Parkinsons Disease Progression

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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The rate of clinical progression of PD is highly variable and unpredictable (77). In clinical studies, several clinical endpoints for progressive functional decline in PD have been used, including the Unified Parkinson's Disease Rating Scale (UPDRS) in the "defined off" state or after drug washout up to two weeks, time to need for dopaminergic therapy, or time to development of motor fluctuations (85-89). Clinical rating scales are extremely useful, but ratings may be investigator-dependent and are frequently confounded by changes in symptomatic treatment. Pathological studies investigating rate of progression have been limited and rely entirely on cross-sectional data (63,64). These studies have in general considered patients with severe illness of long duration. In vivo imaging studies provide the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopaminergic degeneration.

In several studies, neuroreceptor imaging of the nigrostriatal dopaminergic system has been used as a research tool to monitor progressive dopaminergic neuron loss in PD. In longitudinal studies of PD progression both 18F-DOPA and DAT imaging [P CIT(2P-carboxymethoxy-3P(4-iodophenyl)tropane) and CFT] using both

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FIGURE 1 Single photon emission computed tomography (SPECT) [123I]P-CIT images from a patient with PD two years after diagnosis and 46 months later. Note the asymmetric reduction in [123I]P-CIT uptake more marked in the putamen than in the caudate of the patient, and the progressive loss of activity. Levels of SPECT activity are color-encoded from low (black) to high (white).

PET and SPECT have demonstrated an annualized rate of reduction in striatal [18F]DOPA, [18F]CFT, or [123I]P-CIT uptake of about 6% to 13% in PD patients, compared with 0% to 2.5% change in healthy controls (90-94). Similar findings have been reported for VMAT2 imaging (K. Frey, personal communication, 2002) (Fig. 1).

Evidence from studies of hemi-PD subjects provides further insight into the rate of disease progression. In early hemi-PD, there is a reduction in 18F-DOPA and DAT uptake of about 50% in the affected putamen and of 25% to 30% in the unaffected putamen. Since most patients progress clinically from unilateral to bilateral in three to six years, it is 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 annum (11,66).

Imaging has also been used to monitor progression of PD in patients receiving fetal substantia nigral transplants for PD. Several studies have shown an increase in 18F-DOPA uptake six months to six years post-transplant (95,96). The change in 18F-DOPA uptake has been correlated with postmortem survival of grafted dopaminergic nigral cells (97).

The most important role of longitudinal imaging studies is to provide a tool to assess objectively potential neuroprotective and restorative therapies for PD. Several candidate drugs, including coenzyme Q10, a mitochondrial agent; monoamine oxidase-B inhibitors; neuroimmunophilin, a nerve growth factor; riluzole, a gluta-matergic drug; CEP 1347, an antiapoptotic agent; and dopamine agonists, have been or are in ongoing clinical studies of neuroprotection (85-87,89,98-100). Imaging studies assessing progression of disease have provided data to estimate sample sizes required to detect slowing of disease progression due to study drug treatment. The sample size required depends on the effect size of the disease modifying drug and the duration of exposure to the drug. The effect of the drug is generally expressed as the percent reduction in rate of loss of the imaging marker in the group treated with the study drug versus the control group. More specifically, imaging studies have sought a reduction of between 25% and 50% in the rate of loss of 18F-DOPA or [123I]P-CIT uptake (i.e., a reduction from 10%/yr to 5-7.5%/yr). The sample size needed to detect a 25% to 50% reduction in the rate of loss of F-DOPA or P-CIT uptake during a 24-month interval ranges from approximately 30 to 120 research subjects in each study arm (90,101).

Two similar studies compared the effect of initial treatment with a dopamine agonist [pramipexole (CALM-PD CIT) or ropinirole (REAL-PET)] or levodopa on the progression of PD, as measured by [123I]P-CIT or 18F-DOPA imaging. These two clinical imaging studies targeting dopamine function with different imaging ligands and technology both demonstrated slowing in the rate of loss of [123I]P-CIT or 18F-DOPA uptake, in early PD patients treated with dopamine agonists compared to levodopa. These studies evaluated two related, predominantly D2 dopamine receptor agonists, suggesting that the results may indicate a class effect. The relative reduction in the percent loss from baseline of [123I]P-CIT uptake in the pramipexole versus the levodopa group was 47% at 22 months, 44% at 34 months, and 37% at 46 months, after initiating treatment. The relative reduction of 18F-DOPA uptake in the ropinirole group versus the levodopa group was 35% at 24 months. These data suggest that treatment with the dopamine agonists, pramipexole and ropinirole with or without levodopa may either slow or accelerate the dopaminergic degeneration of PD. Furthermore, these studies demonstrated that in vivo imaging can be used effectively to assess potential disease modifying drugs in well controlled, blinded clinical studies (68,102)

In the CALM-PD CIT and REAL-PET studies, there was no correlation between the percent change from baseline in the imaging outcome and the change from baseline in UPDRS at 22 to 24 months. There are several explanations for the lack of correlation between [123I]P-CIT or 18F-DOPA uptake and UPDRS in longitudinal studies. First, the UPDRS is confounded by the effects of the patient's antiparkinson medications, both acutely after initiating therapy and with ongoing treatment. Even evaluation of the UPDRS in the "defined off" state or after prolonged washout does not eliminate the long duration symptomatic effects of these treatments (88,103). Second, in early PD, the temporal patterns for rate of loss of dopamine transporter or 18F-DOPA and the change in UPDRS may not be congruent. This is most evident in the preclinical period when the imaging outcomes are reduced by 40% to 60% prior to diagnosis. In the CALM-PD study, the loss of striatal [123I]P-CIT uptake from baseline was significantly correlated (r=-0.40, P = 0.001) with the change in UPDRS from baseline at the 46-month evaluation, suggesting that the correlation between clinical and imaging outcomes begins to emerge with longer monitoring (102). These data suggest that particularly in 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. Slowing the loss of imaging outcomes in PD is relevant only if these imaging changes ultimately result in meaningful, measurable, and persistent changes in clinical function in PD patients.

Concerns that levodopa may accelerate PD progression led to the design of the ELLDOPA (Early Versus Late Levodopa) study. The purpose of the study was to determine if levodopa alters the natural rate of progression of PD. The ELLDOPA study was a randomized, double-blind, placebo-controlled, parallel-group, multisite clinical trial involving subjects with early, untreated PD (69). Three hundred and sixty subjects were enrolled and randomized to four treatment arms: levodopa 150 mg/day, 300mg/day, 600mg/day, and a placebo arm. The active treatment groups were titrated during a course of nine weeks to their respective doses followed by a 40-week maintenance period. Subjects were titrated off active treatment and underwent a two-week washout period. A subset of 135 subjects had DAT imaging using P-CIT and SPECT at baseline and at 40 weeks, prior to the washout period. The primary outcome measure was the change in severity as measured by the total UPDRS scores from baseline to week 42 (two weeks following washout). The percent change in the striatal DAT uptake between baseline and week 40 was the primary imaging outcome.

The results of the ELLDOPA clinical study revealed an improvement in the UPDRS in the treated arms in a dose-response pattern. Comparing baseline and 42-week UPDRS, the scores worsened by 7.8 ± 9.0 points in the placebo group, 1.9 ± 6.0 points in the levodopa 150 mg/day group, 1.9 ± 6.9 points in the 300 mg/day group, and improved by 1.4 ± 7.7 points in the 600 mg/day group. The clinical outcome of the study was suggestive of a protective effect of levodopa at the 600-mg/day dose; however, a short washout period from levodopa could explain these results.

In the neuroimaging substudy, 21 of 142 (14.7%) subjects had P-CIT uptake in the range expected for healthy controls. These subjects without evidence of dopaminergic deficit (SWEDD's) had no decrease in uptake from baseline to week 40, and did not improve clinically with levodopa therapy making their diagnosis unlikely to be PD. Comparing the baseline and 40-week imaging, the percent decline in P-CIT uptake was more pronounced in the levodopa groups than the placebo group (-7.2%, -4%, -6%, and -1.4% for the 600-, 300-, 150-mg/day, and placebo groups, respectively). These imaging data are suggestive of an increase in the loss of uptake with increasing doses of levodopa, and thus contradicted the clinical findings. A potential pharmacologic effect of levodopa on the imaging outcome measure was entertained as a possible explanation for the decrease in uptake. The clinical outcomes showed that levodopa may have slowed the rate of progression, but in contrast, the imaging substudy suggested that levodopa caused a more rapid decline in the nigrostriatal nerve terminals.

These contradictory results from the clinical and neuroimaging studies, involving dopamine agonists and levodopa, led to the review of existing data regarding potential pharmacologic effects of dopaminergic medications on the imaging outcome measures. There are limited data available concerning the direct effects of medications on the DAT or dopamine turnover (32,104). Preclinical studies have shown inconsistent results (105). Human studies have been limited by small sample sizes, but have failed to show a direct drug effect on the DAT or dopamine turnover (106-109). Given the paucity of data, the INSPECT study was designed to directly address the question of whether dopaminergic medications have a phar-macologic effect on the DAT imaging outcome measure. In this study, subjects are imaged with P-CIT and SPECT at baseline and randomized to one of the three arms: no treatment, treatment with levodopa 600 mg/day, or treatment with pramipexole 3 mg/day. After 12 weeks of treatment (eight weeks titration and four weeks maintenance), a second P-CIT and SPECT scan is obtained. Data from the first 67 subjects completing the two scans show no short-term change in DAT uptake with either lev-odopa (n = 24) or pramipexole (n = 23) compared to the untreated group (n = 20). The mean percent change for those treated with levodopa was 2.2 ± 9.9, for pramipexole -2.8 ±8.3, and for the untreated group 2.5 ±7.7 (110). These small changes are consistent with that of test-retest evaluations using P-CIT and SPECT.

Other studies have also shown no remarkable change in the activity of DAT ligands or 18F-DOPA uptake by levodopa or dopamine agonists. In the CALM-PD CIT study there was no significant change in P-CIT uptake after 10 weeks of treatment with either pramipexole (1.5-4.5 mg) or levodopa (300-600 mg), consistent with previous studies evaluating levodopa and selegiline effects after 6 to 12 weeks (102,106,107). In a similar study, treatment with pergolide for six weeks also showed no significant changes in [123I] P-CIT striatal, putamen, or caudate uptake, but there was an insignificant trend toward increased [123I] P-CIT uptake (108). Data assessing RTI-32, another DAT ligand, demonstrated significant reductions from baseline in striatal DAT after six weeks treatment with both levodopa and pramipexole, but also with placebo, and this pilot study could not detect differences between the treatment and placebo (109).

Although these clinical studies are not conclusive, there does not appear to be a short-term change in DAT uptake with exposure to levodopa or pramipexole. Given that there is no change in DAT uptake after short-term exposure to pramipexole or levodopa, the increased loss of P-CIT uptake in the levodopa-treated group compared to the pramipexole group in the CALM-CIT study is unlikely explained by a pharmacologic effect on the DAT. Likewise, the increased loss in P-CIT uptake in the levodopa 600-mg/day group compared to placebo in the ELLDOPA trial does not appear to be explained by an effect of levodopa on the DAT. Although data from these studies do not address the possibility that pharmacologic effects may emerge in longer-term studies, an effect, if one existed, would be expected to occur within weeks of the initiation of therapy.

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