Abstract
Background: [123I]β-CIT and SPECT imaging of the dopamine transporter is a sensitive biomarker of PD onset and severity.
Objective: In this study, the authors examine the change in [123I]β-CIT uptake in sequential SPECT scans to assess the rate of progression of the dopaminergic terminal loss in patients with PD.
Methods: Patients with PD (n = 32) and healthy controls (n = 24) recruited from the Yale Movement Disorders Center underwent repeat [123I]β-CIT SPECT imaging during a 1- to 4-year period. The primary imaging outcome was the ratio of specific to nondisplaceable striatal activity. Disease severity was assessed by Hoehn and Yahr staging, and Unified Parkinson Disease Rating Scale after 12 hours off drug.
Results: Sequential SPECT scans in PD subjects demonstrated a decline in [123I]β-CIT striatal uptake of approximately 11.2%/year from the baseline scan, compared with 0.8%/year in the healthy controls (p < 0.001). Although [123I]β-CIT striatal uptake in the PD subjects was correlated with clinical severity, the annual percentage loss of [123I]β-CIT striatal uptake did not correlate with the annual loss in measures of clinical function.
Conclusions: The rate of dopaminergic loss in PD is significantly greater than that of healthy controls, and [123I]β-CIT SPECT imaging provides a quantitative biomarker for the progressive nigrostriatal dopaminergic degeneration in PD. As new protective and restorative therapies for PD are developed, dopamine transporter imaging offers the potential to provide an objective endpoint for these therapeutic trials.
The clinical progression of PD, although relentless, is highly variable and unpredictable.1,2⇓ Clinical decline reflects ongoing nigrostriatal degeneration, but it is unclear whether PD symptoms arise from age-related neuronal loss in association with a transient neurodegenerative insult or from an ongoing neurodegenerative process.3-7⇓⇓⇓⇓ Pathologic studies investigating the rate of PD progression have been limited to patients with severe illness of long duration and rely entirely on cross-sectional data. These studies report a decline in nigral degeneration in patients with PD eight- to ten-fold that of healthy controls.7-10⇓⇓⇓ Most clinical studies of PD progression have focused on early patients. These studies have used the Unified PD Ratings Scale (UPDRS) or other functional clinical endpoints to monitor disease progression.11-14⇓⇓⇓ Although clinical studies address the key issue of functional status, they are often confounded by symptomatic effects of anti-Parkinson drugs, making it difficult to isolate clinical change solely due to disease progression.
In vivo imaging of the nigrostriatal dopaminergic system provides the promise of an objective quantitative biomarker of the neuronal degeneration in PD. Sequential [18F]DOPA and PET imaging demonstrated a rate of reduction in striatal [18F]DOPA uptake of approximately 10%/year in patients with PD compared to no significant change in healthy controls.15 This study suggests that [18F]DOPA and PET may be used to monitor dopaminergic neuronal degeneration. However, [18F]DOPA is not a direct measure of neuronal degeneration, but rather a measure of the conversion from [18F] DOPA to [18F] dopamine, which may be upregulated as compensation for neuronal loss.16
More recently, dopamine transporter imaging has emerged as a direct measure of dopamine terminal degeneration in PD.17-21⇓⇓⇓⇓ Sequential [18F](2β-carbomethoxy-3β-[4-fluorophenyl]tropane) ([18F]CFT) and PET imaging has shown that striatal dopamine transporter uptake was reduced by approximately 13%/year in eight patients with PD compared with 2.5%/year in six healthy controls.22 Furthermore, studies with the transporter ligand [123I]β-CIT (2β-carboxymethoxy-3β(4-iodophenyl tropane) and SPECT have demonstrated that, because of its unique binding kinetics and high specific striatal uptake, this ligand may be used to quantify changes in dopamine transporter density.23 Several cross-sectional studies have shown that [123I]β-CIT uptake is markedly reduced in PD patients, that the characteristics of the reduction in striatal uptake (putamen > caudate) are consistent with known pathology, and that the severity of the imaging deficit correlates with the clinical severity of disease.24,25⇓ In other studies that focused on early PD patients, at the threshold of their illness, [123I]β-CIT imaging demonstrated a 50% reduction in dopamine transporter in the putamen contralateral to the symptomatic side.26
These cross-sectional data suggest that sequential in vivo imaging with [123I]β-CIT and SPECT may be used to monitor the progression of PD to assess the fate of the remaining dopaminergic neurons and potentially to evaluate the efficacy of neuroprotective strategies to slow progression of degeneration in these remaining neurons. In this study, we report the results of sequential [123I]β-CIT and SPECT imaging in a cohort of patients with PD and healthy controls. This technique provides the first potentially widely available quantitative imaging biomarker to measure dopamine terminal degeneration.
Methods.
Recruitment and enrollment.
Study participants were recruited from patients already known to the Yale Movement Disorders Center. Healthy controls were recruited either from the community or through personal contact with the study subjects (e.g., spouses).
The criteria for inclusion for PD subjects were age >30 years and at least two of the following: resting tremor, bradykinesia, rigidity, and postural instability (one of which is resting tremor or bradykinesia). Patients were excluded if they had dementia, symptomatic orthostatic hypotension, ophthalmoplegia, or evidence of any significant alternative neurologic illness. Healthy controls were excluded if they had any signs or symptoms of PD or any history of PD in a first-degree relative.
The institutional review boards approved the study, and all subjects gave written informed consent.
Study assessment.
All subjects were evaluated sequentially with clinical and imaging studies at intervals of 12 to 48 months.
Clinical assessment.
Patients with PD were evaluated with UPDRS and Hoehn and Yahr staging before each imaging study.1 Those patients who were taking anti-Parkinson medications were evaluated 12 hours off drug in the “defined off” state.27 A single investigator (K.M.) evaluated all subjects.
Imaging assessment.
Data acquisition.
High specific activity [123I]β-CIT was prepared from the corresponding trimethylstannyl precursor as previously described.28 Eligible subjects were injected with 6 mCi [123I]β-CIT after receiving Lugol’s solution. Projection data were acquired 24 ± 2 hours following injection on a three-headed detector SPECT system (PICKER PRISM 3000, Marconi Medical Systems, Cleveland, OH) fitted with low-energy, high-resolution fanbeam collimators with isotropic spatial resolution of 12.2 mm, measured using a 123I line source in a 20-cm cylindric phantom filled with water. The energy settings had a 20% window centered at 159 keV. Projection data were filtered with a two-dimensional Butterworth filter and reconstructed using filtered back-projection. Images were reoriented such that the transverse plane was parallel to the canthomeatal line. Attenuation correction ellipses were fit using a Chang zero order (homogeneous) correction applied to the reconstructed data.29 Four subfiducial markers filled with 8 to 10 μCi of [99mTc]NaTcO4 were attached to both sides of the subject’s head at the level of the canthomeatal line before imaging to facilitate post hoc computer reorientation of transaxial images. On the reoriented image, the striatal slice with the most intense uptake is determined by thresholding the color scale (index slice). The two slices above this slice, the index slice, and one slice below are summed (total z dimension = 1.3 cm). Using strict criteria previously described, the technologist drew regions of interest and calculated the outcome measures specified.25 The standard regions of interest template for the striatum contains right and left caudate and right and left putamen. The standard regions of interest for the nondisplaceable activity contains the posterior portions of both occipital lobes.
Image analysis.
The primary outcome measure was the specific-to-nondisplaceable striatal uptake ratio, the sum of the caudate and putamen uptake ratios. Specific uptake was determined by subtracting occipital densities from total caudate and/or putamen count densities. A technologist unaware of any patient information completed all analyses.
Statistical analysis.
Baseline characteristics of the diagnostic groups were compared using analysis of variance, t-tests and χ2 tests as appropriate. Annual percentage change in β-CIT uptake (striatum, caudate, and putamen) was calculated for both patients with PD and controls in three steps. First, the actual change was calculated as the difference between the initial and final scans. This change value was then divided by the interval between the two scans. Finally, the annual percentage change was calculated by dividing the annual change by the initial β-CIT uptake value. The annual percentage changes for the PD patient and control groups were compared using t-tests.
For the patients with PD only, Pearson correlation coefficients were calculated comparing striatal, putamen, and caudate β-CIT uptake and UPDRS (total and motor subscale) at the initial and final scan and comparing annual percentage loss in β-CIT uptake and the annual change in UPDRS (total and motor subscale).
Multiple regressions were run using data from the PD patients. The outcome variables were the annual percentage loss variables for the three β-CIT uptake measures. Each regression included the following six prespecified independent variables: age at scan, duration of disease at scan, sex, initial predominant symptom (categorized as either tremor or no tremor), initial UPDRS score, and initial β-CIT uptake value.
Results.
Subject demographics.
Table 1 shows demographic characteristics of the study population. Age distributions of subjects enrolled in the two groups were similar, but the healthy controls were slightly older. Gender also did not differ significantly among the groups. At baseline, the patients with PD ranged from mild to moderate disease with mean total UPDRS of 29.8 ± 13.6 (SD) and motor UPDRS of 18.2 ± 8.7. At the initial scan, the mean duration of illness from diagnosis was 2.5 ± 2.4 years. Sixty-six percent of the patients with PD were untreated at baseline, and 25% remained untreated throughout the study. Others were treated with anti-Parkinson medications including levodopa and carbidopa, dopamine agonists, or selegiline (table 1).
Subject demographics
Sequential imaging analysis.
The mean scan interval between the first and last scans was 1.7 ± 0.3 years for the healthy controls and 2.3 ± 0.9 years for the patients with PD (table 2). Fifteen PD subjects had more than two scans. Sequential images obtained in the PD subjects demonstrated a decline in [123I]β-CIT striatal uptake of approximately 11.2%/year from the baseline scan, compared with 0.8%/year in the healthy controls (p < 0.001). Figure 1 demonstrates a typical sequence of images in a PD subject during a 3-year interval. Although the relative reduction from normal in [123I]β-CIT striatal uptake is greater in the putamen than caudate, the incremental reduction in sequential scans is comparable in the two striatal regions. Similarly, although there was greater loss of [123I]β-CIT striatal uptake in the side contralateral to the initial symptoms, the incremental reduction in each hemistriatum was not significantly different.
Annual percentage change in [123I]β-CIT uptake in sequential scans
Figure 1. SPECT and [123I]β-CIT images of progressive dopamine transporter loss during a 3-year period. Note the loss of activity is more marked in the putamen than caudate. Levels of SPECT activity are color coded from low (black) to high (yellow/white).
Variability in individual progression.
Examination of the individual rate of reduction in [123I]β-CIT uptake demonstrated variability among patients with PD (figure 2). The rate of change from the baseline scan ranged from +6%/year to −36%/year. Thirty of the 32 patients with PD showed a reduction in [123I]β-CIT uptake. The individual variability in the rate of loss of imaging activity reflected the marked clinical variation in progression of PD and presumably the biological variability of disease progression. In the PD cohort, the mean change/year from baseline of total UPDRS scores was −2.8 ± 6.6. The annual change in total UPDRS ranged from +12.9 to −27.5.
Figure 2. Striatal β-CIT uptake (specific/nondisplaceable activity) for all PD subjects scans demonstrates marked intersubject variability in the rate of change of dopamine transporter density.
Correlation of [123I]β-CIT uptake and UPDRS.
The patients with PD showed a significant correlation between the initial scan putamen [123I]β-CIT uptake and the initial UPDRS and between the final scan putamen and caudate[123I]β-CIT uptake and the final UPDRS, (p < 0.05). These correlations were consistent with prior studies that have demonstrated a significant correlation between [123I]β-CIT uptake and UPDRS in a cross-section of PD subjects.24,25⇓ However, when studied longitudinally, the patients with PD showed no correlation between the annual percentage change in putamen, caudate, or total striatal [123I]β-CIT uptake and clinical progression of severity of disease, measured by the annual change in either total or motor UPDRS.
Determinants of disease progression.
Characteristics of the patients with PD were further evaluated for factors that might explain the variability in the progression of [123I]β-CIT uptake during the scanning interval. For example, evidence has indicated that the rate of progression of PD may be dependent on duration of disease, suggesting that differences in individual rate of dopamine transporter loss may reflect evaluation of PD subjects at different stages of their illness.15 Therefore, multiple regression analysis was performed to evaluate the effect on the rate of loss of [123I]β-CIT uptake of the following six prespecified independent variables: age at initial scan, duration of disease from diagnosis to initial scan, sex, initial symptoms (categorized as either tremor or no tremor), initial UPDRS score, and initial [123I]β-CIT uptake value. These analyses demonstrated that only age at the time of the initial scan and initial [123I]β-CIT uptake were significant predictors of the rate of striatal, caudate, and putamen [123I]β-CIT annual percentage loss (p < 0.025). The annual percentage [123I]β-CIT loss is increased by approximately 0.4%/year for each additional year of age at initial scan. The annual percentage [123I]β-CIT loss is increased by approximately 5.6%/year for each additional unit of [123I]β-CIT uptake in the initial scan. When the regressions were repeated using only age at initial scan, sex, and initial [123I]β-CIT uptake value, the results were similar.
Discussion.
In vivo dopamine transporter imaging with SPECT and [123I]β-CIT demonstrated a reduction in striatal [123I]β-CIT uptake of 11%/year from baseline scan in a cohort of PD patients. The reduction in [123I]β-CIT uptake/year in PD subjects was significantly greater than that of healthy controls. These data demonstrate that SPECT and dopamine transporter imaging provides a quantitative biomarker for the progressive nigrostriatal dopaminergic degeneration in PD.
Studies of nonhuman primates, healthy controls, and patients with PD provide substantial evidence that changes in [123I]β-CIT SPECT striatal uptake reflect changes in striatal dopamine neurons. SPECT images in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce parkinsonism show that [123I]β-CIT uptake was closely correlated with dopamine content and behavioral scales.30 Cross-sectional studies of healthy controls have shown an age-related decline in [123I]β-CIT uptake of approximately 0.8%/year, similar to the reduction in dopamine transporter number reported in pathologic studies.31-33⇓⇓ The reduction in [123I]β-CIT uptake of 0.8%/year in the healthy controls in this study demonstrated a similar loss of transporter density with aging in a cohort of healthy controls studied longitudinally. In PD patients, the reduction in striatal [123I]β-CIT uptake has closely mimicked the regional specificity (putamen > caudate) of the pathology of PD. Furthermore, the striatal, putamen, and caudate [123I]β-CIT uptake in a large cohort of PD subjects significantly correlated with severity of PD as measured by UPDRS.24,25⇓
The sequential imaging data reported in this study must be interpreted in the context of the reliability of the imaging outcome measure. Previous studies evaluating the test/retest reliability of [123I]β-CIT SPECT imaging demonstrate that the mean reproducibility of striatal [123I]β-CIT uptake was 12.8% in healthy controls and 16.8% in PD subjects.34,35⇓ Variability is likely because of patient movement, image analysis, and camera sensitivity. This variability previously reported for PET and [18F]DOPA was 8 to 12% for healthy subjects.36
Our longitudinal imaging data showing a reduction in striatal dopamine transporter density of 11%/year from baseline is remarkably similar to studies demonstrating a reduction of approximately 10% to 13%/year from baseline in [18F]DOPA and [18F]CFT activity in PD subjects15,22,36⇓⇓ Our estimate of a 14-fold increase in loss of transporter density in PD compared with healthy controls is also similar to the 6- to 10-fold increase in progression in PD subjects suggested by both longitudinal [18F]DOPA data and cross-sectional pathologic studies.7,36⇓ Therefore, three diverse methods, SPECT and dopamine transporter imaging, PET and [18F]DOPA imaging, and nigral neuronal counts, each measuring different aspects of the dopaminergic system, all suggest that the rate of dopaminergic degeneration in PD is approximately 10%/year. This estimate is further supported by [18F]DOPA and dopamine transporter uptake studies of hemi-PD subjects who are at the threshold of their illness and symptomatic only on one side of their body. [18F]DOPA and dopamine transporter uptake was reduced by approximately 40 to 50% in the affected putamen and by 25 to 30% in the unaffected putamen in these subjects.19,26,37⇓⇓ Because most patients will progress clinically from unilateral to bilateral in 3 to 6 years, it is therefore likely that the loss of these in vivo imaging markers of dopaminergic degeneration in the previously unaffected putamen will progress at about 5% to 10% per year.1
This study demonstrated marked variability in the rate of loss of [123I]β-CIT uptake in the PD subjects. The cohort of patients with PD was a relatively heterogenous group selected simply as a consecutive group from the Yale Movement Disorders Center. The variability in progression in the imaging outcome likely reflects both the biological variability of PD and technical limitations of SPECT imaging. In this study, all images were obtained on a single camera, imaging included the use of external markers to orient the images, and well-trained personnel present throughout the study were used in an attempt to minimize variance. Prior studies suggested that the rate of progression of PD was greater in early as compared with late patients.36 Our data did not show a relationship between progression and stage of illness, but most patients were early in their disease. Multivariate analysis did demonstrate that relatively increased [123I]β-CIT uptake at the initial scan and increased age at the initial scan may predict a more rapid loss of [123I]β-CIT uptake in subsequent scans. Studies with additional subjects evaluated for a longer duration are necessary to clarify factors that might influence the rate of progression.
The lack of correlation between the rate of dopamine transporter loss measured by [123I]β-CIT uptake and the rate of progression of clinical severity measured with the UPDRS raises several important issues. One possible explanation for the poor correlation between the change in imaging and clinical scores is that the UPDRS may be confounded by the effects of the patients anti-Parkinson’s medications, despite evaluating subjects in the “defined off” period. Indeed, the difficulties in evaluating patients with PD while on medications provides a major rationale for developing an objective measure of disease progression, like dopamine transporter imaging. Studies have demonstrated that treatment with l-dopa, dopamine agonists, and selegiline do not affect [123I]β-CIT uptake.38,39⇓ A second explanation for the lack of correlation between imaging and clinical measures of progression is that neither [123I]β-CIT uptake nor UPDRS are linear scales and furthermore the rate of change in these measures may be differentially dependent on duration of illness, age on onset, or predominant symptoms.40 In addition, although the progressive loss of [123I]β-CIT uptake reflects dopaminergic terminal loss, the UPDRS changes may reflect much more general changes in functional status. Therefore, imaging and clinical endpoints, although complementary, may demonstrate different rates of change. Longitudinal follow-up including both imaging and clinical assessment is essential to establish the correlation between imaging progression, which reflects dopamine terminal degeneration, and clinical rating scales progression, which reflects current functional status. It is likely that multiple endpoints of progression will be required to fully clarify the natural history of PD and to explain the clinical course of this disorder.
During the next decade, the experimental neurotherapeutics of PD and other neurodegenerative disorders will focus on drugs that modify the underlying disease process.41 As these new protective and restorative therapies are developed, neuroimaging offers the potential to provide an objective endpoint for these therapeutic trials. Our data demonstrate that SPECT and [123I]β-CIT imaging of the dopamine transporter can be used as a biomarker for dopaminergic degeneration in PD. Although the sample size in this report is limited, these data may be used to estimate the sample size needed for larger clinical studies to evaluate putative neuroprotective or neurorestorative drugs (table 3). Several of these studies are under way, and the results will further refine our use of imaging to monitor PD progression.14,42,43⇓⇓ Currently, caveats to our use of imaging biomarkers to assess progression must be emphasized. Imaging agents like dopamine transporter ligands assess only one aspect of the dopamine neuron, and unseen compensation of the dopaminergic system likely occurs. Subpopulations of PD subjects may progress at different rates, and the factors influencing the rate of progression of disease must be clarified. Most important, meaningful functional changes in clinical endpoints in PD progression studies must ultimately accompany changes in endpoints of imaging progression. However, despite these limitations, dopamine transporter imaging provides an objective biomarker of dopamine degeneration and an additional option for an objective endpoint in future studies of the experimental therapeutics of PD.
Sample size to assess neuroprotection
Acknowledgments
Supported by RO1 NS36197 (K.M.) and a National Parkinson’s Foundation Center of Excellence grant at Yale University.
- Received October 11, 2000.
- Accepted August 16, 2001.
References
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