Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Performance on clinical outcomes, activities of daily living and user experience on head-mounted displays for people with vision impairment.

PURPOSE: To compare the objective performance, acceptance and usability of head-mounted displays (HMDs) to provide evidence-based data that could be used to increase the efficiency of device referrals based upon a person's vision loss and functional needs. METHODS: A cross-sectional, counterbalanced, individually controlled crossover study was performed on 15 adults with various eye conditions. Performance was measured when using four HMDs: eSight4, Eyedaptic EYE3, Eyedaptic EYE4 and IrisVision Inspire. Performance on clinical visual acuity tests and contrast were assessed, as well as vision-related activities of daily living (ADL) which were divided into three categories: Reading, Searching & Identifying and Eye-hand Coordination. User-experience was also assessed. Logistic regression analyses, Friedman one-way repeated measure analyses of variance by ranks and multivariate permutation testing were used for analysis. RESULTS: There was a significant improvement in visual acuity when using all devices. For contrast tasks, only the eSight4 and Eyedaptic EYE3 improved performance relative to baseline. For most Reading and Searching & Identifying tasks, the odds of being able to perform the tasks were significantly higher while using the devices. However, the actual performance with most devices (e.g., number of words read or reading speed) did not improve significantly over baseline for most tasks. For the Eye-hand Coordination tasks, participants performed equivalent to or significantly poorer than baseline when using the devices. No demographic or clinical predictors of outcomes were identified. Participants expressed dissatisfaction with the devices' effectiveness, acceptability and usability. CONCLUSIONS: While performance on clinical tests was better when using the devices, performance on most real-world ADLs was equal to or worse than baseline. No single device improved performance on all tasks, and performance on any one task was not improved with all the devices. The overall dissatisfaction with the devices paralleled the lack of objective improvement in the performance of real-world tasks.

Linked shrinkage to improve estimation of interaction effects in regression models.

Objectives: The addition of two-way interactions is a classic problem in statistics, and comes with the challenge of quadratically increasing dimension. We aim to a) devise an estimation method that can handle this challenge and b) to aid interpretation of the resulting model by developing computational tools for quantifying variable importance. Methods: Existing strategies typically overcome the dimensionality problem by only allowing interactions between relevant main effects. Building on this philosophy, and aiming for settings with moderate n to p ratio, we develop a local shrinkage model that links the shrinkage of interaction effects to the shrinkage of their corresponding main effects. In addition, we derive a new analytical formula for the Shapley value, which allows rapid assessment of individual-specific variable importance scores and their uncertainties. Results: We empirically demonstrate that our approach provides accurate estimates of the model parameters and very competitive predictive accuracy. In our Bayesian framework, estimation inherently comes with inference, which facilitates variable selection. Comparisons with key competitors are provided. Large-scale cohort data are used to provide realistic illustrations and evaluations. The implementation of our method in RStan is relatively straightforward and flexible, allowing for adaptation to specific needs. Conclusions: Our method is an attractive alternative for existing strategies to handle interactions in epidemiological and/or clinical studies, as its linked local shrinkage can improve parameter accuracy, prediction and variable selection. Moreover, it provides appropriate inference and interpretation, and may compete well with less interpretable machine learners in terms of prediction.

Optimising personal continuity for older patients in general practice: a cluster randomised stepped wedge pragmatic trial.

AIM: To evaluate the effectiveness, feasibility and acceptability of a multicomponent intervention for improving personal continuity for older patients in general practice. DESIGN: A cluster randomised three-wedged, pragmatic trial during 18 months. SETTING: 32 general practices in the Netherlands. PARTICIPANTS: 221 general practitioners (GPs), practice assistants and other practice staff were included. Practices were instructed to include a random sample of 1050 patients aged 65 or older at baseline and 12-month follow-up. INTERVENTION: The intervention took place at practice level and included opTimise persOnal cOntinuity for oLder (TOOL)-kit: a toolbox containing 34 strategies to improve personal continuity. OUTCOMES: Data were collected at baseline and at six 3-monthly follow-up measurements. Primary outcome measure was experienced continuity of care at the patient level measured by the Nijmegen Continuity Questionnaire (NCQ) with subscales for personal continuity (GP knows me and GP shows commitment) and team/cross-boundary continuity at 12-month follow-up. Secondary outcomes were measured in GPs, practice assistants and other practice staff and included work stress and satisfaction and perceived level of personal continuity. In addition, a process evaluation was undertaken among GPs, practice assistants and other practice staff to assess the acceptability and feasibility of the intervention. RESULTS: No significant effect of the intervention was observed on NCQ subscales GP knows me (adjusted mean difference: 0.05 (95% CI -0.05 to 0.15), p=0.383), GP shows commitment (0.03 (95% CI -0.08 to 0.14), p=0.668) and team/cross-boundary (0.01 (95% CI -0.06 to 0.08), p=0.911). All secondary outcomes did not change significantly during follow-up. Process evaluation among GPs, practice assistants and other practice staff showed adequate acceptability of the intervention and partial implementation due to the COVID-19 pandemic and a high perceived workload. CONCLUSION: Although participants viewed TOOL-kit as a practical and accessible toolbox, it did not improve personal continuity as measured with the NCQ. The absence of an effect may be explained by the incomplete implementation of TOOL-kit into practice and the choice of general outcome measures instead of outcomes more specific for the intervention. TRIAL REGISTRATION NUMBER: International Clinical Trials registry Platform (ICTRP), trial NL8132 (URL: ICTRP Search Portal (who.int).

Predicting Cognitive Decline in Amyloid-Positive Patients With Mild Cognitive Impairment or Mild Dementia.

BACKGROUND AND OBJECTIVES: Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. METHODS: From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF ß-amyloid (Aß) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). RESULTS: In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aß1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aß1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aß1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. DISCUSSION: We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.