Exome-wide association study of levodopa-induced dyskinesia in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Konig E
PROVIDER: S-EPMC8486836 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6856615 | biostudies-literature
Project description:The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10-5) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10-8) located at 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. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10-5). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 (rs1800497, HR = 1.27, SE = 0.09, P = 8.89 × 10-3) and BDNF (rs6265, HR = 1.21, SE = 0.10, P = 4.95 × 10-2) loci were significantly associated with time to LiD in our large meta-analysis.
| S-EPMC10471743 | biostudies-literature
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.
| S-EPMC10327264 | biostudies-literature
Project description:The most commonly used treatment for Parkinson's disease (PD) is levodopa, prescribed in conjunction with carbidopa. Virtually all patients with PD undergo dopamine replacement therapy using levodopa during the course of the disease's progression. However, despite the fact that levodopa is the "gold standard" in PD treatments and has the ability to significantly alleviate PD symptoms, it comes with side effects in advanced PD. Levodopa replacement therapy remains the current clinical treatment of choice for Parkinson's patients, but approximately 80% of the treated PD patients develop levodopa-induced dyskinesia (LID) in the advanced stages of the disease. A better understanding of the pathological mechanisms of LID and possible means of improvement would significantly improve the outcome of PD patients, reduce the complexity of medication use, and lower adverse effects, thus, improving the quality of life of patients and prolonging their life cycle. This review assesses the recent advancements in understanding the underlying mechanisms of LID and the therapeutic management options available after the emergence of LID in patients. We summarized the pathogenesis and the new treatments for LID-related PD and concluded that targeting pathways other than the dopaminergic pathway to treat LID has become a new possibility, and, currently, amantadine, drugs targeting 5-hydroxytryptamine receptors, and surgery for PD can target the Parkinson's symptoms caused by LID.
| S-EPMC9736114 | biostudies-literature
Project description:Several lines of evidence point to alteration in brain metabolic homeostasis in Parkinson's disease (PD) and levodopa-induced dyskinesia (LID), yet the metabolic mechanism in different brain regions underlying PD and LID remains largely unknown. The present study aimed to uncover the metabolic pathways across anatomical regions in the brain of PD and LID. Using an NMR-based metabolomic approach, we generated the metabolomics profiling data from six different brain regions of PD rats and following the onset of LIDs. The diversity of metabolite patterns across the brain and its relation to PD and LID were further investigated through principal component analysis (PCA) and multivariate general linear model. Compared with control rats, dopamine loss in PD rats produced a marked and persistent metabolic disturbance in neurotransmitter metabolism and energy pathway, resulting in a metabolic imbalance among different brain regions. In LID rats, levodopa replacement did not restore the midbrain-striatum metabolic crosstalk and metabolic disturbance throughout the brain was involved in levodopa related involuntary movements. Most notably, the midbrain and right cortex were identified as the primary regions of metabolic abnormalities in PD and LID rats. Neurochemical differences in metabolic phenotypes were mainly defined by various neurotransmitters including glutamate, glutamine and aspartate. Accordingly, we found that the PD and LID rats exhibited lower levels of synaptophysin (SYP), a marker for synaptic plasticity, compared with control rats. These findings provide key insights into the metabolic mechanism underlying PD and LID by defining brain-region specific metabolic phenotype, with implications for developing targeted therapies.
| S-EPMC7089871 | biostudies-literature
Project description:Choreiform or dystonic movement in the craniocervical region can occur as levodopa-induced dyskinesia (LID). "Sensory tricks" are various alleviating maneuvers for the relief of abnormal postures in patients who have idiopathic focal dystonia, particularly those who have cervical dystonia. The authors report on three men with Parkinson's disease who had been receiving levodopa for more than 3 years and presented with involuntary neck movements during the drug on period. In all three patients, cervical LIDs appeared during the drug on period and completely disappeared during the drug off period. The effects of using sensory tricks to markedly improve the symptoms of cervical LID were studied. In all patients, the cervical LIDs improved more efficiently when sensory tricks were performed on the patient by another person (passive tricks) than by the patient himself (self-sensory tricks). The unique features of the sensory tricks for cervical LID in the current patients may be important clinical evidence of abnormal sensorimotor integration in patients who have PD with LID.
| S-EPMC6407061 | biostudies-literature
Project description:ObjectiveTo investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa-induced dyskinesia (LID) in Parkinson's disease (PD).MethodsAccording to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug-naïve early stage PD (follow-up >3 years) were divided into two groups of PD with minimal WMHs (PD-WMH-; n = 227) and moderate-to-severe WMHs (PD-WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD-WMH + group compared with the PD-WMH- group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID.ResultsPatients in the PD-WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD-WMH- group. Patients in the PD-WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P < 0.001) than those in the PD-WMH- group after adjustment for other confounding factors. A greater WMH burden was associated with earlier occurrence of LID (hazard ratio, 1.04; P = 0.001), although the effects of WMHs on LID development did not exhibit region-specific patterns.InterpretationThe present study demonstrates that the burden of WMHs is associated with occurrence of LID in patients with PD, suggesting comorbid WMHs as a risk factor for LID.
| S-EPMC7034502 | biostudies-literature
Project description:Aim of the study was to evaluate possible associations between cognitive dysfunctions and development of Levodopa Induced Dyskinesia (LID). PD patients from the Parkinson's disease Cognitive impairment Study cohort who underwent a baseline and follow-up neuropsychological evaluations were enrolled. Mild Cognitive Impairment (PD-MCI) was diagnosed according to MDS level II criteria. The following cognitive domains were evaluated: episodic memory, attention, executive function, visuo-spatial function and language. A domain was considered as impaired when the subject scored 2 standard deviation below normality cut-off values in at least one test for each domain. Levodopa equivalent dose, UPDRS-ME and LID were recorded at baseline and follow-up. To identify possible neuropsychological predictors associated with the probability of LID development at follow-up, Cox proportional-hazards regression model was used. Out of 139 PD patients enrolled (87 men, mean age 65.7 ± 9.4), 18 (12.9%) were dyskinetic at baseline. Out of 121 patients non-dyskinetic at baseline, 22 (18.1%) developed LID at follow-up. The impairment of the attention and executive domains strongly predicted the development of LID (HR 4.45;95%CI 1.49-13.23 and HR 3.46; 95%CI 1.26-9.48 respectively). Impairment of the attention and executive domains increased the risk of dyskinesia reflecting the alteration of common cortical network.
| S-EPMC7806828 | biostudies-literature
Project description:A higher levodopa dose is a strong risk factor for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). However, levodopa dose can change during long-term medication. We explored the relationship between levodopa dose and time to onset of LID using longitudinal multicenter data. Medical records of 150 patients who were diagnosed with de novo PD and treated with levodopa until onset of LID were collected. Levodopa dose were assessed as the dose at 6 months from levodopa initiation and rate of dose increase between 6 months and onset of LID. The groups with earlier LID onset had higher levodopa and levodopa-equivalent dose at the first 6 months of treatment and rapid increase in both levodopa and levodopa-equivalent dose. Multivariable linear regression models revealed that female sex, severe motor symptom at levodopa initiation, and higher rate of increase in both levodopa and levodopa-equivalent dose were significantly associated with early onset of LID. The present results demonstrated that rapid increase in levodopa dose or levodopa-equivalent dose is associated with early onset of LID.
| S-EPMC7444533 | biostudies-literature
Project description:Dopamine replacement by levodopa is the most widely used therapy for Parkinson's disease (PD), however patients often develop side effects, known as levodopa-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor antagonist amantadine, which has limited efficacy. The NMDA receptor is indeed the most plausible target to manage LID in PD and recently the kinase Fyn- one of its key regulators- became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intra-striatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with levodopa. The miRNA-Fyn was delivered either before or after levodopa exposure to assess its ability to prevent or revert dyskinesia. Pre-administration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels -a marker of LID- as well as decreased phosphorylation of the NR2B-NMDA subunit, which is a main target of Fyn. On the other hand, post L-DOPA delivery of miRNA-Fyn was less effective to revert already established dyskinesia, suggesting that early blocking of Fyn activity might be a more efficient therapeutic approach. Together, our results provide proof of concept about Fyn as a plausible therapeutic target to manage LID, and validate RNA silencing as a potential approach to locally reduce striatal Fyn, rising new perspectives for RNA therapy interventions in PD.Significance StatementLevodopa induced dyskinesia (LID) is an incapacitant side effect of treatment in Parkinson's disease (PD). LID is a therapeutic challenge, lacking an effective pharmacological treatment, except for the use of inhibitors of the NMDA receptor, which have limited efficacy and may trigger untoward side effects. The kinase Fyn is a key regulator of NMDA function and a potential therapeutic target to control LID. Here, we show that RNA interference therapy to reduce the amount of Fyn mRNA in the adult brain is effective to prevent LID in a mouse model of PD, setting the grounds for future biomedical interventions to manage LID in PD.
| S-EPMC8281260 | biostudies-literature