Ultra-Widefield Imaging of the Retinal Macrovasculature in Parkinson Disease Versus Controls With Normal Cognition Using Alpha-Shapes Analysis.

Purpose: To investigate retinal vascular characteristics using ultra-widefield (UWF) scanning laser ophthalmoscopy in Parkinson disease (PD). Methods: Individuals with an expert-confirmed clinical diagnosis of PD and controls with normal cognition without PD underwent Optos California UWF imaging. Patients with diabetes, uncontrolled hypertension, glaucoma, dementia, other movement disorders, or known retinal or optic nerve pathology were excluded. Images were analyzed using Vasculature Assessment and Measurement Platform for Images of the Retina (VAMPIRE-UWF) software, which describes retinal vessel width gradient and tortuosity, provides vascular network fractal dimensions, and conducts alpha-shape analysis to further characterize vascular morphology (complexity, Opαmin; spread, OpA). Results: In the PD cohort, 53 eyes of 38 subjects were assessed; in the control cohort, 51 eyes of 33 subjects were assessed. Eyes with PD had more tortuous retinal arteries in the superotemporal quadrant (P = 0.043). In eyes with PD, alpha-shape analysis revealed decreased OpA, indicating less retinal vasculature spread compared to controls (P = 0.032). Opαmin was decreased in PD (P = 0.044), suggesting increased vascular network complexity. No differences were observed in fractal dimension in any region of interest. Conclusions: This pilot study suggests that retinal vasculature assessment on UWF images using alpha-shape analysis reveals differences in retinal vascular network spread and complexity in PD and may be a more sensitive metric compared to fractal dimension. Translational Relevance: Retinal vasculature assessment using these novel methods may be useful in understanding ocular manifestations of PD and the development of retinal biomarkers.

Characterizing differences in retinal and choroidal microvasculature and structure in individuals with Huntington's Disease compared to healthy controls: A cross-sectional prospective study.

OBJECTIVE: To characterize retinal and choroidal microvascular and structural changes in patients who are gene positive for mutant huntingtin protein (mHtt) with symptoms of Huntington's Disease (HD). METHODS: This study is a cross-sectional comparison of patients who are gene positive for mHtt and exhibit symptoms of HD, either motor manifest or prodromal (HD group), and cognitively normal individuals without a family history of HD (control group). HD patients were diagnosed by Duke movement disorder neurologists based on the Unified Huntington's Disease Rating Scale (UHDRS). Fovea and optic nerve centered OCT and OCTA images were captured using Zeiss Cirrus HD-5000 with AngioPlex. Outcome metrics included central subfield thickness (CST), peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, and choroidal vascularity index (CVI) on OCT, and foveal avascular zone (FAZ) area, vessel density (VD), perfusion density (PD), capillary perfusion density (CPD), and capillary flux index (CFI) on OCTA. Generalized estimating equation (GEE) models were used to account for inter-eye correlation. RESULTS: Forty-four eyes of 23 patients in the HD group and 77 eyes of 39 patients in the control group were analyzed. Average GCIPL thickness and FAZ area were decreased in the HD group compared to controls (p = 0.001, p < 0.001). No other imaging metrics were significantly different between groups. CONCLUSIONS: Patients in the HD group had decreased GCIPL thickness and smaller FAZ area, highlighting the potential use of retinal biomarkers in detecting neurodegenerative changes in HD.

Ten-Year Trends in Lithium Prescribing in Alberta, Canada.

AIMS: Despite lithium's clinical efficacy, it is commonly thought that its use is declining. The objective of this study is to describe the new and prevalent lithium users as well as rates of discontinuation of lithium use over a 10-year period. METHODS: This study used provincial administrative health data from Alberta, Canada between January 1, 2009 and December 31, 2018. Lithium prescriptions were identified within the Pharmaceutical Information Network database. Total and subgroup specific frequencies of new and prevalent lithium use were determined over the 10-year study period. Lithium discontinuation was also estimated through survival analysis. RESULTS: Between the calendar years of 2009 and 2018, 580,873 lithium prescriptions were dispensed in Alberta to 14,008 patients. The total number of new and prevalent lithium users appears to be decreasing over the 10-year timeframe, although the decline may have stopped or reversed in the latter years of the study period. Prevalent use of lithium was lowest among individuals between the ages of 18-24 years while the highest number of prevalent users were in the 50-64 age group, particularly among females. New lithium use was lowest amongst those 65 years and older. More than 60% (8,636) of patients prescribed lithium, discontinued use during the study timeframe. Lithium users between ages of 18-24 years were at the highest risk of discontinuations. CONCLUSIONS: Rather than a general decline in prescribing, trends in lithium use are dependent on age and sex. Further, the period soon after lithium initiation appears to be a key time period in which many lithium trials are abandoned. Detailed studies using primary data collection are needed to confirm and further explore these findings. These population-based results not only confirm a decline in lithium use, but also suggest that this may have stopped or even reversed. Population-based data on discontinuation pinpoint the period soon after initiation as the time when trials are most often discontinued.

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear. OBJECTIVE: This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers. METHODS: A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures. RESULTS: Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes. CONCLUSIONS: Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society.

Longitudinal Analysis of Retinal Microvascular and Choroidal Imaging Parameters in Parkinson's Disease Compared with Controls.

Purpose: To quantify rate of change of retinal microvascular and choroidal structural parameters in subjects with Parkinson's disease (PD) compared with controls using OCT and OCT angiography (OCTA). Design: Prospective longitudinal study. Participants: Seventy-four eyes of 40 participants with PD and 149 eyes of 78 control individuals from the Eye Multimodal Imaging in Neurodegenerative Disease database. Methods: Subjects underwent OCT and OCTA imaging at 2 time points approximately 12 months apart. Main Outcome Measures: Imaging parameters included central subfield thickness, ganglion cell-inner plexiform layer (GC-IPL) thickness, peripapillary retinal nerve fiber layer thickness, choroidal vascularity index, superficial capillary plexus perfusion density (PFD), vessel density (VD), and foveal avascular zone area. Results: Participants with PD had greater rate of yearly decrease in GC-IPL (PD = -0.403µm, control = + 0.128 µm; P = 0.01), greater yearly decline in PFD in the 3 × 3 mm ETDRS circle (PD = -0.016, control = + 0.002; P < 0.001) and ring (PD = -0.016, control = + 0.002; P < 0.001); 6 × 6 mm ETDRS circle (PD = -0.021, control = 0.00; P = 0.001), and outer ring (PD = -0.022, control = 0.00; P = 0.001). Participants with PD had greater rate of yearly decline in VD in 3 × 3 mm circle (PD = -0.939/mm, control = + 0.006/mm; P < 0.001) and ring (PD = -0.942/mm, control = + 0.013/mm; P < 0.001); 6 × 6 mm circle (PD = -0.72/mm, control = -0.054/mm; P = 0.006), and outer ring (PD = -0.746/mm, control = -0.054/mm; P = 0.005). When stratified by PD severity based on Hoehn and Yahr stage, faster rates of decline were seen in Hoehn and Yahr stages 3 to 4 in the 3 × 3 mm circle PFD and VD as well as 3 × 3 mm ring VD. Conclusions: Individuals with PD experience more rapid loss of retinal microvasculature quantified on OCTA and more rapid thinning of the GC-IPL than controls. There may be more rapid loss in patients with greater disease severity. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Initial Clinical Outcome With Bilateral, Dual-Target Deep Brain Stimulation Trial in Parkinson Disease Using Summit RC + S.

BACKGROUND: Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism. OBJECTIVE: To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study. METHODS: We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power. RESULTS: Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively. CONCLUSION: Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.

Identifying Peripapillary Radial Capillary Plexus Alterations in Parkinson's Disease Using OCT Angiography.

PURPOSE: To compare radial peripapillary capillary (RPC) plexus vascular parameters and retinal nerve fiber layer (RNFL) thickness between those with Parkinson's disease (PD) and controls. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 151 eyes of 81 PD participants and 514 eyes of 266 controls. METHODS: Participants underwent OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss AG). Capillary perfusion density (CPD) and capillary flux index (CFI) were assessed using a 4.5 × 4.5-mm peripapillary scan, and RNFL thickness was assessed using a 200 × 200-µm optic nerve cube OCT scan. Hoehn and Yahr clinical staging for PD was determined by an experienced movement disorders specialist. Generalized estimating equations adjusted for age and sex were used for analysis. MAIN OUTCOME MEASURES: Differences in RNFL thickness, CPD, and CFI as assessed using multivariable generalized estimating equations between individuals with PD and controls. RESULTS: After adjustment for age and sex, average CPD (0.446% ± 0.018% vs. 0.439% ± 0.017%, P < 0.001) and CFI (0.434 ± 0.031 vs. 0.426 ± 0.036, P = 0.008) were significantly higher in PD eyes. Average RNFL thickness was similar between groups (PD 89.71 ± 10.45 µm vs. control 88.20 ± 10.33 µm, P = 0.19). Significant correlations between Hoehn and Yahr stage and OCTA parameters were not observed. The OCTA parameters were not significantly different between eyes of the same patient. CONCLUSIONS: Increased peripapillary microvascular density and flux were detected in a large cohort of individuals with PD compared with controls after adjusting for age and sex; however, RNFL thickness was similar between groups. Peripapillary OCTA parameters may not correlate with the severity of PD. OCTA may serve as a noninvasive method to identify novel biomarkers for the early diagnosis of PD; as such, this methodology deserves further investigation.

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

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

Mindfulness based stress reduction in people with Parkinson's disease and their care partners.

BACKGROUND: Parkinson's Disease (PD) leads to poor quality of life and caregiver burden. Mindfulness-based stress reduction (MBSR) may improve these symptoms. We assessed the impact of a 9-week MBSR course on people with PD (PwP) and their care partners (CPs). METHODS: Participants completed questionnaires at screening, at the end of the course, and at 3-month follow-up: Parkinson's Disease Quality-39 (PDQ-39, PD only), Zarit Burden Inventory (ZBI, CP only) and Mindful Attention Awareness Scale (MAAS, both). The primary outcome measure was change in PDQ-39 (for PwP) or ZBI (for CP). Patient-reported scales were analyzed quantitatively; qualitative data on perceived effectiveness was collected. RESULTS: 53.8% PwP and 100% CPs completed the course. Among PwP, there was a significant reduction in MAAS(p < 0.001) and in PDQ-39 (p = 0.008). CPs experienced an increase in MAAS (p = 0.02) but no change in ZBI (p = 0.239). Qualitatively, both PwP and CPs expressed satisfaction with the course. DISCUSSION: MBSR improves mindful awareness in CPs and improves health-related quality of life in PwP.

Repeatability of Peripapillary OCT Angiography in Neurodegenerative Disease.

Purpose: To assess the repeatability of peripapillary OCT angiography (OCTA) in those with Alzheimer disease (AD), mild cognitive impairment (MCI), Parkinson disease (PD), or normal cognition. Design: Cross-sectional. Participants: Patients with a clinical diagnosis of AD, MCI, PD, or normal cognition were imaged. Those with glaucoma, diabetes mellitus, vitreoretinal pathology, and poor-quality images were excluded. Methods: Each eligible eye of each participant underwent 2 OCTA 4.5 × 4.5-mm peripapillary scans in a single session using a Zeiss Cirrus HD-OCT 5000 with AngioPlex (Carl Zeiss Meditec). The Zeiss software (v11.0.0.29946) quantified measures of perfusion in the radial peripapillary capillary (RPC) plexus in 4 sectors (superior, nasal, inferior, temporal). The average of these sectors was calculated and reported. Main Outcome Measures: Radial peripapillary capillary plexus perfusion was quantified using 2 parameters: capillary perfusion density (CPD) and capillary flux index (CFI). Intraclass correlation coefficients (ICCs) were used to quantify repeatability. For subjects who had both eyes included, the average values of each scan pair were used to assess interocular symmetry of CPD and CFI. Results: Of 374 eyes, 46 were from participants who had AD, 85 were from participants who had MCI, 87 were from participants who had PD, and 156 were from participants who had normal cognition. Capillary perfusion density ICC in AD = 0.88 (95% confidence interval [CI], 0.79-0.93), MCI = 0.95 (0.92-0.96), PD = 0.91 (0.87-0.94), and controls = 0.90 (0.87-0.93). Capillary flux index ICC in AD = 0.82 (0.70-0.90), MCI = 0.87 (0.80-0.91), PD = 0.91 (0.87-0.94) and controls = 0.85 (0.79-0.89). There were no significant differences in interocular variation in average CPD and CFI in AD, MCI, or PD (all P > 0.05). Isolated interocular sectoral CPD differences were noted in AD (nasal, P = 0.049; temporal, P = 0.024), PD (nasal, P = 0.036), and controls (nasal, P = 0.016). Interocular differences in CFI in the superior sector in MCI (P = 0.028) and in average CFI for controls (P = 0.035) were observed. Conclusions: Peripapillary OCTA repeatability in AD, MCI, and PD is good-excellent and similar to those with normal cognition. Insignificant interocular asymmetry in peripapillary OCTA suggests neurodegeneration may proceed uniformly; future studies may reveal the appropriateness of single-eye imaging.

Characterization of Retinal Microvascular and Choroidal Structural Changes in Parkinson Disease.

Importance: Noninvasive retinal imaging may detect structural changes associated with Parkinson disease (PD) and may represent a novel biomarker for disease detection. Objective: To characterize alterations in the structure and microvasculature of the retina and choroid in eyes of individuals with PD and compare them with eyes of age- and sex-matched cognitively healthy control individuals using optical coherence tomography (OCT) and OCT angiography (OCTA). Design, Setting, and Participants: This cross-sectional study was conducted at the Duke Neurological Disorders Clinic in Durham, North Carolina. Individuals aged 50 years or older with a diagnosis of PD were eligible for inclusion and underwent an evaluation and diagnosis confirmation before enrollment. Control individuals aged 50 years or older and without subjective cognitive dysfunction, a history of tremor, or evidence of motor dysfunction consistent with parkinsonism were solicited from the clinic or the Duke Alzheimer's Disease Prevention Registry. Individuals with diabetes, glaucoma, retinal pathology, other dementias, and corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity worse than 20/40 Snellen were excluded. Data were analyzed between January 1, 2020, and March 30, 2020. Exposures: All participants underwent OCT and OCTA imaging. Main Outcomes and Measures: Generalized estimating equation analysis was used to characterize the association between imaging parameters and PD diagnosis. Superficial capillary plexus vessel density (VD) and perfusion density (PFD) were assessed within the ETDRS 6 × 6-mm circle, 6 × 6-mm inner ring, and 6 × 6-mm outer ring, as was the foveal avascular zone area. Peripapillary retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness, central subfield thickness, subfoveal choroidal thickness, total choroidal area, luminal area, and choroidal vascularity index (CVI) were measured. Results: A total of 124 eyes of 69 participants with PD (39 men [56.5%]; mean [SD] age, 71.7 [7.0] years) and 248 eyes of 137 control participants (77 men [56.2%]; mean [SD] age, 70.9 [6.7] years) were analyzed. In the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.37; 95% CI, 0.04-0.71; P = .03) and PFD (ß coefficient = 0.009; 95% CI, 0.0003-0.018; P = .04) were lower in eyes of participants with PD. In the inner ring of the 6 × 6-mm ETDRS circle, VD (ß coefficient = 0.61; 95% CI, 0.20-1.02; P = .003) and PFD (ß coefficient = 0.015; 95% CI, 0.005-0.026; P = .004) were lower in eyes of participants with PD. Total choroidal area (ß coefficient = -1.74 units2; 95% CI, -3.12 to -0.37 units2; P = .01) and luminal area (ß coefficient = -1.02 units2; 95% CI, -1.86 to -0.18 units2; P = .02) were greater, but CVI was lower (ß coefficient = 0.5%; 95% CI, 0.2%-0.8%; P < .001) in eyes of individuals with PD. Conclusions and Relevance: This study found that individuals with PD had decreased retinal VD and PFD as well as choroidal structural changes compared with age- and sex-matched control participants. Given the observed population differences in these noninvasive retinal biomarkers, further research into their clinical utility in PD is needed.

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

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.

Dopamine Transporter Imaging has no Impact on Functional Outcomes in de Novo Probable Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is among the most prevalent neurodegenerative conditions. While motor and non-motor aspects of this disease have been well characterized, no objective biomarker exists to support an accurate clinical diagnosis. However, newer imaging techniques, including [123I]-FP-CIT (DaTSCAN), have demonstrated utility in differentiating between PD and non-neurodegenerative tremor disorders. OBJECTIVE: DaTSCAN has been primarily investigated in situations where diagnostic confusion exists, and in these instances has been shown to significantly impact clinical management. The goal of this pilot study was to evaluate the impact of DaTSCAN on the clinical management of patients with early probable PD, where no diagnostic uncertainty exists. METHODS: This was a prospective, 54-week, comparative pilot study, in which twenty subjects with de novo PD were randomly assigned to DaTSCAN either immediately upon diagnosis (and again at 6 and 12 months) or delayed to 6 months (and again at 12 months). The primary outcome measure was the frequency of deviation from the initial treatment plan from baseline to 54 weeks between the two groups. Secondary outcomes included motor and non-motor assessments. RESULTS: There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11). In addition, there were no group differences in medication requirements, motor performance, or patient expectations of disease. CONCLUSIONS: In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.

Linkage of familial essential tremor to chromosome 5q35.

BACKGROUND: Essential tremor is a neurological condition characterized by tremor during voluntary movement. To date, 3 loci linked to familial essential tremor have been identified. METHODS: We examined 48 essential tremor patients in 5 large essential tremor pedigrees in our data set for genetic linkage using an Affymetrix Axiom array. Linkage analysis was performed using an affecteds-only dominant model in SIMWALK2. To incorporate all genotype information, GERMLINE was used to identify genome segments shared identical-by-descent in pairs of affecteds. Exome sequencing was performed in pedigrees showing evidence of linkage. RESULTS: For one family, chromosomes 5 and 18 showed genome-wide significant linkage to essential tremor. Shared segment analysis excluded the 18p11 candidate region and reduced the 5q35 region by 1 megabase. Exome sequencing did not identify a potential causative variant in this region. CONCLUSION: A locus on chromosome 5 is linked to essential tremor. Further research is needed to identify a causative variant. © 2016 International Parkinson and Movement Disorder Society.

Beyond silence: protocol for a randomized parallel-group trial comparing two approaches to workplace mental health education for healthcare employees.

BACKGROUND: Mental illness is a significant and growing problem in Canadian healthcare organizations, leading to tremendous personal, social and financial costs for individuals, their colleagues, their employers and their patients. Early and appropriate intervention is needed, but unfortunately, few workers get the help that they need in a timely way due to barriers related to poor mental health literacy, stigma, and inadequate access to mental health services. Workplace education and training is one promising approach to early identification and support for workers who are struggling. Little is known, however, about what approach is most effective, particularly in the context of healthcare work. The purpose of this study is to compare the impact of a customized, contact-based education approach with standard mental health literacy training on the mental health knowledge, stigmatized beliefs and help-seeking/help-outreach behaviors of healthcare employees. METHODS/DESIGN: A multi-centre, randomized, two-group parallel group trial design will be adopted. Two hundred healthcare employees will be randomly assigned to one of two educational interventions: Beyond Silence, a peer-led program customized to the healthcare workplace, and Mental Health First Aid, a standardized literacy based training program. Pre, post and 3-month follow-up surveys will track changes in knowledge (mental health literacy), attitudes towards mental illness, and help-seeking/help-outreach behavior. An intent-to-treat, repeated measures analysis will be conducted to compare changes in the two groups over time in terms of the primary outcome of behavior change. Linear regression modeling will be used to explore the extent to which knowledge, and attitudes predict behavior change. Qualitative interviews with participants and leaders will also be conducted to examine process and implementation of the programs. DISCUSSION: This is one of the first experimental studies to compare outcomes of standard mental health literacy training to an intervention with an added anti-stigma component (using best-practices of contact-based education). Study findings will inform recommendations for designing workplace mental health education to promote early intervention for employees with mental health issues in the context of healthcare work. TRIAL REGISTRATION: May 2014 - ClinicalTrials.gov: NCT02158871.

Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease.

Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome-wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome-wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7 x 10(-8); genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17-1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6 x 10(-8); genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62-0.79] T vs. C allele, PAR%= 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.

Impulse control disorders arising in 3 patients treated with rotigotine.

OBJECTIVE: We report 3 cases of impulse control disorders (ICDs) that developed in patients with Parkinson disease treated with the novel dopamine agonist, rotigotine. METHODS: Three patients were identified retrospectively who developed symptoms of an ICD while taking rotigotine. The ICD symptoms developed at 4, 5, and 8 years after diagnosis of Parkinson disease in these patients and while they were taking rotigotine and levodopa. Other drugs included entacapone, amantadine, and selegiline. The first patient developed symptoms of hypersexuality while taking rotigotine 18 mg (40-cm2 patch) daily and levodopa 300 mg/d. The second patient developed pathological gambling while taking rotigotine 22.5 mg (50-cm2 patch) daily and levodopa 300 mg/d. The third patient developed symptoms of hypersexuality, punding, and pathological gambling, losing more than $100,000 while taking rotigotine 18 mg (40-cm2 patch) and levodopa 400 mg/d. In the first 2 patients, the development of the ICD was temporally associated with an increase in rotigotine dosage, whereas the third patient experienced a dramatic increase in his gambling with the addition of rotigotine. Both subjects who developed pathological gambling had a history of recreational gambling for many years, and 1 of the 2 subjects who developed hypersexuality had a history of cross-dressing since childhood. RESULT: The ICDs in these patients were effectively treated with rotigotine reduction or discontinuation. CONCLUSION: Rotigotine has the potential for causing ICD, similar to other dopamine agonists.