Dataset Information

Cerebellar connectivity in Parkinson's disease with levodopa-induced dyskinesia.

ABSTRACT: OBJECTIVE:The precise pathogenesis or neural correlates underlying levodopa-induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID. METHODS:We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score-matched PD patients who had not developed LID, and 24 age- and sex-matched healthy controls. We performed a comparative analysis of resting-state functional connectivity (FC) between the motor cerebellum and whole brain between the groups. RESULTS:The patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID. INTERPRETATION:Increased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.

SUBMITTER: Yoo HS

PROVIDER: S-EPMC6856615 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Cerebellar connectivity in Parkinson's disease with levodopa-induced dyskinesia.

Yoo Han Soo HS Choi Yong Ho YH Chung Seok Jong SJ Lee Yang Hyun YH Ye Byoung Seok BS Sohn Young H YH Lee Jong-Min JM Lee Phil Hyu PH

Annals of clinical and translational neurology 20191023 11

<h4>Objective</h4>The precise pathogenesis or neural correlates underlying levodopa-induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID.<h4>Methods</h4>We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score-matched PD patients who had not de ...[more]

PMID: 31643140

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Project description:ImportanceForty percent of Parkinson's disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies.ObjectiveTo discover common genetic variants in the PD population that increase the probability of developing LiD.Design setting and participantsWe performed survival analyses to study the development of LiD in 5 separate longitudinal cohorts. We performed a meta-analysis to combine the results of genetic association from each study based on a fixed effects model weighting the effect sizes by the inverse of their standard error. The selection criteria was specific to each cohort. We studied individuals that were genotyped from each cohort and that passed our analysis specific inclusion criteria.Main outcomes and measuresWe measured the time for PD patients on levodopa treatment to develop LiD as defined by reaching a score higher or equal than 2 from the MDS-UPDRS part IV, item 1, which is equivalent to a range of 26%-50% of the waking time with dyskinesia. We carried out a genome-wide analysis of the hazard ratio and the association of genome-wide SNPs with the probability of developing LiD using cox proportional hazard models (CPH).ResultsThis study included 2,784 PD patients of European ancestry, of whom 14.6% developed LiD. Consistent with previous studies, we found female gender (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 -5 ) to increase the probability of developing LiD. We identified three loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 -8 ) located in the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06,, SE = 0.19, P = 2.81 × 10 -9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 -9 ) in the XYLT1 locus. Subsequent colocalization analyses on chromosome 1 identified DNAJB4 as a candidate gene associated with LiD through a change in gene expression. We computed a PRS based on our GWAS meta-analysis and found high accuracy to stratify between PD-LID and PD (AUC 83.9). We also performed a stepwise regression analysis for baseline features selection associated with LiD status. We found baseline anxiety status to be significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 -5 ). Finally, we performed a candidate variant analysis and found that genetic variability in ANKK1 ( rs1800497 , Beta = 0.24, SE = 0.09, P = 8.89 × 10 -3 ) and BDNF ( rs6265 , Beta = 0.19, SE = 0.10, P = 4.95 × 10 -2 ) loci were significantly associated with time to LiD in our large meta-analysis.ConclusionIn this association study, we have found three novel genetic variants associated with LiD, as well as confirming reports that variability in ANKK1 and BDNF loci were significantly associated with LiD probability. A PRS nominated from our time-to-LiD meta-analysis significantly differentiated between PD-LiD and PD. In addition, we have found female gender, young PD onset and anxiety to be significantly associated with LiD.

Dataset Information

Cerebellar connectivity in Parkinson's disease with levodopa-induced dyskinesia.

Publications

Cerebellar connectivity in Parkinson's disease with levodopa-induced dyskinesia.

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