 mg tolcapone (a
COMT inhibitor) prior to the FDOPA scan. These pre-
treatment doses were given a mean of 59 (range 47–75,
SD 9) minutes before the FDOPA scan and 65 (range
50–74, SD 7) minutes before the FMTscan. Since tolca-
pone has in rare cases been associated with liver dam-
age (Keating and Lyseng-Williamson, 2005), serum
AST, an index of liver function, was acquired at study
enrollment and 2–4 weeks after the tolcapone dose.
PET images were obtained on a Siemens ECAT
EXACT HR1 PET scanner with an axial intrinsic
resolution of 4.7 mm. Following intravenous injection
of 5.2 mCi610% of radiopharmaceutical, 18 3D
dynamic frames were acquired over 90 minutes. The
mean within-subject difference in injected activity of
FMT and FDOPA was
between FMT and FDOPA PET scans was 35 days.
MRI scans were obtained on a 3T GE SIGNA scan-
ner using an 8-channel head coil, with higher-order
shimming. A magnetization-prepared rapid gradient
echo (MPRAGE) T1-weighted volume (TR 6.6 ms, TE
2.8 ms, flip angle 8 degrees, inversion time 900 ms,
field of view 260 mm, slice thickness 1.2 mm) was
aromatic L-amino acid decarboxylase
digital communications in medicine
monoamine oxidase inhibitors
magnetization-prepared rapid gradient echo
magnetic resonance imaging
Neuroimaging Informatics Technology Initiative
positron emission tomography
regions of interest
vesicular monoamine transporter type 2
ventral tegmental area
C. LI ET AL.
acquired for PET coregistration and automated par-
cellation into neuroanatomical ROIs. Digital commu-
nications in medicine (DICOM) single-slice images
were first converted to Neuroimaging Informatics
Technology Initiative (NIFTI)
(http://afni.nimh.nih.gov) and then automatically seg-
mented in Freesurfer 4.5 (surfer.nmr.mgh.harvar-
d.edu) to yield cortical and subcortical surfaces,
which were visually inspected for errors and cor-
rected as necessary.
For PET image analysis, FDOPA and FMT PET
projection into 18 volumes (time frames), each con-
taining 128 3 128 3 63, 1.84 3 1.84 3 2.43 mm vox-
els, corrected for scatter, attenuation, and F-18 decay.
Each frame was realigned, within-subject, to the total
sum image of the FDOPA study. The FDOPA sum
image was then coregistered to the T1-weighted MRI
scan using a 12-degree affine transformation in
SPM8 (www.fil.ion.ucl.ac.uk/spm). This transforma-
tion was then applied to each of the FDOPA and
FMT volumes, resampling them to the 1 3 1 3 1 mm
FreeSurfer resolution using a 7th degree B-Spline
interpolation. Mean time-activity curves (TAC) were
extracted from the coregistered PET time series for
each Freesurfer ROI as defined by the Desikan et al.
(2006) cortical and Fischl (2002) subcortical labeling
systems. Occipital cortex TAC’s were derived from
hand-drawn volumes of 11,378 (SD 2284) mm3. These
Freesurfer-defined ROI and occipital reference tissue
TAC’s were used to derive a normalized tissue uptake
rate constant (Kocc) using Patlak analysis (Patlak and
Blasberg, 1985). An overview of the method is shown
in Figure 1. Since uptake within right and left ROIs
was similar, Koccwere averaged across hemispheres.
Statistical analyses of the ROI Kocc values were
conducted in SPSS (Version 21, IBM, Chicago). ROIs
whose Koccdid not differ from zero by one-sample t-
test (P<0.05) were removed from further analysis.
These regions of very low uptake were the frontal
pole; rostral and caudal middle frontal gyrus; post-
central gyrus; superior and inferior parietal cortex;
cingulate isthmus; precuneus and cuneus; pericalcar-
ine cortex; and lingual gyrus.
weighted MRI (upper right) was parcellated in Freesurfer 4.5 (middle
and mean time-activity curve(TAC) extracted within each MRI-defined
Schematic representation of methods. High-resolution T1-
region (bottom left). The tissue-derived uptake rate constant (Kocc) was
generated using Patlak analysis from the TAC for each region and that
of the occipital reference region (bottom left). The region shown as an
EXTRASTRIATAL FMT AND FDOPA IN PARKINSON’S
The 26 retained ROIs were then ranked by Kocc
and ROI/putamen ratios calculated for each ROI and
radiotracer. Bivariate (Pearson) correlations were
used to compare the ranks and Koccvalues between
FDOPA and FMT, and with anatomically similar
regions reported in the literature. To explore autocor-
relation in the PET dataset and to develop represen-
tative indices for comparison with clinical data, a
factor analyses (by principal components) was con-
ducted for each radiotracer on the 26 ROI Koccvalues.
Based on these PCA analyses and related correlation
matrix, we generated an index of subcortical uptake
by averaging highly correlated (r50.6–0.9) Koccval-
ues from amygdala, caudate nucleus, nucleus accum-
bens, putamen, pallidum, and brainstem, and a
cortical index by averaging Kocc for the remaining
ROIs with correlated uptake values (r50.6–0.9). Dis-
ease duration and total UPDRS scores were then
compared with these indices using partial correla-
tions controlling for age.
ROI’s are ranked by Koccin Figure 2. Both Koccval-
ues and rankings were highly correlated between
radiotracers (r50.98 and 0.90, respectively), with the
exception of thalamic and brainstem uptake, which
was higher for FMT than FDOPA. Regional uptake
values were roughly proportionate to those described
in previous studies, in spite of differences in region
selection technique (Table I). For example, Moore
et al. (2008) measured FDOPA Kocc within hand-
refined regions analogous to 13 of the Freesurfer
ROIs, deriving proportionate Kocc values (Fig. 3;
While subcortical uptake was higher for FMT,
cortical Koccwas similar between radiotracers, yield-
ing higher ROI/putamen ratios for FDOPA. For
cortical ROIs, mean ROI/putamen Kocc ratio was
0.18 (SD 0.21) for FDOPA and 0.12 (SD 0.12) for
FMT. FMT Kocc/FDOPA Kocc was >1 in subcortical
ROIs such as amygdala, thalamus, and brainstem,
as well as anterior and posterior cingulate cortex,
precentral gyrus, entorhinal cortex, and hippocam-
pus; this ratio was ?1 for the remainder of cortical
The exploratory factor analysis of 26 regional Kocc
values yielded a principal component that was corre-
lated with cerebral cortical and hippocampal uptake
(r50.65–0.88), and explained 40–42% of the var-
amygdala, pallidum, and brainstem uptake (r50.41–
0.85) that explained 20–22% of the variance, and
minor components. Based on these analyses, cortical
“methods”). Partial correlations, controlling for age,
showed that the subcortical index declined with dis-
ease duration (FMT partial correlation coefficient,
pr5–0.86; FDOPA pr5–0.70; 2-tailed P<0.01), but
that the cortical index did not (Fig. 4). Kocc within
individual extrastriatal, sub-cortical structures such
as the amygdala (FDOPA pr5–0.69; 2-tailed P<0.01)
and pallidum (FMT pr5–0.90; 2-tailed P<0.001)
were also related to disease duration. UPDRS total
scores were inversely correlated with the subcortical
Ranking of regions by Kocc. Regions were ranked by mean FMT Kocc(solid bars) with corresponding
C. LI ET AL.
index (FMT pr5–0.63; FDOPA pr5–0.57; 2-tailed
P<0.05), but not with the cortical index.
This is one of the first human studies to compare
extrastriatal uptake between FMT and FDOPA. As
was seen in a similar study of three non-human pri-
mates (Brown et al., 1999a), regional uptake rate con-
stants were higher for FMT in regions of high/specific
uptake, but similar or indistinguishable between
tracers in regions of low uptake. Unfortunately the
study design, which did not include control subjects,
precludes comment on the relative sensitivity of the
two tracers. Regional uptake values and ranks were
largely in agreement with previous FDOPA rankings
in Parkinson’s and normal subjects, in spite of differ-
ences in ROI selection technique (Table I, Fig. 3;
Moore et al., 2008, 2003). The narrow Freesurfer-
defined ROI’s (Fig. 1) generated lower FDOPA Kocc
values than reported in some previous investigations
(Moore et al., 2008) but similar to others (Kaasinen
et al., 2001; Nagano et al., 2000).
In (non-PD) post-mortem brains, concentrations of
dopamine and noradrenaline are highest in hippo-
campus, followed by anterior cingulate, entorhinal,
and dorsolateral prefrontal cortex; concentrations in
PD brains are 2–3 fold lower (Scatton et al., 1983). It
is encouraging that the order of ROI’s ranked by Kocc
in the present study is roughly commensurate with
relative catecholamine concentrations reported by
Scatton et al. The amygdala, entorhinal cortex, and
hippocampal formation participate in an allocortical
loop that funnels sensory information into limbic cir-
cuits and projects to the ventral striatum; pathologic
involvement of brain structures in this pathway is
thought to underlie emotional symptoms of PD
(Braak et al., 1995). Therefore, a reliable system for
quantifying AAAD activity in these regions holds
promise for the study of non-motor symptoms in vivo.
In a study of normal subjects, Brown et al. (1999b)
calculated regional FDOPA uptake as a percentage of
FDOPA, FMT both 80%); hippocampus 30% (current
study, FDOPA 22%, FMT 32%); frontal and temporal
cortices 10–15% (current study FDOPA 10–25%, FMT
4–9%); and anterior cingulate 20% (current study
FDOPA 23%, FMT 21%). A comparison of these ratios
between normal and PD subjects suggests that amyg-
dala Kocc is preserved relative to putamen in early
PD. This is consistent with previous reports of
increased FDOPA uptake in the amygdala, as well as
pallidum, dorsolateral prefrontal, and anterior cingu-
late cortex, in early Parkinson’s disease (Brooks and
Piccini, 2006; Bruck et al., 2005; Kaasinen et al.,
2001; Rakshi et al., 1999).
regions of high/specific uptake, Kocc was similar
between tracers in the cerebral cortex. This effect
probably occurs because in regions of very low
TABLE I. Comparison to comparable regions in FDOPA studies
Moore et al. (2003)
Moore et al. (2008)
0.0025Not different from 0Not different from 00.002
EXTRASTRIATAL FMT AND FDOPA IN PARKINSON’S
uptake, the ROI TAC resembles that of the reference
region (See Fig. 1 for example), producing a “floor
effect” for the accurate measurement of Kocc. None-
theless, we did eliminate regions for which measure-
ment error rendered Koccindistinguishable from zero.
Therefore, the relatively high FDOPA Koccin cortical
regions may reflect differences in the metabolism and
trapping of the radiotracers, as well as effects of
COMT inhibition on FDOPA trapping. The uptake
rate constant reflects the amount of tracer accumu-
lated in regions of specific trapping relative to the
cumulative exposure of these regions to the tracer
circulating in the plasma; when using a tissue input
function for the Patlak analysis, the presence of cir-
culating metabolite in the reference region leads to
an overestimate of the amount of tracer available for
trapping, lowering Kocc. Tolcapone reduces circulating
metabolites, thus increasing FDOPA Kocc, (but not Ki,
which is calculated using a metabolite-corrected
input function) (Doudet et al., 1997; Ruottinen et al.,
1997). In previous work, we estimated peripheral
COMT inhibition in the current study to be as high
as 80% (Gallagher et al., 2011). COMT is highly
expressed in frontal cortex, and its inhibition has
been shown to increase synaptic dopamine in these
regions, thus influencing dopamine-dependent execu-
tive functions (Apud and Weinberger, 2007).
The factor analysis and related correlation matrices
suggested that regional Koccvalues fell primarily into
cortical and subcortical components that differed in
their relationship to disease duration and severity. In
the brain, cells that synthesize dopamine are located in
the substantia nigra (SN), ventral tegemental area
(VTA), and neurohypophyseal system. The VTA sends
projections through several pathways to cortical and
subcortical structures: Mesocortical projections to the
prefrontal cortex and insula; mesolimbic projections to
the nucleus accumbens, amygdala, hippocampus, ento-
rhinal cortex, anterior cingulate cortex, and claustrum;
mesostriatal projections to the anteromedial striatum;
mesodiencephalic projections to several thalamic nuclei
as well as hypothalmaus; and mesorhombencephalic
projections to superior colliculus, reticular formation,
periaqueductal grey, and spinal cord (Oades and Halli-
day, 1987). Although the VTA is relatively preserved in
PD in comparison to the SN, pathological studies have
shown both pathways to be affected (Braak et al., 1995).
Differential vulnerability of SN versus VTA dopaminer-
gic projections may partially explain why cortical and
subcortical uptakes were not well correlated.
We observed that disease duration and severity
(UPDRS scores) were related to subcortical uptake of
both tracers, but showed little relationship to cortical
uptake. Both pathologic and imaging investigations
have suggested that extrastriatal catecholamine lev-
els are lower than normal in PD (Moore et al., 2008;
Scatton et al., 1983). Longitudinal studies have
shown progressive decline in FDOPA uptake within
extrastriatal structures (locus ceruleus, pallidum,
hypothalamus, midbrain raphe) over 3 years in PD
(Pavese et al., 2011)—however, decline in cortical
were correlated with those reported in previous investigations that
used different methods of region selection. “Brainstem” Kocc is
expected to differ because Moore et al. selected the dorsal raphe, a
region of high uptake, whereas the Freesurfer region encompasses
the entire brainstem.
Studies comparison. Present study FDOPA Kocc values
disease duration for cortical versus subcortical structures; cortical
and subcortical indices were derived by averaging Koccwithin the
Koccversus duration disease. Mean Koccas a function of
C. LI ET AL.
regions was not described. In PD patients treated Download full-text
with L-dopa, there is a progressive decline in D2
receptor availability in anterior cingulate, dorsolat-
eral prefrontal, and temporal cortex, as well as tha-
lamic regions, with disease progression (Kaasinen
et al., 2003). Based on these previous investigations
as well as findings from the present study, we
hypothesize that progressive decline in uptake of
dopamine radiotracers will be detected in extrastria-
tal regions of high specific uptake (such as amygdala)
with disease progression, but that decline in cortical
regions will not be detectable.
Neither FMT nor FDOPA provided advantage for
the study of cortical regions; however, FMT may have
advantages for quantification of AAAD activity in
extrastriatal regions of relatively high specific uptake
such as amygdala, pallidum, thalamus, anterior cin-
gulate cortex, entorhinal cortex, and hippocampus.
The cognitive and emotional symptoms of PD may be
related to radiotracer loss within these allocortical
needed to definitively investigate these hypotheses.
This work was supported with use of facilities at the
University of Wisconsin
Research Center Neuroimaging Laboratory as well as
William S. Middleton Memorial Veterans Hospital
Geriatric Research Education and Clinical Center
and the Waisman Laboratory for Brain Imaging and
Behavior, Madison, WI, USA.
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EXTRASTRIATAL FMT AND FDOPA IN PARKINSON’S