Publications by authors named "David Oakes"

103 Publications

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

Mov Disord 2021 Nov 12. Epub 2021 Nov 12.

Cure Parkinsons, London, United Kingdom.

Background: Recent examination of the STEADY-PD III isradipine clinical trial data concluded that early-stage Parkinson's disease (PD) participants who had longer exposure to isradipine had a significant delay in their need for symptomatic medication, as well as a lower medication burden at the end of the trial. These findings suggest that greater exposure to isradipine might slow disease progression.

Objectives: To test this hypothesis, the data from the STEADY-PD II isradipine clinical trial, in which an extended-release (ER) formulation of the drug was used, was re-examined.

Methods: The re-analysis of the STEADY-PD II data was restricted to participants assigned placebo or tolerable isradipine treatment (10 mg isradipine/day or less). The effect of isradipine treatment was assessed by Unified Parkinson's Disease Rating Scale (UPDRS) at the end of the 52-week trial, rather than by last observation carried forward at the beginning of symptomatic therapy.

Results: Participant cohorts were well-matched for baseline disability, initial disease progression, and time to initiation of symptomatic therapy. Participants given 10 mg/day ER isradipine had significantly smaller total and part 3 UPDRS scores at the end of the trial than did the placebo cohort. Post hoc adjustment for symptomatic therapy diminished the statistical significance of these differences. In those participants not taking a monoamine oxidase B inhibitor, the progression in UPDRS scores also was significantly reduced.

Conclusions: These results are consistent with the recent secondary analysis of the STEADY-PD III clinical trial-suggesting that clinically attainable brain exposure to isradipine may slow early-stage PD progression. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28850DOI Listing
November 2021

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

Mov Disord Clin Pract 2021 Oct 3;8(7):1083-1091. Epub 2021 Aug 3.

Department of Neurological Sciences, Section of Movement Disorders Rush University Medical Center Chicago Illinois USA.

Background: Although nontremor and tremor Part 3 Movement Disorder Society-Unified Parkinson's Disease Rating Scale items measure different impairment domains, their distinct progression and drug responsivity remain unstudied longitudinally. The total score may obscure important time-based and treatment-based changes occurring in the individual domains.

Objective: Using the unique advantages of item response theory (IRT), we developed novel longitudinal unidimensional and multidimensional models to investigate nontremor and tremor changes occurring in an interventional Parkinson's disease (PD) study.

Method: With unidimensional longitudinal IRT, we assessed the 33 Part 3 item data (22 nontremor and 10 tremor items) of 336 patients with early PD from the STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine for PD, placebo vs. isradipine) study. With multidimensional longitudinal IRT, we assessed the progression rates over time and treatment (in overall motor severity, nontremor, and tremor domains) using Markov Chain Monte Carlo implemented in Stan.

Results: Regardless of treatment, patients showed significant but different time-based deterioration rates for total motor, nontremor, and tremor scores. Isradipine was associated with additional significant deterioration over placebo in total score and nontremor scores, but not in tremor score. Further highlighting the 2 separate latent domains, nontremor and tremor severity changes were positively but weakly correlated (correlation coefficient, 0.108).

Conclusions: Longitudinal IRT analysis is a novel statistical method highly applicable to PD clinical trials. It addresses limitations of traditional linear regression approaches and previous IRT investigations that either applied cross-sectional IRT models to longitudinal data or failed to estimate all parameters simultaneously. It is particularly useful because it can separate nontremor and tremor changes both over time and in response to treatment interventions.
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http://dx.doi.org/10.1002/mdc3.13311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485609PMC
October 2021

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

JAMA 2021 09;326(10):926-939

University of Cincinnati, Cincinnati, Ohio.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.

Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.

Design, Participants, And Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.

Main Outcomes And Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions And Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.
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http://dx.doi.org/10.1001/jama.2021.10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441591PMC
September 2021

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

J Parkinsons Dis 2021;11(4):1957-1964

Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.

Background: Postural instability is an intractable sign of Parkinson's disease, associated with poor disease prognosis, fall risk, and decreased quality of life.

Objective: 1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls.

Methods: Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11-2.13. T-tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses.

Results: Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11-2.13 measures were predictive of future falls.

Conclusion: Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses.
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http://dx.doi.org/10.3233/JPD-212636DOI Listing
January 2021

Long-Term Efficacy and Safety of Deutetrabenazine for Chorea in Huntington's Disease: Results From the ARC-HD Open-label Study.

CNS Spectr 2021 04;26(2):164-165

Teva Pharmaceutical Industries Ltd., Basel, Switzerland.

Background: Chorea is a prominent motor dysfunction in Huntington's disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington's Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.

Methods: Patients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.

Results: Of 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug-related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was -4.4 (3.1) and -2.1 (3.3) and change in TMS was -7.1 (7.3) and -2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.

Conclusions: The type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002655DOI Listing
April 2021

Evaluation of the Safety of Deutetrabenazine at Higher Doses to Treat Chorea in Huntington's Disease.

CNS Spectr 2021 04;26(2):162-163

Virginia Commonwealth University, Richmond, VA, USA.

Background: In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington's disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator's discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.

Methods: Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.

Results: All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.

Conclusions: Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.

Funding: Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
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http://dx.doi.org/10.1017/S1092852920002618DOI Listing
April 2021

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

Mov Disord 2021 08 13;36(8):1979-1983. Epub 2021 May 13.

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

Background: The Quality of Life in Neurological Disorders (Neuro-QoL) is a publicly available health-related quality-of-life measurement system.

Objective: The aim of this study was to evaluate the utility of Neuro-QoL item banks as outcome measures for clinical trials in Parkinson's disease.

Methods: An analysis of Neuro-QoL responsiveness to change and construct validity was performed in a multicenter clinical trial cohort.

Results: Among 310 participants over 3 years, changes in five of eight Neuro-QoL domains were significant (P < 0.05) but very modest. The largest effect sizes were seen in the cognition and mobility domains (0.35-0.39). The largest effect size for change over the year in which levodopa was initiated was -0.19 for lower extremity function-mobility. For a similarly designed clinical trial, estimated sample size required to demonstrate a 50% reduction in worsening ranged from 420 to more than 1000 participants per group.

Conclusions: More sensitive tools will be required to serve as an outcome measure in early Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376764PMC
August 2021

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

Ann Clin Transl Neurol 2021 03 18;8(3):603-612. Epub 2021 Jan 18.

Department of Neurology, Northwestern University, Chicago, Illinois, USA.

Objectives: Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.

Methods: Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy.

Results: Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, r : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (r : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02).

Interpretation: In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.

Trial Registration: ClinicalTrials.gov NCT02168842.
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http://dx.doi.org/10.1002/acn3.51300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951102PMC
March 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

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

Parkinsonism Relat Disord 2020 11 20;80:127-132. Epub 2020 Sep 20.

Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, ON, Canada.

Background: Cognitive decline creates substantial morbidity and cost in Parkinson's disease (PD) and clinicians have limited tools for counseling patients on prognosis. We aimed to use data from a randomized, controlled trial of isradipine in Parkinson's disease (STEADY-PD III) to determine which objective cognitive domain deficits drive patient complaints of cognitive symptoms.

Methods: Neuro-Quality of Life (Neuro-QoL) Cognition: General Concerns (GC), and Cognition: Executive Function (EF) (subjective measures), were administered at baseline, 1, 2, and 3 years in 324 people with PD. Baseline Montreal Cognitive Assessment (MoCA) was divided into 4 domains: visuospatial/executive, memory, attention, and language (objective measures). Spearman rank correlations and multiple regression models adjusted for other clinical variables evaluated associations between baseline Neuro-QoL domains and individual MoCA domains. Multiple regression models evaluated the association between baseline MoCA domain performance and Neuro-QoL change over three years. Cox proportional hazards predicted development of PD-MCI based on baseline and time-varying Neuro-QoL reporting.

Results: Higher MoCA memory performance was associated with better Neuro-QoL-GC (β = 0.75, SE = 0.391, p = 0.05) and Neuro-QoL-EF (β = 0.81, SE = 0.36, p = 0.02) at baseline. There was a trend for baseline MoCA memory to predict the degree of subjective cognitive decline on the Neuro-QoL-EF (β = 0.70, SE = 0.42, p = 0.09). Baseline depression and anticholinergic use were associated with worsened Neuro-QoL-EF and Neuro-QoL-GC. Increasing subjective cognitive complaints in Neuro-QoL-EF were associated with development of PD-MCI over 3 years of follow-up (HR = 0.95, CI = 0.90-1.0, p = 0.039).

Conclusions: Objective memory impairment may be a stronger predictor than executive or visuospatial dysfunction for the presence of subjective cognitive complaints in early PD.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.028DOI Listing
November 2020

Clinical and Imaging Progression in the PARS Cohort: Long-Term Follow-up.

Mov Disord 2020 09 13;35(9):1550-1557. Epub 2020 Jul 13.

Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA.

Background And Objectives: The PARS (Parkinson Associated Risk Syndrome) study was designed to test whether screening for hyposmia followed by dopamine transporter imaging can identify risk for conversion to clinical PD, and to evaluate progression markers during the prodromal period.

Methods: Subjects with hyposmia completed annual clinical evaluations and biennial [ I]ß-CIT single-photon emission computed tomography scans. Subjects were categorized as normal (>80% age-expected tracer uptake; n = 134), indeterminate (>65-80%; n = 30), and dopamine transporter deficit (≤65%; n = 21) by their baseline scan, and survival analysis was used to compare risk of conversion to motor PD. Progressing to a scan with a dopamine transporter deficit was assessed for those subjects with either normal or indeterminate baseline imaging.

Results: Over a mean of 6.3 [standard deviation: 2.2] years of follow-up, 67% (n = 14) of dopamine transporter deficit subjects, 20% (n = 6) of dopamine transporter indeterminate subjects, and 4% (n = 6) of dopamine transporter normal subjects converted to a PD diagnosis (P < 0.0001). Among subjects without dopamine transporter deficit at baseline, a reduction to ≤65% age-expected uptake occurred in 12 of 30 (40%) with indeterminate dopamine transporter and 7 of 134 (5%) with no dopamine transporter DAT deficit (P < 0.0001). Imaging conversion during follow-up was associated with subsequent clinical conversion (hazard ratio: 9.6; P = 0.0157).

Discussion And Conclusions: Long-term follow-up of the PARS cohort demonstrated a high rate of conversion to clinical PD in subjects who either had abnormal dopamine transporter imaging at baseline or developed abnormal imaging during follow-up. These data extend the earlier PARS findings and present new results showing the sequence of incident imaging deficit, imaging progression, and clinical changes that occur in prodromal PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28139DOI Listing
September 2020

Clinical and Imaging Progression in the PARS Cohort: Long-Term Follow-up.

Mov Disord 2020 09 13;35(9):1550-1557. Epub 2020 Jul 13.

Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA.

Background And Objectives: The PARS (Parkinson Associated Risk Syndrome) study was designed to test whether screening for hyposmia followed by dopamine transporter imaging can identify risk for conversion to clinical PD, and to evaluate progression markers during the prodromal period.

Methods: Subjects with hyposmia completed annual clinical evaluations and biennial [ I]ß-CIT single-photon emission computed tomography scans. Subjects were categorized as normal (>80% age-expected tracer uptake; n = 134), indeterminate (>65-80%; n = 30), and dopamine transporter deficit (≤65%; n = 21) by their baseline scan, and survival analysis was used to compare risk of conversion to motor PD. Progressing to a scan with a dopamine transporter deficit was assessed for those subjects with either normal or indeterminate baseline imaging.

Results: Over a mean of 6.3 [standard deviation: 2.2] years of follow-up, 67% (n = 14) of dopamine transporter deficit subjects, 20% (n = 6) of dopamine transporter indeterminate subjects, and 4% (n = 6) of dopamine transporter normal subjects converted to a PD diagnosis (P < 0.0001). Among subjects without dopamine transporter deficit at baseline, a reduction to ≤65% age-expected uptake occurred in 12 of 30 (40%) with indeterminate dopamine transporter and 7 of 134 (5%) with no dopamine transporter DAT deficit (P < 0.0001). Imaging conversion during follow-up was associated with subsequent clinical conversion (hazard ratio: 9.6; P = 0.0157).

Discussion And Conclusions: Long-term follow-up of the PARS cohort demonstrated a high rate of conversion to clinical PD in subjects who either had abnormal dopamine transporter imaging at baseline or developed abnormal imaging during follow-up. These data extend the earlier PARS findings and present new results showing the sequence of incident imaging deficit, imaging progression, and clinical changes that occur in prodromal PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28139DOI Listing
September 2020

Phenotype-genotype discrepancies in the prospective Huntington at-risk observational study.

Ann Clin Transl Neurol 2019 Jun 1;6(6):1046-1052. Epub 2019 May 1.

Massachusetts General Hospital Boston Massachusetts.

Objective: To examine phenotype-genotype discrepancies (PGDs) wherein genotype-concealed and prospective judgments of the motor onset of Huntington disease (HD) occurred among at-risk adults who had nonexpanded (<37) cytosine-adenine-guanine (CAG) trinucleotide DNA repeats.

Methods: We examined the prospective clinical assessments of investigators who were kept unaware of individual CAG lengths in the Prospective Huntington At-Risk Observational Study (PHAROS) who enrolled and followed undiagnosed adults at risk for HD who chose not to learn their gene status. Subjects ( = 1001) at 43 Huntington Study Group research sites in the US and Canada were evaluated prospectively and systematically between 1999 and 2009. At each site, an investigator was designated to perform comprehensive clinic assessments and another investigator to rate only the motor examination. Phenoconversion from a "premanifest" status to a confidently "manifest" status was based on investigator judgment (diagnostic confidence level) of the extrapyramidal motor features of HD.

Results: There were 20 PGDs that over time had less severe motor scores than the 101 phenoconversions with CAG ≥37, but more severe motor scores than nonconversions. Following conversion, subjects with CAG ≥37 expansions worsened more motorically and cognitively than PGD subjects in the < 37 group. PGDs were concentrated among three sites and a few investigators, especially raters who only assessed the motor examination.

Interpretation: The ability to detect the clinical onset of HD in a timely and reliable fashion remains the key for developing experimental treatments aimed at postponing the clinical onset of HD. Comprehensive clinical evaluation is a more accurate and reliable basis for determining HD clinical onset than sole reliance on judging the extrapyramidal features of HD.
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http://dx.doi.org/10.1002/acn3.781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562068PMC
June 2019

The choice not to undergo genetic testing for Huntington disease: Results from the PHAROS study.

Clin Genet 2019 07 15;96(1):28-34. Epub 2019 May 15.

Department of Neurology, University of Rochester, Rochester, NY.

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry.
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http://dx.doi.org/10.1111/cge.13529DOI Listing
July 2019

Long-term durability of Oakes salvage procedure to preserve Brescia-Cimino arteriovenous fistula.

J Vasc Surg 2019 Sep 2;70(3):853-857. Epub 2019 Mar 2.

Division of Vascular Surgery, Stanford Hospital and Clinics, Stanford, Calif; Division of Vascular Surgery, Santa Clara Valley Medical Center, San Jose, Calif. Electronic address:

Background: In 2002, Oakes et al described a novel procedure designed to salvage the distal cephalic venous outflow of a Brescia-Cimino fistula by placing a prosthetic graft between the brachial artery in the antecubital space and the cephalic vein at the wrist. In this fashion, the more proximal veins were saved for future procedures. Their approach was reported and found to be successful in the short term, but the long-term durability of the Oakes procedure has not been described. This study aimed to determine the long-term primary, primary-assisted, and secondary patency rates of the brachial to distal cephalic vein Oakes procedure.

Methods: This is a retrospective review of a prospective database in a large, single institution. All patients who underwent the Oakes procedure from 1998 to 2012 were followed up to 2018. We reviewed the time to intervention, type of intervention, patency rates, and mortality of this patient population.

Results: Over the 5-year study period, 14 patients were identified who underwent the Oakes procedure, of whom seven (50%) were female. The average age was 55.7 years (range, 38-73 years). All patients had a previously placed Brescia-Cimino that was not suitable for dialysis but was patent. The average number of days to placement of an Oakes brachial to distal cephalic graft was 396 (range, 119-1167) days. A total of 71% (10) of patients underwent an intervention to maintain the graft, of whom 50% (5) underwent an angioplasty and 50% (5) had a thrombectomy/revision procedure. The average number of days to first intervention was 367.3 (range, 21-1048) days from Oakes placement. Of this cohort, 30% (3) of patients had a second intervention, of whom one (33%) underwent an angioplasty and two (66%) had revisions. One patient had a third and a fourth intervention at 39 days and 74 days, respectively, that were both angioplasties. The overall number of days the Oakes procedure remained usable from placement was 843.6 (range, 21-3790) days or 2.3 years.

Conclusions: This study concluded that the Oakes procedure may extend the use of the distal dialysis access site by 2.3 years without increasing infection and is hence a durable solution that should be considered in patients requiring dialysis access.
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http://dx.doi.org/10.1016/j.jvs.2018.12.034DOI Listing
September 2019

Ambient and controlled exposures to particulate air pollution and acute changes in heart rate variability and repolarization.

Sci Rep 2019 02 13;9(1):1946. Epub 2019 Feb 13.

University of Rochester Medical Center, Rochester, New York, USA.

Previous studies have reported increased risks of myocardial infarction in association with elevated ambient particulate matter (PM) in the previous hour(s). However, whether PM can trigger mechanisms that act on this time scale is still unclear. We hypothesized that increases in PM are associated with rapid changes in measures of heart rate variability and repolarization. We used data from panel studies in Augsburg, Germany, and Rochester, New York, USA, and two controlled human exposure studies in Rochester. Data included ECG recordings from all four studies, controlled exposures to (concentrated) ultrafine particles (UFP; particles with an aerodynamic diameter <100 nm) and ambient concentrations of UFP and fine PM (PM, aerodynamic diameter <2.5 μm). Factor analysis identified three representative ECG parameters: standard deviation of NN-intervals (SDNN), root mean square of successive differences (RMSSD), and T-wave complexity. Associations between air pollutants and ECG parameters in the concurrent and previous six hours were estimated using additive mixed models adjusting for long- and short-term time trends, meteorology, and study visit number. We found decreases in SDNN in relation to increased exposures to UFP in the previous five hours in both of the panel studies (e.g. Augsburg study, lag 3 hours: -2.26%, 95% confidence interval [CI]: -3.98% to -0.53%; Rochester panel study, lag 1 hour: -2.69%; 95% CI: -5.13% to -0.26%) and one of the two controlled human exposure studies (1-hour lag: -13.22%; 95% CI: -24.11% to -2.33%). Similarly, we observed consistent decreases in SDNN and RMSSD in association with elevated PM concentrations in the preceding six hours in both panel studies. We did not find consistent associations between particle metrics and T-wave complexity. This study provided consistent evidence that recent exposures to UFP and PM can induce acute pathophysiological responses.
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http://dx.doi.org/10.1038/s41598-019-38531-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374365PMC
February 2019

Reply to "Studying reproducibility of data-driven Parkinson's disease subtypes".

Parkinsonism Relat Disord 2019 09 28;66:245-246. Epub 2018 Dec 28.

Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, ON, Canada.

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http://dx.doi.org/10.1016/j.parkreldis.2018.12.028DOI Listing
September 2019

Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial.

J Am Coll Cardiol 2018 08;72(6):636-645

Department of Medicine, University of Rochester Medical Center, Rochester, New York.

Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs).

Objectives: This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD.

Methods: This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy.

Results: Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 ± 10 years and 18% were women. During 28 ± 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life.

Conclusions: In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In prespecified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).
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http://dx.doi.org/10.1016/j.jacc.2018.04.086DOI Listing
August 2018

Reproducibility of data-driven Parkinson's disease subtypes for clinical research.

Parkinsonism Relat Disord 2018 11 20;56:102-106. Epub 2018 Jul 20.

Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Canada.

Introduction: PD subtype classification systems attempt to address heterogeneity in PD, a widely recognized feature of the disease with implications in prognosis and therapeutic development. There is no consensus on a valid PD subtype classification system, and its use in clinical research is sparse. Reproducibility has not been systematically assessed as a step for the validation of a PD subtype classification system. We aimed at assessing reproducibility of previously published data-driven PD subtype classification systems in a well-characterized cohort created for clinical research purposes, the Longitudinal and Biomarker Study in Parkinson's Disease (LABS-PD).

Methods: We identified all published studies of data-driven PD subtype classification systems and included those with variables that conceptually matched the variables available in LABS-PD. We reproduced the cluster analyses of the included studies in LABS-PD. Reproducibility was determined by a panel of experts using a modified Delphi consensus process.

Results: We included eight studies of data-driven PD subtype classification systems and completed the replication in LABS-PD of the analyses conducted in each original study. After two iterations of the modified Delphi consensus process, no study was reproducible in LABS-PD.

Conclusions: Currently published data-driven PD subtype classification systems lack reproducibility in a well-characterized cohort of patients initially recruited for a clinical trial of a disease-modifying intervention. The results raise concerns about the utility of the widely-discussed concept of data-driven PD subtypes. This gap is a barrier for a meaningful use of PD subtypes and calls for the establishment of standards for the validation and use of these subtype classification systems.
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http://dx.doi.org/10.1016/j.parkreldis.2018.07.009DOI Listing
November 2018

Survival models and health sequences: discussion.

Authors:
David Oakes

Lifetime Data Anal 2018 10 11;24(4):592-594. Epub 2018 Jul 11.

Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 630, Rochester, NY, 14642, USA.

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http://dx.doi.org/10.1007/s10985-018-9441-8DOI Listing
October 2018

Selected health and lifestyle factors, cytosine-adenine-guanine status, and phenoconversion in Huntington's disease.

Mov Disord 2018 03 3;33(3):472-478. Epub 2018 Jan 3.

Department of Neurology, Georgetown University, Washington, D.C., USA.

Background: In Huntington's disease, 60% of the variance in onset age is not explained by the huntingtin gene mutation. Huntington's disease onset was earlier in caffeine users.

Objective: The objective of this study was to assess the relationship of lifestyle factors with motor phenoconversion among persons at risk for Huntington's disease.

Methods: The associations of motor phenoconversion and exposure to selected lifestyle and health factors were examined using Cox proportional hazards analyses adjusted for age, gender, and repeat length.

Results: Of 247 participants, 36 (14.6%) phenoconverted. Mean follow-up was 4.2 years. Greater caffeinated soda use was associated with an increased hazard of phenoconversion: moderate use hazard ratio 2.26 (95% confidence interval 0.59-8.71), high use hazard ratio 4.05 (95% confidence interval 1.18-13.96).

Conclusions: Huntington's disease onset was earlier among consumers of caffeinated soda, but not other caffeinated beverages. This finding may be spurious or not related to caffeine. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986294PMC
March 2018

Cognition and the course of prodromal Parkinson's disease.

Mov Disord 2017 Nov 24;32(11):1640-1645. Epub 2017 Oct 24.

Eli Lilly and Company, Indianapolis, Indiana, USA.

Background: Prospective data on cognition in prodromal Parkinson's disease are limited. The objectives of this study were to assess in prodromal PD (1) if baseline cognition predicts conversion to clinical PD, (2) if baseline dopamine transporter binding predicts longitudinal changes in cognition, and (3) if impaired olfaction predicts future cognitive decline.

Methods: Prodromal participants were 136 hyposmic individuals enrolled in the Parkinson Associated Risk Study. We examined baseline neuropsychological test performance in PD converters versus nonconverters and the association between baseline dopamine transporter binding and change in cognition. An additional 73 normosmic individuals were included in analyses of the relationship between hyposmia and cognitive decline.

Results: In prodromal participants, baseline cognitive scores did not significantly predict conversion, but converters performed numerically worse on 5 of the 6 cognitive domains assessed, with the greatest differences in executive function/working memory (0.68 standard deviation lower) and global cognition (0.64 standard deviation lower). Lower baseline dopamine transporter binding predicted greater future decline in processing speed/attention (P = 0.02). Hyposmia predicted greater future decline in language (P = 0.005) and memory (P = 0.01) abilities.

Conclusions: Given hyposmia in the general population predicts cognitive decline, the role of cognition in predicting conversion in prodromal PD needs to be assessed in large cohorts followed long-term. The dopamine system may be associated with changes in processing speed/attention in individuals at risk for PD. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722226PMC
November 2017

The CREST-E study of creatine for Huntington disease: A randomized controlled trial.

Neurology 2017 Aug 12;89(6):594-601. Epub 2017 Jul 12.

From the Department of Neurology (S.M.H., H.D.R.), Massachusetts General Hospital and Harvard Medical School, Boston; Departments of Neurology and Biostatistics (G.S., D.O.), University of Rochester Medical Center, NY; Department of Pediatrics (A.-L.B.), Medical University of South Carolina, Charleston; and NIH (C.M.M., R.N.), National Center for Complementary and Integrative Health, Bethesda, MD.

Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies.

Results: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits -0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment.

Conclusions: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD.

Clinicaltrialsgov Identifier: NCT00712426.

Classification Of Evidence: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline.
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http://dx.doi.org/10.1212/WNL.0000000000004209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562960PMC
August 2017

Safety of Converting From Tetrabenazine to Deutetrabenazine for the Treatment of Chorea.

JAMA Neurol 2017 08;74(8):977-982

Department of Neurology, Virginia Commonwealth University, Richmond.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study.

Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD).

Design, Setting, And Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control.

Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen.

Main Outcomes And Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points.

Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001).

Conclusions And Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.
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http://dx.doi.org/10.1001/jamaneurol.2017.1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710322PMC
August 2017

Ambient and Controlled Particle Exposures as Triggers for Acute ECG Changes.

Res Rep Health Eff Inst 2016 May(186):5-75

Introduction: Previous studies have examined changes in heart rate variability (HRV*) and repolarization associated with increased particulate matter (PM) concentrations on the same and previous few days. However, few studies have examined whether these health responses to PM occur within a few hours or even less. Moreover, it is not clear whether exposure of subjects to ambient or-controlled PM concentrations both lead to similar health effects or whether any of the subjects' individual characteristics modify any of their responses to PM. The aims of the cur- rent study were to investigate whether exposure to PM was associated with rapid changes (< 60 minutes or con- current hour up to a delay of 6 hours) in markers of car- diac rhythni or changes in total antioxidant capacity (a marker of protection against oxidative stress) and whether any PM effects on cardiac rhythm markers were modified by total antioxidant capacity, age, obesity, smoking, hypertension, exertion, prior myocardial infarction (MI), or medication.

Methods: We obtained data from a completed study in Augsburg, Germany (a panel study in N= 109 subjects, including a group with type 2 diabetes or impaired glucose tolerance [IGT; also known as prediabetes]) and a group of other- wise healthy subjects with a potential genetic susceptibil- ity to detoxifying and inflammatory pathways (Hampel et al. 2012b), as well as three completed studies in Rochester, New York (the REHAB panel study of N= 76 postinfarction patients in a cardiac rehabilitation pro- gram [Rich et al. 2012b]; the UPDIABETES study of con- trolled exposure to ultrafine particles [UFPs, particles with an aerodynamic diameter < 100 nm] of N = 19 patients with type 2 diabetes [Stewart et al. 2010; Vora et al. 2014j; and the UPCON controlled-exposure study of concentrated UFP exposure in N = 20 young, healthy, life- time nonsmokers). Data included 5-minute and 1-hour values for HRV and repolarization parameters from elec- trocardiogram (ECG) recordings and total antioxidant capacity measured in stored blood samples. Ambient con- centrations of UFPs, accumulation-mode particles (AMP, particles with an aerodynamic diameter of 100-500 nm), fine PM (PM2.5, particles with an aerodynamic diameter 2.5 pm), and black carbon (BC) were also available. We first conducted factor analyses in each study to find subgroups of correlated ECG outcomes and to reduce the number of outcomes examined in our statistical models. We then restricted the statistical analyses to the factors and representative.outcomes that were common to all four studies, including total HRV (measured as the standard deviation of normal-to-normal [NN] beat intervals [SDNNj), parasympathetic modulation (measured as the root mean square of the successive differences [RMSSD between adjacent NN beat intervals), and T-wave morphol- ogy (measured as T-wave complexity). Next, we used addi- tive mixed models to estimate the change in each outcome associated with increased pollutant concentrations in the . concurrent and previous 6 hours and with 5-minute inter- vals up to the previous 60 minutes, accounting for the correlation of repeated outcome measures for each subject and adjusting for time trend, hour of the day, temperature, relative humidity, day of the week, month, and visit number. Because multiple comparisons were an issue in our. analyses, we used a discovery-and-replication approach to draw conclusions across studies for each research question.

Results: In the Augsburg study, interquartile range (IQR) increases in UFP concentrations lagged 2 to 5 hours were associated with 1%-3% decreases in SDNN (e.g., lagged 3 hours in the group with a genetic susceptibility: -2.26%; 95% confidence interval [CI], -3.98% to -0.53%). In the REHAB study, similarly, IQR increases in UFP concentra- tions in the previous 5 hours were associated with < 3% decreases in SDNN (e.g., lagged 1 hour: -2.69%; 95% CI, -5.13% to -0.26%). We also found decreases in SDNN associated with IQR increases in total particle count-(a surrogate for UFP) in the UPDIABETES study (lagged 1 hour: -13.22%; 95% CI, -24.11% to -2.33%) but not in the UPCON study. In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and lagged 1-5 hours, AMP concentrations lagged 1 and 3 hours, and BC con- centrations lagged 1-5 hours were associated with -1%-5% decreases in SDNN (e.g., PM2.5 lagged 2 hours in the group with diabetes or IGT: -4.59%; 95% CI, -7.44% to -1.75%). In the REHAB study, IQR increases in PM2.5 concentrations lagged 5 and 6 hours and AMP concentra- tions in the concurrent hour and lagged up to 5 hours were associated with 1%-2% decreases in SDNN (e.g., PM2.5 lagged 4 hours: -2.13%; 95% CI, -3.91% to -0.35%). In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and BC lagged 1 and 6 hours were associated with 3%-7% decreases in RMSSD (e.g., PM2.5 concurrent hour in the group with diabetes or IGT: -7.20%; 95% CI, -12.11% to -2.02%). In the REHAB study, similarly, increases in PM2.5 concen- trations lagged 4 to 6 hours-though not AMP or BC con- centrations at any lag hour-were associated with -2.5%-3.5% decreases in RMSSD (e.g., PM2.5 lagged 5 hours: -3.49%; 95% CI, -6.13% to -0.84%). We did not find consistent evidence of any pollutant effects on T-wave complexity in 1-hour recordings. For 5-minute record- ings, there was no consistent evidence of UFP effects on SDNN, RMSSD, or T-wave complexity at any 5-minute interval within 60 minutes. We further concluded that these replicated hourly effects of UFP and PM2.5 on short-term measures of SDNN and RMSSD generally did not differ between the groups in the studies (i.e., type 2 diabetes, pre-diabetes/IGT, post- infarction, and healthy subjects). Last, we found no con- sistent evidence of effects of any pollutant on total anti- oxidant capacity and no consistent evidence of modification of our PM2.5-outcome associations by any of the potential effect modifiers.

Onclusions: Increased UFP concentrations were associated with decreased SDNN in both of the panel studies and one of the two controlled-exposure studies. We also found that decreased SDNN was associated with both increased PM2.5 and AMP concentrations in the previous 6 hours in the panel studies and that decreased RMSSD was associ- ated with increased PM2.5 concentrations in the previous 6 hours in the panel studies. We therefore concluded that the research questions were replicated. Our findings suggest that both UFPs and PM2.5 are associated with autonomic dysfunction within hours of exposure, which may in part. explain the previously reported risk of acute cardiovascular events associated with increased PM in the previous few hours. Despite the heterogeneity of the study populations,and protocols, our findings provided consistent evidence for the induction of rapid pathophysiological responses by UFPs and PM2.5- The absence of consistent associations between UFPs, PM2.5, and these outcomes when examining shorter time intervals indicates that the 5- to 60-minute responses may be less pronounced than the responses occurring within hours. However, the findings from the 5-minute intervals may have been affected by the variety of proto- cols and conditions from study to study as well as by the potential effects of underlying diseases (e.g., healthy indi- viduals versus individuals with diabetes or a recent cor- onary artery. event), physical activity, circadian rhythms, stress, and/or medications.
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May 2016

Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter-Deficit Prodromal Cohort.

JAMA Neurol 2017 08;74(8):933-940

Institute for Neurodegenerative Disorders, New Haven, Connecticut.

Importance: Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD.

Objective: To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD.

Design, Setting, And Participants: Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up.

Main Outcomes And Measures: Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4-year follow-up.

Results: Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit.

Conclusions And Relevance: The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.
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http://dx.doi.org/10.1001/jamaneurol.2017.0985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710321PMC
August 2017

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III).

Ann Clin Transl Neurol 2017 06 9;4(6):360-368. Epub 2017 May 9.

Department of Neurology Northwestern University Chicago Illinois.

Objective: To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).

Methods: STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.

Results: The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).

Interpretation: STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.
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http://dx.doi.org/10.1002/acn3.412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454402PMC
June 2017

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

JAMA 2016 Jul;316(1):40-50

Boston University Medical Campus, Boston, Massachusetts.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.

Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.

Main Outcomes And Measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.

Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.

Conclusions And Relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.

Trial Registration: clinicaltrials.gov Identifier: NCT01795859.
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http://dx.doi.org/10.1001/jama.2016.8655DOI Listing
July 2016

Does total antioxidant capacity modify adverse cardiac responses associated with ambient ultrafine, accumulation mode, and fine particles in patients undergoing cardiac rehabilitation?

Environ Res 2016 08 10;149:15-22. Epub 2016 May 10.

Division of Epidemiology, Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, USA. Electronic address:

Background: Previous studies suggest that pathways reducing oxidative stress may have a protective effect against adverse cardiac responses associated with ambient PM. However, few studies have directly assessed total antioxidant capacity (TAC) as a potential effect modifier of cardiac responses to increased ambient PM.

Objectives: We examined if TAC modifies the association between ambient PM and markers of heart rate variability (HRV), repolarization, systemic inflammation, and systolic blood pressure (SBP) in post-infarction patients.

Methods: We recruited 76 patients with a recent coronary event (myocardial infarction or unstable angina) who participated in a cardiac rehabilitation program from June 2006 to November 2009 in Rochester, New York. Ambient fine particle (PM2.5,≤2.5µm in aerodynamic diameter), accumulation mode particle (AMP, 100-500nm) and ultrafine particle (UFP, 10-100nm) concentrations were measured continuously by fixed-site monitors. Markers of HRV and repolarization were measured by continuous Holter electrocardiogram (ECG) recordings before and during exercise sessions of the rehabilitation program. Blood pressure was measured and venous blood samples were collected before exercise to measure TAC and inflammation markers. We applied linear mixed models to assess changes in markers of HRV, repolarization, systemic inflammation, and SBP associated with increased PM concentrations in the low, medium and high TAC tertile groups, after adjusting for covariates including temperature, calendar time since the beginning of the study, visit number, month of year, and hour of day.

Results: Based on subject-visits with available TAC, we observed increases in SBP, C-reactive protein, and fibrinogen, and decreases in rMSSD (square root of the mean of the sum of the squared differences between adjacent normal to normal intervals) and SDNN (standard deviation of normal to normal beat intervals) associated with increased PM2.5, AMP and UFP in the previous 6-120h (e.g. change in SBP associated with each interquartile range (IQR) increase in PM2.5 lagged 0-5h was 1.27mmHg [95%CI: 0.09, 2.46mmHg]). However, we did not observe a consistent pattern of effect measure modification by TAC for any combination of pollutant and outcome (e.g. changes in SBP associated with each IQR increase in PM2.5 lagged 0-5h for the low, medium and high TAC tertile groups were 1.93mmHg [95%CI: 0.23, 3.63 mmHg], -0.31 mmHg [95%CI: -2.62, 2.01 mmHg], and 1.29mmHg [95%CI: -0.64, 3.21 mmHg], respectively. P for interaction=0.28).

Conclusions: In a post-infarction population, total antioxidant capacity does not appear to modify the association between biomarkers of heart rate variability, repolarization, systemic inflammation, and systolic blood pressure and ambient PM concentrations in the previous 6-120h.
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http://dx.doi.org/10.1016/j.envres.2016.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907837PMC
August 2016

Early Clinical Predictors of Treatment-Resistant and Functional Outcomes in Parkinson's Disease.

Mov Disord Clin Pract 2016 Jan-Feb;3(1):53-58. Epub 2015 Dec 14.

Georgetown University Washington District of Columbia USA.

Background: The aim of this work was to identify early clinical predictors of important outcomes in Parkinson's disease (PD). In PD, treatment-resistant (e.g., dementia, falling) and other important functional outcomes (e.g., declines in quality of life [QOL] and activities of daily living [ADL]) emerge and become increasingly disabling.

Methods: We analyzed longitudinal data from 491 early, untreated PD subjects who enrolled in the PreCEPT trial, had baseline SPECT dopamine transporter deficit, and have continued in the PostCEPT observational cohort. After PreCEPT, antiparkinsonian medications were added if needed. Baseline clinical precursors were examined as potential predictors of selected outcomes. Separate and multivariate logistic regressions, adjusted for certain baseline factors, were performed for dichotomized outcomes evaluated at the last PostCEPT visit.

Results: On enrollment, subjects had average disease duration of 0.8 years and were followed for an average of 5.5 years. Some baseline precursors were found to be predictive: disease stage, cognitive, and ADL scores for dementia; disease stage, ADL, and motor and freezing scores for hallucinations; disease stage, depression, ADL, and freezing and walking scores for falling; and ADL, depression, and motor and walking scores and disease stage for QOL decline. No baseline clinical feature predicted decline in ADL. Being on levodopa was not a significant predictor of any outcome, but subjects on a dopamine agonist were significantly impaired with respect to falling, abnormal Mini-Mental State Examination, and QOL.

Conclusions: Although there are limitations, results support the value of longitudinal follow-up of clinical trial populations to identify early clinical precursors of important outcomes and thereby identify high-risk patients early on.
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http://dx.doi.org/10.1002/mdc3.12273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178710PMC
December 2015
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