Objective: To assess safety, tolerability, and central effects of L-Dihydroxyphenylserine (L-DOPS), in Parkinson’s disease (PD) patients treated with DOPA decarboxylase inhibition.

Background: Norepinephrine (NE) is deficient in PD patients and clinical symptoms such as apathy, visual attention, and fatigue may be, in part, related to its deficit. We have applied arterial spin labeling (ASL) methods to assay L-DOPS effects on cerebral metabolism and applied these methods to a cohort of PD patients in a safety and tolerability study.

Method: An open-label safety and tolerability dose-escalation study of high dose L-DOPS and high dose Carbidopa (200mg) was performed in patients with the Postural Instability Gait Disorder (PIGD) subtype of PD. Participants (n=15; 9/6 female/male, Mean age = 70, H&Y stage = 3), were assessed at baseline (best medical treatment, carbidopa 200mg BID), and at maximum tolerated dose of L-DOPS and carbidopa. The duration of the assessment was 11-weeks. 11 completed 3 Tesla MRI in the baseline and treated visit. Imaging measures included anatomical T1-weighed imaging and perfusion-weighted ASL. Additionally, participants completed a probabilistic reward and punishment learning task. Our endpoints were tolerability of treatment, regional cerebral blood flow (CBF) changes at baseline and visit 3, and rates of reward and punishment learning performance. A Wilcoxon signed-rank test was used to assess treatment differences with two-sided defined significance p<0.05.

Results: L-DOPS was well tolerated in our cohort as 75% of patients remained at 600mg BID. At treatment, decreases in CBF were observed in the ventral striatum (p=0.03), the caudal middle frontal cortex (p=0.02), and a trend for increases in CBF to the isthmus of the cingulate (p=0.05). Treatment improved learning from a negative outcome (p = 0.009) but not from a positive outcome. More specifically, patients showed an improvement in learning to act to avoid negative outcomes (p=0.009) and a trend toward withholding acting to avoid negative outcomes (p=0.054).

Conclusion: L-DOPS treatment resulted in measurable changes to brain hemodynamics and improvements in learning from negative outcomes. These data support the central-acting nature of NE treatments, and support future studies assessing NE effects on mood, learning, and reward-based decision-making.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/open-label-safety-and-tolerability-of-l-dihydroxyphenylserine-l-dops-and-high-dose-carbidopa-therapy-in-parkinsons-disease-patients/