de Bie, Rob M A

Abstract Background Levodopa‐induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2 . Objectives Our goal was to investigate the effects of genetic variants on risk and time to LID. Methods We performed a genome‐wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. Results We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21–2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09–1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth_quartile = 1.27; 95% CI, 1.03–1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third_quartile = 1.38; 95% CI, 1.07–1.79; P = 0.0128; HR fourth_quartile = 1.38; 95% CI = 1.06–1.78; P = 0.0147). Conclusions This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ABSTRACTBackgroundThe criteria for PD‐MCI allow the use of global cognitive tests. Their predictive value for conversion from PD‐MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown.MethodsThe MDS PD‐MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD‐MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD.ResultsPD‐MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P = <0.001). The C‐statistics for MMSE (0.72) and MoCA (0.70) were lower than those based on neuropsychological tests (Level I = 0.82; Level II = 0.81). Sensitivity, specificity and diagnostic accuracy balance was best in Level II.ConclusionMMSE and MoCA predict conversion to PDD. However, Level II neuropsychological assessment seems the preferred assessment for PD‐MCI.

AbstractBackgroundThe International Parkinson and Movement Disorders Society criteria for mild cognitive impairment in PD need validation. The objectives of this present study were to evaluate prognostic validity of level I (abbreviated) International Parkinson and Movement Disorders Society mild cognitive impairment in PD criteria for development of PD dementia and compared them with level II (comprehensive) criteria.MethodsWe analyzed data from 8 international studies (1045 patients) from our consortium that included baseline data on demographics, motor signs, depression, detailed neuropsychological testing, and longitudinal follow‐up for conversion to Parkinson's disease dementia. Survival analysis evaluated their contribution to the hazard of Parkinson's disease dementia.ResultsLevel I mild cognitive impairment in PD, increasing age, male sex, and severity of PD motor signs independently increased the hazard of Parkinson's disease dementia. Level I and level II mild cognitive impairment in PD classification had similar discriminative ability with respect to the time to Parkinson's disease dementia.ConclusionsLevel I mild cognitive impairment in PD classification independently contributes to the hazard of Parkinson's disease dementia. This finding supports the prognostic validity of the abbreviated mild cognitive impairment in PD criteria. © 2019 International Parkinson and Movement Disorder Society

AbstractBackground: Numerous neuropsychological tests and test versions are used in Parkinson's disease research, but their relative capacity to detect mild cognitive deficits and their comparability across studies are unknown. The objective of this study was to identify neuropsychological tests that consistently detect cognitive decline in PD across studies.Methods: Data from 30 normed neuropsychological tests across 20 international studies in up to 2908 nondemented PD patients were analyzed. A subset of 17 tests was administered to up to 1247 healthy controls. A 2‐step meta‐analytic approach using standardized scores compared performance in PD with normative data.Results: Pooled estimates of the differences between PD and site‐specific healthy controls identified significant cognitive deficits in PD patients on 14 test scores across 5 commonly assessed cognitive domains (attention or working memory, executive, language, memory, and visuospatial abilities), but healthy control performance was statistically above average on 7 of these tests. Analyses based on published norms only, as opposed to direct assessment of healthy controls, showed high between‐study variability that could not be accounted for and led to inconclusive results.Conclusions: Normed neuropsychological tests across multiple cognitive domains consistently detect cognitive deficits in PD when compared with site‐specific healthy control performance, but relative PD performance was significantly affected by the inclusion and type of healthy controls versus the use of published norms only. Additional research is needed to identify a cognitive battery that can be administered in multisite international studies and that is sensitive to cognitive decline, responsive to therapeutic interventions, and superior to individual cognitive tests. © 2018 International Parkinson and Movement Disorder Society

ABSTRACT Background The International Parkinson and Movement Disorder Society criteria for mild cognitive impairment in PD were recently formulated. Objectives The aim of this international study was to evaluate the predictive validity of the comprehensive (level II) version of these criteria by assessment of their contribution to the hazard of PD dementia. Methods Individual patient data were selected from four separate studies on cognition in PD that provided information on demographics, motor examination, depression, neuropsychological examination suitable for application of level II criteria, and longitudinal follow‐up for conversion to dementia. Survival analysis evaluated the predictive value of level II criteria for cognitive decline toward dementia as expressed by the relative hazard of dementia. Results A total of 467 patients were included. The analyses showed a clear contribution of impairment according to level II mild cognitive impairment criteria, age, and severity of PD motor symptoms to the hazard of dementia. There was a trend of increasing hazard of dementia with declining neuropsychological performance. Conclusions This is the first large international study evaluating the predictive validity of level II mild cognitive impairment criteria for PD. The results showed a clear and unique contribution of classification according to level II criteria to the hazard of PD dementia. This finding supports their predictive validity and shows that they contribute important new information on the hazard of dementia, beyond known demographic and PD‐specific factors of influence. © 2017 International Parkinson and Movement Disorder Society