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Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3–5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

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.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.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.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.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.

Objective Emotional distress is common in both survivors and their informal caregivers following admission to a neuroscience intensive care unit (Neuro-ICU) and can negatively affect their individual recovery and quality of life. Neuro-ICU survivor-caregiver dyads can influence each other's emotional distress over time, but whether such influence emerges during dyadic treatment remains unknown. The present study involved secondary data analysis of Neuro-ICU dyads enrolled in a randomized clinical trial of a dyadic resiliency intervention, Recovering Together (RT), versus a health education attention placebo control to test dyadic similarities in emotional distress before and after treatment. Method Data were collected from 58 dyads following Neuro-ICU admission. Emotional distress (depression, anxiety, and posttraumatic stress) was assessed at baseline, 6 weeks (postintervention), and 12 weeks later. Nonindependence within survivor-caregiver dyads was examined (i.e., correlations between cross-sectional symptoms and changes in symptoms over time); mutual influence of emotional functioning over time (i.e., "partner effects") was examined using cross-lagged path analyses. Results There were strong, positive cross-sectional correlations between survivor and caregiver distress at postintervention and follow-up and between changes in survivor and caregiver distress from baseline to postintervention and postintervention to follow-up. There were no partner effects. Conclusions Neuro-ICU survivors and their informal caregivers show similar changes in emotional distress after treatment. These findings highlight the potential benefits of intervening on both survivor and caregiver distress following Neuro-ICU admission. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background and ObjectivesRepresentation of persons from marginalized racial and ethnic groups in Parkinson disease (PD) trials has been low, limiting the generalizability of therapeutic options for individuals with PD. Two large phase 3 randomized clinical trials sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), STEADY-PD III and SURE-PD3, screened participants from overlapping Parkinson Study Group clinical sites under similar eligibility criteria but differed in participation by underrepresented minorities. The goal of this research is to compare recruitment strategies of PD participants belonging to marginalized racial and ethnic groups.MethodsA total of 998 participants with identified race and ethnicity consented to STEADY-PD III and SURE-PD3 from 86 clinical sites. Demographics, clinical trial characteristics, and recruitment strategies were compared. NINDS imposed a minority recruitment mandate on STEADY-PD III but not SURE-PD3.ResultsTen percent of participants who consented to STEADY-PD III self-identified as belonging to marginalized racial and ethnic groups compared to 6.5% in SURE-PD3 (difference = 3.9%, 95% confidence interval [CI] 0.4%–7.5%,pvalue = 0.034). This difference persisted after screening (10.1% of patients in STEADY-PD III vs 5.4% in SURE-PD 3, difference = 4.7%, 95% CI 0.6%–8.8%,pvalue = 0.038).DiscussionAlthough both trials targeted similar participants, STEADY-PD III was able to consent and recruit a higher percentage of patients from racial and ethnic marginalized groups. Possible reasons include differential incentives for achieving minority recruitment goals.Trial Registration InformationThis study used data from The Safety, Tolerability, and Efficacy Assessment of Isradipine for Parkinson Disease (STEADY-PD III;NCT02168842) and the Study of Urate Elevation in Parkinson’s Disease (SURE-PD3;NCT02642393).

Detecting obstructive sleep apnea (OSA) is important to both prevent significant comorbidities in people with Down syndrome (DS) and untangle contributions to other behavioral and mental health diagnoses. However, laboratory-based polysomnograms are often poorly tolerated, unavailable, or not covered by health insurance for this population. In previous work, our team developed a prediction model that seemed to hold promise in identifying which people with DS might not have significant apnea and, consequently, might be able to forgo a diagnostic polysomnogram. In this study, we sought to validate these findings in a novel set of participants with DS. We recruited an additional 64 participants with DS, ages 3-35 years. Caregivers completed the same validated questionnaires, and our study team collected vital signs, physical exam findings, and medical histories that were previously shown to be predictive. Patients then had a laboratory-based polysomnogram. The best modeling had a validated negative predictive value of 50% for an apnea-hypopnea index (AHI) 1/hTST and 73.7% for AHI5/hTST. The positive predictive values were 60% and 39.1%, respectively. As such, a clinically reliable screening tool for OSA in people with DS was not achieved. Patients with DS should continue to be monitored for OSA according to current healthcare guidelines.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

A randomized controlled trial established initial efficacy of a novel parent training (PT) intervention for improving oral hygiene and oral health in underserved children with ASD (Fenning et al., 2022), a population at risk for unmet dental needs. The present study describes our emic approach to PT development alongside treatment outcome data examining feasibility, acceptability, and engagement. Families with Medicaid-eligible children with ASD ages 3 to 13 years (85% male, 62% with intellectual disability) were assigned to receive PT (n = 60) or a psychoeducational toolkit (n = 59). Results indicate strong retention, fidelity, and adherence, with quantitative and qualitative metrics revealing high treatment satisfaction and utilization. Discussion focuses on implications for individualizing treatment to optimize engagement of underrepresented families.

Satisfaction with current treatment options for irritable bowel syndrome with constipation (IBS-C) is low, with many patients turning to complementary treatments. Tai Chi is a mind-body medicine practice with proven efficacy in other functional disorders. As a proof-of-concept, we tested the feasibility and preliminary clinical outcomes associated with a Tai Chi program designed for IBS-C.A total of 27 IBS-C patients participated in a single-arm trial of 8 sessions of Tai Chi delivered weekly over 7 weeks via live videoconferencing in group format. Clinical improvement was assessed via change in IBS Symptom Severity Score (IBS-SSS) from baseline to 4 weeks posttreatment (week 11) with secondary outcomes exploring symptom ratings, IBS-related quality of life (IBS-QOL), GI-specific anxiety, abdominal distention, and psychological factors.Despite substantial dropout (n = 7; 26%), the treatment protocol had moderate to excellent feasibility for other criteria. Treatment satisfaction was excellent. Exit interviews confirmed high satisfaction with the program among completers, but a high burden of data collection was noted. One participant experienced an adverse event (mild, exacerbation of sciatica). There was a significant improvement in intra-individual IBS-SSS between baseline and posttreatment (average change -66.5, 95% CI -118.6 to -14.3, p = 0.01). Secondary outcomes were notable for improvements in other IBS symptom scoring measures, IBS-QOL, measured abdominal diameter, and leg strength.Our data provide preliminary evidence of the feasibility of a Tai Chi intervention for IBS-C, show promise for improving outcomes, and identify more streamlined data collection as an area for further program improvement.

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.

We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs—personalized checklists—are used during annual wellness visits with the patient’s PCP. A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half-time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.

OBJECTIVE Children with autism spectrum disorder (ASD) have difficulty participating in dental care and experience significant unmet dental needs. We examined the efficacy of parent training (PT) for improving oral hygiene and oral health in underserved children with ASD. METHOD Families of Medicaid-eligible children with ASD (ages 3–13 years, 85% boys, 62% with intellectual disability) reporting difficulty with dental care participated in a 6-month randomized controlled trial comparing PT (n = 60) with a psychoeducational dental toolkit (n = 59). Primary outcomes were parent-reported frequency of twice-daily toothbrushing and dentist-rated visible plaque. Secondary outcomes included parent-reported child behavior problems during home oral hygiene and dentist-rated caries. Dentists were blind to intervention assignment. Analyses were intention to treat. RESULTS Retention was high at posttreatment (3 months, 93%) and 6-month follow-up (90%). Compared with the toolkit intervention, PT was associated with increased twice-daily toothbrushing at 3 (78% vs 55%, respectively; P < .001) and 6 (78% vs 62%; P = .002) months and a reduction in plaque at 3 months (intervention effect, −0.19; 95% confidence interval [CI], −0.36 to −0.02; P = .03) and child problem behaviors at 3 (−0.90; 95% CI, −1.52 to −0.28; P = .005) and 6 (−0.77; 95% CI, −1.39 to −0.14; P = .02) months. Comparatively fewer caries developed in children receiving the PT intervention over 3 months (ratio of rate ratios, 0.73; 95% CI, 0.54 to 0.99; P = .04). CONCLUSIONS PT represents a promising approach for improving oral hygiene and oral health in underserved children with ASD at risk for dental problems.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Higher serum urate concentration is associated with decreased risk of Parkinson’s disease (PD) as well as slower disease progression, but its relationship with severity of PD remains unclear. This study investigated whether changes in serum urate concentration over 5 years were associated with disease progression assessed by MDS-UPDRS Part III score, Hoehn and Yahr stage, or DaTscan imaging. Average serum urate concentration was stable over time and change in serum urate concentration did not correlate with worsening of measures of PD progression. These results suggest that serum urate concentration is not a monitoring biomarker of PD progression in early stages.

Background Spinal manipulation may reduce migraine frequency, but effects of multimodal chiropractic care on migraine frequency have not been evaluated. Methods We conducted a pilot randomized controlled trial comparing multimodal chiropractic care + enhanced usual care (MCC+) versus enhanced usual care alone (EUC) among adult women with episodic migraine. EUC was comprised of usual medical care and migraine education literature. MCC+ participants received 10 sessions of chiropractic care over 14 weeks. Primary aims evaluated feasibility of recruitment, retention, protocol adherence, and safety. Change in migraine days was a secondary aim. Results Of 422 patients screened, 61 were randomized over 20 months. Fifty-seven (93%) completed daily migraine logs during the intervention, 51 (84%) completed final follow-up, and 45 (74%) completed all assessments. Twenty-four of 29 MCC+ participants (83%) attended > 75% of the chiropractic sessions. Ninety-eight non-serious adverse events were reported by 26 participants (43%) with 39 events among 11 EUC participants and 59 events among 15 MCC+ participants. MCC+ participants experienced greater reductions in migraine days (−2.9 days for MCC+ vs. −1.0 days for EUC, difference = −1.9; 95% confidence interval: −3.5, −0.4). Conclusions Pre-specified feasibility criteria were not met, but deficits were remediable. Preliminary data support a definitive trial of MCC+ for migraine. Trial Registration This study is registered at Clinicaltrials.gov (NCT03177616).

ObjectiveTo identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation.MethodsPlasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2−/PD+, and 65 LRRK2−/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons.ResultsPlasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2− participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001).ConclusionsMetabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.

An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p

Background Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. Methods We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. Results Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus −1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (−11.0 minutes versus placebo, 95% confidence interval −28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (−7.7 minutes versus placebo, 95% confidence interval −22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (−1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. Conclusion This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

To examine effects of a virtual mind–body group for adolescents with neurofibromatoses (NF1 and NF2; Resilient Youth with Neurofibromatosis; RY-NF) on multiple resiliency factors against a health education attention control (Health Education for Youth with Neurofibromatosis; HE-NF) using data from a randomized controlled trial. Specifically, our research question was whether adolescents randomized to the RY-NF (versus the HE-NF) would have greater improvements in resiliency factors at post-intervention and whether these gains would be maintained at 6-month follow-up. Adolescents with NF (n = 51; M age 12–17) were randomly assigned to RY-NF (n = 27) or HE-NF (n = 24). Resiliency factors (mindfulness, coping, gratitude, optimism, and social support) were collected at baseline, post-intervention (88%), and 6-month follow-up (82%). Participation in the RY-NF was associated with greater pre-to-post improvements in gratitude (Mdifference = 4.38; 95% CI—0.52–8.23; p = .027) and mindfulness (Mdifference= 9.41; 95% CI 4.40–14.42.; p

Background and ObjectivesIn a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.MethodsParticipants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 106 cells/kg and 3 × 106 cells/kg at 4-week intervals.ResultsThe Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of −2.7 points per the ALS Functional Rating Scale–Revised, whereas the other 2 changed by an average of −10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.DiscussionTreg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).Classification of EvidenceThis study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.

Clinical trials testing interventions for prodromal Parkinson disease (PD) hold particular promise for preserving neuronal function and thereby slowing or even forestalling progression to overt PD. Selection of the appropriate target population and outcome measures presents challenges unique to prodromal PD. We propose 3 clinical trial designs, spanning phase 2a, phase 2b, and phase 3 development, that might serve as templates for prodromal PD trials. The proposed phase 2a trial is of a 3-arm design of short duration and focuses on proof of concept with respect to target engagement and change in a motor outcome in a subset of prodromal participants who already manifest asymptomatic but measurable motor dysfunction as an exploratory aim. The proposed phase 2b trial suggests progression of dopamine transporter imaging specific binding ratio as a primary outcome evaluated annually over 2 years with phenoconversion to PD as a key secondary outcome. The proposed phase 3 trial is a large, simple design of a nutraceutical or behavioral intervention with remote administration and phenoconversion as the primary outcome. We then consider what additional data are needed in the short term to better design prodromal PD trials and examine what longer-term goals would accelerate discovery of safe and effective therapies for individuals at risk of PD. Clear and potentially context-specific definitions of phenoconversion and validation of intermediate endpoints are needed in the short term. The use of adaptive trial designs, master protocols, and research registries would help accelerate therapy development in the long term.

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 (

Background Stress and negative emotions contribute to atrial fibrillation (AF). Mind-body practices decrease stress and negative emotions and may reduce AF episodes and improve quality of life for patients with AF. Objective We examined the effects of a multimodal mind-body program, the SMART Program, on AF-related quality of life in patients with paroxysmal AF (PAF). Methods In this randomized, waitlist-controlled pilot trial, 18 subjects with PAF participated in an 8-week SMART Program delivered online immediately or 3 months later. Validated measures were completed at baseline and at 3 and 6 months (waitlist group only). Results Comparing pre- vs post-program scores among all 18 participants, subjects reported improvement in AF-related quality of life (Cohen's d=0.75, P = .005) and depression (d = 0.50, P = .05) but not anxiety (d = 0.35, P = .16). Subjects also reported improvements in AF symptom severity (P = .026), distress (P = .014), positive affect (P = .003), and ability to cope with stress (P = .001). Compared to waitlist control subjects, those in the immediate group reported improvement in positive affect (d = 1.20, P = .021) and coping with stress (d = 1.36, P = .011) after participating in the program. Conclusion The SMART Program, delivered virtually, may enhance positive emotions and coping with stress as well as decrease negative emotions and AF symptoms. These results warrant a larger trial to better understand the potential benefits of such programs for patients with PAF.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM, SLC2A2, MATE1, MATE2, and OCT1. Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

Objectives Tai Chi (TC) may benefit older adults with a variety of diseases and disabilities. We tested the hypothesis that TC improves physical function in older adults living in low-income housing facilities. Design Cluster randomized controlled trial. Setting Subsidized housing facilities in Boston, Massachusetts, and neighboring communities. Participants Volunteers were recruited from 15 facilities. The 180 randomized participants were 60 years of age or older, able to understand English and participate in TC, expected to remain in the facility for 1 year, and able to walk independently. Intervention TC classes were conducted in the housing facilities twice/week for 1 year and compared with monthly health promotion educational classes and social calls. Measurements The primary outcome was physical function measured by the Short Physical Performance Battery (SPPB). Secondary outcomes included other aspects of physical and cognitive function, and falls. Results An interim analysis revealed less improvement over 12 months in SPPB scores among TC participants (+.20 units; 95% confidence interval [CI] = -.20 to +.60; P = .69) vs control participants (+.51 units; 95% CI = +.15 to +.87; P = .007), a difference of -.31 units (95% CI = -.66 to .04; P = .082). This met the criterion for futility, and the Data Safety Monitoring Board recommended trial termination. No differences were found in 6- or 12-month changes favoring TC in any secondary outcomes or adverse events. Conclusion In older adults with multiple chronic conditions living in subsidized housing facilities, 6 and 12 months of twice/week TC classes were not associated with improvements in functional health. J Am Geriatr Soc 67:1812-1819, 2019.

Background: Nutritional status is an important prognostic factor in Amyotrophic Lateral Sclerosis (ALS). We wished to study the safety, tolerability and efficacy of nutritional counseling with or without an mHealth application to maintain or increase body weight in ALS, compared to standard care. Methods: In this randomized open-label, standard-of-care-controlled, single-center clinical trial, we randomly assigned adults with ALS to one of three nutritional interventions: counseling by their physician or nurse (“standard care”), counseling by a registered dietitian (RD) (“in-person”), or counseling supported by a mHealth app (“mHealth”). Both intervention arms received tailored nutrition recommendations and recorded dietary intake and weight biweekly (mHealth) or monthly (in-person). The primary outcome of weight and secondary and tertiary outcomes of calorie intake, ALSFRS-R, and quality of life (QOL) were recorded at each clinic visit and analyzed in an ITT mixed model analysis. Results: A total of 88 participants were enrolled of whom 78 were included in this analysis. The three arms were well-balanced except for excess males in the mHealth arm and greater weight lost at baseline in the in-person arm. Participants in the mHealth arm increased their calorie intake at month 3 to an average of 94% (95% CI: 85, 103) of recommended calories, compared to 81% (95% CI: 72, 91, p= 0.06 vs. mHealth) in the standard care arm. After 6 months, calorie intake and change in weight was not different among the three arms. QOL scores in the mHealth arm were stable over three months (0.3 points, 95% CI: -1.7, 2.2) compared to worsening in standard care (-2.1 points, 95% CI: -4.0, -0.2, p = 0.09 vs. mHealth), but all scores declined by six months. ALSFRS-R total scores declined by an average of -2.6 points (95% CI: -5.1, -0.1) over six months in the mHealth arm (p=0.13 vs. standard care) compared to -5.8 points (95% CI: -8.2, -3.4, p=0.74 vs. standard care) in the in-person and -5.2 points (95% CI: -7.6, -2.9) in the standard care arm. Conclusions: Nutritional counseling is safe but did not increase weight compared to standard care in ALS patients. Trial Registration: Clinicaltrials.gov identifier NCT02418546. Registered April 16, 2015. Keywords: Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease, mobile health technology, mHealth, nutrition, nutritional counseling, randomized controlled trial

OBJECTIVE LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p

Introduction: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. Methods: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. Discussion: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531–531, 2019. Fil: Pattee, Gary L.. No especifíca; Fil: Plowman, Emily K.. University of Florida; Estados Unidos Fil: Garand, Kendrea L.. University of Alabama at Birmingahm; Estados Unidos Fil: Costello, John. No especifíca; Fil: Brooks, Benjamin Rix. No especifíca; Fil: Berry, James D.. No especifíca; Fil: Smith, Richard A.. No especifíca; Fil: Atassi, Nazem. No especifíca; Fil: Chapin, Jennifer L.. University of Florida; Estados Unidos Fil: Yunusova, Yana. University of Toronto; Canadá Fil: McIlduff, Courtney E.. No especifíca; Fil: Young, Eufrosina. No especifíca; Fil: Macklin, Eric A.. No especifíca; Fil: Locatelli, Eduardo R.. No especifíca; Fil: Silani, Vincenzo. Università degli Studi di Milano; Italia Fil: Heitzman, Daragh. No especifíca; Fil: Wymer, James. University of Florida; Estados Unidos Fil: Goutman, Stephen A.. No especifíca; Fil: Gelinas, Deborah F.. No especifíca; Fil: Perry, Bridget. No especifíca; Fil: Nalipinski, Paige. No especifíca; Fil: Stipancic, Kaila. Children's Hospital Boston; Estados Unidos Fil: O'Brien, Meghan. Children's Hospital Boston; Estados Unidos Fil: Sullivan, Stacey L.. No especifíca; Fil: Pioro, Erik P.. No especifíca; Fil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Green, Jordan R.. No especifíca

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Introduction/aims We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Methods Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to 3 tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 weeks in a double-blind fashion for 16 weeks and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the IL6R gene. Results Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P Discussion Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL6R C allele. These results warrant further study in ALS patients where IL6R genotype and CRP levels may be useful enrichment biomarkers. Classification of evidence This study provides Class I evidence that tocilizumab therapy is safe and well tolerated in ALS patients with high mRNA expression of inflammatory markers. Clinical trial registration Registered at ClinicalTrials.gov (NCT02469896). This article is protected by copyright. All rights reserved.

Objective Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials’ failures to demonstrate disease-modifying benefit, and potential solutions. Methods The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. Results Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. Conclusions We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

© 2021 International Parkinson and Movement Disorder Society, Background: Expectations of benefit have an important therapeutic impact. How well study participants understand the concept of slowing disease progression and how their expectations of benefit are shaped in related clinical trials is not well known. Objective: We aimed to assess expectancy and treatment arm preference of participants in a disease-modification trial in Parkinson disease (PD). Methods: Participant expectations and treatment preference were assessed before treatment randomization in the SURE-PD3 trial (NCT02642393). Results: We included 297 PD patients (0.71 ± 0.67 years after diagnosis). Pre-randomization, 90% of participants expressed a preference for inosine (active treatment) allocation (n = 266/297), and 53% (n = 158) expected to be "somewhat" or "a lot better" in their symptoms over 2 years of treatment with inosine. Conclusions: Participants of a disease-modification trial in PD had likely unrealistic expectations of benefit (ie, improvement in symptoms over years), which may affect clinical trial interpretation and calls for improved education in future disease-modification trials in PD. © 2021 International Parkinson and Movement Disorder Society.