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April 01, 1999; 52 (6) Articles

SPECT imaging of pre- and postsynaptic dopaminergic alterations in l-dopa–untreated PD

M. Ichise, Y.J. Kim, J.R. Ballinger, D. Vines, S.S. Erami, F. Tanaka, A.E. Lang
First published April 1, 1999, DOI: https://doi.org/10.1212/WNL.52.6.1206
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Abstract

Background: In PD, presynaptic dopamine transporters are known to be decreased, whereas postsynaptic striatal D2 receptors are proposed to be upregulated. However, the relationship between these alterations is not clear.

Objective: To evaluate the ability of SPECT to detect both the pre- and postsynaptic dopaminergic alterations of the striatum in patients with l-dopa–untreated PD.

Methods: We studied 10 l-dopa–untreated patients with clinically mild PD and 21 age-matched normal controls. Individuals had both presynaptic [123I]β-CIT dopamine transporter and postsynaptic [123I]IBF D2 SPECT studies 1 week apart.

Results: In PD patients, the dopamine transporter binding potential Rv ipsilateral/contralateral to the most affected limbs was 30%/41%, 41%/50%, and 59%/68% lower than controls for caudate, anterior putamen, and posterior putamen, respectively. These bilateral Rv decreases showed a lateralized difference more reduced in the contralateral striatum as well as intrastriatal differences most reduced in the posterior putamen. In contrast, in PD patients the D2 binding potential Rv ipsilateral/contralateral was 15%/16% higher for caudate, 18%/14% higher for anterior putamen, and 28%/31% higher for posterior putamen. These bilateral Rv increases showed no lateralized differences and less marked intrastriatal differences. The motor Unified Parkinson’s Disease Rating Scale scores negatively correlated with dopamine transporter Rv but not with D2 Rv.

Conclusions: SPECT imaging can detect characteristic dopaminergic alterations in the striatum of dopa-untreated PD patients including the upregulation of postsynaptic D2 receptors (denervation supersensitivity). SPECT is widely available and is a promising clinical tool to evaluate PD patients.

PD is pathologically characterized by degeneration of presynaptic nigrostriatal dopamine neurons, particularly those projecting to the putamen.1,2 Loss of these neurons leads to striatal dopamine deficiency and subsequent development of parkinsonism, clinically characterized by initial unilateral onset of rest tremor, rigidity, and bradykinesia, progressing to bilateral involvement over a few years.3 It has been suggested that in l-dopa–untreated PD patients, postsynaptic striatal dopamine D2 receptors become upregulated to compensate for the dopaminergic denervation.4,5 Because l-dopa requires the presence of dopamine receptors to exert a therapeutic effect, information on the state of dopamine D2 receptors may be useful in predicting responsiveness to l-dopa therapy in patients with parkinsonism.6

Currently, it is feasible to obtain information on the in vivo state of both presynaptic nigrostriatal dopamine neurons and postsynaptic dopamine D2 receptors using PET or SPECT. In particular, the widespread availability and lower capital and operating costs of SPECT compared with PET suggest that SPECT imaging of neuroreceptors may become an important clinical tool.7 SPECT imaging of dopamine transporters using a cocaine analogue, iodine-123-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT), for example, has shown promise as a clinically useful tool to diagnose and evaluate PD patients.8-10 [123I]β-CIT binds with high affinity to dopamine transporters that are located in the presynaptic terminals of the nigrostriatal dopamine neurons11 and, therefore, is a marker of the neurons that degenerate in PD.8 [123I]β-CIT SPECT studies, including our previous study, have shown that striatal dopamine transporters are markedly reduced in PD patients and that dopamine transporter reductions show regionally uneven patterns.8-10,12 First, there is a lateralized difference in that dopamine transporters are more reduced in the striatum contralateral to the clinically more affected side. Second, dopamine transporters are more reduced in the putamen than than they are in the caudate within the same striatum.

In contrast to these characteristic presynaptic dopaminergic alterations, the precise in vivo role of postsynaptic D2 receptors, particularly that of D2 upregulation, is unclear because PET and SPECT studies of D2 receptors in PD patients have shown contradictory results. Although some studies suggest that putamen but not caudate D2 sites may be upregulated in the early course of disease,13-18 other studies have shown no such increases.6,19,20 Some of these studies have used contralateral-ipsilateral tracer uptake ratios to evaluate the state of D2 receptors. This is due to either a lack of normal controls or a limited number of normal controls whose ages are not matched with those of patients. The limitation of this approach is that even in patients with clinically hemi-PD, a significant nigrostriatal damage is usually evident on the ipsilateral side,2,10 which would invalidate the use of the ipsilateral side as control. Furthermore, few studies have used concurrent imaging of the presynaptic dopamine system in elucidating the postulated D2 upregulation in PD.

The objective of this study was to evaluate both the pre- and postsynaptic dopaminergic alterations of the striatum using [123I]β-CIT and [123I]iodobenzofuran ([123I]IBF) SPECT in patients with l-dopa–untreated PD. These SPECT techniques allow quantitative imaging of presynaptic dopamine transporters using the radioligand [123I]β-CIT and postsynaptic D2 receptors using the radioligand [123I]IBF.21-24 We compared the detailed striatal dopamine transporter/D2 binding measurements, as opposed to the hemispheric ratios, of 10 l-dopa–untreated PD patients with those of 21 age-matched normal controls.

Methods.

Patients.

Ten PD patients (6 men and 4 women; mean age 60.0 ± 8.5 years, range 49 to 74) who had no prior l-dopa treatment were selected for this study from the referrals to the Movement Disorders Clinic at The Toronto Hospital. Five were drug-naïve, and the remaining five took antiparkinsonian medication, which did not include l-dopa or dopamine agonists (i.e., dopa-naïve) (table 1). These patients had mild PD as assessed by the Hoehn and Yahr Scale (stage = 2.0 ± 0.6) and the Unified Parkinson’s Disease Rating Scale (UPDRS)25 (total mean UPDRS score = 23.5 ± 10.0) (see table 1). Diagnosis of PD was made according to the UK Parkinson’s Disease Brain Bank clinical diagnostic criteria.26 Patients with dementia and other major neuropsychiatric disorders were excluded. The patients in the current study, excluding Patient 1, were included in our previous methodologic study in which a new diagnostic imaging index for PD was evaluated based on the analysis of the functional topography of the striatum on the presynaptic dopamine transporter image using [123I]β-CIT SPECT.12

View this table:
Table 1.

Demographic characteristics of PD patients

Patients who were on treatment discontinued their drugs for at least 12 hours before the commencement of SPECT studies and until their completion. All UPDRS scores shown in table 1 were obtained before SPECT studies when the drug-treated patients were off medication for at least 12 hours. Although [123I]β-CIT or [123I]IBF binding may not be affected by these antiparkinsonian medications, the underlying clinical severity of PD is typically masked by the symptomatic effects of these medications. Therefore, the UPDRS scores obtained when patients are on antiparkinsonian medication may not reflect the underlying clinical severity. For this reason, we withdrew antiparkinsonian medications temporarily in the current study. None of our patients had any significant discomfort from withdrawing their antiparkinsonian medications, which were of minor potency.

Twenty-one age-matched healthy individuals (12 men and 9 women; mean age 65.8 ± 9.6 years, range 48 to 83) served as controls. None had a current or past history of neuropsychiatric disorders or a family history of movement disorders based on a screening interview, and they were free of drugs for at least 3 months before the study. All control individuals had normal MRI of the head, EEG, and Mini-Mental State Examination.27 These control individuals were evaluated for extrapyramidal motor function by using Part III (motor) of the UPDRS. None had significant extrapyramidal deficits as determined by previously published criteria (resting tremor ≥1 or rigidity ≥2, or both).28 All patients and controls gave written informed consent. The project was approved by the Human Research Review Committee of the University of Toronto.

Labeling of [123I]β-CIT and [123I]IBF.

Labeling of [123I]β-CIT and [123I]IBF was performed using the corresponding trialkylstannyl precursor, supplied by Guilford Pharmaceuticals (Baltimore, MD) (β-CIT) and Nihon Medi-Physics Co., Ltd. (Tokyo, Japan) (IBF), as well as [123I]NaI (Nordion International, Ltd., Vancouver, BC, Canada) as described previously.23,29 The radiochemical yield was 54.9% ± 11.1% for [123I]β-CIT and 80.9% ± 6.6% for [123I]IBF. The radiochemical purity was 98.3% ± 1.8% for [123I]β-CIT and 99.4% ± 0.3% for [123I]IBF. Retrospective sterility testing was negative.

SPECT imaging.

Imaging was performed using a triple-headed SPECT system (Prism 3000XP, Picker International, Inc., Cleveland, OH) equipped with ultra–high-resolution fan beam collimators (for [123I]IBF) or high-resolution fan beam collimators (for [123I]β-CIT) and interfaced to a dedicated computer (Odyssey VP; Picker International). All individuals had both [123I]β-CIT and [123I]IBF studies separated by 1 week, except for one normal control individual who had only a [123I]β-CIT study. [123I]β-CIT scans were acquired every 5 minutes for 30 minutes beginning at 20 ± 1.5 hours after a bolus IV injection of [123I]β-CIT (dose, 248 ± 61 MBq). [123I]IBF scans were acquired every 5 minutes during 0 to 20, 50 to 70, and 160 to 180 minutes after a bolus IV injection of [123I]IBF (dose, 295 ± 43 MBq). For each scan, 120 7.5-second projection images were obtained using 3°-angle intervals on a 128 × 128 matrix over 360° by rotating each head 120°. The radius of rotation was fixed at 13.5 cm. Four fiducial markers containing 1.5 μCi of 99mTc were taped, two on each side of the individual’s head at the level of the canthomeatal line (CML), throughout the imaging experiment. Full width half-maximum of the system was 9.1 and 9.6 mm in water at the center of the field of view equipped with ultra–high- and high-resolution fan beam collimators, respectively. The mean sensitivities of the system were 994 ± 24 cpm/μCi (high-resolution fan beam collimators) and 612 ± 12 cpm/μCi (ultra–high-resolution collimators) and varied less than 2% within the experiments and less than 5% between the experiments. Before each SPECT study, individuals were given 400 mg of potassium perchlorate orally.

SPECT images were reconstructed for 30 minutes on a 128 × 128 matrix ([123I]β-CIT) and every 10 minutes on a 64 × 64 matrix ([123I]IBF). One-pixel–thick transaxial slices from the vertex of the brain to the level of the CML, as identified by the fiducial markers, were reconstructed parallel to the CML using a three-dimensional Butterworth postreconstruction filter (order 10, cutoff frequency 0.25 cycles/pixel) after applying a ramp back projection filter. Attenuation correction was performed by assuming uniform attenuation equal to that of water (μ = 0.150 cm−1) within an ellipse drawn around the skull as identified by the fiducial markers.

Quantification of dopamine transporter/D2 binding.

Postmortem study has indicated that within the striatum there is also an uneven topographic gradient of dopamine loss in PD where the posterior putamen is more severely affected than the anterior putamen, which is in turn more affected than the caudate.3 Therefore, we measured dopamine transporter/D2 binding potentials (Rv) for caudate and anterior and posterior putamens separately in each hemispheric side. For the patients, contralateral side was defined as the side contralateral to the most affected limbs. For control individuals, contralateral was arbitrarily assigned to the left side based on our normal control data, which showed no significant lateralized differences in dopamine transporter Rv (p > 0.06, Student’s t-tests for paired samples). Tracer activity in brain regions of interest (ROIs) was measured as described previously.12 The ROIs used were three striatal subregions—caudate head (volume, 0.83 cm3), anterior putamen (0.66 cm3), and posterior putamen (0.94 cm3)—and six circular frontal cortex ROIs (total volume, 3.00 cm3). ROI placement depended on visual identification of anatomic regions aided by the stereotaxic atlas and the individual patient’s MRI as well as the early (first 10-minute) [123I]IBF scan, which reflects mostly regional perfusion. In PD, striatal perfusion is intact, and this strategy was to facilitate placing striatal ROIs on [123I]β-CIT images. The same individual applied all ROIs to eliminate interoperator variation. The mean coefficient of intraoperator variability in the outcome measure, Rv, was 3.3% ± 0.6%.

Dopamine transporter binding was quantified by using the method described by Laruelle et al.21 in which SPECT measurement of the specific-to-nondisplaceable tissue activity ratio during 18 to 24 hours after a bolus injection of [123I]β-CIT provides a measure (binding potential) of dopamine transporter density Rv = V3/V2 = k3/k4 = Bmax/KdV2, where V3 is the specific volume of distribution and V2 is the nondisplaceable volume of distribution, k3 and k4 are the first-order rate constants between the specific and nondisplaceable tissue compartments, Bmax is the concentration of receptors, and Kd is the equilibrium dissociation constant for tracer-binding site complex. Frontal cortex was used as the nondisplaceable tissue. D2 binding was quantified using our previously described multilinear regression technique,23,24 which permits measurement of binding potential, Rv = V3/V2, without blood data according to the following equation: Embedded Image where Cst(t) represents time-activity measurements in the striatum and Cfc(t) represents time-activity measurements in the frontal cortex, and a, a′, b, and b′ are con-stants. Rv is related to the partial regression coefficient a/a′ in equation 1 as follows: Embedded Image The b in equation 1 reaches constant after some time t* when the transport of ligand from plasma to tissue becomes unidirectional. This time point t* was determined on the two-dimensional plot of observed versus predicted values of the dependent variable after multilinear regression analysis as described previously.24

Statistical analysis.

Because all Rv measurements were normally distributed (Kolmogorov-Smirnov test for normality, p > 0.10), parametric statistical tests were used in the current study. Hotelling’s T2 tests and two-tailed Student’s t-tests for unpaired samples were performed to compare the values of Rv between the PD and control groups. Two-tailed Student’s t-tests for paired samples were performed for within-group comparisons of Rv between ipsilateral and contralateral sides and between ipsilateral or contralateral substriatal regions. Our a priori hypothesis was that dopamine transporters would be decreased while D2 receptors would be increased in PD patients. Hence, no correction for multiple comparisons, which is deliberately conservative and is appropriate only for exploratory types of study design,30 was made in this study. Instead, multiple t-tests were guided by a multivariate test (Hotelling’s T2 test). The relationships between the dopamine transporter Rv and D2 Rv were evaluated by linear regression analysis. Those UPDRS motor scores that pertain to extremities were separated into ipsilateral and contralateral sides (see table 1). The relationships between dopamine transporter/D2 Rv and these lateralized motor UPDRS scores or disease duration were determined also by linear regression analysis. Finally, the drug-naïve and non-drug–naïve patient groups were compared by two-tailed Student’s t-tests for unpaired samples in terms of clinical (Hoehn and Yahr stage, UPDRS scores, and disease duration), demographic (age), and SPECT measures. Statistical significance was defined as p < 0.05. Summaries of study variables were expressed as mean ± standard deviation (SD). All statistical analyses were implemented in STATISTICA (StatSoft, Inc., Tulsa, OK).

Results.

Dopamine transporters/D2 receptors.

The PD group and the control group were significantly different in their overall dopamine transporter Rv values (F(6,24) = 75, Hotelling’s T2 = 513, p < 10−5), and all six t-tests (caudate and anterior and posterior putamens in each hemisphere) individually showed significantly decreased mean Rv values in the PD group compared with the controls (for all tests, the level of significance was at least p < 10−5). A summary of the mean Rv values of the PD and control groups is shown in table 2, and scatter diagrams of individual Rv values are shown in figure 1A. The mean Rv ipsilateral/contralateral values of the PD patients for caudate and anterior and posterior putamens were, respectively, 30%/41%, 41%/50%, and 59%/68% lower than the corresponding control values (p < 10−5) (see figure 1A and figure 2A). These reductions in the mean dopamine transporter Rv values were more marked in the contralateral side than in the ipsilateral side (p < 0.01, three paired t-test comparisons). Furthermore, the mean reductions of dopamine transporter Rv of PD patients were more marked in the posterior putamen than in the anterior putamen, and the latter Rv values were in turn more marked than in the caudate on both ipsilateral and contralateral sides (p < 10−4, two paired t-test comparisons for each side) (see figure 2A). Individual dopamine transporter Rv values in the anterior putamen contralaterally and in the posterior putamen bilaterally were below the respective normal range for all patients (see figure 1A).

View this table:
Table 2.

Mean dopamine transporter and D2-receptor binding potentials (Rv) in the striatal subregions of l-dopa–untreated PD patients and normal controls

Figure

Figure 1. Scatter diagrams of individual dopamine transporter ([123I]β-CIT) binding potentials (Rv) (A) and D2 ([123I]IBF) binding potentials (Rv) (B) in the caudate and anterior and posterior putamens of l-dopa–untreated PD patients compared with normal controls. Individual Rv values of normal controls are indicated by solid circles and those of patients by solid squares. Horizontal bars indicate a mean value for the respective group. Ipsi = ipsilateral side, Contra = contralateral side.

Figure

Figure 2. [123I]β-CIT binding (dopamine transporter) (A) and [123I]IBF binding (D2 receptor) (B) in the caudate and anterior and posterior putamens of l-dopa–untreated PD patients expressed as mean percentages of normal mean Rv values. Ipsi = ipsilateral side, Contra = contralateral side. Error bars indicate + SD (n = 10).

The PD group and the control group were also significantly different in their overall D2 Rv values (F(6, 23) = 3.9, Hotelling’s T2 = 28, p < 0.01). However, in contrast to the dopamine transporter Rv, all six t-tests individually showed significantly increased mean D2 Rv values in the PD group compared with the control group (for all tests, the level of significance was at least p < 0.05) (see table 2 and figure 2B). The mean D2 Rv ipsilateral/contralateral values of the PD group for caudate and anterior and posterior putamens were, respectively, 15%/16%, 18%/14%, and 28%/31% higher than the corresponding control values (p < 0.05) (see figure 2B). There were no differences of the mean D2 Rv increases of the PD group between ipsilateral and contralateral sides (p > 0.4). Likewise, there were no differences of these Rv increases between caudate and anterior putamen on either ipsilateral or contralateral side (p > 0.3). However, the mean Rv increases in the posterior putamen of the PD patients were more marked than in the caudate or the anterior putamen bilaterally (p < 0.05, two paired t-test comparisons for each side) (see figure 2B). None of the individual D2 Rv values was below the respective normal range for all patients (figure 1B).

Because one patient (no. 7) whose disease duration was 10 years showed much greater increases of D2 Rv values particularly in the posterior putamen (by 80%) compared with the other patients, analyses were repeated excluding this patient. The PD group, excluding Patient 7, and the control group were also significantly different in their overall D2 Rv values (F(6,23) = 3.9, Hotelling’s T2 = 28, p < 0.01). The mean D2 Rv ipsilateral/contralateral values of this PD group for caudate and anterior and posterior putamens were, respectively, 13%/15%, 15%/12%, and 22%/26% higher than the corresponding control values (p < 0.05 for all comparisons except for ipsilateral caudate, p = 0.09, and contralateral anterior putamen, p = 0.09). There were no lateralized differences of the mean D2 Rv increases of this PD group (p > 0.2). SPECT images showing decreased striatal [123I]β-CIT activity particularly in the putamen and increased striatal [123I]IBF of a PD patient (no. 7) are illustrated in figure 3 (top row) contrasted with the corresponding images (bottom row) of an age-matched control.

Figure

Figure 3. [123I]β-CIT (dopamine transporter) scans (two images on the left) and [123I]IBF (D2) scans (two images on the right) of a 63-year-old woman with l-dopa–untreated PD (Patient 7) (two images on the top) and a 64-year-old normal control (two images on the bottom). This patient’s [123I]β-CIT image (left top) shows decreased activity particularly in the putamen bilaterally, whereas her [123I]IBF image (right top) shows increased activity both in the caudate and putamen bilaterally compared with the corresponding images of the normal control (bottom). Image intensity has been adjusted so that striatal activity roughly reflects the relative differences in the mean striatal Rv values between the two individuals.

Correlation analysis.

There was no significant correlation between dopamine transporter Rv and D2 Rv for either the control or the PD groups (for all analyses the level of significance was at least p > 0.29). The lateralized motor UPDRS scores negatively correlated with dopamine transporter Rv for all three striatal subregions: caudate (r = −0.49, p = 0.028), anterior putamen (r = −0.50, p = 0.026), and posterior putamen (r = −0.59, p = 0.006) (figure 4A). However, there was no significant correlation between the lateralized UPDRS scores and D2 Rv for caudate and anterior or posterior putamen, although there was a positive trend for posterior putamen (r = 0.37, p = 0.11) (figure 4B). All patients had disease duration of ≤4.5 years except one who had disease duration of 10 years (see table 1). Excluding this outlier, there was no significant correlation between disease duration and dopamine transporter Rv or D2 Rv. However, the patient with the longest duration of 10 years showed the greatest increases (by 80% in the posterior putamen) in D2 Rv compared with controls. The exclusion of this patient, however, did not affect the relationships between dopamine transporter/D2 Rv and lateralized motor UPDRS scores except that the positive trend seen with this patient included (see figure 4B) was no longer seen with this patient excluded (r = 0.32, p = 0.18).

Figure

Figure 4. Correlation of lateralized motor Unified Parkinson’s Disease Rating Scale (UPDRS) scores and dopamine transporter (A) and D2-receptor (B) binding in the posterior putamen expressed as percentages of normal mean Rv. The lateralized motor UPDRS scores negatively correlated with dopamine transporter Rv. However, there was no significant relationship between the lateralized motor UPDRS scores and D2 Rv, although there was a trend toward a positive correlation. Straight lines are linear regression lines.

Drug-naïve versus non-drug–naïve PD.

There were no differences between these two groups in terms of clinical, demographic, or SPECT measures (dopamine transporter/D2 Rv). However, the significance of these comparisons was limited by the small numbers of patients, i.e., five per group.

Discussion.

The results of our study suggest that [123I]β-CIT and [123I]IBF SPECT imaging can detect characteristic dopaminergic alterations in the striatum of l-dopa–untreated PD patients, including the upregulation of postsynaptic D2 receptors. SPECT is widely available, and hence it is a promising clinical tool. Previously Wenning et al.18 reported SPECT studies and Sawle et al.17 reported PET studies in which a combination of pre- and postsynaptic imaging techniques similar to ours was used to study l-dopa–naïve PD patients. In both studies, the presynaptic striatal dopaminergic function as measured by [123I]β-CIT and [18F]fluorodopa was reduced in PD patients. In contrast, the upregulation of postsynaptic D2 binding on SPECT, as measured by the contralateral-ipsilateral uptake ratio of [123I]iodobenzamide ([123I]IBZM), was seen in patients with clinically unilateral symptoms but not in patients with bilateral involvement. In the PET study, the [11C]raclopride D2 binding potential in the contralateral putamen was increased in PD patients.

Our findings of markedly decreased striatal dopamine transporter binding in the contralateral putamen of PD patients are consistent with those of others.9,10 In addition, the uneven dopamine transporter deficit within the putamen is consistent with the postmortem findings3 and those of a recent PET study.31 In the current study, [123I]β-CIT scans discriminated between all PD patients and controls. Furthermore, there was a negative correlation between motor UPDRS scores and striatal dopamine transporter Rv. Thus, our findings and those of others9,10 suggest that [123I]β-CIT SPECT may be used not only as a “trait marker” of the disease but also as a “state marker” that correlates with the severity of the underlying neurodegenerative process, which is typically masked by the symptomatic effects of antiparkinsonian medication.

Our findings of increased D2 binding in both the caudate (by 15%) and the putamen (by 20 to 30%) in l-dopa–untreated PD patients generally agree with those of previous postmortem studies, which suggest denervation supersensitivity of D2 receptors.4,5 In the study reported by Guttman et al.,5 D2 density of six striatal samples of drug-naïve PD patients was elevated in both the caudate (by 29%) and the putamen (by 20%) compared with controls. Similarly, Lee et al.4 found a 55% increase in the D2 density in the putamen and a 20% increase in the caudate in six l-dopa–untreated PD brains. However, other postmortem studies have shown no such changes.32-34 It has been suggested that these discrepancies arise from technical factors involved in assays of in vitro receptor binding in which no full saturation analysis was done on each tissue assayed in the postmortem studies reporting no D2 upregulation.35 Similarly, conflicting findings reported by previous imaging studies have been suggested to arise from such factors as radioligands used, data analysis methods, and presence or absence of an adequate number of age-matched controls.35 [123I]IBF used in the current study binds to D2 receptors with higher affinity compared with [123I]IBZM, provides higher image contrast, and is suited for quantitative receptor studies.23,24 Rv reflects D2 densities if V2 is similar across individuals.23 Previously we showed that D2 Rv measurements are reliable, reproducible, and unaffected by regional blood flow or peripheral ligand clearance.23,24 Unlike another PET D2 ligand, [11C]methylspiperone, [123I]IBF does not bind to serotonin receptors.20 We have also included a considerable number of age-matched controls. However, our findings of bilaterally symmetric increases in D2 binding in both the caudate and putamen of l-dopa–untreated PD patients are somewhat different from those of PET studies reported by Antonini et al.14 and Sawle et al.17 In the former, the putamenal but not caudate D2 binding was increased bilaterally but asymmetrically, with more marked changes on the contralateral side. In the latter, only the contralateral putamenal D2 binding was increased. These discrepant findings may be related to the differences in SPECT versus PET methodology as well as the relatively few patients in these studies, including ours. Future studies involving a larger number of patients appear warranted to clarify some of these discrepancies. However, the contralateral-to-ipsilateral ratio method used in other studies would not have detected these bilaterally symmetric increases. Human postmortem studies traditionally have made no lateralized distinction of striatal tissue samples.4,5

Unlike in vitro binding studies in which extracellular dopamine is excluded, increased D2 binding in in vivo studies may be due to either an increase in the receptor number or decrease in synaptic dopamine concentrations, or both. However, the lack of lateralized differences in increased D2 binding in our study suggests that D2 upregulation must be contributing to some of the increases in D2 binding. This is because striatal dopamine depletion is known to show lateralized differences,3 as supported in the current study by the lateralized difference of the dopamine transporter deficit. There were slightly greater increases of D2 binding in the posterior putamen than in the caudate or anterior putamen in the current study. However, the lack of lateralized differences in increased striatal D2 binding, if this can be confirmed in further studies involving larger samples, would also suggest that the mechanisms of D2 upregulation may be complex. This is reflected in our finding of no apparent relationships between dopamine transporter binding and D2 binding, although Sawle et al.17 in their PET studies found a correlation between the left/right [11C]raclopride D2 binding potential and the left/right presynaptic [18F]fluorodopa influx constant. However, in the unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated baboons, where contralateral dopamine levels are normal, bilaterally symmetric increases in putamenal dopamine D2-receptor number have been found by some investigators.36 However, in unilaterally MPTP-treated monkeys, only ipsilateral increases in striatal D2 binding have been found by other investigators.37,38

In our study, five patients took antiparkinsonian medication, including selegiline (deprenyl) and amantadine. One of the actions of these drugs is thought to enhance endogenous dopamine release in the striatum,39 which might then prevent upregulation of striatal dopamine D2 receptors. In an animal study reported by Paetsch and Greenshaw,40 there was no change in striatal D2 receptors of healthy rats after chronic treatment with deprenyl. Further studies involving a larger sample size appear warranted to evaluate the effects of these drugs on D2 binding. However, dopamimetic drugs, particularly l-dopa, have been shown to downregulate D2 receptors.4,5,15,19,41 In fact, two other PD patients on l-dopa therapy who were not included in the current study had striatal D2 Rv values in the lower normal range (data not shown).

Finally, the findings of a longitudinal D2 receptor PET study reported by Antonini et al.15 suggest that striatal D2 upregulation in PD may be seen only in early stages of the disease, and the number of D2 receptors subsequently decrease. This downregulation of D2 receptors is considered to reflect structural adaptation of the postsynaptic dopaminergic system to the progressive decline of nigrostriatal neurons and possibly to account for the development of l-dopa–refractory motor symptoms. However, the exact mechanisms or the time course of this D2 downregulation is not clear. In our study, none of the patients showed decreased striatal D2 Rv values below the respective normal range (more than 2 SD from the mean). In fact, all our PD patients were early in the disease course (<4.5 years), except for one patient who had the disease for 10 years. This patient’s [123I]IBF SPECT study showed, contrary to what might have been predicted from the findings reported by Antonini et al.,15 the greatest increases in D2 binding of the posterior putamen. This patient (no. 7) was on amantadine for 1.5 years, to which she had responded well. Shortly after SPECT studies, she was placed on a new dopamine agonist, ropinerole, 2 mg/d, and she showed further improvements in her tremor and rigidity. This case therefore illustrates that D2 upregulation can still be seen after many years with the disease and supports the concept that intact dopamine receptors are needed for dopaminergic therapy to be effective.6

Acknowledgments

Supported by a grant from the Medical Research Council of Canada (HT-13367) and by the SPECT Research Fund from the Department of Medical Imaging, Mount Sinai Hospital, with contributions from Picker International Canada Inc., and through a Center of Excellence Award from National Parkinson Foundation (Miami, FL).

Acknowledgment

The authors acknowledge the provision of CIT precursors from Guilford Pharmaceuticals and IBF precursors from Nihon Medi-Physics Co., Ltd.

  • Received September 16, 1998.
  • Accepted December 12, 1998.

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