In Their Own Words: Fears Expressed by People with Parkinson's Disease in an Online Symptom Database.

Parkinson's disease (PD) carries substantial psychosocial burden. Using a database of responses by people with PD reporting up to five "most bothersome problems," we identified 225 fear-based verbatims, which were organized using the framework method into 26 categories. Commonly-reported fears included uncertainty of progression (n = 60, 26.7%), fear of future cognitive impairment (n = 24, 10.7%) and fear of becoming a burden on others (n = 23, 10.2%). Fears in PD are wide-ranging and can constitute the most bothersome aspect of the condition. These data can be used to design interventions to lessen the psychosocial burden of PD.

Association between Subjective Cognitive Complaints and Incident Functional Impairment in Parkinson's Disease.

BACKGROUND: Early identification of subjective cognitive complaints (SCC) in Parkinson's disease (PD) may improve patient care if it predicts cognition-related functional impairment (CFI). OBJECTIVES: The aim was to determine the cross-sectional and longitudinal association between SCC and CFI in PD. METHODS: Data were obtained from Fox Insight, an online longitudinal study that collects PD patient-reported outcomes. Participants completed a PD Patient Report of Problems that asked participants for their five most bothersome disease problems. SCCs were placed into eight categories through human-in-the-loop curation and classification. CFI had a Penn Parkinson's Daily Activities Questionnaire (PDAQ-15) score ≤49. Cox proportional hazards models and Kaplan-Meier survival analyses determined if baseline SCC was associated with incident CFI. RESULTS: The PD-PROP cohort (N = 21,160) was 55.8% male, mean age was 65.9 years, and PD duration was 4.8 years. At baseline, 31.9% (N = 6750) of participants reported one or more SCCs among their five most bothersome problems, including memory (13.2%), language/word finding (12.5%), and concentration/attention (9.6%). CFI occurred in 34.7% (N = 7332) of participants. At baseline, SCC was associated with CFI (P-value <0.001). SCC at baseline was associated with incident CFI (hazard ratio [HR] = 1.58 [95% confidence interval: 1.45, 1.72], P-value <0.001), as did cognitive impairment not otherwise specified (HR = 2.31), executive abilities (HR = 1.97), memory (HR = 1.85), and cognitive slowing (HR = 1.77) (P-values <0.001). Kaplan-Meier curves showed that by year 3 an estimated 45% of participants with any SCC at baseline developed new-onset CFI. CONCLUSIONS: Self-reported bothersome cognitive complaints are associated with new-onset CFI in PD. Remote electronic assessment can facilitate widespread use of patient self-report at population scale. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Internal tremor in people with Parkinson's Disease: Demographic characteristics and comorbid symptoms.

Introduction: Internal tremor (IT) occurs in > 30 % of people with Parkinson's Disease (PwPD), but remains largely uninvestigated. Our objective was to describe demographic characteristics and associated symptoms in PwPD who reported IT. Methods: This was a matched case-control survey study. Data were from PwPD in the Fox Insight study who answered the Patient Report of Problems (PD-PROP) assessment, a series of open-ended questions that asks people to report in their own words their most bothersome PD-related problems. Cases were those who reported IT ≥ 1 times compared with PwPD controls who did not report IT and were matched 1:3 by age and disease duration. Results: 243 PwPD reported IT as a bothersome problem. Mean (SD) age of cases was 64.9 (9.4) years and disease duration was 3.8 (4.0) years. The proportion of women was greater among cases compared to controls (74 % vs 47 %, p < 0.0001). External tremor as a PD-PROP symptom was reported by 98 % cases and 48 % controls (p < 0.0001). Several non-motor symptoms were more common among cases than controls, including anxiety (35 % vs 20 %), fatigue (41 % vs 31 %), and pain (57 % vs 37 %). The odds of IT was significantly higher in women when adjusting for anxiety and motor experiences of daily living score (OR 3.07, 95 %CI 2.14-4.41, p < 0.0001). Conclusion: PwPD with IT report a range of associated symptoms, including external tremor, anxiety, and pain. Sex differences in the experience of IT may exist. Studies of IT are needed to understand its etiology and inform clinical care.

Cox (1972): recollections and reflections.

I present some personal memories and thoughts on Cox's 1972 paper "Regression Models and Life-Tables".

Military culture and collaborative decision-making in mental healthcare: cultural, communication and policy considerations.

Military culture relies on hierarchy and obedience, which contradict the implementation and use of collaborative care models. In this commentary, a team of lived experience, clinical and research experts discuss, for the first time, cultural, communication and policy considerations for implementing collaborative care models in military mental healthcare settings.

What Patients Say: Large-Scale Analyses of Replies to the Parkinson's Disease Patient Report of Problems (PD-PROP).

BACKGROUND: Free-text, verbatim replies in the words of people with Parkinson's disease (PD) have the potential to provide unvarnished information about their feelings and experiences. Challenges of processing such data on a large scale are a barrier to analyzing verbatim data collection in large cohorts. OBJECTIVE: To develop a method for curating responses from the Parkinson's Disease Patient Report of Problems (PD-PROP), open-ended questions that asks people with PD to report their most bothersome problems and associated functional consequences. METHODS: Human curation, natural language processing, and machine learning were used to develop an algorithm to convert verbatim responses to classified symptoms. Nine curators including clinicians, people with PD, and a non-clinician PD expert classified a sample of responses as reporting each symptom or not. Responses to the PD-PROP were collected within the Fox Insight cohort study. RESULTS: Approximately 3,500 PD-PROP responses were curated by a human team. Subsequently, approximately 1,500 responses were used in the validation phase; median age of respondents was 67 years, 55% were men and median years since PD diagnosis was 3 years. 168,260 verbatim responses were classified by machine. Accuracy of machine classification was 95% on a held-out test set. 65 symptoms were grouped into 14 domains. The most frequently reported symptoms at first report were tremor (by 46% of respondents), gait and balance problems (>39%), and pain/discomfort (33%). CONCLUSION: A human-in-the-loop method of curation provides both accuracy and efficiency, permitting a clinically useful analysis of large datasets of verbatim reports about the problems that bother PD patients.

Using a stakeholder-engaged, iterative, and systematic approach to adapting collaborative decision skills training for implementation in VA psychosocial rehabilitation and recovery centers.

BACKGROUND: Adaptation of interventions is inevitable during translation to new populations or settings. Systematic approach to adaptation can ensure that fidelity to core functions of the intervention are preserved while optimizing implementation feasibility and effectiveness for the local context. In this study, we used an iterative, mixed methods, and stakeholder-engaged process to systematically adapt Collaborative Decision Skills Training for Veterans with psychosis currently participating in VA Psychosocial Rehabilitation and Recovery Centers. METHODS: A modified approach to Intervention Mapping (IM-Adapt) guided the adaptation process. An Adaptation Resource Team of five Veterans, two VA clinicians, and four researchers was formed. The Adaptation Resource Team engaged in an iterative process of identifying and completing adaptations including individual qualitative interviews, group meetings, and post-meeting surveys. Qualitative interviews were analyzed using rapid matrix analysis. We used the modified, RE-AIM enriched expanded Framework for Reporting Adaptations and Modifications to Evidence-based interventions (FRAME) to document adaptations. Additional constructs included adaptation size and scope; implementation of planned adaptation (yes-no); rationale for non-implementation; and tailoring of adaptation for a specific population (e.g., Veterans). RESULTS: Rapid matrix analysis of individual qualitative interviews resulted in 510 qualitative codes. Veterans and clinicians reported that the intervention was a generally good fit for VA Psychosocial Rehabilitation and Recovery Centers and for Veterans. Following group meetings to reach adaptation consensus, 158 adaptations were completed. Most commonly, adaptations added or extended a component; were small in size and scope; intended to improve the effectiveness of the intervention, and based on experience as a patient or working with patients. Few adaptations were targeted towards a specific group, including Veterans. Veteran and clinician stakeholders reported that these adaptations were important and would benefit Veterans, and that they felt heard and understood during the adaptation process. CONCLUSIONS: A stakeholder-engaged, iterative, and mixed methods approach was successful for adapting Collaborative Decision Skills Training for immediate clinical application to Veterans in a psychosocial rehabilitation center. The ongoing interactions among multiple stakeholders resulted in high quality, tailored adaptations which are likely to be generalizable to other populations or settings. We recommend the use of this stakeholder-engaged, iterative approach to guide adaptations.

The Safety of Deutetrabenazine for Chorea in Huntington Disease: An Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved in the USA, China, Australia, Israel, Brazil, and South Korea for the treatment of chorea associated with Huntington disease. OBJECTIVE: We aimed to evaluate the long-term safety and tolerability of deutetrabenazine for the treatment of Huntington disease. METHODS: This open-label, single-arm, multi-center study included patients who completed a double-blind study (Rollover) and patients who converted overnight from a stable tetrabenazine dose (Switch). Exposure-adjusted incidence rates (adverse events per person-year) were calculated. Efficacy was analyzed using a stable post-titration timepoint (8 weeks). Changes in the Unified Huntington's Disease Rating Scale total motor score and total maximal chorea score from baseline to week 8, as well as those from week 8 to week 145 (or the last visit on the study drug if that occurred earlier), were evaluated as both efficacy and safety endpoints during the study. RESULTS: Of 119 patients (Rollover, n = 82; Switch, n = 37), 100 (84%) completed ≥ 1 year of treatment. End-of-study exposure-adjusted incidence rates for adverse events in Rollover and Switch, respectively, were: any, 2.57 and 4.02; serious, 0.11 and 0.14; leading to dose suspension, 0.05 and 0.04. Common adverse events (≥ 4% either cohort) included somnolence (Rollover, 20%; Switch, 30%), depression (32%; 22%), anxiety (27%; 35%), insomnia (23%; 16%), and akathisia (6%; 11%). Adverse events of interest included suicidality (9%; 5%) and parkinsonism (4%; 8%). Mean dose at week 8 was 38.1 mg (Rollover) and 36.5 mg (Switch). Mean dose across cohorts after titration was 37.6 mg; at the final visit, mean dose across cohorts was 45.7 mg. Patients showed minimal change in the Unified Huntington's Disease Rating Scale total maximal chorea scores with stable dosing from weeks 8-145 or at the end of treatment, but total motor score increased versus week 8 (mean change [standard deviation]: 8.2 [11.9]). There were no unexpected adverse events upon drug withdrawal, and mean (standard deviation) total maximal chorea scores increased 4.7 (4.6) units from week 8 to 1-week follow-up. CONCLUSIONS: Adverse events observed with long-term deutetrabenazine exposure were consistent with previous studies. Reductions in chorea persisted over time. Upon treatment cessation, there was no unexpected worsening of chorea. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01897896.

Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Dissecting the Domains of Parkinson's Disease: Insights from Longitudinal Item Response Theory Modeling.

BACKGROUND: Longitudinal item response theory (IRT) models previously suggested that the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor examination has two salient domains, tremor and nontremor, that progress in time and in response to treatment differently. OBJECTIVE: Apply longitudinal IRT modeling, separating tremor and nontremor domains, to reanalyze outcomes in the previously published clinical trial (Study of Urate Elevation in Parkinson's Disease, Phase 3) that showed no overall treatment effects. METHODS: We applied unidimensional and multidimensional longitudinal IRT models to MDS-UPDRS motor examination items in 298 participants with Parkinson's disease from the Study of Urate Elevation in Parkinson's Disease, Phase 3 (placebo vs. inosine) study. We separated 10 tremor items from 23 nontremor items and used Bayesian inference to estimate progression rates and sensitivity to treatment in overall motor severity and tremor and nontremor domains. RESULTS: The progression rate was faster in the tremor domain than the nontremor domain before levodopa treatment. Inosine treatment had no effect on either domain relative to placebo. Levodopa treatment was associated with greater slowing of progression in the tremor domain than the nontremor domain regardless of inosine exposure. Linear patterns of progression were observed. Despite different domain-specific progression patterns, tremor and nontremor severities at baseline and over time were significantly correlated. CONCLUSIONS: Longitudinal IRT analysis is a novel statistical method addressing limitations of traditional linear regression approaches. It is particularly useful because it can simultaneously monitor changes in different, but related, domains over time and in response to treatment interventions. We suggest that in neurological diseases with distinct impairment domains, clinical or anatomical, this application may identify patterns of change unappreciated by standard statistical methods. © 2022 International Parkinson and Movement Disorder Society.

Longitudinal Cohort Study of Verbatim-Reported Postural Instability Symptoms as Outcomes for Online Parkinson's Disease Trials.

BACKGROUND: The Parkinson's Disease Patient Report of Problems (PD-PROP) captures the problems and functional impact that patients report verbatim. Online research participation and advances in language analysis have enabled longitudinal collection and classification of symptoms as trial outcomes. OBJECTIVE: Analyze verbatim reports longitudinally to examine postural-instability symptoms as 1) precursors of subsequent falling and 2) newly occurring symptoms that could serve as outcome measures in randomized controlled trials. METHODS: Problems reported by >25,000 PD patients in their own words were collected online in the Fox Insight observational study and classified into symptoms by natural language processing, clinical curation, and machine learning. Symptoms of gait, balance, falling, and freezing and associated reports of having fallen in the last month were analyzed over three years of longitudinal observation by a Cox regression model in a cohort of 8,287 participants. New onset of gait, balance, falling, and freezing symptoms was analyzed by Kaplan-Meier survival techniques in 4,119 participants who had not previously reported these symptoms. RESULTS: Classified verbatim symptoms of postural instability were significant precursors of subsequent falling among participants who were older, female, and had longer PD duration. New onset of symptoms steadily increased and informed sample size estimates for clinical trials to reduce the onset of these symptoms. CONCLUSION: The tools to analyze symptoms reported by PD patients in their own words and capacity to enroll large numbers of research participants online support the feasibility and statistical power for conducting randomized clinical trials to detect effects of therapeutic interventions.

Re-Analysis of the STEADY-PD II Trial-Evidence for Slowing the Progression of Parkinson's Disease.

BACKGROUND: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression. OBJECTIVES: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined. METHODS: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy. RESULTS: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced. CONCLUSIONS: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.

Novel Approach to Movement Disorder Society-Unified Parkinson's Disease Rating Scale Monitoring in Clinical Trials: Longitudinal Item Response Theory Models.

BACKGROUND: Although nontremor and tremor Part 3 Movement Disorder Society-Unified Parkinson's Disease Rating Scale items measure different impairment domains, their distinct progression and drug responsivity remain unstudied longitudinally. The total score may obscure important time-based and treatment-based changes occurring in the individual domains. OBJECTIVE: Using the unique advantages of item response theory (IRT), we developed novel longitudinal unidimensional and multidimensional models to investigate nontremor and tremor changes occurring in an interventional Parkinson's disease (PD) study. METHOD: With unidimensional longitudinal IRT, we assessed the 33 Part 3 item data (22 nontremor and 10 tremor items) of 336 patients with early PD from the STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine for PD, placebo vs. isradipine) study. With multidimensional longitudinal IRT, we assessed the progression rates over time and treatment (in overall motor severity, nontremor, and tremor domains) using Markov Chain Monte Carlo implemented in Stan. RESULTS: Regardless of treatment, patients showed significant but different time-based deterioration rates for total motor, nontremor, and tremor scores. Isradipine was associated with additional significant deterioration over placebo in total score and nontremor scores, but not in tremor score. Further highlighting the 2 separate latent domains, nontremor and tremor severity changes were positively but weakly correlated (correlation coefficient, 0.108). CONCLUSIONS: Longitudinal IRT analysis is a novel statistical method highly applicable to PD clinical trials. It addresses limitations of traditional linear regression approaches and previous IRT investigations that either applied cross-sectional IRT models to longitudinal data or failed to estimate all parameters simultaneously. It is particularly useful because it can separate nontremor and tremor changes both over time and in response to treatment interventions.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Predictive Value of Verbatim Parkinson's Disease Patient-Reported Symptoms of Postural Instability and Falling.

BACKGROUND: Postural instability is an intractable sign of Parkinson's disease, associated with poor disease prognosis, fall risk, and decreased quality of life. OBJECTIVE: 1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls. METHODS: Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11-2.13. T-tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses. RESULTS: Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11-2.13 measures were predictive of future falls. CONCLUSION: Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses.

Longitudinal Change in Quality of Life in Neurological Disorders Measures Over 3 Years in Patients with Early Parkinson's Disease.

BACKGROUND: The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system. OBJECTIVE: The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease. METHODS: An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort. RESULTS: Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35-0.39). The largest effect size for change over the year in which levodopa was initiated was -0.19 for lower extremity function-mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group. CONCLUSIONS: More sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Isradipine plasma pharmacokinetics and exposure-response in early Parkinson's disease.

OBJECTIVES: Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression. METHODS: Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy. RESULTS: Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, rs : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (rs : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02). INTERPRETATION: In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02168842.

Design of a virtual longitudinal observational study in Parkinson's disease (AT-HOME PD).

OBJECTIVE: The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site-centric therapeutic trials in Parkinson's disease and generate novel insights. The value of this approach has never been more evident than during the current COVID-19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow-up of clinical trial participants, (2) compare changes in smartphone-based assessments, online patient-reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson's disease disability and progression. METHODS: Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele-Health Outcomes in Multiyear Extensions of Parkinson's Disease trials (AT-HOME PD), a two-year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone-based assessments of motor function and socialization, and patient-reported outcomes online. RESULTS: From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study's smartphone application and 161 (71%) have completed patient-reported outcomes on the online platform. INTERPRETATION: It is feasible to conduct a large-scale, international virtual observational study following the completion of participation in brick-and-mortar clinical trials in Parkinson's disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow-up of clinical trial participants and design of future clinical trials.

Cognitive impairment in Parkinson's disease: Associations between subjective and objective cognitive decline in a large longitudinal study.

BACKGROUND: Cognitive decline creates substantial morbidity and cost in Parkinson's disease (PD) and clinicians have limited tools for counseling patients on prognosis. We aimed to use data from a randomized, controlled trial of isradipine in Parkinson's disease (STEADY-PD III) to determine which objective cognitive domain deficits drive patient complaints of cognitive symptoms. METHODS: Neuro-Quality of Life (Neuro-QoL) Cognition: General Concerns (GC), and Cognition: Executive Function (EF) (subjective measures), were administered at baseline, 1, 2, and 3 years in 324 people with PD. Baseline Montreal Cognitive Assessment (MoCA) was divided into 4 domains: visuospatial/executive, memory, attention, and language (objective measures). Spearman rank correlations and multiple regression models adjusted for other clinical variables evaluated associations between baseline Neuro-QoL domains and individual MoCA domains. Multiple regression models evaluated the association between baseline MoCA domain performance and Neuro-QoL change over three years. Cox proportional hazards predicted development of PD-MCI based on baseline and time-varying Neuro-QoL reporting. RESULTS: Higher MoCA memory performance was associated with better Neuro-QoL-GC (ß = 0.75, SE = 0.391, p = 0.05) and Neuro-QoL-EF (ß = 0.81, SE = 0.36, p = 0.02) at baseline. There was a trend for baseline MoCA memory to predict the degree of subjective cognitive decline on the Neuro-QoL-EF (ß = 0.70, SE = 0.42, p = 0.09). Baseline depression and anticholinergic use were associated with worsened Neuro-QoL-EF and Neuro-QoL-GC. Increasing subjective cognitive complaints in Neuro-QoL-EF were associated with development of PD-MCI over 3 years of follow-up (HR = 0.95, CI = 0.90-1.0, p = 0.039). CONCLUSIONS: Objective memory impairment may be a stronger predictor than executive or visuospatial dysfunction for the presence of subjective cognitive complaints in early PD.