Does levodopa accelerate the pathologic process in Parkinson disease brain?

Background: Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of alpha-synuclein. We investigated the relationship between cumulative lifetime dose of L-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). Methods: Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with well-documented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. Results: Mean lifetime dose of L-dopa correlated significantly (p < 0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p = 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density. Conclusion: Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities. Neurology (R) 2011;77:1420-1426