Study Outlines Risk Factors for Levodopa-induced Dyskinesia in Newly Diagnosed PD Patients

Severe motor, functional, and gait impairment; cumulative levodopa exposure; anxiety, and sex are among the risk factors for developing levodopa-induced dyskinesia (LID) in people newly diagnosed  with Parkinson’s disease, according to results from the Parkinson’s Progression Markers Initiative (PPMI).

The research, “Risk factors of levodopa-induced dyskinesia in Parkinson’s disease: results from the PPMI cohort,” was published in the journal npj Parkinson’s Disease.

Long-term dopamine repletion therapy in Parkinson’s patients can lead to motor fluctuations, including dyskinesia — involuntary, jerky movements. According to observational studies, over 50% of Parkinson’s patients on levodopa — the gold-standard treatment for Parkinson’s — for more than five years develop LID.

Proposed risk factors for LID include levodopa dosage — associated with the loss of dopamine-producing neurons in the brain — treatment duration, low body weight, and being a woman. However, available studies have employed different methodological approaches and follow-up duration.

The PPMI is an ongoing, large-scale, collaborative study initiated in 2010 to identify markers of disease progression in de novo patients — newly diagnosed and still untreated. Patients’ clinical, neuroimaging and cerebrospinal fluid (the liquid surrounding the brain and the spinal cord)/blood biomarkers are collected yearly in this international study.

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Analyzed biomarkers include the total amount of the tau protein as well as its altered (phosphorylated) version — which forms tangles inside neurons in Parkinson’s patients — total alpha-synuclein (the main component of Lewy bodies), and amyloid-beta (1-42), a protein that is also relevant in Alzheimer’s disease.

Researchers from Ospedale S. Maria della Misericordia, in Perugia, Italy, wanted to define factors predictive of LID development in de novo Parkinson’s patients.

Data from 423 patients were analyzed. Median follow-up duration was 4.6 years and average time to start dopaminergic therapy was one year.

A combination of factors, such as disease duration, anxiety — assessed with the State-Trait Anxiety Inventory (STAI) — and higher (worse) score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, which assesses motor function, predicted the initiation of dopaminergic therapy.

Overall, 109 of 390 patients analyzed experienced LID (27.9%), 33 of whom lacked data regarding levodopa treatment and/or LID onset. The median time to LID was 3.6 years (range 0.8-7.1 years), with a mean onset time of 5.81 years from Parkinson’s diagnosis, and an incidence rate of 64 per 1,000 person-years. This measure comprises actual follow-up duration in each patient and is higher with the length of the study.

Individual risk factors for LID development included being a woman, not being completely functional independent as measured by the modified Schwab & England Activities of Daily Living scale, higher MDS-UPDRS part III score, postural instability-gait disturbance (PIGD) or intermediate phenotype, higher DaTscan caudate asymmetry index — which reflects the difference in the levels of dopamine transport between two areas of the brain involved in motor control — higher genetic risk score, and anxiety.

Of note, no cerebral spinal fluid biomarker predicted LID development.

Researchers also found that the onset of dyskinesia was associated with depression and anxiety.

Combining all factors with an additional variable of 1,000 mg/day of levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — was also found to be fairly accurate to predict dyskinesia onset.

“In summary, our findings indicate that data deriving from a large cohort of de novo PD patients monitored longitudinally are useful in understanding the composite aspects involved in the progression of disease,” researchers stated.

The team also said the findings may help “future design of both biomarker studies and randomized clinical trials.”