Background

Disease-related gait dysfunction causes extensive disability for persons with Parkinson's disease (PD), with no effective therapies currently available. The potassium channel blocker dalfampridine has been used in multiple neurological conditions and improves walking in persons with multiple sclerosis.

Objectives

We aimed to evaluate the effect of dalfampridine extended release (D-ER) 10mg tablets twice daily on different domains of walking in participants with PD.

Methods

Twenty-two participants with PD and gait dysfunction were randomized to receive D-ER 10mg twice daily or placebo for 4weeks in a crossover design with a 2-week washout period. The primary outcomes were change in the gait velocity and stride length.

Results

At 4weeks, gait velocity was not significantly different between D-ER (0.89m/s±0.33) and placebo (0.93m/s±0.27) conditions. The stride length was also similar between conditions: 0.96m±0.38 for D-ER versus 1.06m±0.33 for placebo. D-ER was generally well tolerated with the most frequent side effects being dizziness, nausea and balance problems.

Conclusions

D-ER is well tolerated in PD patients, however it did not show significant benefit for gait impairment.

Objective

To explore the association between metabolic syndrome and the Unified Parkinson's Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT).

Methods

This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome.

Results

Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p < 0.0001), were more likely to be male (75.3% vs 57.0%; p < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores.

Conclusions

Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding.

Clinicaltrialsgov identifier

NCT00449865.

Objective

Increased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake.

Methods

Data were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from 45 movement disorders centers across the United States and Canada. A total of 1741 subjects with PD participated in the primary clinical study, and caffeine intake data were available for 1549 of these subjects. The association of caffeine intake with rate of progression of PD as measured by the change in the total Unified Parkinson Disease Rating Scale score and the interaction of this association with creatine intake were assessed.

Results

Caffeine intake was not associated with the rate of progression of PD in the main analysis, but higher caffeine intake was associated with significantly faster progression among subjects taking creatine.

Conclusions

This is the largest and longest study conducted to date that addresses the association of caffeine with the rate of progression of PD. These data indicate a potentially deleterious interaction between caffeine and creatine with respect to the rate of progression of PD.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10-second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD. The severity of PD was measured using the global statistical test (GST). In a subset, the heart rate corrected QT-interval (QTcB) was calculated for each electrocardiogram (ECG). The HRV was measured for each ECG and then transformed to fit a normal distribution. The baseline analysis included 653 subjects, with 256 completing the 5-year follow up study. There was an association (P<0.05) between QTcB and PD severity in individuals that were taking QT-interval affecting drugs. A longer QT-interval at baseline was associated with more advanced PD at 5years (P<0.05), and greater disease progression over 5years (P<0.05). There was an association between diminished HRV and an orthostatic decrease in standing blood pressure at baseline in individuals with PD (P<0.05). HRV was not associated with PD severity or progression. In conclusion, we were able to detect measurable associations between the QTcB interval and PD severity, PD severity 5years later, and the change in disease over time. However, routine ECG tracings appear inadequate for the evaluation of autonomic function in PD.

Background

Depression is one of the most common nonmotor symptoms associated with Parkinson's disease (PD), yet the impact of depression on progression of disease is unclear.

Objective

The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD.

Methods

Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years. Multivariate analysis of predictors of change in BDI was performed.

Results

Of 1,741 participants, 746 completed 5-year assessments and were included. Mean age was 62.00 years (standard deviation [SD]: 9.22) and mean disease duration was 1.69 years (SD, 1.16). Mean BDI score was 6.24 (SD, 5.02) at baseline and 8.57 (SD, 6.60) at 5 years. Baseline BDI score was strongly associated with rate of change in all examined measures of disease severity. In multivariate analysis, BDI 5-year change was associated with change in UPDRS Part I (excluding depression item; P < 0.01), 33-item Parkinson's Disease Questionnaire (P < 0.01), EuroQOL Five Dimensional Questionnaire (P = 0.02), and Total Functional Capacity (P < 0.01), but was not associated with motor or cognitive measures. This model explained 68.8% of the variance 5-year change of the BDI score.

Conclusions

Worse baseline BDI scores are associated with a decline in multiple measures of disease severity in PD. Worsening of BDI at 5 years was associated with worsening in UPDRS Part I and quality-of-life measures, but not with motor or cognitive measures.

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinsons disease; however, individuals with Parkinsons disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinsons disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinsons disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinsons disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more high risk factors for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinsons disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinsons disease.

Background

Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited.

Materials and methods

Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study.

Results

During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year.

Conclusions

Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

Objective

To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.

Methods

In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire-39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.

Results

A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] -2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70-120; p < 0.0001) and 38 miles per visit (95% CI 36-56; p < 0.0001).

Conclusions

Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience.

Clinicaltrialsgov identifier

NCT02038959.

Classification of evidence

This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntingtons disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntingtons Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.