Publications by authors named "Eric A Macklin"

145 Publications

Expectations of Benefit in a Trial of a Candidate Disease-Modifying Treatment for Parkinson Disease.

Mov Disord 2021 May 4. Epub 2021 May 4.

Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1002/mds.28630DOI Listing
May 2021

Can a Dyadic Resiliency Program Improve Quality of Life in Cognitively Intact Dyads of Neuro-ICU Survivors and Informal Caregivers? Results from a Pilot RCT.

Neurocrit Care 2021 Apr 21. Epub 2021 Apr 21.

Integrated Brain Health Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, One Bowdoin Square, 1st Floor, Suite 100, Boston, MA, USA.

Background: Neuro-ICU hospitalization for an acute neurological illness is often traumatic and associated with heightened emotional distress and reduced quality of life (QoL) for both survivors and their informal caregivers (i.e., family and friends providing unpaid care). In a pilot study, we previously showed that a dyadic (survivor and caregiver together) resiliency intervention (Recovering Together [RT]) was feasible and associated with sustained improvement in emotional distress when compared with an attention placebo educational control. Here we report on changes in secondary outcomes assessing QoL.

Methods: Survivors (n = 58) and informal caregivers (n = 58) completed assessments at bedside and were randomly assigned to participate together as a dyad in the RT or control intervention (both 6 weeks, two in-person sessions at bedside and four sessions via live video post discharge). We measured QoL domain scores (physical health, psychological, social relations, and environmental), general QoL, and QoL satisfaction using the World Health Organization Quality of Life Abbreviated Instrument at baseline, post treatment, and 3 months' follow-up. We conducted mixed model analyses of variance with linear contrasts to estimate (1) within-group changes in QoL from baseline to post treatment and from post treatment to 3 months' follow-up and (2) between-group differences in changes in QoL from baseline to post treatment and from post treatment to 3 months' follow-up.

Results: We found significant within-group improvements from baseline to post treatment among RT survivors for physical health QoL (mean difference 1.73; 95% confidence interval [CI] 0.39-3.06; p = 0.012), environmental QoL (mean difference 1.29; 95% CI 0.21-2.36; p = 0.020), general QoL (mean difference 0.55; 95% CI 0.13-0.973; p = 0.011), and QoL satisfaction (mean difference 0.87; 95% CI 0.36-1.37; p = 0.001), and those improvements sustained through the 3-month follow-up. We found no significant between-group improvements for survivors or caregivers from baseline to post treatment or from post treatment to 3 months' follow-up for any QoL variables (i.e., domains, general QoL, and QoL satisfaction together).

Conclusions: In this pilot study, we found improved QoL among survivors, but not in caregivers, who received RT and improvements sustained over time. These RT-related improvements were not significantly greater than those observed in the control. Results support a fully powered randomized controlled trial to allow for a definitive evaluation of RT-related effects among dyads of survivors of acute brain injury and their caregivers.
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http://dx.doi.org/10.1007/s12028-021-01222-3DOI Listing
April 2021

Development of a mind body program for obese knee osteoarthritis patients with comorbid depression.

Contemp Clin Trials Commun 2021 Mar 28;21:100720. Epub 2021 Jan 28.

Integrated Brain Health Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, 1 Bowdoin Square, 1st Floor, Suite 100, Boston, 02114, MA, USA.

Knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Depression and obesity are highly comorbid among knee OA patients, and the combination of obesity and depression is associated with decreased physical activity, higher pain and disability, and more rapid cartilage degradation. Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Mind-body interventions to lessen depressive symptoms and increase physical activity offer the ability to target biological, mechanical and psychological mechanisms of OA progression. Our long-term goals are to evaluate the mechanisms by which the Relaxation Response Resiliency Program (3RP) delivered via secure telehealth, and adapted for patients with depression, obesity and knee OA (GetActive-OA) promotes increases in physical activity and improved knee health. We hypothesize that the synergistic interaction between mindfulness, adaptive thinking, positive psychology and healthy living skills of the GetActive-OA will slow the progression of symptomatic knee OA by reducing pro-inflammatory cytokine expression and promoting optimal mechanical loading of the cartilage. Here we present the protocol for a mixed methods study that will adapt the 3RP for the needs of knee OA patients with depression and obesity with a focus on increasing physical activity (GetActive-OA), and iteratively maximize the feasibility, credibility and acceptability of the programs and research procedures.
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http://dx.doi.org/10.1016/j.conctc.2021.100720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859301PMC
March 2021

Correlates of oral health fatalism in caregivers of children with autism spectrum disorder.

Spec Care Dentist 2021 Mar 15;41(2):145-153. Epub 2021 Jan 15.

The Center for Autism and Neurodevelopmental Disorders, Department of Pediatrics, University of California, Irvine, Irvine, California.

Aims: To study correlates of oral health fatalism (OHF) in caregivers of children with autism spectrum disorder (ASD).

Methods And Results: This exploratory analysis used baseline data from 118 Medicaid-eligible families of children with ASD in a multi-site randomized clinical trial of a parent training intervention supporting home oral hygiene and dental visits. About half (46%) of caregivers agreed with the statement "most children eventually develop dental cavities," endorsing OHF. Hispanic caregivers more strongly endorsed OHF than non-Hispanics (cumulative odds ratio = 2.4, 95% confidence interval [CI]: 1.2-4.7, P = .014). Caregivers living alone with children less strongly endorsed OHF than caregivers cohabitating with other adults (cumulative odds ratio = 0.39, 95% CI 0.17-0.86, P = .019). Multivariable analysis maintained significance of ethnicity (P = .030) but not living situation (P = .052). Additional analyses included demographics, parenting beliefs, and children's oral hygiene and oral health status.

Conclusion: About half the caregivers endorsed OHF, with Hispanic caregivers more strongly endorsing OHF. OHF was not significantly associated with oral health behaviors or status, consistent with emerging literature suggesting fatalism is not necessarily linked to health behavior. Further exploration of OHF correlates in families of children with ASD is needed; ethnicity, living situation, child age, and caries status are of interest.
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http://dx.doi.org/10.1111/scd.12564DOI Listing
March 2021

A Live Video Mind-Body Treatment to Prevent Persistent Symptoms Following Mild Traumatic Brain Injury: Protocol for a Mixed Methods Study.

JMIR Res Protoc 2021 Jan 14;10(1):e25746. Epub 2021 Jan 14.

Integrated Brain Health Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Background: Every year, approximately 42 million people sustain a mild traumatic brain injury (mTBI, also known as concussion), with particularly high rates among college-aged individuals. A substantial proportion of these people (44%-64%) develop persistent symptoms that are challenging to treat, costly, and associated with significant disability. Anxiety has emerged as a risk factor for progression from acute to persistent mTBI symptoms.

Objective: This study aims to develop, adapt, and establish the feasibility of the Toolkit for Optimal Recovery after Concussions (TOR-C), an innovative mind-body program aimed at preventing persistent symptoms among young adults with mTBI and comorbid anxiety. Here, we describe the proposed study design, methodology, measurement, and treatment manuals.

Methods: In phase 1, we will conduct individual, live video qualitative interviews (up to n=20) with college-aged individuals with mTBI and comorbid anxiety to inform adaptation of the intervention and study procedures. In phase 2, an open pilot of the live video TOR-C (n=5) with exit interviews will be conducted to explore the initial feasibility, acceptability, and credibility of the program and to refine the study procedures. Phase 3 will involve conducting a feasibility randomized controlled trial (N=50) of the TOR-C versus a health education control (Health Enhancement for Concussions; HE-C), both delivered via live video, to establish feasibility of recruitment procedures (screening, eligibility, and enrollment) and data collection; feasibility, credibility, and acceptability of the live video TOR-C and HE-C (adherence, retention, fidelity, and satisfaction) following prespecified benchmarks; and a signal of improvement in outcomes.

Results: Phase 1 of the study has been approved by the Massachusetts General Hospital Institutional Review Board. Study completion is anticipated by early 2025.

Conclusions: We will develop and test the first mind-body intervention focused on prevention of persistent symptoms following mTBI in young adults with comorbid anxiety problems. This will allow us to establish feasibility markers in postconcussive symptoms, anxiety, disability, and fear avoidance to inform a future efficacy trial of the TOR-C versus HE-C.

International Registered Report Identifier (irrid): PRR1-10.2196/25746.
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http://dx.doi.org/10.2196/25746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843203PMC
January 2021

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

Ann Clin Transl Neurol 2021 02 22;8(2):308-320. Epub 2020 Dec 22.

Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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.
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http://dx.doi.org/10.1002/acn3.51236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886038PMC
February 2021

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients.

Front Neurol 2020 3;11:590573. Epub 2020 Dec 3.

Department of Radiology, A. A. Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States.

Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients. Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters. Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging. We found GSH in motor cortex ( = -0.431, = 0.04) and corticospinal tract ( = -0.497, = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated ( = -0.416, = 0.049), while mean water diffusivity ( = 0.437, = 0.033) and T1ρ ( = 0.482, = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine. Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.
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http://dx.doi.org/10.3389/fneur.2020.590573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744722PMC
December 2020

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial.

Muscle Nerve 2021 03 31;63(3):371-383. Epub 2020 Dec 31.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: 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 or 600 mg daily for 4 wk 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 wk of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (P = .039). Reductions of motor evoked potential (MEP) amplitude (P = .013) and accommodation half-time (P = .002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 wk 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.
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http://dx.doi.org/10.1002/mus.27146DOI Listing
March 2021

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

JAMA Neurol 2021 Feb;78(2):186-196

Department of Neurology, University of California Irvine, Irvine.

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.

Objective: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.

Design, Setting, And Participants: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.

Interventions: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.

Main Outcomes And Measures: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.

Results: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).

Conclusions And Relevance: Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT02450552.
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http://dx.doi.org/10.1001/jamaneurol.2020.4300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684515PMC
February 2021

Effects of a mind-body program on symptoms of depression and perceived stress among adults with neurofibromatosis type 2 who are deaf: A live-video randomized controlled trial.

Complement Ther Med 2021 Jan 20;56:102581. Epub 2020 Oct 20.

Integrated Brain Health Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, USA; Harvard Medical School, USA. Electronic address:

Introduction: Neurofibromatosis type 2 (NF2) is a rare, progressive and incurable genetic disorder associated with progressive hearing loss and eventual deafness. As a group, patients with NF report high levels of stress and depressive symptoms. However, no studies have explored improvement in these symptoms after psychosocial interventions. We have previously shown that a mind-body program tailored to adults with NF2 who are deaf (the Relaxation Response and Resiliency Program for Deaf NF2, d3RP-NF2) improves quality of life and resiliency over and above a Health Enhancement program when both are delivered via live-video and assisted by Communication Access Realtime Translation (CART). Here we tested the effects of the programs on depression and perceived stress.

Methods: Forty-five patients with NF2 and significant hearing loss were randomized to the d3RP-NF2 or Health-Enhancement program and completed measures of depression (PHQ-9) and perceived stress (PSS-10) at baseline, post-intervention, and six-month follow-up.

Results: Patients randomized to the d3RP-NF2 program, but not to the control condition, experienced significant decreases on both measures from baseline to post-test, which were maintained at follow-up (within group tests). However, improvements following the d3RP-NF2 program was not significantly higher than those observed in the control group (between group tests).

Conclusion: Results provide the first evidence of improvement in symptoms of depression and perceived stress among deaf patients living with NF2 who participate in a virtual mind-body program.
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http://dx.doi.org/10.1016/j.ctim.2020.102581DOI Listing
January 2021

Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 30;63(1):31-39. Epub 2020 Oct 30.

Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

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.
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http://dx.doi.org/10.1002/mus.27091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820979PMC
January 2021

Multimodal chiropractic care for migraine: A pilot randomized controlled trial.

Cephalalgia 2021 Mar 13;41(3):318-328. Epub 2020 Oct 13.

Division of Preventive Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

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).
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http://dx.doi.org/10.1177/0333102420963844DOI Listing
March 2021

Association of caffeine and related analytes with resistance to Parkinson disease among mutation carriers: A metabolomic study.

Neurology 2020 12 30;95(24):e3428-e3437. Epub 2020 Sep 30.

From the Department of Neurology (G.F.C., R.B., X.C., M.A.S.) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.

Objective: To identify markers of resistance to developing Parkinson disease (PD) among mutation carriers (+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the mutation.

Methods: Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 +/PD+, 115 +/UC, 70 -/PD+, and 65 /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 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with value corrections for multiple comparisons.

Results: Plasma caffeine concentration was lower in patients with PD vs UC ( < 0.001), more so among + carriers (by 76%) than among - participants (by 31%), with significant interaction between and PD status ( = 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 PD+ compared to UC with significant interaction effect with the mutation ( < 0.001).

Conclusions: Metabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic 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 mutation carriers.
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http://dx.doi.org/10.1212/WNL.0000000000010863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836665PMC
December 2020

A randomized controlled trial of an online health tool about Down syndrome.

Genet Med 2021 Jan 3;23(1):163-173. Epub 2020 Sep 3.

Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.
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http://dx.doi.org/10.1038/s41436-020-00952-7DOI Listing
January 2021

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

N Engl J Med 2020 09;383(10):919-930

From the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School (S.P., J.D.B., S.B., M.C., D.D., M.M., J.O., L.P., A.V.S., E.T., P.V., J. Walker, H.Y., R.E.T., M.E.C.), the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School (E.A.M., J. Chan, D.S.), and Spaulding Rehabilitation Hospital, Harvard Medical School (S.P.), Boston, the University of Massachusetts Memorial Medical Center, Worcester (M.A.O.), and Amylyx Pharmaceuticals (J. Cohen, J. Klee, K.L., P.D.Y.) and Harvard University (W.G.), Cambridge - all in Massachusetts; Pentara, Millcreek, UT (S.H., S.P.D., N.E., K.H.); Swedish Neuroscience Institute, Seattle (M.A.E.); Hennepin Healthcare, Minneapolis (S.M.); the Department of Neurology, Oregon Health and Science University, Portland (C.K.); the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (J.B.C.); the Department of Neurology, Ohio State University College of Medicine, Columbus (A.Q.); the Department of Neurology, University of Florida College of Medicine, Gainesville (J. Wymer); the Department of Neurology, University of Michigan, Ann Arbor (S.A.G.); Texas Neurology, Dallas (D.H.); the Department of Neurology, Lewis Katz School of Medicine, Temple University (T.H.-P.), and the Department of Neurology, University of Pennsylvania Perelman School of Medicine (C.Q.) - both in Philadelphia; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disease, University of Texas Health Science Center at San Antonio, San Antonio (C.E.J.); the Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore (J.D.R.); the Department of Neurology, University of Kentucky College of Medicine, Lexington (E.J.K.); California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco (J. Katz, L.J.); Barrow Neurological Institute, Phoenix, AZ (S.L., M.H., G.K., R.R., J.M.S.); the Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis (T.M.M.); the Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York (S.N.S.); the Department of Neurology, University of South Florida Morsani College of Medicine, Tampa (T.H.V.); the Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta (C.N.F., J.D.G.); Ochsner Health System, New Orleans (K.M.J.); the Department of Neurology, University of Iowa Carver College of Medicine, Iowa City (A.S.); the Department of Neurology, University of California, Irvine, School of Medicine, Irvine (N.A.G.); Neurology Associates, Lincoln, NB (G.L.P.); independent consultant, Nobleboro, ME (P.L.A.); and Statistics Collaborative, Washington, DC (J. Wittes).

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.

Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.

Results: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.

Conclusions: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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http://dx.doi.org/10.1056/NEJMoa1916945DOI Listing
September 2020

Does Serum Urate Change as Parkinson's Disease Progresses?

J Parkinsons Dis 2020 ;10(4):1571-1576

Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.3233/JPD-202064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683051PMC
January 2020

A Mind-Body Physical Activity Program for Chronic Pain With or Without a Digital Monitoring Device: Proof-of-Concept Feasibility Randomized Controlled Trial.

JMIR Form Res 2020 Jun 8;4(6):e18703. Epub 2020 Jun 8.

Integrated Brain Health Clinical and Research Program, Massachusetts General Hospital, Boston, MA, United States.

Background: Chronic pain is associated with poor physical and emotional functioning. Nonpharmacological interventions can help, but improvements are small and not sustained. Previous clinical trials do not follow recommendations to comprehensively target objectively measured and performance-based physical function in addition to self-reported physical function.

Objective: This study aimed to establish feasibility benchmarks and explore improvements in physical (self-reported, performance based, and objectively measured) and emotional function, pain outcomes, and coping through a pilot randomized controlled trial of a mind-body physical activity program (GetActive) with and without a digital monitoring device (GetActive-Fitbit), which were iteratively refined through mixed methods.

Methods: Patients with chronic pain were randomized to the GetActive (n=41) or GetActive-Fitbit (n=41) programs, which combine relaxation, cognitive behavioral, and physical restoration skills and were delivered in person. They completed in-person assessments before and after the intervention. Performance-based function was assessed with the 6-min walk test, and step count was measured with an ActiGraph.

Results: Feasibility benchmarks (eg, recruitment, acceptability, credibility, therapist adherence, adherence to practice at home, ActiGraph wear, and client satisfaction) were good to excellent and similar in both programs. Within each program, we observed improvement in the 6-min walk test (mean increase=+41 m, SD 41.15; P<.001; effect size of 0.99 SD units for the GetActive group and mean increase=+50 m, SD 58.63; P<.001; effect size of 0.85 SD units for the GetActive-Fitbit group) and self-reported physical function (P=.001; effect size of 0.62 SD units for the GetActive group and P=.02; effect size of 0.38 SD units for the GetActive-Fitbit group). The mean step count increased only among sedentary patients (mean increase=+874 steps for the GetActive group and +867 steps for the GetActive-Fitbit group). Emotional function, pain intensity, pain coping, and mindfulness also improved in both groups. Participants rated themselves as much improved at the end of the program, and those in the GetActive-Fitbit group noted that Fitbit greatly helped with increasing their activity.

Conclusions: These preliminary findings support a fully powered efficacy trial of the two programs against an education control group. We present a model for successfully using the Initiative on the Methods, Measurement, and Pain Assessment in Clinical Trials criteria for a comprehensive assessment of physical function and following evidence-based models to maximize feasibility before formal efficacy testing.

Trial Registration: ClinicalTrial.gov NCT03412916; https://clinicaltrials.gov/ct2/show/NCT03412916.
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http://dx.doi.org/10.2196/18703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308894PMC
June 2020

Addressing Challenging Behavior During Hospitalizations for Children with Autism: A Pilot Applied Behavior Analysis Randomized Controlled Trial.

Autism Res 2020 07 23;13(7):1072-1078. Epub 2020 Apr 23.

Department of Psychiatry and Behavior Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

This study evaluated the feasibility, acceptance, and potential clinical benefit of brief applied behavior analysis (ABA)-based interventions for children and adolescents with autism spectrum disorder (ASD) displaying challenging behaviors during hospitalizations. Participants included 36 children diagnosed with ASD, 6-17 years of age, who were medically or psychiatrically hospitalized. Children in the intervention group received a brief ABA intervention and were compared to children in the evaluation and monitoring-only group. Families and staff recommended the intervention, children receiving the intervention demonstrated significantly more improvement in unblinded ratings of clinical severity, data from physicians indicated a positive effect of the intervention on levels of staffing and restraints and attending medical providers universally reported satisfaction and benefit of the intervention. Improvements in challenging behaviors were not significantly different as reported by parents, and the length of hospitalization did not differ between the groups. Ultimately, the outcomes of this pilot study suggest incorporating specialized ABA-based assessment and intervention during hospitalization may be feasible and well accepted by clinicians and families. However, future research must address potent methodological challenges related to capturing meaningful data during hospitalizations in order to answer questions of ultimate pragmatic, clinical, and system-level benefits. Trial Registration ClinicalTrials.gov Identifier NCT02339935, Registered 16 January 2015, First participant consented 23 February 2015. Autism Res 2020, 13: 1072-1078. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Inpatient hospitalizations for children with autism spectrum disorder (ASD) and severe behavior are common, challenging, and costly in terms of human experience. This study evaluated the benefit of brief applied behavior analysis-based interventions to children and adolescents with ASD displaying challenging behaviors during hospitalizations. Families and staff evaluating the procedures noted perceived potential benefits of the intervention, but this initial pilot study did not document changes in hospitalization length or blinded rating of improvement.
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http://dx.doi.org/10.1002/aur.2308DOI Listing
July 2020

Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson's Disease in the Harvard Biomarkers Study.

J Parkinsons Dis 2020 ;10(2):505-510

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

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.
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http://dx.doi.org/10.3233/JPD-191882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416447PMC
January 2020

Factors Associated With Seizure Onset in Children With Autism Spectrum Disorder.

Pediatrics 2020 04;145(Suppl 1):S117-S125

Departments of Neurology and Pediatrics, University of Louisville Autism Center, Louisville, Kentucky.

Background And Objectives: Children with autism spectrum disorder (ASD) have a higher prevalence of epilepsy compared with general populations. In this pilot study, we prospectively identified baseline risk factors for the development of seizures in individuals with ASD and also identified characteristics sensitive to seizure onset up to 6 years after enrollment in the Autism Speaks Autism Treatment Network.

Methods: Children with ASD and no history of seizures at baseline who either experienced onset of seizures after enrollment in the Autism Treatment Network or remained seizure free were included in the analysis.

Results: Among 472 qualifying children, 22 (4.7%) experienced onset of seizures after enrollment. Individuals who developed seizures after enrollment exhibited lower scores at baseline on all domains of the Vineland Adaptive Behavior Scales, greater hyperactivity on the Aberrant Behavior Checklist (25.4 ± 11.8 vs 19.2 ± 11.1; = .018), and lower physical quality of life scores on the Pediatric Quality of Life Inventory (60.1 ± 24.2 vs 76.0 ± 18.2; < .001). Comparing change in scores from entry to call-back, adjusting for age, sex, length of follow-up, and baseline Vineland II composite score, individuals who developed seizures experienced declines in daily living skills (-8.38; 95% confidence interval -14.50 to -2.50; = .005). Adjusting for baseline age, sex, and length of follow-up, baseline Vineland II composite score was predictive of seizure development (risk ratio = 0.95 per unit Vineland II composite score, 95% confidence interval 0.92 to 0.99; = .007).

Conclusions: Individuals with ASD at risk for seizures exhibited changes in adaptive functioning and behavior.
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http://dx.doi.org/10.1542/peds.2019-1895ODOI Listing
April 2020

Improvement in resiliency factors among adolescents with neurofibromatosis who participate in a virtual mind-body group program.

J Neurooncol 2020 Apr 20;147(2):451-457. Epub 2020 Feb 20.

Integrated Brain Health Clinical and Research Program, Psychiatry Department, Massachusetts General Hospital, One Bowdoin Square, 1st Floor, Boston, MA, 02114, USA.

Purpose: 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.

Methods: 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%).

Results: Participation in the RY-NF was associated with greater pre-to-post improvements in gratitude (M = 4.38; 95% CI-0.52-8.23; p = .027) and mindfulness (M= 9.41; 95% CI 4.40-14.42.; p < .001) compared to HE-NF; improvements sustained at 6 months. There were no group differences on any additional resiliency factors. However, participation in the RY-NF was associated with pre-to-post- improvements in coping (M= 9.16; 95% CI 2.93-15.39; p = .005), and social support (M= 6.79; 95% CI 1.96-11.63; p = .007); improvements sustained at 6 months.

Conclusions: Participation in the RY-NF resulted in sustained improvement in several resiliency factors. Promoting resiliency may help adolescents successfully navigate challenges associated with NF.
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http://dx.doi.org/10.1007/s11060-020-03441-8DOI Listing
April 2020

Randomized, Placebo-Controlled Trial of Ferrous Sulfate to Treat Insomnia in Children With Autism Spectrum Disorders.

Pediatr Neurol 2020 03 2;104:30-39. Epub 2019 Aug 2.

Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee.

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.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.07.015DOI Listing
March 2020

Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database.

Genet Med 2020 04 26;22(4):767-776. Epub 2019 Nov 26.

Division of Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA.

Purpose: An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease.

Methods: 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.

Results: 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 < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition.

Conclusions: Our case-control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.
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http://dx.doi.org/10.1038/s41436-019-0706-8DOI Listing
April 2020

Cultivating resiliency in patients with neurofibromatosis 2 who are deafened or have severe hearing loss: a live‑video randomized control trial.

J Neurooncol 2019 Dec 1;145(3):561-569. Epub 2019 Nov 1.

Integrated Brain Health Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, One Bowdoin Square, 1st Floor, Suite 100, Boston, USA.

Introduction: Patients with NF2 who are deaf or have significant hearing loss face numerous and unique challenges which lead to poor quality of life, and thus may benefit from resiliency programs.

Methods: We performed secondary data analyses on a single blind, randomized controlled trial of an 8 week mind-body resiliency program (the Relaxation Response and Resiliency program for Deaf NF2; d3RP-NF2) versus a health education control (Health Enhancement Program for Deaf NF2;dHEP-NF2) which showed improvement in quality of life (Funes in JAMA 2019, https://doi.org/10.1007/s11060-019-03182-3). Here we report on improvements in resiliency factors (i.e. optimism, gratitude, perceived social support, mindfulness, and perceived coping abilities) assessed at baseline, post-test and 6-month follow-up. Both programs were delivered via Skype using Communication Access Real-Time Translation.

Results: Patients who were randomized to the d3RP-NF2 program exhibited significant improvements from baseline to post-program in gratitude (M = 4.04, 95% CI 1.58-6.50; p = 0.002), perceived social support (M = 16.36, 95% CI 9.20-23.51; p < 0.001), mindfulness (M = 4.02, 95% CI 1.10-6.94; p = 0.008), perceived coping (M = 15.25, 95% CI 10.21-20.28; p < 0.001), and a non-significant trend of improvement in optimism (M = 1.15, 95% CI -0.14-12.44; p = 0.079). These improvements were all maintained through the 6-month follow up. Improvements in perceived coping (M = 12.34, 95% CI 4.75-19.93; p = 0.002), social support (M = 13.11, 95% CI 2.19-24.03; p = 0.02), and gratitude (M = 4.59, 95% CI 0.83-8.36; p = 0.018) were over and above the changes observed in those randomized to dHEP-NF2.

Conclusion: The d3RP-NF2 sustainably improves multiple dimensions of resiliency. Promoting resiliency may be of utmost importance for this uderserved population.
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http://dx.doi.org/10.1007/s11060-019-03326-5DOI Listing
December 2019

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 14;21(1-2):15-23. Epub 2019 Oct 14.

Department of Neurology, Sean M Healey & AMG Center for ALS at Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, MA, USA.

: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. : Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. : CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. : Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.
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http://dx.doi.org/10.1080/21678421.2019.1672750DOI Listing
February 2020

The revised El Escorial criteria "clinically probable laboratory supported ALS"-once a promising now a superfluous category?

Amyotroph Lateral Scler Frontotemporal Degener 2020 02 27;21(1-2):24-28. Epub 2019 Sep 27.

Neuromuscular Diseases Unit/ALS Clinic, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Over the past two decades, the El Escorial criteria (EEC) have been used as eligibility criteria in major randomized controlled trials. One of the goals of the revised EEC was to allow earlier diagnosis and, thus earlier trial inclusion by introducing a new category, namely "clinically probable laboratory supported" ALS. This category allowed EMG findings to be taken into account assuming that EMG is more sensitive than the clinical examination in detecting lower motor neuron signs. Recently, Edaravone has been licensed in several countries for the treatment of ALS based on a randomized controlled trial in a selected group of ALS patients excluding the EEC category "clinically probable laboratory supported". The major reason was that in a post hoc analysis of the first Edaravone trial this group comprised many slow progressors. As it is unclear whether this bias towardslow progressors was a study-specific problem or related to the category itself, we performed an analysis in the PRO-ACT dataset. In the PRO-ACT dataset, progression in ALS patients included at baseline into the "clinically probable laboratory supported" category was significantly slower (-0.53 in ALSFRS/month) compared to the other EEC categories (-0.68 in ALSFRS/month;  < 0.001) and exhibited a significantly longer diagnostic delay (13.5 months vs. 11.7 months,  < 0.001). This suggests that the bias toward slow progressors in the "clinically probable laboratory supported" category is an inherent problem of the category and thus does not fulfill the previous goal of earlier diagnosis, raising several questions concerning the application of this category.
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http://dx.doi.org/10.1080/21678421.2019.1666875DOI Listing
February 2020

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

Neurology 2019 10 4;93(14):e1328-e1338. Epub 2019 Sep 4.

From the Departments of Neurology (M.A.S., R.B., S.B., R.L., A.Y.H., G.B.) and Medicine (E.A.M.), Massachusetts General Hospital, Boston; University of Cincinnati (A.J.E.), OH; Rush University (C.G.G.), Chicago, IL; Michigan State University (J.L.G.), East Lansing; Struthers Parkinson's Center (S.A.P.), Minneapolis, MN; Boston University (M.H.S.-H.), MA; University of Rochester (A.R.), NY; University of Miami (J.M.H.), FL; Brigham and Women's Hospital (G.C.C.), Boston, MA; Yale University School of Medicine (D.S.R.), New Haven, CT; and Department of Nutrition (A.A.), Harvard School of Public Health, Boston, MA.

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The 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.

Results: Inosine 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% [ < 0.001] and +98% [ < 0.001], respectively) than on placebo (in contrast to men: +10% [ = 0.6] and +14% [ = 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 ( = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate ( = -0.52; = 0.001), and with greater increases in plasma antioxidant capacity ( = -0.44; = 0.006). No significant associations were observed in men.

Conclusions: Inosine 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.

Clinicaltrialsgov Identifier: NCT00833690.

Classification Of Evidence: This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.
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http://dx.doi.org/10.1212/WNL.0000000000008194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814412PMC
October 2019

Pharmacogenetics of Metformin for Medication-Induced Weight Gain in Autism Spectrum Disorder.

J Child Adolesc Psychopharmacol 2019 08 12;29(6):448-455. Epub 2019 Jun 12.

1Department of Psychiatry, Columbia University Medical Center, New York, New York.

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. 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: , , , , and . In the primary analysis, both and showed significant effects of genotype on change in body mass index -scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. 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.
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http://dx.doi.org/10.1089/cap.2018.0171DOI Listing
August 2019

Reply to "Mitochondrial DNA deletions discriminate affected from unaffected LRRK2 mutation carriers".

Ann Neurol 2019 08 12;86(2):326-327. Epub 2019 Jun 12.

Department of Neurology, Massachusetts General Hospital, Boston, MA.

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http://dx.doi.org/10.1002/ana.25509DOI Listing
August 2019