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In Parkinson Disease, Levodopa-Induced Dyskinesia is Linked to Frontal Dysfunction Progression

Investigators concluded that the findings are suggestive of a link between faster cognitive decline, especially frontal lobe dysfunction, in patients with Parkinson who develop levodopa-induced dyskinesia.

Han Soo Yoo, MD

New study results have found that levodopa-induced dyskinesia is closely associated with the progression of cognitive decline and the development of Parkinson disease.1

Specifically, the dyskinesia was shown to be linked to frontal executive dysfunction. Over the >5-year course of the study, the longitudinal change in slope of frontal executive function was —0.034 (standard error [SE], 0.029) for the group which did not develop levodopa-induced dyskinesia (LID-; n = 81) compared to –0.184 (SE, 0.040) in the group which developed levodopa-induced dyskinesia (LID+; n = 38; difference, –0.149 [SE, 0.049]; P = .002).

Clinical Dementia Rating—Sum of Boxes (CDR-SOB) scores were significantly different between groups as well (difference, 0.233 [SE, 0.069]; P = .001), with the LID- group reporting CDR-SOB scores of 0.092 (SE, 0.040) and the LID+ group reporting scores of 0.326 (SE, 0.056).

The investigators, led by Han Soo Yoo, MD, from the Department of Neurology at Severance Biomedical Science Institute, and the Biostatistics Collaboration Unit at Yonsei University College of Medicine, in Seoul, South Korea, noted that the major findings were “first, neuropsychological performances and the percentage of patients with [mild cognitive impairment] at baseline did not differ between the [LID+] and [LID−] groups. Second, the patients in the [LID+] group showed faster cognitive declines in frontal executive function and global cognitive function than those in the [LID−] group. Finally, the conversion rate to dementia was significantly higher in the [LID+] group than in the [LID−] group.”

They concluded that the study is suggestive of a link between faster cognitive decline, especially frontal lobe dysfunction, in patients with Parkinson who develop levodopa-induced dyskinesia.

In total, 119 patients with Parkinson who had been treated with levodopa for more than 5 years were included in the assessment, with a mean latency from the start of levodopa to levodopa-induced dyskinesia in all patients with Parkinson was 4.94 (±1.18) years.

Ultimately, the neuropsychological performances and the percentage of patients with mild cognitive impairment (MCI) at baseline did not differ between the groups. However, those in the LID+ group with MCI had a higher risk of converting to Parkinson dementia than those with normal cognitive function (adjusted hazard ratio [HR], 6.08; 95% CI, 1.25 to 29.56), and those with MCI in the LID- group (adjusted HR, 4.05; 95% CI, 1.14 to 14.43).

Additionally, the LID+ group had a significantly higher conversion rate to dementia than the LID- group (adjusted HR, 3.94; 95% CI, 1.76 to 8.82).

“Many studies have reported potential demographic and clinical risk factors for the development of dementia in patients with [Parkinson] such as onset age, disease severity, levodopa dose, postural instability/gait difficulty subtype, and the nonmotor symptoms of [REM sleep behavior disorder] and visual hallucinations,” Soo Yoo and colleagues wrote. They acknowledged that until this assessment, only a single study has examined the relationship between levodopa-induced dyskinesia and Parkinson disease dementia. While that study showed the severity of dyskinesia was a predictor of dementia development, it was not a significant association.2

Although, Soo Yoo et al. measured the onset of levodopa-induced dyskinesia post-levodopa intake—not its severity. This detection of the dyskinesia and Parkinson disease dementia from the de novo state longitudinally, “is much more natural and powerful to investigate the relationship between the two,” they noted. Onset timing of levodopa-induced dyskinesia, they wrote, would have more sensitivity and accuracy in an investigation of patients with Parkinson who are susceptible to levodopa-induced dyskinesia, rather than the severity of the dyskinesia.

“Our data suggest that [levodopa-induced dyskinesia] may be a risk factor for the development of dementia and cognitive decline in [Parkinson] rather than a simple comorbid factor that is secondary to longer disease duration or faster progression of disease,” they wrote, adding that altogether, the data are indicative of a need for closer monitoring of conversion to dementia in patients with Parkinson-MCI who develop levodopa-induced dyskinesia early on.

“It may add another important clinical signal to the known factors associated with cognitive decline,” Soo Yoo and colleagues wrote.

The study did have limitations, which the investigators acknowledged. These included the arbitrary division of patients with and without levodopa-induced dyskinesia, the data consisting of less than half of the eligible participants due to intensive exclusion, the use of retrospective reports to determine the onset of levodopa-induced dyskinesia, and a lack of regular intervals for cognitive function evaluation. As well, not measuring levodopa-induced dyskinesia severity and onset together was regarded as a limitation, along with a lack of follow-up MRI scans.

Additionally, they noted a lack of clinical measures reflecting disease severity during the follow-up period, “thus, we could not exclude completely that the association between the deterioration of cognition and the occurrence of [levodopa-induced dyskinesia] is a manifestation that occurs together with the rapid progression of [Parkinson] even though we thoroughly adjusted for confounding parameters,” they wrote.


1. Soo Yoo H, Jong Chung S, Hyun Lee Y, et al. Levodopa-induced dyskinesia is closely linked to progression of frontal dysfunction in PD. Neurology. 2019;92:1-11. doi:10.1212/WNL.0000000000007189

2. Zhu K, van Hilten JJ, Marinus J. Predictors of dementia in Parkinson’s disease; findings from a 5-year prospective study using the SCOPA-COG. Parkinsonism Relat Disord. 2014;20(9):980-985. doi: 10.1016/j.parkreldis.2014.06.006.