Three-dimensional flow instability in a lid-driven isosceles triangular cavity

Linear three-dimensional modal instability of steady laminar two-dimensional states developing in a lid-driven cavity of isosceles triangular cross-section is investigated theoretically and experimentally for the case in which the equal sides form a rectangular corner. An asymmetric steady two-dimensional motion is driven by the steady motion of one of the equal sides. If the side moves away from the rectangular corner, a stationary three-dimensional instability is found. If the motion is directed towards the corner, the instability is oscillatory. The respective critical Reynolds numbers are identified both theoretically and experimentally. The neutral curves pertinent to the two configurations and the properties of the respective leading eigenmodes are documented and analogies to instabilities in rectangular lid-driven cavities are discussed

Progress towards therapies for disease modification in Parkinson's disease

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease

Building a Community-Academic Partnership to Improve Underrepresented Group Awareness of Parkinson’s Disease and Research

BACKGROUND: Members of underrepresented groups (URGs) are more likely to have delays in PD diagnosis and less likely to receive specialized care when compared to non-Hispanic Caucasians. URGs are not proportionately represented in PD clinical research. Barriers to optimal diagnosis and treatment and research participation are multifaceted but include insufficient community knowledge of PD and research. OBJECTIVES: To establish a community-academic partnership (CAP) for increasing knowledge of Parkinson’s Disease (PD) and research opportunities in underrepresented Chicago communities. Here, we describe the development, structure, and outcomes of this pilot program. METHODS: The Chicago Movement Coalition (CMC) was established with academic leaders from two Chicago institutions, community leaders, people with PD and care-partners from two URG-predominant communities. Two community focus groups identified community needs regarding PD and PD research, informing the development of an educational intervention. Educational workshops (EW) were developed and executed to increase knowledge of PD symptoms, treatment, available resources, and research opportunities. RESULTS: Qualitative analysis from two focus groups with 13 participants identified themes related to PD knowledge, perceptions of clinical research and the CMC, and EW ideas. Four community EWs were completed with 162 total participants. Of 97 completed pre- and post-workshops surveys, 98% were satisfied with the workshop and 94% felt more comfortable understanding PD signs, symptoms and treatments. CONCLUSIONS: The CMC is a novel CAP established to address inequities in PD. The coalition experience can be used to inform and structure future community-engaged education and research initiatives aiming to decrease PD clinical and research disparities

Predicting Progression in Parkinson's Disease Using Baseline and 1-Year Change Measures.

BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding

Digital mobility sub-study in the Parkinson's Progressive Marker Initiative (PPMI) study

This poster details the gait sub-study project in PPMI. The sub-study aims to test the feasibility and validity of digital mobility data for enrichment of the prodromal screening and to assess the sensitivity of these measures to early phase progression in prodromal and recently diagnosed patients with Parkinson’s disease. The poster details the protocol and the initial preliminary results of the first 21 participants. The post5er was presented in the Movement Disorders Society Conference held in Copenhagen, Denmark in Sept 2023

Pioglitazone in early Parkinson\u27s disease: a phase 2, multicentre, double-blind, randomised trial

Background A systematic assessment of potential disease-modifying compounds for Parkinson\u27s disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson\u27s disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson\u27s disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson\u27s Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55-6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17-7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35-8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1.83 (80% CI -3.56 to -0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo groups was -1.12 (80% CI -2.93 to 0.69)and the null hypothesis was rejected in favour of futility (p=0.09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers\u27 only sample, suggested that the 15 mg dose is also futile (p=0.09 for LVCF, p= 0.09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0.12 for LVCF, p=0.19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson\u27s disease. Further study of pioglitazone in a larger trial in patients with Parkinson\u27s disease is not recommended

The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort.

ObjectiveThe Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.MethodsA total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.ResultsApproximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01).InterpretationPPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials

Identifying prodromal symptoms at high specificity for Parkinson’s disease

IntroductionTo test drugs with the potential to prevent the onset of Parkinson’s disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems).ObjectiveWe aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls.MethodsWe investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6.ResultsConstipation had an adjusted odds ratio, 6.14 [95% CI: 2.94–12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88–48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively.DiscussionClinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression

Background: The objective of this study was to assess neurofilament light chain as a Parkinson’s disease biomarker. Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson’s disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson’s disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results: In the Parkinson’s Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson’s disease patients (13 � 7.2 pg/mL) than in controls (12 � 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson’s disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions: Neurofilament light chain in serum samples is increased in Parkinson’s disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson’s disease severity. Although the specificity of neurofilament light chain for Parkinson’s disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson’s disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed