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November 28, 2000; 55 (10) Articles

A multicenter assessment of dopamine transporter imaging with DOPASCAN/SPECT in parkinsonism

Parkinson Study Group
First published November 28, 2000, DOI: https://doi.org/10.1212/WNL.55.10.1540
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A multicenter assessment of dopamine transporter imaging with DOPASCAN/SPECT in parkinsonism
Parkinson Study Group
Neurology Nov 2000, 55 (10) 1540-1547; DOI: 10.1212/WNL.55.10.1540

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Abstract

Background: In vivo imaging of the dopamine transporter (DAT) with SPECT is a quantitative biomarker for PD onset and severity.

Objective: To use a multicenter study to evaluate the diagnostic accuracy of DOPASCAN and SPECT in patients with PD, progressive supranuclear palsy (PSP), and essential tremor (ET), and in healthy controls (HC).

Methods: Ninety-six individuals with known clinical diagnosis were imaged with DOPASCAN at five sites with different multidetector SPECT systems. Both masked visual interpretation and region of interest (ROI) analysis were performed at each site and at a core analysis center.

Results: Visual interpretation of the images by an expert panel demonstrated a sensitivity of 0.98 and specificity of 0.83 comparing parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) controls. Quantitative analysis of putamen and caudate DOPASCAN uptake for each region in the PD or PSP groups was significantly reduced compared to the ET or HC groups. Comparison of parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals demonstrated a reduction of 76% in mean putamen and 48% in mean caudate DOPASCAN uptake.

Conclusions: DOPASCAN and SPECT imaging reliably and effectively distinguish between subjects with Parkinson’s syndrome (PD + PSP) and without Parkinson’s syndrome (HC + ET). This is the first multicenter assessment of dopamine transporter imaging demonstrating that this tool may be used widely to assess dopaminergic degeneration in patients with parkinsonism.–1547

The diagnosis of PD is dependent on clinical judgment based on the assessment of patient’s signs and symptoms. However, the insidious onset and varied presentation of PD often obscures diagnosis especially early in the disease.1 Studies of accuracy of clinical diagnosis compared to a pathologic gold standard demonstrate that 10 to 20% of patients thought to have PD have a different diagnosis.2,3⇓ In vivo imaging of the nigrostriatal system provides an objective measure of the dopaminergic deficit in PD and a potential tool that may improve the accuracy of early diagnosis of PD and related disorders.

The dopamine transporter, a protein located on the dopamine presynaptic nerve terminal, provides an in vivo imaging target that is a measure of dopamine terminal integrity.4-6⇓⇓ Dopamine transporter ligands and SPECT or PET imaging have been used as markers of dopamine neuronal loss in PD. In vivo dopamine transporter imaging studies have demonstrated a reduction in dopamine transporter density in PD patients compared to healthy controls (HC). The reduction in dopamine transporter density is both region specific (putamen > caudate) and asymmetric, consistent with both pathologic assessment of dopamine transporter loss and clinical presentation of PD.7-12⇓⇓⇓⇓⇓ Dopamine transporter imaging of patients with progressive supranuclear palsy and with multiple system atrophy demonstrate a reduction in dopamine transporter density, but with a similar reduction in caudate and putamen. This is consistent with pathology studies that show the more extensive neurodegeneration in these disorders.6,13-15⇓⇓⇓

Studies with SPECT and [123I]β-CIT (2β-carboxymethoxy-3β-[4-iodophenyl]tropane), also known as DOPASCAN (Guilford Pharmaceutical, Inc., Baltimore, MD), have demonstrated that using a linear discriminate function, measurement of [123I]β-CIT uptake in putamen and caudate distinguished between patients with PD and HC with 100% accuracy.16 In patients with early hemi-PD, [123I]β-CIT uptake is reduced by 50% in putamen, indicating that even at the threshold of clinical diagnosis in vivo imaging is markedly abnormal.10,17⇓ These data demonstrate that dopamine transporter imaging and SPECT may be used as an objective and quantitative marker of in vivo dopaminergic degeneration in PD.

In this study we used DOPASCAN and SPECT to image HC and patients with PD, progressive supranuclear palsy (PSP), and essential tremor (ET). The diagnostic categories were grouped into individuals with Parkinson’s syndrome (PD + PSP) and individuals with non-Parkinson’s syndrome (ET + HC). PSP and ET were chosen as disorders related to and often confused with PD. Our goal was to assess the diagnostic accuracy of DOPASCAN and SPECT in patients with PD and related disorders and to assess the effectiveness of this tool in a multicenter setting.

Methods.

Organization.

This multicenter study was designed and carried out by the Parkinson Study Group (PSG) and Guilford Pharmaceutical, Inc. (Baltimore, MD). The study was reviewed and approved by the institutional review board at each of the participating sites and all study participants gave written informed consent.

Recruitment and enrollment.

A consecutive series of patients (PD, PSP, and ET) was recruited through the movement disorders center at each of the participating sites. Study participants were recruited from patients already known to these centers and from referrals made by a wider network of neurologists. HC were recruited either from the community at large or through personal contact with the study participants (e.g., spouses).

Standard clinical criteria as applied by movement disorders specialists were the reference standard (i.e. gold standard) for each of the diagnostic groups. Appendix 1 shows the standard clinical definitions used for each group. These reference standard definitions were reinforced at an orientation program attended by study investigators before the start of patient enrollment. These diagnostic criteria were uniformly applied throughout patient enrollment without knowledge of the SPECT imaging results. Appendix 2 shows additional eligibility criteria applied to all individuals in the study.

Diagnostic testing.

Radiopharmaceutical preparation.

High specific activity DOPASCAN was prepared by Nordion International, Ltd., Vancouver, BC, Canada, and supplied to the participating sites by Guilford Pharmaceutical, Inc., Baltimore, MD. In previous studies radiochemical purity was 98 + 1% as measured by high-performance liquid chromatography (HPLC). Specific activity was > 5000 Ci/mmol.16

Data acquisition.

Eligible patients and HC were injected with 5 mCi dose of DOPASCAN. All participants received Lugol’s solution before [123I]β-CIT injection to minimize radioactive uptake by the thyroid.

Projection data were acquired 24 + 2 hours following injection at each participating site on the following multidetector SPECT systems; Picker Prism 3000XP (Marconi Medical Systems, Cleveland, OH) (Yale University, New Haven, CT), Digital Scintigraphics Ceraspect (Waltham, MA) (Brigham and Womens Hospital), ADAC Vertex (Milpitas, CA) (North Shore University Hospitals), Trionix Triad (Twinsburg, OH) (Johns Hopkins School of Medicine, Baltimore, MD), and Summit/Hitachi VisionT-22 (Wilmington, DE) (Mount Sinai School of Medicine). One acquisition was obtained for 30 minutes and data was compared at 15 minutes and 30 minutes. Cameras were fitted with a low-energy, high-resolution fanbeam collimator or equivalent parallel hole system. The energy settings had a 20% window centered at 159 keV. The raw data were checked for patient movement before image reconstruction. Attenuation correction ellipses were fit using a Chang zero order (homogeneous) correction applied to the reconstructed data.18 Data were reconstructed using a standardized filtered back-projection technique and reoriented such that the transverse plane was parallel to the canthomeatal line. Four fiducial markers filled with 8 to 10 μCi of [99mTc]NaTcO4 were attached to both sides of the study participant’s head at the level of the canthomeatal line before imaging to facilitate post hoc computer reorientation of transaxial images. On the reoriented image file the striatal slice with the most intense uptake was determined by thresholding (index slice). The two slices above this slice, the index slice, and one slice below were summed (total z dimension = 1.3 cm). Using strict criteria the technologist drew regions of interest (ROI) and calculated the outcome measures specified. The standard ROI template for the striatum contains right and left caudate and right and left putamen. The standard ROI for the nonspecific activity contains the posterior portions of both occipital lobes.16

Outcome variables.

Image analysis.

Both masked visual interpretation and ROI analysis were performed at each site and at a core analysis center.

Visual analysis.

A teaching file of approximately 20 sample labeled SPECT images acquired during previous studies,16-17,19⇓⇓ including healthy controls ranging in age from 45 to 80, patients with PD (Stages I, II, III), ET, and PSP, were provided to each site to assist with the visual interpretation of the study scans and were used to train three nuclear medicine experts who reanalyzed all scans at the central imaging analysis site. The readers graded the DOPASCAN images as “normal” or “abnormal” dopamine transporter pathology, looking at the whole image, striata (left and right), as well as the individual caudate and putamen (left and right).

Quantitative analysis.

The outcome measure is the specific: nondisplaceable striatal uptake ratio for DOPASCAN. Specific activity was determined by subtracting occipital densities (nondisplaceable uptake) from total caudate or putamen count densities.

Safety evaluations.

All study participants were evaluated before and after DOPASCAN injection to assess the safety of the radiotracer. In particular, the cardiovascular system was tested with Holter monitoring and 12 lead ECG and neuropsychiatric symptoms were evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Profile of Moods (POMS).

Statistical analysis.

Baseline characteristics of the diagnostic groups were compared using analysis of variance, t-tests, and chi-square tests as appropriate.

Mean putamen and caudate DOPASCAN uptake values were calculated. The four groups were compared using analysis of variance, with and without adjusting for age. p Values were not adjusted for multiple comparisons.

Receiver operating characteristic (ROC) curves were calculated to compare all SPECT scan diagnoses (test outcome) to the reference standard clinical diagnoses (disease state) using both the qualitative visual analysis data and the quantitative ROI data. (An ROC curve is a plot of the true-positive rate [sensitivity] of a test versus the false-positive rate [1 − specificity].) The point at the upper left corner of the graph has a true-positive rate of 1 and a false positive rate of 0, so the closer the ROC curve is to this point, the more accurate the test. Two independent sources of data were analyzed: the individual site readings (“site data”) and the central blinded review readings (“central data”). Here we report the central data. Comparison of the central and site data will be detailed in a separate report.

Visual analysis of the SPECT images at a central site by three readers, who were unaware of the clinical diagnosis, was used to calculate ROC curves for the qualitative visual imaging data. For each individual and each reader an 11-point scale was developed to reflect the reader’s confidence in the diagnosis (Parkinson’s syndrome [PS] versus non-Parkinson’s syndrome [non-PS]). The median of the confidence values from the three readers was used as the final confidence scale value for each individual. ROC curves were generated for each of the three readers in addition to a median reading among the three readers.

The ratio of specific to nondisplaceable caudate and putamen DOPASCAN uptake was used to calculate ROC curves comparing the following diagnostic groups (Parkinson’s syndrome [PS] versus non-Parkinson’s syndrome [non-PS], PD versus PSP, PD versus ET, and PD versus HC). The best striatal region for each comparison was selected empirically based on cut-off points generated from the point of the ROC curve that gave the shortest distance to the upper left corner. For PD and PSP the brain regions corresponding to the side of the body with initial symptoms were defined as ipsilateral and those opposite to the side of initial symptom as contralateral. The clinical presentation of 39 of 43 PD patients and seven of 17 PSP patients was asymmetric. For those PD and PSP patients with symmetric presentation and for ET and HC the right side was defined as ipsilateral and the left side as contralateral. Analysis of the central data was performed prior to and subsequent to application of correction factors derived from each site’s imaging of a transportable uniform 57cobalt striatal phantom to account for differences between SPECT cameras. We report the uncorrected ROI data.

Binormal ROC curves were fitted using the programs of Metz, and empirical curves were plotted from PROC LOGISTIC in SAS. Sensitivity, specificity, and likelihood ratios were calculated for the quantitative data from the empirical curves. The likelihood ratios of a positive and negative test are defined respectively as the sensitivity/1 − specificity and 1 − sensitivity/specificity. They provide the Bayes factor for determining the posterior odds of disease or no disease from the prior odds and a positive or negative test result.

Safety data were examined by tabulation of adverse events either first reported or worsening subsequent to DOPASCAN administration. Trends in routine laboratory surveillance tests prior to and subsequent to DOPASCAN injection were also examined.

Results.

Baseline characteristic of diagnostic groups.

The demographic characteristics of the study population are shown in table 1 . Age distributions of individuals enrolled in the four groups were similar. The PSP patients were slightly older than other groups, but the four mean ages were not significantly different by analysis of variance. Gender also did not differ significantly among the diagnostic groups. UPDRS scores for the PD and PSP patients were obtained after twelve hours off drug and reflect the more severe neurologic impairment in the PSP than the PD patients. Most of the PD and PSP patients were treated with anti-Parkinson’s medications including levodopa-carbidopa, dopamine agonists and amantadine and most ET patients were treated with propranolol or primidone.

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Table 1.

Subject characteristics

Visual analysis of SPECT and DOPASCAN.

Figure 1 shows examples of images of each of the four diagnostic groups demonstrating the reduction in DOPASCAN striatal activity in the PD and PSP patients. Images from 89 of the 96 individuals were declared evaluable by at least two of the three readers. Those not included were considered not technically adequate most often due to movement. Table 2 summarizes the operating characteristics of the consensus reading compared to the clinical diagnosis for individuals with and without Parkinson’s syndrome. The sensitivity was 0.98 and specificity was 0.83 comparing parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals. Five of the six individuals incorrectly classified as PD/PSP were ET patients. Figure 2 contains the binormal ROC curves for each reader and for the consensus (median) reading among the three readers. One reader differs noticeably from the consensus. Visual analysis did not enable readers to distinguish PD from PSP (data not shown).

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Figure 1. SPECT DOPASCAN images from each diagnostic group. (A) Healthy control, symmetric striatal activity; (B) PD, asymmetric reduction of DOPASCAN activity more marked in the putamen than caudate compared to the healthy control; (C) essential tremor, no reduction in DOPASCAN activity compared to healthy control; (D) progressive supranuclear palsy, reduction in DOPASCAN activity compared to the healthy control, but the reduction of DOPASCAN activity is more symmetric and less region specific than in the PD patient. Levels of SPECT activity are color-encoded from low (black) to high (yellow/white).

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Table 2.

DOPASCAN central visual analysis

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Figure 2. Receiver operator characteristic (ROC) curves of diagnostic accuracy based on visual analysis of SPECT images. Expert readers, masked from any clinical information, rated images as Parkinson’s syndrome or non-Parkinson’s syndrome, and an 11-point scale was used to describe the readers’ confidence in their diagnoses. For each cutpoint on the 11-point scale, the sensitivity (true positive fraction) is defined as the proportion who exceed the cutpoint among all subjects whose clinical diagnosis is Parkinson’s syndrome. For each cutpoint on the scale, 1 − the specificity (false positive fraction) is defined as the proportion who exceed the cutpoint among all subjects whose clinical diagnosis is non-Parkinson’s syndrome. ROC curves for the median reading and for each of the individual readers are shown.

Quantitative analysis of SPECT and DOPASCAN.

Images from 92 of the 96 individuals could be quantitatively analyzed, those not included were considered not technically adequate. The data presented are not corrected for variability between sites due to differences in the SPECT cameras or imaging software. Results using a transportable imaging phantom to correct for between site variability showed similar results (data not shown).

Table 3 shows that the putamen and caudate DOPASCAN uptake for each region in the PD or PSP groups was significantly reduced compared to the ET or HC groups. Comparison of parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals demonstrated a reduction of 76% in mean putamen and 48% in mean caudate DOPASCAN uptake. Whereas the PSP and PD groups showed a similar uptake in the putamen, there was a significant reduction in the specific:nondisplaceable DOPASCAN ipsilateral caudate uptake in the PSP group compared to the PD group. The reduction in ipsilateral and contralateral caudate uptake (compared to the ET + HC group) was 63% and 65% for the PSP group the and 42% and 50% for the PD group, respectively. There was no significant difference in DOPASCAN uptake between the ET and HC groups in any region, but there is a relative reduction in putamenal DOPASCAN uptake in the ET patients reflecting the lower putamen activity in those ET patients misdiagnosed as parkinsonian in the visual analysis above.

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Table 3.

DOPASCAN uptake

Figure 3 shows the empirical ROC curve comparing SPECT scan diagnoses based on DOPASCAN uptake to the clinical diagnoses; parkinsonian (PD + PSP) versus non-parkinsonian (ET + HC). Table 4 shows the sensitivity, specificity, likelihood ratios and area under the curve for this comparison and for PD versus HC, PD versus ET, and PD versus PSP. The striatal region chosen empirically for each comparison is indicated. The results demonstrate that quantitative imaging analysis of striatal DOPASCAN uptake is excellent at distinguishing between PD + PSP and ET + HC, PD and ET, and PD and HC, but is less effective at distinguishing between PD and PSP.

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Figure 3. Receiver operator characteristic (ROC) curve of diagnostic accuracy of DOPASCAN uptake comparing subjects clinically diagnosed as Parkinson’s syndrome versus those diagnosed as non-Parkinson’s syndrome. The contralateral putamen was empirically chosen to provide the best comparison. Because low putamen values distinguish Parkinson’s syndrome from non-Parkinson’s syndrome, for each cutpoint on the putamen measurement, the sensitivity (true positive fraction) is defined as the proportion who are below the cutpoint among all subjects whose clinical diagnosis is Parkinson’s syndrome. For each cutpoint on the putamen measurement, 1 − the specificity (false positive fraction) is defined as the proportion who fall below the cutpoint among all subjects whose clinical diagnosis is non-Parkinson’s syndrome. The 95% CI is shown in the dashed line.

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Table 4.

Diagnostic accuracy of quantitative DOPASCAN imaging analysis

Analysis of safety data.

There were no clinically significant trends in adverse events or laboratory surveillance values observed following DOPASCAN injection. Specifically cardiovascular monitoring including electrocardiogram and 24 hour Holter monitoring were unchanged prior to and subsequent to injection.

Discussion.

DOPASCAN and SPECT imaging reliably and effectively distinguish between individuals with Parkinson’s syndrome (PD + PSP) and without Parkinson’s syndrome (HC + ET). These data further demonstrate that DOPASCAN imaging discriminates between patients with PD and ET and between patients with PD and HC, but is less effective in distinguishing between patients with PD and PSP. Our results are consistent with single center studies demonstrating that dopamine transporter density is reduced in PD and PSP compared with HC and ET.10,13,15-16⇓⇓⇓ This study is the first multicenter imaging assessment of dopamine transporter imaging and has been designed to investigate whether DOPASCAN and SPECT imaging may be a useful diagnostic tool for PD and related disorders.

This study has been both a multicenter and multidisciplinary collaborative effort involving movement disorder specialists and nuclear medicine physicians. The goal was to test the diagnostic accuracy of dopamine transporter imaging in a setting relevant to clinical neurology and nuclear medicine practice. Diagnostic uncertainty in individuals with symptoms of possible PD predominantly occurs in comparison to three other diagnostic groups; elderly gait disorder often associated with motor slowing, essential tremor, and other extrapyramidal syndromes (i.e., PSP, MSA). The primary comparison in this study between Parkinson’s syndrome (PD + PSP) and non-Parkinson’s syndrome (ET + HC) was chosen to reflect the clinical diagnostic dilemma most commonly faced by primary care practitioners evaluating individuals with initial symptoms of possible PD. The PSP group was included to assess whether DOPASCAN could distinguish between the more subtle categories within Parkinson’s syndrome, a diagnostic question often faced by neurologists and in particular the movement disorders specialist.

Images acquired at each site were analyzed both visually and quantitatively both at each center and at a single central analysis laboratory. It is anticipated that assessment of DOPASCAN uptake in the nuclear medicine clinic will rely primarily on visual image analysis. In this study the operating characteristics of the visual imaging outcome has been defined by three expert nuclear medicine readers at a central site masked to diagnosis and provided with no clinical information. These readers received training for approximately three hours prior to reading the images. Therefore, relying solely on visual read of the DOPASCAN images and without extensive training beyond their nuclear medicine expertise, these readers were able to discriminate between individuals with Parkinson’s syndrome (PD + PSP) and without Parkinson’s syndrome (ET + HC) with a high degree of accuracy.

The visual imaging analysis outcomes have been confirmed by quantitative imaging outcome measures. DOPASCAN striatal uptake was markedly reduced in putamen and caudate in individuals with Parkinson’s syndrome (PD + PSP) compared to those without Parkinson’s syndrome (ET + HC). These reductions were greater in the putamen than caudate consistent with previous imaging and pathology studies.5,16,20⇓⇓ In the PD group the reduction in DOPASCAN striatal uptake was also asymmetric with more severe transporter loss on the side contralateral to symptoms. Therefore, both current and prior imaging data and pathology data suggest that the contralateral putamen would be the best region at accurately discriminating between the PD + PSP and ET + HC groups. As predicted, empirical ROC curves demonstrated that contralateral putamen DOPASCAN uptake accurately distinguished between Parkinson’s syndrome and non-Parkinson’s syndrome individuals with a sensitivity of 0.96 and a specificity of 0.94.

Further analyses demonstrated that DOPASCAN uptake accurately discriminated between PD and HC and between PD and ET and did not differ between the ET and HC groups. Five patients with a clinical diagnosis of ET were misclassified in the visual analysis as having PD. Quantitative analysis of dopamine transporter density in these five individuals also showed reduced striatal DOPASCAN uptake. One explanation for these apparently misclassified individuals is that they may have been incorrectly clinically diagnosed as ET instead of PD. Alternatively, the reduction in DOPASCAN uptake may reflect developing parkinsonism in these patients. Finally the reduction in DOPASCAN uptake may reflect a true loss of dopamine transporter in some patients with ET. These data provide support for the concept that ET may be an overlap syndrome with PD in a subset of cases.21-23⇓⇓ DOPASCAN imaging may help to resolve this question with additional studies with increased patient numbers and longitudinal follow-up.

Both PD and PSP patients showed a dramatic reduction in striatal DOPASCAN uptake. These data are consistent with previous imaging and pathologic studies which have demonstrated a reduction in presynaptic dopaminergic striatal markers in PD and PSP.15,24⇓ Visual analysis of the DOPASCAN image did not distinguish between PD and PSP, but quantitative analysis showed a significant difference in the regional striatal reduction of dopamine transporter density with a greater reduction in caudate DOPASCAN uptake in PSP than PD. This relatively increased loss of dopamine transporter density in caudate reflects the more widespread striatal pathology of PSP. These data demonstrate however, that the difference between PD and PSP in regional striatal uptake is not of sufficient magnitude to use DOPASCAN as a diagnostic test to discriminate between these two disorders. Studies with F-DOPA and PET also indicate that presynaptic dopaminergic markers cannot adequately discriminate between PD, PSP, and MSA.25 Further studies combining dopamine transporter imaging with either dopamine receptor imaging or metabolic imaging may enable more reliable discrimination among the parkinsonian syndromes.26,27⇓

Early and rigorous assessment of evolving diagnostic technologies is essential to determine their appropriate role in clinical practice. DOPASCAN and SPECT effectively discriminates between Parkinson’s syndrome and non-Parkinson’s syndrome individuals, but is it useful and how will it be used in a clinical setting? In this study, visual analysis of DOPASCAN images was sufficient to discriminate between Parkinson’s syndrome and non-Parkinson’s syndrome subjects. Study images were obtained on several SPECT instruments including three triple-headed and two double-headed cameras. Whereas these data suggest that DOPASCAN images can be obtained using available technology, further studies should be completed on additional double headed SPECT cameras, which are the most commonly used in clinical practice. In clinical practice most nuclear medicine facilities would primarily rely on visual analysis. This study has validated the likely clinical visual analysis by quantitative analysis of image results by a central imaging laboratory. Therefore, it is likely that imaging technology and imaging analysis generally available at nuclear medicine sites could take advantage of this diagnostic tool.

We compared individuals with known diagnosis and moderate disease to healthy controls. In clinical practice this diagnostic tool may be most useful in assessing patients with parkinsonian signs and symptoms, but with uncertain diagnosis. In hemi-PD patients the reduction in dopamine transporter density measured with DOPASCAN at the onset of symptoms is approximately 50% in the striatum contralateral to symptoms and 30% in the striatum ipsilateral to symptoms.17 These data suggest that even patients with early, mild symptoms who have Parkinsonism will demonstrate a significant reduction in DOPASCAN uptake. However, additional studies to evaluate DOPASCAN uptake in a cohort of patients with uncertain diagnosis of Parkinson’s syndrome are essential to further demonstrate the diagnostic validity of this test in this population.

Appendix 1

Reference standard diagnoses Idiopathic PD

  1. At least two of the following: resting tremor, rigidity, bradykinesia, postural reflex impairment, and freezing phenomenon

  2. Hoehn and Yahr stage of 1.0 to 3.028

  3. Has a known positive response to antiparkinsonian medications

  4. No other known or suspected cause of parkinsonism

Progressive supranuclear palsy

  1. At least two of the following: axial rigidity, bradykinesia, postural reflex impairment, speech impairment

  2. Ophthalmoparesis including restriction of downgaze

  3. No significant response to antiparkinsonian medication

  4. Ability to ambulate without assistance

  5. No other known or suspected cause of parkinsonism

Essential tremor

  1. Tremor for > 2 years

  2. Has a UPDRS action tremor score of ≥329

  3. No other reason for the tremor

Healthy control subjects

  1. No signs or symptoms of PD, PSP, or ET

  2. No first degree relatives with a history of PD, PSP, or ET

Appendix 2

Study eligibility criteria Inclusion criteria

All eligible individuals must have the following criteria:

  1. Fulfilled the clinical criteria for one of the diagnostic groups

  2. Aged ≥45 years

  3. Sex: male or female. Women must be either surgically sterile, a least 2 years postmenopausal, or have had a negative serum hCG pregnancy test at screening and a negative urine pregnancy test immediately prior to injection

  4. A negative urine screen for drugs of abuse within 2 weeks prior to study drug injection

  5. Willingness and ability to comply with study requirements

Exclusion criteria

  1. Clinically significant neurologic disease other than PD, PSP, or ET

  2. Clinically significant current illness, either untreated or poorly responsive to treatment, with the exception of PD, PSP, or ET

  3. Mini-Mental State Examination score of ≤22

  4. A DSM-IV Axis 1 diagnosis except major depression, nicotine dependence, or caffeine dependence

  5. Any of the following during the past 1 month: benzotropine, trihexyphenidyl, and amphetamines including methylphenidate, sertraline, fluvoxamine, and paroxetine; during the past 3 months: electroconvulsive therapy; during the past 6 months: fluoxetine, methyldopa, or reserpine

  6. Allergy to iodine or contrast dye

  7. Participation in another investigational study within 1 month prior to the DOPASCAN injection

Appendix 3

Authors of the Parkinson Study Group: Steering Committee: Kenneth Marek, MD, principal investigator, and John Seibyl, MD, co-principal investigator, Yale University School of Medicine, New Haven, CT; Robert Holloway, MD, Karl Kieburtz, MD and David Oakes, PhD, University of Rochester, Rochester, NY; Anthony Lang, MD, Toronto Western Hospital, Toronto, Ontario.

Participating Investigators, Coordinators, and Nuclear Medicine Technologists: Jeremiah Yim, MD, Holley Dey, MD, Janet Cellar, MSN, Barbara Fussell, RN, Susan Broshjeit, Michele Early, Eileen O. Smith, MBA, Yale University School of Medicine, New Haven, CT; Lewis Sudarsky, MD, Keith A.Johnson, MD, Claire Corwin, PAC,BS, Diane Johnson, Sharon Lajoie, Brigham and Women’s Hospital, Boston, MA; Stephen G. Reich, MD, JamesJ. Frost, MD, PhD, Paula Goldberg, RN, AAS, John E. Flesher, Johns Hopkins University School of Medicine, Baltimore, MD; Andrew Feigin, MD, Jennifer Mazurkiewicz, North Shore University Hospital, Manhasset, NY; Joseph Castronuovo, MD, Feder Joseph, CNMT, North Shore University Hospital, Glen Cove, NY; Allessandro DiRocco, MD, C. Warren Olanow, MD, Josef Machac, MD, Debbie Coteí, RN, Peter Webner, Mount Sinai Medical Center, New York, NY.

Biostatistics and Clinical Trials Coordination Centers Staff: Alice Rudolph, PhD, Dennie Day, RN, MSPN, University of Rochester, Rochester, NY; Cynthia Casaceli, MBA, Andrea Freimuth, BA, Constance Orme, BA, Karen Hodgeman, Shirley Eberly, PhD, University of Rochester, Rochester, NY.

Guilford Pharmaceuticals, Inc: Earl Henry, MD, Gillian Morgan, PhD, Deborah Westwater,BSN, John B. Haley, III, Eugenia Henry, PhD, Baltimore, MD.

Footnotes

  • ↵*See Appendix 3 on page 1546 for a complete list of investigators.

    Supported by Guilford Pharmaceutical, Inc., and a National Parkinson’s Foundation Center of Excellence grant at Yale University.

  • Received May 4, 1999.
  • Accepted July 21, 2000.

References

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