Does levodopa slow or hasten the rate of progression of Parkinson’s disease?

Abstract

The clinical outcomes not only indicate that levodopa is effective in a dose-dependent manner in overcoming the signs and symptoms of PD, they also support the concept that the drug does not hasten the disease progression, but rather may slow down the rate of the disease. The clinical study failed to demonstrate any evidence of levodopa worsening early PD. However, the beta-CIT SPECT substudy indicates the opposite effect, namely that levodopa causes a more rapid decline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals in the striatum. These contradictory findings warrant further investigation into the effect of levodopa on PD. OTHER OBSERVATIONS: The ELLDOPA study was the first levodopa dose-response study ever conducted. It showed that dose is a factor in the cause of producing motor complications of dyskinesias and wearing-off, and that these can develop as early as 5 to 6 months. On the other hand, freezing of gait could be delayed or its occurrence reduced by high dosage levodopa, compared to placebo or low-dose levodopa. Withdrawal of levodopa over a 3-day step-down can be safely carried out without inducing the neuroleptic-like syndrome. The UPDRS was shown to be a reliable linear marker for disease progression. The ELLDOPA study also called into question the interpretation of beta-CIT SPECT in the presence of dopaminergic agents. Neuroimaging in ELLDOPA also showed that some people diagnosed with early PD do not have a dopaminergic deficit, calling into question how difficult the correct diagnosis may be in people with early symptoms of PD.

Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort

“…A number of previously reported studies have provided data on the longitudinal change of UPDRS total score in early at baseline untreated PD cohorts 13, 14, 15, 16, 17. The change in UPDRS ranges between 6 and 12 points over 1 year.…”

Neuroimaging and therapeutics in movement disorders

“…Moreover, clinical ratings reflect long-term symptomatic effects, which are apt to persist following protracted medication washout. 9 Imaging assessment of presynaptic nigrostriatal function has been used for evaluation of disease progression in PD patients (see above) and may therefore provide a useful adjunct to clinical assessment in assessing disease progression in pharmacologic therapeutic trials of potential neuroprotective agents. 2 Two large randomized, blinded studies have employed imaging to investigate disease progression in patients receiving dopamine agonists relative to those treated with levodopa.…”

“…Similarly, in the subsequent ELLDOPA trial, 9 subjects treated with high-dose levodopa had the best clinical outcome even following up to 4 weeks of medication washout, despite a more rapid decline in putamen DAT binding as measured by ␤-CIT SPECT. 9 These trials reveal discrepancies between the clinical assessment and radiotracer-based imaging of the presynaptic dopaminergic system, and raise the question of comparability of these measures as neuroprotection outcome variables. Even though most imaging descriptors of nigrostriatal dopaminergic function correlate with independent disease severity measures (see Ravina et al 2 for review), these techniques do not directly assess the number or density of nigral dopaminergic neurons.…”

Unmet needs in Parkinson's disease: New horizons in a changing landscape

“…At present, levodopa remains unchallenged as the most efficacious and best tolerated antiparkinsonian drug, albeit one that is often limited by the development of response fluctuations and dyskinesia [42,43]. Motor fluctuations are almost invariably associated with often disabling non motor fluctuations [44].…”