Source: JAMA. 2002;287:1653-1661 Date: 04/03/2002 The following article appeared in the Journal of the American Medical Association 3 April 2002. The report was modified by Dr Abe Lieberman for educational purposes to make it more readable for lay people with PD. SPECT Imaging to Assess the Effects of Mirapex compared to Levodopa on Parkinson Disease Progression Parkinson Study Group Abstract Dopamine Transporter Imaging to Assess the Effects of Pramipexole versus Levodopa on the Progression of Parkins Disease (original title) Context Pramipexole (mirapex) and levodopa are effective medications to treat motor symptoms of early Parkinson disease (PD). In vitro and animal studies suggest that pramipexole may protect and that levodopa may either protect or damage dopamine neurons. Neuroimaging offers the potential of an objective biomarker of dopamine neuron degeneration in PD patients. Objective To compare rates of dopamine neuron degeneration after initial treatment with pramipexole or levodopa in early PD by means of dopamine transporter imaging using single-photon emission computed tomography (SPECT) with 2-carboxymethoxy-3(4-iodophenyl)tropane (-CIT) labeled with iodine 123. Design Substudy of a parallel-group, double-blind randomized clinical trial. Setting and Patients 82 patients with early PD who were recruited at 17 clinical sites in the United States and Canada and required dopaminergic therapy to treat emerging disability, enrolled between November 1996 and August 1997. Interventions Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3 times per day with pramipexole placebo (n = 40). For patients with residual disability, the dosage was escalated during the first 10 weeks, and subsequently, open-label levodopa could be added. After 24 months of follow-up, the dosage of study drug could be further modified. Main Outcome Measures The primary outcome variable was the percentage change from baseline in striatal [123I]-CIT uptake after 46 months. The percentage changes and absolute changes in striatal, putamen, and caudate [123I]-CIT uptake after 22 and 34 months were also assessed. Clinical severity of PD was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours off anti-PD medications. Results Sequential SPECT imaging showed a decline in mean (SD) [123I]-CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months 15.3% (12.8%) at 34 months and 20.7% (14.4%) at 46 monthsapproximately 5.2% per year. (Comment: it's estimated the 'normal' age related loss of of striatal uptake is 0.6% per year. This is a measure of the loss of dopamine nerve cells in the substantia nigra. In PD the 5.2% loss per year in this study is 8.6 times higher than the 'normal' age related loss. In other words, PD represents about an 8 fold increase in the loss of dopamine neurons per year). The mean percentage loss in striatal [123I]-CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% for pramipexole versus vs 13.5% for levodopa at 22 months. This change was NOT significant 10.9% for pramipexole versus vs 19.6% for levodopa at 34 months. This change was significant. 16.0% for pramipexole versus 25.5% for levodopa at 46 months. This change was significant. The percentage loss from baseline in striatal [123I]-CIT uptake was correlated with the change from baseline in UPDRS at the 46-month evaluation. Conclusions Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [123I]-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies. JAMA. 2002;287:1653-1661 Introduction: Parkinson disease (PD) is a slow but relentlessly progressive neurodegenerative disorder characterized clinically by bradykinesia, tremor, rigidity, and gait dysfunction. The clinical decline reflects ongoing nigral dopamine degeneration.Dopamine replacement therapy with levodopa or agonists that stimulate the dopamine receptor is effective in ameliorating many signs and symptoms of early PD. However, progressive neuronal degeneration ultimately results in severe motor, mental, and functional disability. Increasing evidence from laboratory and animal studies suggests that in addition to their symptomatic effects, levodopa and dopamine receptor agonists may either accelerate or slow the dopaminergic degeneration of PD. Recent data regarding the effects of levodopa have been controversial with in vitro data supporting both a potential toxic and protective effect on dopaminergic neurons Studies have demonstrated that dopamine receptor agonists protect cultured dopaminergic neurons from potential levodopa toxicity and may exert direct antioxidant and receptor-mediated ant-iapoptotic effects (slow down cell suicide). During the past decade, in vivo imaging of the nigrostriatal dopaminergic system has been developed as a research tool to monitor progressive dopaminergic neuron loss in PD. Several reports have demonstrated that at the time of emergence of PD symptoms there is a loss of approximately 40% to 60% of dopamine markers in the striatum. In longitudinal studies of PD progression, imaging ligands targeting both dopamine metabolism fluorine 18 fluorodopa ([18F]DOPA) and dopamine transporter density iodine 123 (2-carboxymethoxy-3[4-iodophenyl]tropane [123I]-CIT) and fluorine 18 (2-carboxymethoxy-3tropane [18F]CFT) using both positron emission tomography and single-photon emission computed tomography (SPECT) have demonstrated an annualized rate of reduction in striatal [18F]DOPA, [18F]CFT, or [123I]-CIT uptake of approximately 6% to 13% in patients with PD compared with 0% to 2.5% change in healthy controls. The above imaging studies are consistent with pathological studies showing that the rate of nigral degeneration in patients with PD was 8- to 10-fold that of healthy, age-matched controls. We have used in vivo imaging of the dopamine transporter with [123I]-CIT and SPECT to assess the progression of dopaminergic degeneration in a subset of patients with early PD participating in a clinical trial that compared the option of initial treatment with pramipexole with the option of initial treatment with levodopa. The clinical study (called CALM-PD) was a multicenter, parallel-group, double-blind, randomized clinical trial comparing the option of initial treatment with pramipexole or levodopa with regard to the development of dopamine motor complications and changes associated with function and quality of life. After 2 years of prospective follow-up, initial treatment with pramipexole delayed the onset of dopaminergic motor complications compared with levodopa therapy but initial levodopa therapy was more effective than pramipexole in ameliorating signs and symptoms of PD. In this report, we present the 4-year follow-up of the subset of study patients who have undergone sequential [123I]-CIT SPECT imaging to compare the rate of loss of the dopamine transporter, a marker for dopamine nerve terminal loss, between the groups treated initially with pramipexole or levodopa. METHODS: The methods and outcomes of the imaging substudy, called CALM-PD-CIT, are described herein. The CALM-PD clinical outcomes at 4 years are reported separately. A total of 82 of the 301 patients in the CALM-PD trial, enrolled between November 1996 and August 1997, participated in the imaging substudy. Research participants in the imaging substudy were recruited at 17 clinical sites (14 in the United States and 3 in Canada) and traveled to the imaging center in New Haven, Conn, for up to 4 imaging assessments. CALM-PD: Eligible patients were randomized with equal allocation to each of the 2 treatment groups (pramipexole group or carbidopa/levodopa group) using a computer-generated randomization plan. All patients enrolled at sites that chose to participate in the imaging substudy were offered the option, but were not required to participate in the -CIT SPECT substudy. Baseline imaging was completed prior to randomization. Patients took study drugs orally 3 times daily, approximately 6 (SD, 2) hours apart, throughout the study. Initially patients entered a 10-week dosage escalation period to reach one of the predetermined dosage levels: 1.5 mg of pramipexole or 75 or 300 mg of carbidopa/levodopa (level 1 dosage); 3.0 mg of pramipexole or 112.5 or 450 mg of carbidopa/levodopa (level 2 dosage); or 4.5 mg of pramipexole or 150 or 600 mg of carbidopa/levodopa (level 3 dosage). Study drug was then maintained at that level until 24 months after baseline, and subsequently the dosage level could be modified during an additional 22- to 36-month evaluation period. Patients with emerging disability posing a threat to ambulation, activities of independent living, or gainful employment were prescribed open-label carbidopa/levodopa as needed. CALM-PD-CIT[123I]-CIT and SPECT Substudy All patients in CALM-PD-CIT were evaluated sequentially with imaging studies at baseline and 22, 34, and 46 months after baseline Four contiguous brain slices with the highest uptakes in striatum were identified for anaylysis. All study participants were evaluated after 12 hours without study drug and anti-PD medications, the "defined off" state, with Unified Parkinson Disease Rating Scale (UPDRS) and Hoehn and Yahr scores determined at the imaging center before each imaging study. The clinical investigator was blinded to treatment assignment. The primary outcome variable in this study was the percentage change from baseline to month 46 in the specific striatal [123I]-CIT uptake ratio, a tissue equilibrium distribution volume that is linearly related to the density of dopamine transporter binding sites in brain. RESULTS During the 46-month evaluation period, 9 patients (21.4%) initially treated with pramipexole and 8 patients (20%) initially treated with levodopa withdrew For patients who completed 46 months of follow-up, the mean baseline striatal -CIT uptake was 3.0 in the pramipexole group (n = 33) vs 2.9 in the levodopa group (n = 32). One patient in the pramipexole group withdrew because of worsening PD with hallucinations; 1 patient in the pramipexole group and 3 patients in the levodopa group withdrew because of worsening medical illness not related to PD. The mean percentage loss from baseline of striatal -CIT uptake was 10.3% at 22 months, 15.3% at 34 months, and 20.7% t 46 months, declining approximately 5.2% per year during the 46-month evaluation period. The mean percentage loss from baseline of [123I]-CIT uptake at 46 months was greater in the putamen (22.5%) than in the caudate (19.6%). Although there was a greater baseline reduction in the side contralateral to initial symptoms the progressive loss of [123I]-CIT uptake in each hemistriatum did not differ. Analysis of the treatment groups demonstrated that the rate of decline in striatal [123I]-CIT uptake from baseline was significantly reduced in the group treated initially with pramipexole compared with the group treated initially with levodopa (see abstact above).. Correlation of [123I]-CIT Uptake and UPDRS Score The mean total and motor UPDRS scores obtained in the "defined off" state were reduced in the levodopa group at 22 months compared with baseline and the pramipexole group, but were not significantly different from baseline or the pramipexole group by 34 or 46 months. There was a correlation of the percentage loss of striatal [123I]-CIT uptake from baseline with the change in total UPDRS score from baseline in all patients. The percentage loss of putamen and caudate [123I]-CIT uptake from baseline showed increasing correlation with the change in UPDRS score from baseline as the duration of assessment increased). COMMENT In vivo dopamine transporter imaging with [123I]-CIT SPECT demonstrated reduced loss of striatal [123I]-CIT uptake in patients with PD treated initially with pramipexole compared with those treated initially with levodopa during a 46-month evaluation period. As [123I]-CIT SPECT is a quantitative biomarker for striatal dopamine neuron terminals, these data indicate that treatment with pramipexole, levodopa, or both may modify the dopaminergic neuronal degeneration of PD. The identification of disease-modifying therapies for PD is a major unmet need. Studies that evaluate neuroprotective effects of medications have been limited by the lack of a clear end point defining neuroprotection and confounded by potential simultaneous symptomatic and neuroprotective benefit In vivo imaging offers the potential of an objective method to monitor neuronal degeneration unaffected by a short-term symptomatic drug effect. Several recent studies have used neuroimaging to investigate the possible neuroprotective effects of dopamine agonists. A preliminary study that assessed the effects of ropinirole hydrochloride did not demonstrate a change in neuronal loss as measured by [18F]DOPA positron emission tomography, but showed a trend toward reduction in the change of [18F]DOPA uptake in the patients treated with the dopamine agonist. . We now present data demonstrating a significant and persistent reduction in the rate of loss of [123I]-CIT uptake in patients with PD initially treated with pramipexole compared with levodopa during the 46-month evaluation period. Evidence from animal studies, healthy humans, and patients with PD has demonstrated that [123I]-CIT uptake is a biomarker for striatal dopamine transporter density and also dopamine neuronal terminal integrity. Progressive nigrostriatal dopamine neuron loss is the predominant pathologic finding of PD. Therefore, the relative reduction in the rate of loss of [123I]-CIT uptake in those patients treated with pramipexole compared with levodopa most likely reflects a reduction (by pramipexole) in the progressive loss of striatal dopamine neuronal function. Approximately 20% of the study cohort withdrew from CALM-PD-CIT before the month 46 visit. However, in both treatment groups, the baseline transporter density measurements in patients who withdrew from the trial were similar to those in patients who completed the trial. The frequency and reasons for withdrawal were also similar in the 2 groups and the treatment effects were reasonably consistent over time. For all of these reasons, we do not believe that participant withdrawal had a major impact on the overall results. Since this study compared 2 active medications without a placebo group, these data cannot directly distinguish whether the difference in the rate of loss of [123I]-CIT uptake in the treatment groups results from a decrease due to pramipexole, an increase due to levodopa, or both. However, indirect evidence from preclinical studies and prior imaging studies suggests that a decrease in the percentage loss of [123I]-CIT uptake due to exposure to pramipexole rather than an increase due to exposure to levodopa is more likely. In prior imaging studies, the annual percentage loss of [123I]-CIT striatal uptake of untreated patients with PD was 6.8%, similar to the levodopa group in this study. These imaging data suggest that treatment with pramipexole may have decreased the rate of loss of [123I]-CIT uptake despite treatment with levodopa. However, the duration and dose of exposure to supplemental levodopa and the effect of pretreatment with a dopamine agonist on a possible levodopa disease-modifying effect have not been fully evaluated. Studies are under way to directly assess the effect of treatment with levodopa compared with placebo on the rate of loss of [123I]-CIT uptake in patients with early PD that will further elucidate the relative effects of pramipexole and levodopa on [123I]-CIT uptake.5 A key issue is whether the effects of pramipexole and levodopa on the rate of loss of [123I]-CIT uptake are associated with a persistent change in clinical function in patients with PD. Several clinical end points for progressive functional decline in PD have been used, including UPDRS in the "defined off" state or after drug washout up to 2 weeks, time to need for dopaminergic therapy, or time to the development of motor fluctuations. These end points reflect the complex clinical progression of PD symptoms and disability. The changes in imaging outcome measures such as [123I]-CIT provide a method to assess the striatal dopamine pathologic features of PD. In several cross-sectional studies of PD cohorts, the reduction in [123I]-CIT correlates with the increasing severity measured by the UPDRS.However, in prior longitudinal studies, there has been no clear correlation between change in either [123I]-CIT or [18F]DOPA uptake and the change in UPDRS score. Several explanations for this poor correlation have been suggested. First, the UPDRS score is likely confounded by the effects of anti-PD medications, despite patient evaluation in the "defined off" state because of long-duration effects of these treatments. Second, in early PD the temporal patterns for rate of loss of dopamine transporter and the change in UPDRS score may not be congruent. This is best illustrated by data demonstrating a loss of approximately 40% to 50% of striatal [123I]-CIT uptake at the time of diagnosis when clinical symptoms measured by the UPDRS may be minimal. These data suggest that in patients with early PD clinical and imaging outcomes provide complementary data and that long-term follow-up will be required to correlate changes in clinical and imaging outcomes. In this study, the loss of striatal [123I]-CIT uptake from baseline was significantly correlated with the change in UPDRS score from baseline at the 46-month evaluation, suggesting that the correlation between clinical and imaging outcomes will emerge with longer monitoring. This study demonstrates that [123I]-CIT SPECT imaging can detect treatment-related changes in the progressive rate of loss of striatal dopamine transporters in patients with early PD. During a 46-month evaluation period, these data show a decrease in the rate of loss of striatal [123I]-CIT uptake in patients initially treated with pramipexole compared with levodopa. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn