Genomic determinants of motor and cognitive outcomes in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Chung SJ
PROVIDER: S-EPMC3606821 | biostudies-literature | 2012 Aug
REPOSITORIES: biostudies-literature
Publications
Genomic determinants of motor and cognitive outcomes in Parkinson's disease.
Chung Sun Ju SJ Armasu Sebastian M SM Biernacka Joanna M JM Anderson Kari J KJ Lesnick Timothy G TG Rider David N DN Cunningham Julie M JM Eric Ahlskog J J Frigerio Roberta R Maraganore Demetrius M DM
Parkinsonism & related disorders 20120530 7
<h4>Background</h4>Little is known regarding genetic factors associated with motor or cognitive outcomes in Parkinson's disease (PD).<h4>Objective</h4>To identify common genetic variants associated with motor and cognitive outcomes in PD.<h4>Methods</h4>The sample consisted of 443 PD cases included in the first genome-wide association study (GWAS) of PD. Methods included telephone interview assessments of motor and cognitive outcomes, a median 9 years following the initial clinical assessments. ...[more]
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Project description:BackgroundThere are few established predictors of the clinical course of PD. Prognostic markers would be useful for clinical care and research.ObjectiveTo identify predictors of long-term motor and cognitive outcomes and rate of progression in PD.MethodsNewly diagnosed PD participants were followed for 7 years in a prospective study, conducted at 55 centers in the United States and Canada. Analyses were conducted in 244 participants with complete demographic, clinical, genetic, and dopamine transporter imaging data. Machine learning dynamic Bayesian graphical models were used to identify and simulate predictors and outcomes. The outcomes rate of cognition changes are assessed by the Montreal Cognitive Assessment scores, and rate of motor changes are assessed by UPDRS part-III.ResultsThe most robust and consistent longitudinal predictors of cognitive function included older age, baseline Unified Parkinson's Disease Rating Scale (UPDRS) parts I and II, Schwab and England activities of daily living scale, striatal dopamine transporter binding, and SNP rs11724635 in the gene BST1. The most consistent predictor of UPDRS part III was baseline level of activities of daily living (part II). Key findings were replicated using long-term data from an independent cohort study.ConclusionsBaseline function near the time of Parkinson's disease diagnosis, as measured by activities of daily living, is a consistent predictor of long-term motor and cognitive outcomes. Additional predictors identified may further characterize the expected course of Parkinson's disease and suggest mechanisms underlying disease progression. The prognostic model developed in this study can be used to simulate the effects of the prognostic variables on motor and cognitive outcomes, and can be replicated and refined with data from independent longitudinal studies.
| S-EPMC5467836 | biostudies-literature
Project description:Background: Parkinson's disease (PD) is a neurodegenerative disease in which the progressive loss of dopaminergic neurons (DA) leads to initially sporadic and eventually widespread damage of the nervous system resulting in significant musculoskeletal and cognitive deterioration. Loss of motor function alongside increasing cognitive impairment is part of the natural disease progression. Gait is often considered an automatic activity; however, walking is the result of a delicate balance of multiple systems which maintain the body's center of mass over an ever-changing base of support. It is a complex motor behavior that requires components of attention and memory to prevent falls and injury. In addition, evidence points to the critical role of salient visual information to gait adaptability. There is a growing understanding that treatment for PD needs to address movement as it occurs naturally and walking needs to be practiced in more complex environments than traditional therapy has provided.MethodsIn this single-blinded randomized-controlled pilot study, an immersive treadmill training was piloted to determine feasibility and preliminary efficacy on gait and cognition in people with PD. Eighteen participants with Hoehn and Yahr stages I-III PD were randomized to either an intervention or a waitlist control group. Following baseline data collection, the intervention group trained for 30 min, three times/week for 4 weeks on a split belt treadmill combined with a first-person immersive video game targeting visuospatial skills and working memory. Assessment was repeated after 4 weeks of training for the experimental group and 1-month after baseline for the control group. Primary motor outcomes were captured with the APDM Opal sensors during 6 MWT, TUG, and TUG Cognitive. Secondary outcomes of cognition were measured with the Montreal Cognitive Assessment (MoCA), Verbal Fluency (Fruit, Vegetable, and Animal) and the Symbol Digit Modality Test (SDMT). Within subject differences were calculated using the Wilcoxon Signed Ranked Test and between subject comparisons were analyzed using the Mann Whitney U-test.ResultsThis novel treadmill training program was well-tolerated with all participants in the intervention group completing 4 weeks of training three times a week without any adverse effects. After immersive cognitive motor training, the experimental group made clinically relevant improvements in gait speed and walking distance during the 6 MWT while members of the control group showed no change or decreased gait speed and walking distance over the 1-month trial. In addition, the experimental group demonstrated significant improvement for the TUG Cognitive (p = 0.05) and those changes were greater than the control group (between group p = 0.040). The experimental group also improved scores on MoCA (p = 0.007) and SDMT (p = 0.01) cognitive outcome measures while the control group did not.ConclusionThe use of immersive gaming technology to engage specific areas of cognition related to gait is feasible in PD. The treadmill training program paired with a customized interactive video game improved walking velocity in addition to non-significant but consistent improvements in other gait measures and cognitive performance in participants with early to mid-stage PD.
| S-EPMC9124833 | biostudies-literature
Project description:INTRODUCTION:Numerous studies have been carried out to explore the potential association between neurologic deficits and variable clinical manifestations of Parkinson's disease (PD). The aim of our study was to investigate the association between cognitive performance and motor dysfunction in Chinese patients with PD. METHODS:Data from 96 patients with PD were obtained from the Parkinson's disease patient cohort database of Huashan Hospital. All participants underwent a comprehensive neuropsychological evaluation to assess cognitive status, that included scoring on the Mini-mental state examination (MMSE), followed by more detailed cognitive assessment on five main cognitive domains (verbal memory, nonverbal memory, visuospatial function, language and attention/executive function). Correlations between cognitive and motor scores were investigated after controlling for age, disease duration, education, and gender. RESULTS:We report a significant correlation between subdomains of cognitive impairment and motor dysfunction using analyses of the multiple linear regression. Notably, executive function and attention was significantly associated with bradykinesia and rigidity, while visuospatial function was associated with bradykinesia and tremor. CONCLUSIONS:The association between motor dysfunction and cognitive decline in PD might highlight deficits represented by a shared neurochemical pathway.
| S-EPMC5474720 | biostudies-literature
Project description:OBJECTIVES:To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS:1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS:We identified four clusters: (1) ? fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and ? poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS:We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials.
| S-EPMC6288789 | biostudies-other
Project description:Background: Cognitive impairment is very common in Parkinson's disease (PD) and constitutes the most debilitating complication of this disease. However, to date, few studies have investigated a genome-wide association in the development of cognitive impairment of PD. We aimed to identify the genetic loci associated with cognitive impairment in patients with sporadic PD by ethnicity-specific genotyping. Materials and methods: We recruited 1,070 patients with PD and performed a genome-wide association study using the Korean Chip, a microarray chip containing 827,400 single-nucleotide polymorphisms (SNPs) optimized for the Korean population. Multiple logistic regression models adjusting for age, sex, years of education, and disease duration were used to compare between patients with and without cognitive impairment, which was defined using the Mini-Mental Status Examination (MMSE) score (MMSE score ? 26 vs. < 26) or the Montreal Cognitive Assessment (MoCA) score (MoCA score ?24 vs. < 24). Results: RYR2 SNP rs10495397 was most significantly associated with cognitive impairment based on the MMSE scores (OR = 3.21; 95% CI = 1.96-5.25, P = 3.36 × 10-6) and CASC17 showed the strongest association with cognitive impairment based on the MoCA scores. However, none of the SNPs were statistically significant after Bonferroni correction. Conclusion: RYR2 may play a role in cognitive impairment in PD by the pathogenic mechanism of neuroinflammation. However, more studies are needed to replicate and validate the results of our functional study.
| S-EPMC7890115 | biostudies-literature
Project description:Deep brain stimulation (DBS) is a surgical procedure that has been shown effective in improving the cardinal motor signs of advanced Parkinson's disease, however, declines in cognitive function have been associated with bilateral subthalamic nucleus (STN) DBS. Despite the fact that most activities of daily living clearly have motor and cognitive components performed simultaneously, postoperative assessments of cognitive and motor function occur, in general, in isolation of one another. The primary aim of this study was to determine the effects of unilateral and bilateral STN DBS on upper extremity motor function and cognitive performance under single- and dual-task conditions in advanced Parkinson's disease patients. Data were collected from eight advanced Parkinson's disease patients between the ages of 48 and 70 years (mean 56.5) who had bilaterally placed STN stimulators. Stimulation parameters for DBS devices were optimized clinically and were stable for at least 6 months prior to study participation. Data were collected while patients were Off anti-parkinsonian medications under three stimulation conditions: Off stimulation, unilateral DBS and bilateral DBS. In each stimulation condition patients performed a cognitive (n-back task) and motor (force tracking) task under single- and dual-task conditions. During dual-task conditions, patients performed the n-back and force-maintenance task simultaneously. Under relatively simple dual-task conditions there were no differences in cognitive or motor performance under unilateral and bilateral stimulation. As dual-task complexity increased, cognitive and motor performance was significantly worse with bilateral compared with unilateral stimulation. In the most complex dual-task condition (i.e. 2-back + force tracking), bilateral stimulation resulted in a level of motor performance that was similar to the Off stimulation condition. Significant declines in cognitive and motor function under modest dual-task conditions with bilateral but not with unilateral STN DBS suggest that unilateral procedures may be an alternative to bilateral DBS for some patients, in particular, those with asymmetric symptomology. From a clinical perspective, these results underscore the need to assess cognitive and motor function simultaneously during DBS programming as these conditions may better reflect the context in which daily activities are performed.
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Project description:BackgroundQuality of life (QoL) was worse in Parkinson's disease patients with mild cognitive impairment (PD-MCI) or dementia (PDD) than PD patients with normal cognition (PD-NC). The aim of this study was to investigate and compare the potential heterogeneous determinants of QoL in PD patients with different cognitive statuses.MethodsWe recruited 600 PD patients, including 185 PD-NC patients, 336 PD-MCI patients and 79 PDD patients, in this cross-sectional study. All patients completed the QoL assessment by the 39-item Parkinson's Disease Questionnaire (PDQ-39), as well as clinical evaluations and neuropsychological tests. The determinants of the QoL were analyzed by multiple stepwise regression analysis.ResultsQoL was more impaired across the three groups (PD-NC < PD-MCI < PDD). The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, Geriatric Depression Rating Scale (GDS) score and daily levodopa equivalent dose (LED) were independent variables of PDQ-39 in PD-NC patients. The GDS score, disease duration, UPDRS-III score, Epworth Sleepiness Score (ESS) and sex were independent variables of PDQ-39 in PD-MCI patients. The GDS score and disease duration were independent variables of PDQ-39 in PDD patients.ConclusionThe determinants of QoL in PD-NC, PD-MCI and PDD patients were heterogeneous. Motor function was considered to be the most crucial determinant for QoL in PD-NC, while depression was indicated to be the most vital determinant for PD-MCI and PDD. For QoL improvement, clinicians might need to focus more on motor function in PD-NC patients and on depression in PD-MCI and PDD patients.
| S-EPMC7468499 | biostudies-literature
Project description:Mutations in GBA1, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. A higher prevalence and increased severity of motor and non-motor symptoms is observed in PD patients harboring mutant GBA1 alleles, suggesting a link between the gene or gene product and disease development. Interestingly, PD patients without mutations in GBA1 also exhibit lower levels of glucocerebrosidase activity in the central nervous system (CNS), implicating this lysosomal enzyme in disease pathogenesis. Here, we investigated whether modulation of glucocerebrosidase activity in murine models of synucleinopathy (expressing wild type Gba1) affected ?-synuclein accumulation and behavioral phenotypes. Partial inhibition of glucocerebrosidase activity in PrP-A53T-SNCA mice using the covalent inhibitor conduritol-B-epoxide induced a profound increase in soluble ?-synuclein in the CNS and exacerbated cognitive and motor deficits. Conversely, augmenting glucocerebrosidase activity in the Thy1-SNCA mouse model of PD delayed the progression of synucleinopathy. Adeno-associated virus-mediated expression of glucocerebrosidase in the Thy1-SNCA mouse striatum led to decrease in the levels of the proteinase K-resistant fraction of ?-synuclein, amelioration of behavioral aberrations and protection from loss of striatal dopaminergic markers. These data indicate that increasing glucocerebrosidase activity can influence ?-synuclein homeostasis, thereby reducing the progression of synucleinopathies. This study provides robust in vivo evidence that augmentation of CNS glucocerebrosidase activity is a potential therapeutic strategy for PD, regardless of the mutation status of GBA1.
| S-EPMC5181635 | biostudies-literature
Project description:Parkinson's disease (PD) symptoms have been collectively ascribed to malfunctioning of dopamine-related nigro-striatal and cortico-striatal loops. However, some doubts about this proposition are raised by controversies about the temporal progression of the impairments, and whether they are concomitant or not. The present study consists of a systematic revision of literature data on both functional PD impairments and dopaminergic medication effects in order to draw a coherent picture about the disease progression. It was done in terms of an explanatory model for the disruption of implicit knowledge acquisition, motor and cognitive impairments, and the effects of dopaminergic medication on these functions. Cognitive impairments arise at early stages of PD and stabilizes while disruption of implicit knowledge acquisition and motor impairments, are still in progression; additionally, dopaminergic medication reduces motor impairments and increases disruption of implicit knowledge acquisition. Since this model revealed consistency and plausibility when confronted with data of others studies not included in model's formulation, it may turn out to be a useful tool for understanding the multifaceted characteristics of PD.
| S-EPMC3415726 | biostudies-literature
Project description:ObjectiveTo investigate whether baseline olfactory dysfunction in Parkinson's disease (PD) patients is associated with baseline and longitudinal motor and cognitive function.MethodsWe recruited 228 drug-naïve PD patients who were followed for a mean of 6 years. Patients underwent the Cross-Cultural Smell Identification Test (CCSIT), a neuropsychological test, and N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography within 6 months of the baseline evaluation. Olfactory dysfunction was categorized as normosmia (CCSIT score ≥ 9), hyposmia (CCSIT score 5-8), and anosmia (CCSIT score ≤ 4). During the follow-up period, we investigated changes in the levodopa-equivalent dose (LED) and the occurrence of wearing-off, levodopa-induced dyskinesia, and dementia.ResultsAmong the PD patients, 80.7% were hyposmic at the time of diagnosis, and 26.1% were anosmic. Baseline olfactory dysfunction was not associated with either initial parkinsonian motor symptoms or with the longitudinal LED increment and motor complications. Meanwhile, the anosmic group had lower baseline scores on the Korea version of the Boston Naming Test and Stroop color reading test than the normosmic and hyposmic groups. The anosmic group exhibited a higher rate of conversion to dementia than the normosmic [adjusted hazard ratio (HR) 3.99, 95% confidence interval (CI) 1.08-14.72] and hyposmic (adjusted HR 2.48, 95% CI 1.15-5.32) PD groups, regardless of baseline motor deficits and cognitive status.ConclusionBaseline olfactory dysfunction was not associated with motor deficits and complications, but it was associated with cognitive dysfunction and prognosis, suggesting that severe olfactory impairment may reflect early cortical involvement, probably in the frontotemporal region, and rapid spreading of Lewy body pathology.
| S-EPMC7280943 | biostudies-literature