Objective: To investigate the influence of a standardized, placebo-controlled administration of levodopa on cerebral bioenergetics in patients with Parkinson’s disease (PwPD) and healthy controls (HCs).

Background: The underlying disease mechanisms in Parkinson’s disease (PD) are highly interwoven and complex. One proposed mechanism includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, no systematic in-vivo evaluation of cerebral bioenergetics following exogenous dopamine administration, still the main therapeutic strategy to date, has been performed.

Method: We performed a double-blinded, cross-sectional, placebo-controlled trial. Here, each participant received either 200/50 mg Levodopa/Benserazide or placebo at one of the two subsequent study visits. Established clinical assessments of symptom severity (e.g., the MDS-UPDRS-III) and 31 phosphorus magnetic resonance spectroscopy (31P-MRSI) of the basal ganglia and the midbrain were performed.

Results: In total, 20 (female = 7, male = 13) PwPD and 22 sex- and age-matched HCs (female = 9, male = 13) were enrolled. In both groups, a substantial drop in high-energy phosphorus-containing metabolites (HEPs) was observed in the basal ganglia (PwPD: -41%, HCs: -39%), but not in the midbrain following levodopa but not placebo administration. These alterations did not correlate with any measures of symptom severity following levodopa treatment. In addition, there were no marked differences in HEPs for PwPD compared to HCs in the OFF-medication state.

Conclusion: In contrast to previous studies, our results indicate no subcortical bioenergetic deficit in PwPD in the OFF state. Exogenously administered levodopa, however, strongly interferes with the energy metabolism of the basal ganglia independent of the investigated group. The lack of effects on the midbrain suggests that the observed changes are limited to the site of action of levodopa. This can be due to the short-term effects of downstream levodopa metabolites, e.g., due to dopamine oxidation, that may interfere with mitochondrial homeostasis. The influence of levodopa on cerebral bioenergetics has to be considered for future target-engagement strategies in neuroprotective treatment strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/marked-reduction-of-energy-supply-due-to-levodopa-treatment-in-patients-with-parkinsons-disease-and-healthy-controls/