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Blinded positron emission tomography study of dopamine cell implantation for Parkinson's disease.

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Blinded Positron Emission Tomography
Study of Dopamine Cell Implantation for
Parkinson’s Disease
Toshitaka Nakamura, MD,1,2 Vijay Dhawan, PhD,1,2 Thomas Chaly, PhD,1,2 Masafumi Fukuda, MD,1,2
Yilong Ma, PhD,1,2 Robert Breeze, MD,3 Paul Greene, MD,4 Stanley Fahn, MD,4 Curt Freed, MD,5
and David Eidelberg, MD1,2
We assessed nigrostriatal dopaminergic function in Parkinson’s disease (PD) patients undergoing a double-blind,
placebo-controlled surgical trial of embryonic dopamine cell implantation. Forty PD patients underwent positron emission tomography (PET) imaging with [18F]fluorodopa (FDOPA) prior to randomization to transplantation or placebo
surgery. The 39 surviving patients were rescanned one year following surgery. Images were quantified by investigators
blinded to treatment status and clinical outcome. Following unblinding, we determined the effects of treatment status
and age on the interval changes in FDOPA/PET signal. Blinded observers detected a significant increase in FDOPA
uptake in the putamen of the group receiving implants compared to the placebo surgery patients (40.3%). Increases in
putamen FDOPA uptake were similar in both younger (age <60 years) and older (age >60 years) transplant recipients.
Significant decrements in putamen uptake were evident in younger placebo-operated patients (– 6.5%) but not in their
older counterparts. Correlations between the PET changes and clinical outcome were significant only in the younger
patient subgroup (r ⴝ 0.58). The findings suggest that patient age does not influence graft viability or development in
the first postoperative year. However, host age may influence the time course of the downstream functional changes that
are needed for clinical benefit to occur.
Ann Neurol 2001;50:181–187
We have recently reported the clinical results of the
first double-blind, placebo-controlled surgical trial of
human embryonic dopaminergic (DA) tissue transplantation in advanced Parkinson’s disease (PD).1 Under local anesthesia, four twist drill holes penetrating the forehead were placed in 40 PD patients who were randomly
assigned to either tissue implant or placebo surgery. In
the transplanted patients, cultured mesencephalic tissue
was placed bilaterally into the putamen; the dura was
not penetrated in the placebo-operated group. All patients were followed for one year with blinded clinical
evaluations. Following unblinding, we found that the
transplanted patients improved significantly in standardized motor ratings, whereas no change was observed in the placebo group. Additionally, we sought to
assess the effects of age on transplantation by enrolling
patients in younger (age 60 years or under) and older
(age 61–75 years) subgroups, with each of these subgroups randomly assigned to implant or placebo. We
found that the major clinical benefit of implantation
was seen in the younger patients; minimal improvement was observed in their older counterparts.
As part of this blinded study, we used positron
emission tomography (PET) with [18F]fluorodopa
(FDOPA) to assess nigrostriatal dopaminergic function
at baseline and 12 months following surgery. FDOPA/
PET is an assay for dopa decarboxylase (DDC) activity
in presynaptic DA terminals2,3 and is an indirect measure of nigral DA neurons.4,5 Indeed, striatal FDOPA
uptake has been consistently found to correlate with
clinical indices of motor dysfunction in PD.6 –9 Therefore, quantitative FDOPA/PET may be suitable as an
objective marker of parkinsonian severity. This imaging
technique has also been employed to assess graft survival following the implantation of human DA cells for
PD.10 Previous unblinded PET studies in small cohorts
of PD patients have demonstrated persisting increases
in FDOPA uptake at the site of implantation,11,12 last-
From the 1Functional Brain Imaging Laboratory, North ShoreLong Island Jewish Research Institute, Manhasset, NY; 2Department of Neurology, New York University School of Medicine,
and 3Department of Neurology, Columbia College of Physicians
and Surgeons, New York, NY; and 4Department of Neurosurgery
and 5Neuroscience Center and Division of Clinical Pharmacology
and Toxicology, University of Colorado Health Sciences Center,
Denver, CO.
Received Dec 6, 2000, and in revised form Mar 27, 2001. Accepted
for publication Mar 27, 2001.
Published online May 16, 2001.
Address correspondence to Dr Eidelberg, Functional Brain Imaging
Laboratory, North Shore-Long Island Jewish Research Institute, 350
Community Drive, Manhasset, NY 11030.
E-mail: david1@nshs.edu
© 2001 Wiley-Liss, Inc.
181
ing as long as a decade following surgery.13 Postmortem examination revealed histopathological evidence of
graft survival and dopaminergic reinnervation in several
patients in whom increased striatal FDOPA uptake was
noted in life.1,14 Nonetheless, correlations between
FDOPA/PET indices of graft viability and clinical outcome have been assessed quantitatively in only two
small unblinded studies.15,16
In the current study, we performed FDOPA/PET at
each time point without knowledge of treatment status.
This design allowed us to assess graft viability objectively and determine whether tissue engraftment was
influenced by host age. We also analyzed the data obtained under the blind to determine whether the measured changes in striatal PET signal correlated with
clinical outcome. Finally, the longitudinal imaging data
from the placebo-operated control group provided a
unique opportunity to quantify the rate of disease progression in PD patients with advanced disease.
Patients and Methods
Patients
Forty patients with advanced idiopathic PD entered the clinical study as described previously.1 All patients had symptoms of PD for at least 7 years and were responsive to levodopa (ⱖ33% improvement in total UPDRS after a first
morning dose). Exclusion criteria included the presence of
significant cognitive impairment, depression, or magnetic
resonance imaging (MRI) evidence of cerebrovascular disease
or other brain lesion. Informed consent was obtained from
all patients through a protocol approved by the ethics committees of the participating institutions and the National Institutes of Health.
The patients were randomized to either tissue implantation or placebo placement of twist drill holes without dural
penetration. The randomization process incorporated a stratification by age. In each treatment arm, similar numbers of
patients were assigned to “younger” (ⱕ60 years) and to
“older” (⬎60 years) age subgroups. This allowed for the assessment of the effect of age on treatment outcome.1
Patient age, disease duration, baseline clinical severity, and
striatal FDOPA uptake were similar for the 2 treatment
groups (see Table 1). Thirty-nine of the patients [21 men
and 18 women, aged 56.7 ⫾ 9.6 years (mean ⫾ standard
deviation; SD), range 34 –75 years] completed both baseline
and 12 month postoperative FDOPA/PET imaging. One patient died in the first postoperative year.1 At both imaging
time points (baseline and 12 months postoperatively; mean
interval between scans 18.4 ⫾ 2.5 months), UPDRS ratings
were obtained in the off state (⬎12 hour medication washout) by blinded clinical observers at Columbia University
who were not involved in the PET procedures. Composite
UPDRS motor scores (items 19 –31)17 were obtained on
each of the 2 consecutive days prior to FDOPA/PET. The
average of the 2 daily measures was utilized for correlation
with the imaging data. The clinical change over the scanning
interval was defined as (POST – PRE)/POST, where PRE
and POST refer to the composite UPDRS motor ratings
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taken at baseline and 12 months postoperatively, respectively.
Imaging
All patients underwent MRI on the day of baseline
FDOPA/PET imaging. These scans were performed using
the GE Signa 1.5 T MRI system at North Shore University
Hospital. A fast spin echo pulse sequence (TE ⫽ 20 msec,
TR ⫽ 5,200 msec, slice thickness ⫽ 3 mm) was employed to
obtain anatomical images for MR-PET alignment and region
of interest (ROI) definition.
MRI.
Baseline and postoperative PET scanning and image
processing were performed exclusively by investigators at
North Shore University Hospital who were blinded to treatment status and clinical outcome. Prior to PET imaging, the
patients fasted overnight and antiparkinsonian medications
were discontinued for at least 12 hours. Scanning was conducted on a whole-body, high-resolution PET scanner (Advance; General Electric Medical Systems, Milwaukee, WI).
This 18-ring bismuth germanate tomograph produces 35
slices with 4.2 mm resolution in all directions (FWHM).
The performance characteristics of this instrument have been
described elsewhere.18 Patients were positioned in the scanner in a Laitinen stereoadaptor with three dimensional laser
alignment.19 To minimize repositioning errors, identical stereoadaptor settings were used for the baseline and the postoperative PET scans. The gantry angle of the tomograph was
adjusted to be parallel to the orbitomeatal line. All studies
were performed with the subject’s eyes open in a dimly lit
room and minimal auditory stimulation. FDOPA was produced according to the radiochemical synthesis of Luxen et
al20 and was ⬎95% radiochemically pure (specific activity
approximately 400 mCi/mmole). All subjects received 200
mg carbidopa 1.5 hours before the study to inhibit decarboxylation. FDOPA (185–370 MBq; 5–7 mCi) in 25 ml
saline was injected into an antecubital vein over 45 seconds
with an automated infusion pump. Emission scan data were
acquired between 40 and 100 minutes postinjection. PET
reconstructions were also corrected for random coincidences,
electronic deadtime, and scatter effects. Attenuation correction was made using orbiting 68Ge rod sources.
PET.
Image Quantification: ROI Analysis
ROI analysis was performed interactively on 128 ⫻ 128
PET reconstructions as described previously.9 In the baseline
scans, caudate, putamen, and occipital cortex ROIs were
placed manually on composite PET brain slices with reference to coplanar MRI. The mean volume (⫾SD) of these
regions was 2.2 ⫾ 0.5, 4.8 ⫾ 0.5, and 27.7 ⫾ 5.1 cc, respectively. These ROIs were placed on the aligned postoperative scans such that identical PET volumes were compared
across the two scanning sessions.
For each FDOPA/PET scan, we calculated the ratio of
specific to nonspecific activity in the caudate and putamen
ROIs during the final 10 minute frame (approximately 90 –
100 minute postinjection) by subtracting occipital from striatal activity and dividing by occipital activity.7–9 This index
of striatal FDOPA uptake was computed separately for the
caudate and the putamen ROIs placed on the PET images
acquired at baseline and at 12-month follow-up. We have
found that this ratio correlates with off-state UPDRS motor
ratings with accuracy comparable to graphically derived estimates of FDOPA uptake rate constants.9 The ratio PET
measure also correlates with kinetic rate constants of DDC
activity,7 with comparatively low intersubject variability (coefficient of variation ⬃10%).7–9 This method provided a
simple, noninvasive descriptor of presynaptic nigrostriatal
dopamine function suitable for this blinded longitudinal
PET study. Right and left values for the caudate and the
putamen were averaged for statistical analysis.
Statistical Analysis
At each time point, FDOPA uptake values for the caudate
and putamen were computed by investigators at North Shore
University Hospital who were blinded to treatment status
and to the clinical ratings acquired off site in the days prior
to the PET studies. Image analysis and quantification were
completed and the data submitted to an independent off site
data manager within 3 months of each scanning procedure.
For each patient, all data submission was finalized prior to
the opening of the study blind. In each treatment group,
baseline and postoperative FDOPA uptake values for the
caudate and the putamen were compared separately using
paired Student’s t tests (two-tailed). Additionally, separate
posthoc analyses were performed separately on the younger
(ⱕ60 years) and the older (⬎60 years) patient subgroups.1
Interval changes in FDOPA uptake were defined as
(POST – PRE)/PRE, where PRE and POST refer, respectively, to baseline and postoperative uptake measurements.
We compared the interval changes in the caudate and the
putamen between the two treatment groups with Student
t tests (two-tailed). Correlations between the interval PET
changes and the corresponding changes in composite
UPDRS motor ratings were assessed across the whole cohort
using multiple linear regression analysis and adjusting for patient age.21 Additionally, we separately correlated alterations
in striatal PET signal with changes in composite motor ratings in the younger and the older subgroups by computing
Pearson product-moment correlation coefficients. In a secondary analysis, we also evaluated PET correlations with interval changes in the individual UPDRS subscores for rigid-
ity, bradykinesia, and tremor. All statistical analyses were
considered significant at p ⬍ 0.05.
In addition to traditional ROI-based image analysis, we
analyzed the data using an automated voxel-based statistical
parametric mapping (SPM) approach. This technique was
utilized to localize the spatial distribution of the PET
changes associated with engraftment and natural disease progression in the transplant and placebo-operated groups, respectively. SPM was also used to compare longitudinal
changes between the 2 treatment groups. Nonspecific
FDOPA uptake values were computed by averaging regional
data from the occipital cortex over 4 slices encompassing the
striatal structures. Volumetric ratio images of FDOPA uptake (voxel ⫺ occipital)/(occipital) were computed between
90 and 100 minutes postinjection and smoothed with a 8
mm 3D Gaussian filter. The resulting images underwent stereotactic normalization utilizing the mean count image acquired over the entire scanning epoch. Following unblinding,
patient scans were divided into transplanted and placebooperated groups. We used Statistical Parametric Mapping
(SPM99; Wellcome Institute of Cognitive Neurology, London, United Kingdom) to detect significant within-group
changes in FDOPA uptake between time points. Secondary
SPM analyses were also conducted on each of the treatment
groups following subdivision by age. We also used this
method to compare the PET changes in the transplant group
(n ⫽ 19) to those of the placebo-operated controls (n ⫽ 20).
SPM contrasts were considered significant at p ⬍ 0.001. We
elected not to correct for multiple comparisons because, by
hypothesis, uptake changes in either treatment group are expected to be restricted to the striatum.
Results
Baseline Measurements
Baseline clinical and FDOPA/PET data for the 39 patients who completed both PET examinations are provided in Table 1. Baseline FDOPA uptake was significantly reduced ( p ⬍ 0.0001) to 62% and 39% of
respective normal mean values for the caudate and the
putamen.9 In all patients, baseline putamen uptake was
at least 2 SD below the normal mean. Thus, significant
Table 1. Baseline Measurements
Implant group (n ⫽ 19)
Younger (n ⫽ 10)
Older (n ⫽ 9)
Placebo group (n ⫽ 20)
Younger (n ⫽ 11)
Older (n ⫽ 9)
Age (yrs)
Duration
(yrs)
Scan
Interval
(months)
FDOPA
Uptakea
(putamen)
FDOPA
Uptakea
(caudate)
UPDRS
(motor)b
56.9 ⫾ 10.3c
49.7 ⫾ 8.5
64.9 ⫾ 4.5
56.5 ⫾ 10.1
48.9 ⫾ 5.8
65.8 ⫾ 4.8
13.4 ⫾ 5.0
12.5 ⫾ 3.1
14.3 ⫾ 6.6
14.0 ⫾ 6.2
12.9 ⫾ 5.8
15.3 ⫾ 6.8
19.1 ⫾ 2.3
18.6 ⫾ 1.7
19.7 ⫾ 2.8
17.7 ⫾ 2.4
17.8 ⫾ 2.7
17.7 ⫾ 1.8
0.53 ⫾ 0.09
0.52 ⫾ 0.10
0.54 ⫾ 0.09
0.50 ⫾ 0.12
0.50 ⫾ 0.14
0.50 ⫾ 0.09
0.79 ⫾ 0.12
0.75 ⫾ 0.13
0.84 ⫾ 0.09
0.77 ⫾ 0.15
0.78 ⫾ 0.18
0.75 ⫾ 0.09
60.9 ⫾ 23.3
59.2 ⫾ 21.1
62.9 ⫾ 26.6
65.6 ⫾ 21.0
61.1 ⫾ 19.7
71.3 ⫾ 22.3
a
Region-occipital/occipital; see text.
Ratings conducted at least 12 hours after antiparkinsonian medication. The higher ratings reflect more severe parkinsonism.
c
Mean ⫾ SD.
b
UPDRS ⫽ Unified Parkinson’s Disease Rating Scale; younger ⫽ ⱕ60 years old; older ⫽ ⬎ 60 years old.
Nakamura et al: PET in Implantation for PD
183
Fig 1. Scatter diagram illustrating changes in the putamen
FDOPA uptake ratio (see text) in 19 Parkinson’s disease (PD)
patients (circles) scanned at baseline and at 1 year following
bilateral implantation of embryonic nigral dopamine cells into
the putamen. Positron emission tomographic (PET) measurements at both time points were acquired blind to treatment
status. Dotted lines represent the lower limit of normal putamen FDOPA uptake (defined as 2 SD below the mean value
for 15 normal control subjects reported by us previously9). For
the entire PD transplant group, operative increases in putamen FDOPA uptake were highly significant (p ⬍ 0.001),
whereas no PET change was evident in the nongrafted caudate nucleus (see text).
nigrostriatal dopaminergic defects were demonstrable
by PET in all PD patients who entered this study.
Interval Changes
Postoperative clinical and FDOPA/PET data for these
patients are provided in Table 2. Relative to baseline,
postoperative putamen FDOPA uptake increased significantly in the transplant group [40.3% ⫾ 10.0%
(mean ⫾ standard error; SE), p ⬍ 0.001; Fig 1]. In 8
transplant patients, postoperative putamenal FDOPA
uptake rose to within 2 SD of the normal mean.9 No
significant change in FDOPA uptake was evident in
the ungrafted caudate nucleus ( p ⫽ 0.3). When the
subjects were grouped by age, similar increases in pu-
tamen FDOPA uptake were evident in both the
younger and older transplant subgroups (ⱕ60 years:
35.1% ⫾ 12.4%, p ⬍ 0.02; ⬎60 years: 46.0% ⫾
16.7%, p ⬍ 0.01; Fig 1). SPM analysis of the data
from the entire transplant group (n ⫽ 19) localized the
maximal effect of engraftment to the posterior putamen (maxima: x ⫽ –28, y ⫽ –2, z ⫽ 2 mm and x ⫽
30, y ⫽ – 8, z ⫽ 2 mm; Zmax ⫽ 4.7 and 4.6, respectively, p ⬍ 0.001).
There were no significant interval changes in striatal
FDOPA uptake in the placebo-operated group (caudate: – 0.9% ⫾ 3.0%, p ⫽ 0.3; putamen: –2.1% ⫾
4.1%, p ⫽ 0.2). However, when the patients were
grouped by age, a significant interval decline in putamen FDOPA uptake was present in the younger controls (– 6.5% ⫾ 5.0%, p ⬍ 0.05) but not in their older
counterparts ( p ⫽ 0.3; Fig 2). SPM analysis of the
data from the younger control group (n ⫽ 11) localized this significant longitudinal decrement to the rostral putamen (maximum: x ⫽ 20, y ⫽ 8, z ⫽ – 8 mm;
Zmax ⫽ 3.5, p ⬍ 0.001).
Group Comparison
The interval changes in FDOPA uptake differed significantly between the transplant and the placebooperated groups. Putamen FDOPA uptake was increased in the transplantation patients relative to
controls ( p ⬍ 0.005). Changes in caudate uptake did
not differ between the two treatment groups ( p ⫽
1.0). SPM comparison of the interval changes in
FDOPA uptake between the 2 treatment groups localized the relative increase in the transplant group to the
posterior putamen (maxima: –28, –2, 2 mm and 32,
– 6, 0 mm; Zmax ⫽ 5.3 and 4.6, respectively, p ⬍
0.001; Fig 3).
Clinical-PET Correlations
We correlated interval changes in putamen FDOPA
uptake with corresponding changes in off-state composite motor UPDRS ratings. Controlling for age in
Table 2. Operative Changes
All patients (n ⫽ 39)
Implant group (n ⫽ 19)
Younger (n ⫽ 10)
Older (n ⫽ 9)
Placebo group (n ⫽ 20)
Younger (n ⫽ 11)
Older (n ⫽ 9)
⌬ FDOPA Uptake
(putamen)
⌬ FDOPA Uptake
(caudate)
⌬ UPDRS
(motor)
18.5 ⫾ 6.3a
40.3 ⫾ 10.0b
35.1 ⫾ 12.4b
46.0 ⫾ 16.7b
⫺2.1 ⫾ 4.1
⫺6.5 ⫾ 5.0c
3.4 ⫾ 6.4
⫺0.9 ⫾ 2.7
⫺0.9 ⫾ 4.5
0.3 ⫾ 6.4
⫺2.1 ⫾ 6.7
⫺0.9 ⫾ 3.0
⫺2.6 ⫾ 2.6
1.2 ⫾ 6.1
⫺9.8 ⫾ 4.5
⫺19.6 ⫾ 6.8b
⫺31.3 ⫾ 9.9b
⫺6.6 ⫾ 7.6
⫺0.5 ⫾ 5.3
0.2 ⫾ 8.3
⫺1.4 ⫾ 6.6
Mean ⫾ SEM.
p ⬍ 0.01.
c
p ⬍ 0.05.
a
b
⌬ ⫽ (postoperative ⫺ baseline)/baseline ⫻ 100%. The more negative values reflect greater improvement in parkinsonian signs.
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Fig 2. Scatter diagram illustrating changes in the putamen
FDOPA uptake ratio (see text) in 20 PD patients (circles)
scanned at baseline and at 1 year following placebo surgery.
No significant change in putamen FDOPA was evident for
the entire placebo-operated control group. However, when the
patients were grouped by age, a significant decline was present
in the 11 younger controls (4.4%/yr, p ⬍ 0.05; left) but not
in their older counterparts (right). Dotted lines represent the
lower limit of normal putamen FDOPA uptake (defined as 2
SD below the mean value for 15 normal control subjects reported by us previously.)9
the regression analysis, we detected a significant correlation (r ⫽ 0.56, p ⬍ 0.05) between the clinical and
the PET measures across the entire study population
(n ⫽ 39). When the subjects were grouped by age, this
correlation was significant only in the younger patients
(ⱕ60 years: r ⫽ 0.58, p ⬍ 0.01; ⬎60 years: r ⫽ 0.01,
p ⫽ 0.9; Fig 4). In the younger subgroup, the changes
in putamenal FDOPA uptake correlated with improved UPDRS subscores for bradykinesia (r ⫽ 0.53,
p ⬍ 0.02) but not for rigidity or tremor. Clinical correlations with changes in caudate uptake were not significant ( p ⫽ 0.7).
embryonic tissue employed in the transplant procedures. Prior PET studies of neurotransplantation have
not been conducted blindly. Therefore, confounds relating to operator knowledge of treatment status may
have contributed to the highly significant transplantation effects that were noted.
In this study, patient age was a critical factor in determining clinical outcome following implantation. As
we reported in detail elsewhere,1 patients aged 60 years
or younger demonstrated significant improvement in
UPDRS off-state ratings, whereas older patients did
not. Nonetheless, our PET findings demonstrating
comparable increases in striatal FDOPA uptake in the
2 age groups suggest that the grafts were viable, regardless of host age. Indeed, the change in putamenal signal
in the younger transplant patients was approximately
10% less than that found in their older counterparts.
This may reflect ongoing nigrostriatal degeneration, as
was found in the younger placebo-operated subgroup.
In postmortem studies, successful transplantation has
been associated with fiber outgrowth and the developFig 3. Statistical parametric map comparing interval changes
in FDOPA uptake between the transplanted and placebooperated groups. PET signal in the putamen increased significantly in the transplant group relative to controls, most pronounced posteriorly (see text). The color stripe represents Z
scores thresholded at 3.27 (p ⫽ 0.001). Representative sagittal, coronal, and transverse sections are displayed with reference to the anterior-posterior commissure line.
Discussion
This is the first report of PET findings from a blinded,
placebo-controlled study of dopamine cell implantation
in humans with PD. By performing all imaging procedures and data analysis under blinded conditions, we
demonstrated that the postoperative changes in PET
signal were not influenced by biases inherent in user
interaction with the imaging data. In keeping with the
results of previous unblinded PET studies in transplantation,10 –15 we discerned a highly significant increase
in FDOPA uptake in the putamenal transplant target
but not in the nongrafted caudate nucleus. In this
study, the average increase in putamen FDOPA binding following transplantation was approximately 40%.
We note that this change in PET signal was lower than
that previously reported at 12 months following implantation.15,22 Although PET quantification techniques differ among centers, it is possible that this disparity relates in part to differences in the amount of
Nakamura et al: PET in Implantation for PD
185
Fig 4. Results of correlation analysis between changes in
UPDRS motor ratings and changes in putamen FDOPA uptake over the 18.4-month interval between PET scans. Both
the PET and the clinical measures were obtained by independent observers blinded to treatment status. Transplanted patients are depicted by solid circles; placebo-operated patients
are depicted by open circles. A significant correlation (p ⬍
0.01) between the PET changes and the clinical outcome was
present in the younger subgroup of PD patients. No clinicalPET correlation was identified in the older subgroup.
ment of tyrosine hydroxylase-positive terminals.1,14 By
contrast, the increases in striatal FDOPA uptake noted
with PET in the transplant group are largely attributable to the expression of DDC in engrafted embryonic
DA neurons. Our findings indicate that this aspect of
graft survival and development takes place in the brains
of PD patients with advanced symptoms, regardless of
age. However, clinical improvement following transplantation is contingent upon the development of
functioning synaptic contacts with host striatal neurons, resulting ultimately in the suppression of inhibitory pallidal outflow and the concomitant potentiation
of movement-related cortical function.23 Our data indicate that this aspect of functional integration is likely
to be age-dependent. Indeed, in our previous report,1
we noted that the baseline responses to levodopa were
lower in older PD patients, whether randomized to
placebo operation or to transplantation. This suggests
that striatocortical modulation by dopamine replacement,24 whether endogenous or exogenous, is reduced
in older subjects. Our results are in accordance with
recent rodent studies suggesting that the therapeutic response to embryonic DA cell transplantation is less in
aged animals.25
This hypothesis is supported by our observation that
the correlation between the changes in striatal FDOPA
uptake and clinical outcome is influenced by patient
age. When age was controlled across the entire cohort,
we found that changes in PET signal were significantly
correlated with concurrent changes in off-state UPDRS
motor scores. Indeed, when patient data were grouped
by age, this correlation was significant only in the
younger subgroup, even following the exclusion of the
2 subjects with interval declines in putamenal FDOPA
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uptake following transplantation. Thus, the degree of
clinical benefit observed in the younger patients was
associated with individual differences in putamen
FDOPA uptake. This suggests not only that were the
grafts viable but that they also effectively modulated
postsynaptic striatal output. By contrast, the increases
in PET signal observed in the older group lacked a
clinical correlate, with or without the inclusion of the
three transplant patients with no evidence of graft viability by PET measurement. It has been proposed that
increases in FDOPA uptake at the site of implantation
are not specific for graft viability.26 Nonetheless, postmortem findings from a patient scanned with FDOPA/
PET before and after transplantation demonstrated
that increases in radiotracer uptake are associated with
successful graft development.14 However, even with
successful engraftment, other anatomicofunctional
changes in the aging brain27 may limit the value of
transplantation in elderly patients. We are performing
longitudinal clinical-PET assessments to determine the
precise relationship between functional restoration and
patient age.
The results of the reported clinical-PET correlations
should be interpreted with caution. These analyses
were performed on combined data from transplant patients and placebo-operated controls. Hence, the presence of a significant correlation between interval
changes in clinical ratings and PET signal, such as that
detected in the younger patients, may not be specific
for transplantation. We did find, however, that the
magnitude of clinical-PET correlation in transplant recipients under age 60 years was similar to that for the
entire younger cohort comprising both implanted patients and controls. Because of the small number of
patients in the younger transplant subgroup, statistical
significance was achieved only with the addition of
placebo-operated controls. FDOPA/PET studies in additional transplant recipients will be required to confirm that the benefit of this procedure is associated
with a greater degree of tissue engraftment. The analysis of data from the unblinded phases of this study
will be useful in this regard.
In addition to assessing the efficacy of implantation,
our study design allowed us to estimate the natural rate
of disease progression in the 20 placebo-operated control patients. We found that putamen FDOPA uptake
did not decline significantly in this cohort during the
mean 18-month interval between PET scans, suggesting that the overall rate of neurodegeneration in advanced PD is slow. This finding is in general agreement with a prior long-term longitudinal FDOPA/
PET study in PD patients with established disease.28,29
We did, however, detect a significant 6.5% interval decline (⬃4.4% annually) in putamen FDOPA uptake in
the younger placebo-operated patients. We note that
disease duration was similar in both the younger and
the older placebo-operated subgroups and that patient
age at the time of the study was highly correlated with
age at time of symptom onset (r ⫽ 0.87, p ⬍ 0.0001).
This suggests that patient age as well as the time of
clinical presentation (ie, young vs older onset) may influence the rate of disease progression at advanced
stages of parkinsonism. Moreover, using a voxel-based
mapping technique, we were able to localize the dopaminergic attrition in this group to more anterior putamenal projection fields. Thus, degeneration of nigral
DA projections to the posterior putamen may be virtually complete by the late stages of PD. However, in
younger patients with advanced disease, the loss of nigrostriatal dopaminergic projections may continue
along a caudorostral putamenal gradient.30 The slow
rate of progression in advanced PD, as well as potential
changes in the topography of the neurodegenerative
process over time, should be considered in planning
therapeutic interventions for late-stage disease.
This work was supported by NIH grants RO1 NS 32368 and RO1
NS 35069.
Drs Nakamura and Fukuda were Veola T. Kerr Fellows of the Parkinson Disease Foundation. We thank Dr Abdel Belakhlef and Mr
Claude Margouleff for technical support and Ms Christine Edwards
for editorial assistance.
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