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Levodopa-induced dyskinesia (LID) is a common complication of Parkinson's disease (PD) therapy. Nitric oxide in the central nervous system may have a role in its pathophysiology. The present work investigates plasma and CSF levels of nitric oxide metabolites nitrite and nitrate in patients with PD, LID, and healthy control. We measured plasma and CSF nitrite and nitrate levels in patients with PD with and without LID and in healthy controls. The levels of plasma and CSF nitrite and nitrate were measured by ozone-based chemiluminescence. Sixty-seven participants were enrolled. CSF nitrite levels in patients with PD and LID were higher than in patients with PD without LID and healthy controls. CSF/plasma ratio of nitrite was higher in patients with PD and LID than in patients with PD without LID. The CSF/plasma ratio of nitrite in patients with PD and LID was higher than 1, indicating an intrathecal production of NO in patients with this motor complication. There was an increase in nitrate levels of CSF and CSF/plasma ratio of nitrate in patients with PD and LID compared to the healthy controls. Sex, age at evaluation, disease duration, and levodopa equivalent daily doses, as well as processing and storage time, did not critically influence these results. The present study demonstrated an increase in nitrite and nitrate levels in the central nervous system of patients with PD and LID. This finding strengthens the role of NO on LID pathophysiology.

The existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) require new approaches, as the metabolomic analysis, for discoveries. We aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort and to confirm the results in an external cohort (BioFIND). In the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed. We identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of the glycosphingolipid metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Furthermore, bile acid biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis pathway. There is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

Essential tremor (ET) is a common clinical syndrome characterized by action tremors affecting both upper limbs that can compromise manual tasks' execution and impair functional and social performance. The primary pharmacological treatment is symptomatic, but effective medicines are somewhat limited. There is a clear need to find new effective therapies for the treatment of ET. Cannabidiol (CBD) is a modulator of CB1 receptor and CB1 agonists can reduce tremors in experimental models. We hypothesized that a single acute CBD intake would reduce tremors in ET patients. We performed a randomized, controlled, double-blind, crossover study on 19 patients with ET. They were 10 males and 9 females, had mean 63 years of age, and mean 23 years of disease duration and had insufficient control of their tremors with the usual pharmacological treatment. They ingested a single oral dose of CBD (300 mg) or placebo in two experimental sessions performed 2-weeks apart. Patients were evaluated immediately before and after oral ingestion (60 min and 210 min), using the Fahn-Tolosa-Marin clinical scale. There was no carryover effect. There were no significant differences in upper limb tremors score, specific motor task tremor scores (writing and drawing/pouring) or clinical impression of change after treatment with placebo or CBD. In conclusion, a single 300 mg oral dose of CBD had no significant effect on the severity of upper limb tremors of ET patients. Our findings did not exclude the possibility that chronic treatment with CBD could have a symptomatic effect.

Structured AbstractBackgroundThe existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) require new approaches, as the metabolomic analysis, for discoveries.ObjectivesWe aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort, and to confirm the results in an external cohort (BioFIND).MethodsIn the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed.ResultsWe identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of glycosphingolipids metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Further, bile acid biosynthesis and C21-steroid hormone biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Levels of cortisol and cortisone were reduced in patients with PD and LID compared to patients with PD without LID. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis and C21-steroid hormone biosynthesis pathways.ConclusionThere is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

IntroductionLevodopa-induced dyskinesias (LID) in Parkinson’s disease (PD) are frequent complications, and nitric oxide has a role on its pathophysiology. The present work aims to investigate CSF levels of nitric oxide metabolites nitrite and nitrate (NOx) in patients with PD and LID.MethodsWe measured CSF NOx levels in patients with PD with and without LID, and in healthy controls. The levels of CSF NOx levels were measured by ozone-based chemiluminescence.Results67 participants were enrolled. CSF NOx levels were higher in patients with PD with LID than in healthy controls (Kruskal-Wallis statistics = 7.24, p = 0.02). CSF NOx levels did not correlate with other clinical variables.ConclusionWe reported higher levels of nitric oxide in the CSF of patients with PD and LID.Highlights–Nitric oxide has a role on levodopa-induced dyskinesias in Parkinson’s disease–We measured CSF nitrite and nitrate in Parkinson’s disease patients with dyskinesias–CSF nitrite and nitrate were higher in Parkinson’s disease patients with dyskinesias