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Lateralization of Motor Signs Affects Symptom Progression in Parkinson Disease.

ABSTRACT: Background: Asymmetry of motor signs is a cardinal feature of Parkinson disease which may impact phenotypic expression. Objective: To investigate the relationship between lateralization of motor signs and symptom progression and severity during longitudinal observation for up to 4 years in a naturalistic study. Methods: We analyzed data prospectively collected during the NINDS Parkinson Disease Biomarker Project (PDBP). We defined the Movement Disorder Society Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II as the primary measure of symptom progression. Left side predominant subjects were those whose lateralized motor scores on the MDS-UPDRS part III were ≥2 points higher on the left side than on the right side of the body. Multiple regression models (controlled for age, gender, education years, ethnicity, levodopa equivalent daily dose (LEDD) at baseline, and years with PD) were used to estimate the rate of symptom progression comparing left predominant (LPD) with non-left predominant (NLPD) subjects. A sensitivity analysis was performed using the same multiple regression models in the subgroups of low (0-26) or high (>27) MDS-UPDRS II score at baseline to determine if PD severity influenced the results. Results: We included 390 participants, 177 LPD and 213 NLPD. We found that MDS-UPDRS part II progression from baseline to 48 months was faster in LPD compared to NLPD (0.6 points per year faster in LPD, p = 0.05). Additionally, the LPD group was statistically significantly worse at baseline and at 48 months in several subparts of the MDS-UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) mobility score. Significantly slower progression (difference of -0.8, p = 0.01) and lower score at 48 months (difference of -3.8, p = 0.003) was seen for NLPD vs. LPD in the group with lower baseline MDS-UPDRS part II score. Conclusion: Left side lateralization was associated with faster symptom progression and worse outcomes in multiple clinical domains in our cohort. Clinicians should consider using motor predominance in their counseling regarding prognosis.

SUBMITTER: Elkurd M

PROVIDER: S-EPMC8353110 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance. Objective:To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD. Design, Setting, and Participants:This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression. Main Outcomes Measures:The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring. Results:Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01). Conclusions and Relevance:Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

Project description:BackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Project description:Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (??=?4.65; 95% CI, 1.72-7.58; P?=?.002), E326K (??=?3.42; 95% CI, 0.66-6.17; P?=?.02), and GBA variants combined as a single group (??=?4.01; 95% CI, 1.95-6.07; P?=?1.5?×?10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (??=?0.38; 95% CI, 0.23-0.53; P?=?.01) and E326K (??=?0.64; 95% CI, 0.43-0.86; P?=?.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P?=?.01) and GBA variant carriers (15 of 39 [38.5%]; P?=?.04) progressed to mild cognitive impairment or dementia.GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Project description:Parkinsonian motor signs are common in the aging population and are associated with adverse health outcomes. Compared with Parkinson disease (PD), potential genetic risk factors for mild parkinsonian signs have been largely unexplored.To determine whether PD susceptibility loci are associated with parkinsonism or substantia nigra pathology in a large community-based cohort of older persons.Eighteen candidate single-nucleotide polymorphisms from PD genome-wide association studies were evaluated in a joint clinicopathologic cohort. Participants included 1698 individuals and a nested autopsy collection of 821 brains from the Religious Orders Study and the Rush Memory and Aging Project, 2 prospective community-based studies.The primary outcomes were a quantitative measure of global parkinsonism or component measures of bradykinesia, rigidity, tremor, and gait impairment that were based on the motor Unified Parkinson's Disease Rating Scale. In secondary analyses, we examined associations with additional quantitative motor traits and postmortem indices, including substantia nigra Lewy bodies and neuronal loss.Parkinson disease risk alleles in the MAPT (rs2942168; P?=?.0006) and CCDC62 (rs12817488; P?=?.004) loci were associated with global parkinsonism, and these associations remained after exclusion of patients with a PD diagnosis. Based on motor Unified Parkinson's Disease Rating Scale subscores, MAPT (P?=?.0002) and CCDC62 (P?=?.003) were predominantly associated with bradykinesia, and we further discovered associations between SREBF1 (rs11868035; P?=?.005) and gait impairment, SNCA (rs356220; P?=?.04) and rigidity, and GAK (rs1564282; P?=?.03) and tremor. In the autopsy cohort, only NMD3 (rs34016896; P?=?.03) was related to nigral neuronal loss, and no associations were detected with Lewy bodies.In addition to the established link to PD susceptibility, our results support a broader role for several loci in the development of parkinsonian motor signs and nigral pathology in older persons.

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Lateralization of Motor Signs Affects Symptom Progression in Parkinson Disease.

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