Parkinson's Disease Study Research Articles

Genetically stratified Parkinson's disease with freezing of gait is related to specific pattern of cognitive impairment and non-motor dominant endophenotype.

Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. iPDFOG+ individuals presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.

Diffusion tensor metrics, motor and non-motor symptoms in de novo Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurons' degeneration of the substantia nigra, presenting with motor and non-motor symptoms. We hypothesized that altered diffusion metrics are associated with clinical symptoms in de novo PD patients. Fractional Anisotropy (FA) and Mean (MD), Axial (AD), and Radial Diffusivity (RD) were assessed in 55 de novo PD patients (58.62 ± 9.85 years, 37 men) and 55 age-matched healthy controls (59.92 ± 11.25 years, 34 men). Diffusion-weighted images and clinical variables were collected from the Parkinson's Progression Markers Initiative study. Tract-based spatial statistics were used to identify white matter (WM) changes, and fiber tracts were localized using the JHU-WM tractography atlas. Motor and non-motor symptoms were evaluated in patients. We observed higher FA values and lower RD values in patients than controls in various fiber tracts (p-TFCE < 0.05). No significant MD or AD difference was observed between groups. Diffusion metrics of several regions significantly correlated with non-motor (state and trait anxiety and daytime sleepiness) and axial motor symptoms in the de novo PD group. No correlations were observed between diffusion metrics and other clinical symptoms evaluated. Our findings suggest microstructural changes in de novo PD fiber tracts; however, limited associations with clinical symptoms reveal the complexity of PD pathology. They may contribute to understanding the neurobiological changes underlying PD and have implications for developing targeted interventions. However, further longitudinal research with larger cohorts and consideration of confounding factors are necessary to elucidate the underlying mechanisms of these diffusion alterations in de novo PD.

Mixed effects models but not t-tests or linear regression detect progression of apathy in Parkinson’s disease over seven years in a cohort: a comparative analysis

IntroductionWhile there is an interest in defining longitudinal change in people with chronic illness like Parkinson’s disease (PD), statistical analysis of longitudinal data is not straightforward for clinical researchers. Here, we aim to demonstrate how the choice of statistical method may influence research outcomes, (e.g., progression in apathy), specifically the size of longitudinal effect estimates, in a cohort.MethodsIn this retrospective longitudinal analysis of 802 people with typical Parkinson’s disease in the Luxembourg Parkinson's study, we compared the mean apathy scores at visit 1 and visit 8 by means of the paired two-sided t-test. Additionally, we analysed the relationship between the visit numbers and the apathy score using linear regression and longitudinal two-level mixed effects models.ResultsMixed effects models were the only method able to detect progression of apathy over time. While the effects estimated for the group comparison and the linear regression were smaller with high p-values (+ 1.016/ 7 years, p = 0.107, -0.056/ 7 years, p = 0.897, respectively), effect estimates for the mixed effects models were positive with a very small p-value, indicating a significant increase in apathy symptoms by + 2.345/ 7 years (p < 0.001).ConclusionThe inappropriate use of paired t-tests and linear regression to analyse longitudinal data can lead to underpowered analyses and an underestimation of longitudinal change. While mixed effects models are not without limitations and need to be altered to model the time sequence between the exposure and the outcome, they are worth considering for longitudinal data analyses. In case this is not possible, limitations of the analytical approach need to be discussed and taken into account in the interpretation.

Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

Converging peripheral blood microRNA profiles in Parkinson's disease and progressive supranuclear palsy.

MicroRNAs act via targeted suppression of messenger RNA translation in the DNA-RNA-protein axis. The dysregulation of microRNA(s) reflects the epigenetic changes affecting the cellular processes in multiple disorders. To understand the complex effect of dysregulated microRNAs linked to neurodegeneration, we performed a cross-sectional microRNA expression analysis in idiopathic Parkinson's disease (n = 367), progressive supranuclear palsy (n = 35) and healthy controls (n = 416) from the Luxembourg Parkinson's Study, followed by prediction modelling, enriched pathway analysis and target simulation of dysregulated microRNAs using probabilistic Boolean modelling. Forty-six microRNAs were identified to be dysregulated in Parkinson's disease versus controls and 16 in progressive supranuclear palsy versus controls with 4 overlapping significantly dysregulated microRNAs between the comparisons. Predictive power of microRNA subsets (including up to 100 microRNAs) was modest for differentiating Parkinson's disease or progressive supranuclear palsy from controls (maximal cross-validated area under the receiver operating characteristic curve 0.76 and 0.86, respectively) and low for progressive supranuclear palsy versus Parkinson's disease (maximal cross-validated area under the receiver operating characteristic curve 0.63). The enriched pathway analysis revealed natural killer cell pathway to be dysregulated in both, Parkinson's disease and progressive supranuclear palsy versus controls, indicating that the immune system might play an important role in both diseases. Probabilistic Boolean modelling of pathway dynamics affected by dysregulated microRNAs in Parkinson's disease and progressive supranuclear palsy revealed partially overlapping dysregulation in activity of the transcription factor EB, endoplasmic reticulum stress signalling, calcium signalling pathway, dopaminergic transcription and peroxisome proliferator-activated receptor gamma coactivator-1α activity, though involving different mechanisms. These findings indicated a partially convergent (sub)cellular end-point dysfunction at multiple levels in Parkinson's disease and progressive supranuclear palsy, but with distinctive underlying molecular mechanisms.

Retrograde procedural memory is impaired in people with Parkinson's disease with freezing of gait.

Freezing of gait (FOG), is associated with impairment of different cognitive functions. Previous studies hypothesized that FOG may be due to a loss of automaticity. To explore whether FOG is associated with impairment in cognitive functions, focusing on retrograde procedural memory, the memory responsible for the automatic, implicit stored procedures that have been acquired in earlier life stages. In this cross-sectional, case-control study, 288 people with typical Parkinson's disease (PD) from the Luxembourg Parkinson's Study were assigned to Freezers (FOG+) and non-Freezers (FOG-) based on the MDS-UPDRS 2.13 (self-reported FOG episodes) and 3.11 (FOG evaluated by clinicians during gait assessment). Both groups were matched on age, sex and disease duration. Global cognition (MoCA), retrograde procedural memory and visuo-constructive abilities (CUPRO), psychomotor speed and mental flexibility (TMT) were assessed. Furthermore, we repeated our analyses by additionally controlling for depression (BDI-I). Besides lower global cognition (MoCA; p = 0.007) and mental flexibility (TMT-B and Delta-TMT; p < 0.001), FOG+ showed a lower performance in retrograde procedural memory (CUPRO-IS1; p < 0.001) compared to FOG-. After controlling additionally for depression, our main outcome variable CUPRO-IS1 remained significantly lower in FOG+ (p = 0.010). Our findings demonstrated that besides lower global cognition and mental flexibility scores, FOG+ showed lower performance in retrograde procedural memory compared to matched FOG-control patients, even when accounting for factors such as age, sex, disease duration or depression. In the context of limited treatment options, especially for non-invasive therapeutic approaches, these insights on procedural memory and FOG may lead to new hypotheses on FOG etiology and consequently the development of new treatment options.

Molecular characterization of the circadian clock in patients with Parkinson's disease-CLOCK4PD Study protocol.

Circadian rhythms (CRs) orchestrate intrinsic 24-hour oscillations which synchronize an organism's physiology and behaviour with respect to daily cycles. CR disruptions have been linked to Parkinson's Disease (PD), the second most prevalent neurodegenerative disorder globally, and are associated to several PD-symptoms such as sleep disturbances. Studying molecular changes of CR offers a potential avenue for unravelling novel insights into the PD progression, symptoms, and can be further used for optimization of treatment strategies. Yet, a comprehensive characterization of the alterations at the molecular expression level for core-clock and clock-controlled genes in PD is still missing. The proposed study protocol will be used to characterize expression profiles of circadian genes obtained from saliva samples in PD patients and controls. For this purpose, 20 healthy controls and 70 PD patients will be recruited. Data from clinical assessment, questionnaires, actigraphy tracking and polysomnography will be collected and clinical evaluations will be repeated as a follow-up in one-year time. We plan to carry out sub-group analyses considering several clinical factors (e.g., biological sex, treatment dosages, or fluctuation of symptoms), and to correlate reflected changes in CR of measured genes with distinct PD phenotypes (diffuse malignant and mild/motor-predominant). Additionally, using NanoStringⓇ multiplex technology on a subset of samples, we aim to further explore potential CR alterations in hundreds of genes involved in neuropathology pathways. CLOCK4PD is a mono-centric, non-interventional observational study aiming at the molecular characterization of CR alterations in PD. We further plan to determine physiological modifications in sleep and activity patterns, and clinical factors correlating with the observed CR changes. Our study may provide valuable insights into the intricate interplay between CR and PD with a potential to be used as a predictor of circadian alterations reflecting distinct disease phenotypes, symptoms, and progression outcomes.

Genetic landscape of Parkinson's disease and related diseases in Luxembourg.

To explore the genetic architecture of PD in the Luxembourg Parkinson's Study including cohorts of healthy people and patients with Parkinson's disease (PD) and atypical parkinsonism (AP). 809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs. We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk. We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson's Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.

Luxembourg Parkinson's study -comprehensive baseline analysis of Parkinson's disease and atypical parkinsonism.

Deep phenotyping of Parkinson's disease (PD) is essential to investigate this fastest-growing neurodegenerative disorder. Since 2015, over 800 individuals with PD and atypical parkinsonism along with more than 800 control subjects have been recruited in the frame of the observational, monocentric, nation-wide, longitudinal-prospective Luxembourg Parkinson's study. To profile the baseline dataset and to explore risk factors, comorbidities and clinical profiles associated with PD, atypical parkinsonism and controls. Epidemiological and clinical characteristics of all 1,648 participants divided in disease and control groups were investigated. Then, a cross-sectional group comparison was performed between the three largest groups: PD, progressive supranuclear palsy (PSP) and controls. Subsequently, multiple linear and logistic regression models were fitted adjusting for confounders. The mean (SD) age at onset (AAO) of PD was 62.3 (11.8) years with 15% early onset (AAO < 50 years), mean disease duration 4.90 (5.16) years, male sex 66.5% and mean MDS-UPDRS III 35.2 (16.3). For PSP, the respective values were: 67.6 (8.2) years, all PSP with AAO > 50 years, 2.80 (2.62) years, 62.7% and 53.3 (19.5). The highest frequency of hyposmia was detected in PD followed by PSP and controls (72.9%; 53.2%; 14.7%), challenging the use of hyposmia as discriminating feature in PD vs. PSP. Alcohol abstinence was significantly higher in PD than controls (17.6 vs. 12.9%, p = 0.003). Luxembourg Parkinson's study constitutes a valuable resource to strengthen the understanding of complex traits in the aforementioned neurodegenerative disorders. It corroborated several previously observed clinical profiles, and provided insight on frequency of hyposmia in PSP and dietary habits, such as alcohol abstinence in PD.Clinical trial registration: clinicaltrials.gov, NCT05266872.

Correlation of slow-wave sleep with motor and nonmotor progression in Parkinson's disease.

This study aimed to explore the association between slow-wave sleep and the progression of motor and nonmotor symptoms in patients with PD. Data were collected from the Parkinson's Progression Markers Initiative study. Slow-wave sleep, also known as deep non-rapid eye movement (DNREM) sleep, was objectively assessed using the Verily Study Watch. Motor function was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III score, Hoehn and Yahr stage, freezing of gait, motor fluctuations, and dyskinesia severity. Comprehensive assessments were conducted on nonmotor symptoms, including depression, anxiety, global cognitive function, and autonomic dysfunction. Statistical analyses involved repeated-measures analysis of variance and linear regression. A total of 102 patients with PD were included in the study, with a median follow-up duration of 3.4 years. In the long DNREM sleep duration group (n = 55), better motor function (DNREM × time interaction: F(1,100) = 4.866, p = 0.030), less severe sexual dysfunction (p = 0.026), and improved activities of daily living (p = 0.033) were observed at the last follow-up visit compared with the short DNREM sleep duration group (n = 47). Reduced DNREM sleep duration is a risk factor for motor progression (β = -0.251, p = 0.021; 95% confidence interval = -0.465 to -0.038). The findings suggest an association between longer DNREM sleep duration and slower motor and nonmotor progression in patients with PD.

Association between the blood pressure variability and cognitive decline in Parkinson's disease.

High visit-to-visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit-to-visit BPV on cognition in patients with early-stage Parkinson's disease (PD). This is a retrospective analysis of a prospective cohort. A total of 297 patients with early-stage PD (103 mild cognitive impairments [PD-MCI] and 194 normal cognitions [PD-NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD-MCI and PD-NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aβ-42, Aβ, α-synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD-MCI (β=-.15 [95% CI -.29, -.01]). No association was found between BPV and biomarkers. Higher systolic VIM predicted a steeper decline in cognitive tests in PD-MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.

The Foundational Data Initiative for Parkinson Disease: Enabling efficient translation from genetic maps to mechanism.

The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.

Striatal Dopamine Loss in Early Parkinson's Disease: Systematic Review and Novel Analysis of Dopamine Transporter Imaging.

Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Systematic review and novel analysis of DaT imaging studies in early PD. In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.

GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.

The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase affecting its activity. Our results nominate GALC as the gene associated with PD in this locus and suggest that the association of variants in the GALC locus may be driven by their effect of increasing galactosylceramidase expression and activity. Whether altering galactosylceramidase activity could be considered as a therapeutic target should be further studied.

The Impact of Type 2 Diabetes in Parkinson's Disease.

ABSTRACTBackgroundType 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood.ObjectiveThe aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD.MethodsWe analyzed data from the Tracking Parkinson's study to examine the effects of comorbid T2DM on PD progression and quality of life by comparing symptom severity scores assessing a range of motor and nonmotor symptoms.ResultsWe identified 167 (8.7%) patients with PD and T2DM (PD + T2DM) and 1763 (91.3%) patients with PD without T2DM (PD). After controlling for confounders, patients with T2DM had more severe motor symptoms, as assessed by Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (25.8 [0.9] vs. 22.5 [0.3] P = 0.002), and nonmotor symptoms, as assessed by Non‐Motor Symptoms Scale total (38.4 [2.5] vs. 31.8 [0.7] P < 0.001), and were significantly more likely to report loss of independence (odds ratio, 2.08; 95% confidence interval [CI]: 1.34–3.25; P = 0.001) and depression (odds ratio, 1.62; CI: 1.10–2.39; P = 0.015). Furthermore, over time, patients with T2DM had significantly faster motor symptom progression (P = 0.012), developed worse mood symptoms (P = 0.041), and were more likely to develop substantial gait impairment (hazard ratio, 1.55; CI: 1.07–2.23; P = 0.020) and mild cognitive impairment (hazard ratio, 1.7; CI: 1.24–2.51; P = 0.002) compared with the PD group.ConclusionsIn the largest study to date, T2DM is associated with faster disease progression in Parkinson's, highlighting an interaction between these two diseases. Because it is a potentially modifiable metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for alleviating parkinsonian symptoms and slowing progression to disability and dementia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

A Multi-Agent Formalism Based on Contextual Defeasible Logic for Healthcare Systems.

In the last decade, smart computing has garnered much attention, particularly in ubiquitous environments, thus increasing the ease of everyday human life. Users can dynamically interact with the systems using different modalities in a smart computing environment. The literature discussed multiple mechanisms to enhance the modalities for communication using different knowledge sources. Among others, Multi-context System (MCS) has been proven quite significant to interlink various context domains dynamically to a distributed environment. MCS is a collection of different contexts (independent knowledge sources), and every context contains its own set of defined rules and facts and inference systems. These contexts are interlinked via bridge rules. However, the interaction among knowledge sources could have the consequences such as bringing out inconsistent results. These issues may report situations such as the system being unable to reach a conclusion or communication in different contexts becoming asynchronous. There is a need for a suitable framework to resolve inconsistencies. In this article, we provide a framework based on contextual defeasible reasoning and a formalism of multi-agent environment is to handle the issue of inconsistent information in MCS. Additionally, in this work, a prototypal simulation is designed using a simulation tool called NetLogo, and a formalism about a Parkinson's disease patient's case study is also developed. Both of these show the validity of the framework.

An efficient modified Hunger Games Search Algorithm for dimensionality reduction: Parkinson's disease phonation case study

An efficient modified Hunger Games Search Algorithm for dimensionality reduction: Parkinson's disease phonation case study

Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease.

Background and ObjectivesOwing to the lack of long-term observations or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson disease (PD) have yet to be drawn. Here, using data from the Parkinson's Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD.MethodsIn this retrospective, observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate to vigorous exercise levels, measured with the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa equivalent dose, and disease duration. We also calculated bootstrapping 95% confidence intervals (CIs) and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using propensity score matching to match for all baseline background factors.ResultsTwo hundred thirty-seven patients with early PD (median [interquartile range] age, 63.0 [56.0–70.0] years, male 69.2%, follow-up duration 5.0 [4.0–6.0] years) were included. Regular physical activity and moderate to vigorous exercise levels at baseline did not significantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were significantly associated with slower deterioration of postural and gait stability (standardized fixed-effects coefficients of the interaction term [βinteraction] = −0.10 [95% CI −0.14 to −0.06]), activities of daily living (βinteraction = 0.08 [95% CI 0.04–0.12]), and processing speed (βinteraction = 0.05 [95% CI 0.03–0.08]) in patients with PD. Moderate to vigorous exercise levels were preferentially associated with slower decline of postural and gait stability (βinteraction = −0.09 [95% CI −0.13 to −0.05]), and work-related activity levels were primarily associated with slower deterioration of processing speed (βinteraction = 0.07 [95% CI 0.04–0.09]). Multiple imputation and propensity score matching confirmed the robustness of our results.DiscussionIn the long term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects.Trial Registration InformationClinicalTrials.gov Identifier: NCT01176565.Classification of EvidenceThis study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early PD was associated with slower decline of several clinical parameters.

Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach.

Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. We used MR to assess the association between age at menopause and age at menarche with PD risk. We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29). A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.

Neuroanatomical changes in early Parkinson's disease with mild cognitive impairment: a VBM study; the Parkinson's Disease Cognitive Impairment Study (PaCoS).

Mild cognitive impairment (MCI) is common in Parkinson's disease (PD), but the underlying pathological mechanism has not been fully understood. Voxel-based morphometry could be used to evaluate regional atrophy and its relationship with cognitive performances in early PD-MCI. One hundred and six patients with PD were recruited from a larger cohort of patients, the Parkinson's Disease Cognitive Impairment Study (PaCoS). Subject underwent a T1-3D MRI and a complete clinical and neuropsychological evaluation. Patients were divided into PD with normal cognition (PD-NC) and PD-MCI according to the MDS level II criteria-modified for PD-MCI. A subgroup of early patients with short disease duration (≤ 2years) was also identified. VBM analysis between PD-NC and PD-MCI and between early PD-NC and PD-MCI was performed using two-sample t tests with whole-brain statistical threshold of p < 0.001 uncorrected in the entire PD group and p < 0.05 FWE inside ROIs, in the early PD. Forty patients were diagnosed with MCI and 66 were PD-NC. PD-MCI patients showed significant gray matter (GM) reduction in several brain regions, including frontal gyrus, precuneus, angular gyrus, temporal lobe, and cerebellum. Early PD-MCI showed reduction in GM density in superior frontal gyrus and cerebellum. Moreover, correlation analysis between neuropsychological performances and GM volume of early PD-MCI patients showed associations between performances of Raven and superior frontal gyrus volume, Stroop time and inferior frontal gyrus volume, accuracy of Barrage and volume of precuneus. The detection of frontal and cerebellar atrophy, even at an early stage, could be used as an early marker of PD-related cognitive impairment.