Study Rationale:
Levodopa is the gold-standard drug for treatment of Parkinson’s disease (PD), but chronic use is associated with serious motor complications called levodopa-induced dyskinesia (LID). Once established, LID is very hard to treat and adjustments in medication often result in reduced control of Parkinson’s symptoms. The aim of this project is to find biofluid markers associated with increased risk of developing LID to help understand the cause of LID and help improve drug treatments in PD.
Hypothesis:
We hypothesize that specific signalling molecules or metabolites related to neurotransmission and neuromodulation are altered in PD patients with LID or patients at risk of developing LID.
Study Design:
We will study biomarkers for LID in plasma and cerebrospinal fluid (CSF) using quantitative immunoassays, microRNA profiling and metabolomics.
We will collect blood and CSF from about 50 PD patients with moderate to severe LID and about 50 PD patients without LID. The severity of disease and dyskinesia will be scored using the Unified Parkinson’s Disease Rating Scale and the Unified Dyskinesia Rating Scale. We will collect blood and CSF at a fixed time point after intake of the first morning medication, and a group of age-matched non-neurological controls will also be included.
We will analyze the samples for proteins and other small molecules that have been associated with LID in pre-clinical models, including phosphorylated extracellular regulated kinase (ERK), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and metabolites related to neurotransmission and neuromodulation. We also will measure micro-RNA molecules to look for altered regulation of protein expression in patients with LID. The biochemical data will be correlated with the clinical rating scores of disease severity and dyskinesia.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Prognostic biomarkers for LID will help adjust drug treatment in early phases of PD and thereby help prevent or delay the onset of LID. In addition, the findings in this project are expected to help understand the mechanisms causing LID and thereby aid in generating novel ideas for treatment and prevention.
Next Steps for Development:
If promising biomarkers for LID are identified in this study, the next step will be a longitudinal follow-up study to validate whether the identified biomarkers have prognostic value and whether early intervention with anti-dyskinetic drugs — based on biomarker profile — improves clinical outcome.