ELectronic Archimedes spiral Neural Network (ELANN).

The Archimedes spiral is a clinical tool that aids in the diagnosis and monitoring of essential tremor. However, spiral ratings may vary based on experience and training of the rating physician. This study sought to generate an objective standard model for tremor evaluation using convolutional neural networks. One senior movement disorders neurologist (Neurologist 1) with over 30 years of clinical experience used the Bain and Findley Spirography Rating Scale to rate 1653 Archimedes spiral images from 46 essential tremor patients (mild to severe tremor) and 75 control subjects (no to mild tremor). Neurologist 1's labels were used as the reference standard to train the model. After training the model, a randomly selected subset of spiral testing data was re-evaluated by Neurologist 1, by a second senior movement disorders neurologist (Neurologist 2) with over 27 years of clinical experience, and by our model. Cohen's Weighted Kappa 95% confidence intervals were calculated from all rater comparisons to determine if our model performs with the same proficiency as two senior movement disorders neurologists. The Cohen's Weighted Kappa 95% confidence intervals for the agreement between the reference standard scores and Neurologist 1's rerated scores, for the agreement between the reference standard scores and Neurologist 2's scores, and for the agreement between the reference standard scores and our model's scores were 0.93-0.98, 0.86-0.94, and 0.89-0.96, respectively. With overlapping Cohen's Weighted Kappa 95% confidence intervals for all agreement comparisons, we demonstrate that our model evaluates spirals with the same proficiency as two senior movement disorders neurologists.

Stigma and Social Avoidance in Adults with Essential Tremor.

Background: People with essential tremor (ET) can be subject to stigma, and some adopt avoidance behaviors. Characteristics associated with ET stigma and the relationship between perceived stigma and social dysfunction have not been studied. Objectives: To discern predictors of perceived stigma and social dysfunction in ET, and to identify potentially treatable psychological factors associated with social dysfunction. Methods: We surveyed ET patients (n = 158) on recalled stigma incidents and social dysfunction related to tremor, as well as clinical and demographic characteristics including tremor severity, and psychological constructs including anxiety, depression, mindfulness, resilience, and narcissism. Results: Worse tremor severity (Standardized beta [SB] 1.4, P < 0.001) especially among younger participants (interaction of age and tremor severity SB -0.9, P < 0.001) and presence of vocal tremor (SB 0.7, P = 0.002) predict perceived stigma. 53/157 (33.8%) participants met criteria for social dysfunction, employing maladaptive avoidance strategies. Scores for perceived stigma (Odds Ratio [OR] 1.2, P = 0.002), depression (OR 1.5, P = 0.004) and stigma psychological distress (OR 1.2, P = 0.001) as well as sex (OR 4.3 for females, P = 0.045) predicted social dysfunction. Conclusions: Depression and stigma psychological distress contribute to social dysfunction related to ET stigma. Treating these psychological factors may mitigate social avoidance behaviors prevalent among susceptible individuals: those who most perceive ET stigma, i.e. relatively younger patients with worse tremor or with vocal tremor, and in particular females who are more prone to social dysfunction than males with the same degree of perceived stigma.

Improving tremor response to focused ultrasound thalamotomy.

MRI-guided high-intensity focused ultrasound thalamotomy is an incisionless therapy for essential tremor. To reduce adverse effects, the field has migrated to treating at 2 mm above the anterior commissure-posterior commissure plane. We perform MRI-guided high-intensity focused ultrasound with an advanced imaging targeting technique, four-tract tractography. Four-tract tractography uses diffusion tensor imaging to identify the critical white matter targets for tremor control, the decussating and non-decussating dentatorubrothalamic tracts, while the corticospinal tract and medial lemniscus are identified to be avoided. In some patients, four-tract tractography identified a risk of damaging the medial lemniscus or corticospinal tract if treated at 2 mm superior to the anterior commissure-posterior commissure plane. In these patients, we chose to target 1.2-1.5 mm superior to the anterior commissure-posterior commissure plane. In these patients, post-operative imaging revealed that the focused ultrasound lesion extended into the posterior subthalamic area. This study sought to determine if patients with focused ultrasound lesions that extend into the posterior subthalamic area have a differnce in tremor improvement than those without. Twenty essential tremor patients underwent MRI-guided high-intensity focused ultrasound and were retrospectively classified into two groups. Group 1 included patients with an extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. Group 2 included patients without extension of the thalamic-focused ultrasound lesion into the posterior subthalamic area. For each patient, the percent change in postural tremor, kinetic tremor and Archimedes spiral scores were calculated between baseline and a 3-month follow-up. Two-tailed Wilcoxon rank-sum tests were used to compare the improvement in tremor scores, the total number of sonications, thermal dose to achieve initial tremor response, and skull density ratio between groups. Group 1 had significantly greater postural, kinetic, and Archimedes spiral score percent improvement than Group 2 (P values: 5.41 × 10-5, 4.87 × 10-4, and 5.41 × 10-5, respectively). Group 1 also required significantly fewer total sonications to control the tremor and a significantly lower thermal dose to achieve tremor response (P values: 6.60 × 10-4 and 1.08 × 10-5, respectively). No significant group differences in skull density ratio were observed (P = 1.0). We do not advocate directly targeting the posterior subthalamic area with MRI-guided high-intensity focused ultrasound because the shape of the focused ultrasound lesion can result in a high risk of adverse effects. However, when focused ultrasound lesions naturally extend from the thalamus into the posterior subthalamic area, they provide greater tremor control than those that only involve the thalamus.

Development of ETStig, a measure for stigma in essential tremor.

INTRODUCTION: People with essential tremor commonly experience psychological difficulties that are not addressed. The effect of stigma, i.e., negative judgement by others because of a perceived difference in this case shaky movement, is a heretofore unstudied element. This project was undertaken to develop and field test a new measure for stigma associated with essential tremor. METHODS: Under guidance from a patient panel and an expert panel of neurologists and psychologists, the essential tremor stigma construct was delineated, and survey items were written to quantify three dimensions of interest: cumulative experience of stigma; related psychological distress; and resulting behavioral dysfunction. After pilot testing and revision, the essential tremor stigma measure underwent field testing by 198 essential tremor patients at two academic neurology clinics. RESULTS: The experience, distress and dysfunction scales were shown to have good internal consistency and test-retest reliability. Retained items demonstrated acceptable correlations and response properties. The validity of the distress scale was supported by concurrence with an existing stigma scale for neurologic disease, while a patient's openness to psychologic referral was predicted by higher scores on the dysfunction scale. CONCLUSION: This new measure is introduced to study the phenomenon of stigma associated with essential tremor. It may prove useful in assessing potential treatments for the psychological distress and maladaptive behavior that result from this stigma.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

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

Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial.

BACKGROUND: Progressive supranuclear palsy is a rare neurodegenerative disease associated with dysfunctional tau protein. BIIB092 is a humanised monoclonal antibody that binds to N-terminal tau and is thus being assessed as a potential novel treatment for progressive supranuclear palsy. We aimed to investigate the safety and tolerability of BIIB092 in individuals with progressive supranuclear palsy. METHODS: This 12-week, double-blind, randomised, placebo-controlled, multiple ascending dose, phase 1b trial was done at 13 outpatient sites in the USA. Participants aged 41-86 years with probable or possible progressive supranuclear palsy with a score of 20 or greater on the Mini-Mental State Examination (MMSE) were enrolled. Three BIIB092 dose escalation cohorts (150 mg, 700 mg, or 2100 mg; eight participants per cohort) were tested sequentially. For each dose cohort, the first two participants were randomly assigned by a computer-generated scheme to receive either BIIB092 or placebo intravenously every 4 weeks for 57 days. After 2 days, the six remaining participants in each cohort were randomly assigned (5:1) to receive BIIB092 or placebo for 57 days. An additional expansion panel of 24 patients was randomly assigned (3:1) to receive 2100 mg or placebo every 4 weeks for 57 days. All participants were followed up to day 85. The primary outcome was safety, which was analysed in the treated population (all enrolled participants who received at least one dose of the study drug). This trial is registered with ClinicalTrials.gov, NCT02460094. FINDINGS: Between Oct 2, 2015, and Oct 19, 2016, 48 participants were enrolled and randomly assigned to the BIIB092 (n=36) and placebo (n=12) groups. No apparent demographic differences were observed between the two groups at baseline. All 48 participants completed the treatment phase of the study. Adverse events were generally mild to moderate in severity; the most common in the placebo and BIIB092 groups were falls (in two [17%] of 12 patients and in ten [28%] of 36 patients), urinary tract infections (in one [8%] of 12 and in six [17%] of 36), contusions (in one [8%] of 12 and in five [14%] of 36), and headaches (in none and in five [14%] of 36). Four serious adverse events resulting in admission to hospital were reported in three participants who received BIIB092 2100 mg: two severe adverse events of urinary tract infection, one severe adverse event of change in mental status, and one moderate adverse event of aspiration pneumonia. None was considered to be related to the study drug, all were resolved, and no deaths were reported. INTERPRETATION: Repeated administration of the anti-tau monoclonal antibody BIIB092, at doses of up to 2100 mg, appears to be well tolerated in participants with progressive supranuclear palsy. Results of this phase 1b trial have informed the design of the ongoing phase 2 PASSPORT (NCT03068468) study to examine the efficacy and safety of BIIB092. FUNDING: Bristol-Myers Squibb, Biogen.

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.

Developing a Deep Brain Stimulation Neuromodulation Network for Parkinson Disease, Essential Tremor, and Dystonia: Report of a Quality Improvement Project.

OBJECTIVE: To develop a process to improve patient outcomes from deep brain stimulation (DBS) surgery for Parkinson disease (PD), essential tremor (ET), and dystonia. METHODS: We employed standard quality improvement methodology using the Plan-Do-Study-Act process to improve patient selection, surgical DBS lead implantation, postoperative programming, and ongoing assessment of patient outcomes. RESULTS: The result of this quality improvement process was the development of a neuromodulation network. The key aspect of this program is rigorous patient assessment of both motor and non-motor outcomes tracked longitudinally using a REDCap database. We describe how this information is used to identify problems and to initiate Plan-Do-Study-Act cycles to address them. Preliminary outcomes data is presented for the cohort of PD and ET patients who have received surgery since the creation of the neuromodulation network. CONCLUSIONS: Careful outcomes tracking is essential to ensure quality in a complex therapeutic endeavor like DBS surgery for movement disorders. The REDCap database system is well suited to store outcomes data for the purpose of ongoing quality assurance monitoring.

Validation of a serum screen for Alzheimer's disease across assay platforms, species, and tissues.

BACKGROUND: There is a significant need for rapid and cost-effective biomarkers of Alzheimer's disease (AD) for advancement of clinical practice and therapeutic trials. OBJECTIVE: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson's disease, PD). METHODS: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD. RESULTS: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90-100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls. CONCLUSIONS: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers.

ß-Hexachlorocyclohexane levels in serum and risk of Parkinson's disease.

Pesticide exposure has been implicated as an environmental risk factor for the development of Parkinson's disease (PD). However, few studies have identified specific pesticides. Previously, we identified elevated serum levels of the organochlorine pesticide ß-hexachlorocyclohexane (ß-HCH) in PD patients from a small clinical sample. Here, we conducted a case-control study to confirm the association between ß-HCH and PD in a larger sample size (n=283) with serum samples of PD patients and controls obtained from UT Southwestern Medical Center and Emory University. Samples were obtained from two discrete periods at both sites, 2001-2003 and 2006-2008, and were analyzed for ß-HCH levels. Adjusted odds ratios (ORs) for PD were estimated using logistic regression and generalized estimating equations. The mean serum ß-HCH level across all cohorts in this study was 22.3 ng/mg cholesterol (range: 0-376.7), and the levels were significantly higher and samples collected in 2001-2003 vs. 2006-2008. After controlling for age and gender, the OR for increased risk of PD for every 1 ng/mg increase in serum ß-HCH ranged from 1.02 to 1.12 across the four different cohorts, and 1.03 (95% CI: 1.00-1.07, p value=0.031) in the pooled analysis. Furthermore, the OR for increased risk of PD of subjects having serum ß-HCH levels above the inter-quartile range of 39.08 ng/mg cholesterol was 2.85 (95% CI: 1.8, 4.48; p value<0.001). These data are consistent with environmental decreases in ß-HCH levels between 2001 and 2008, but they indicate that elevated levels of serum ß-HCH are still associated with heightened risk for PD.

Huntington chorea presenting with motor neuron disease.

BACKGROUND: There have been a few case reports of motor neuron disease in association with Huntington disease (HD). OBJECTIVE: To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation. DESIGN: Case report. SETTING: University of Texas Southwestern Medical Center, Dallas. Patient  A 69-year-old man with chorea and fasciculations. INTERVENTIONS: Genetic and electrophysiologic testing. MAIN OUTCOME MEASURES: Genetic test result, electrophysiologic test result, and physical examination. RESULTS: A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination. Electrophysiologic studies revealed evidence of motor neuron disease. Genetic test showed CAG repeat of 40 on chromosome 4, confirming the diagnosis of HD. CONCLUSION: Motor neuron disease can rarely occur in patients with HD and could be one of its presenting features.

Elevated serum pesticide levels and risk of Parkinson disease.

BACKGROUND: Exposure to pesticides has been reported to increase the risk of Parkinson disease (PD), but identification of the specific pesticides is lacking. Three studies have found elevated levels of organochlorine pesticides in postmortem PD brains. OBJECTIVE: To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD. DESIGN: Case-control study. SETTING: An academic medical center. PARTICIPANTS: Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease. MAIN OUTCOME MEASURES: Levels of 16 organochlorine pesticides in serum samples. RESULTS: beta-Hexachlorocyclohexane (beta-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of beta-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of beta-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67-11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum beta-HCH and PD. CONCLUSIONS: These data suggest that beta-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of beta-HCH as a etiologic agent for some cases of PD.

Risk factors for pathologic gambling and other compulsions among Parkinson's disease patients taking dopamine agonists.

Three hundred patients with Parkinson's disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder.

Serum biomarkers for Alzheimer's disease: proteomic discovery.

For Alzheimer's disease (AD), the most common neurodegenerative disease, there is no simple, cost-effective biomarker for disease identification. Using novel mass spectrometry (MS)-based techniques, and analysis of the albumin-enriched low molecular weight proteome, minute amounts of human serum were analyzed for the measurement of thousands of peptides and proteins in parallel. The mass spectrograms were then evaluated with a novel computer algorithm to identify spectral peaks that discriminate between samples from patients with and without AD. There are four peaks that distinguish AD from control subjects and AD subjects from those with Parkinson's disease (PD). Additionally, after analyzing data from a recently published study of AD and control subjects, we found three discriminating peaks in common with the four from our patient serum samples. The identification of these peptides/proteins, and their direct measurement in patient serum, may allow the development of a simple, cost-effective test for AD.

Cardiac valve regurgitation with pergolide compared with nonergot agonists in Parkinson disease.

BACKGROUND: Although most studies have suggested an increased risk of valvulopathy (primarily regurgitation) with pergolide mesylate use, one study suggested that this problem may also occur with use of the non-ergot-derived dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride. OBJECTIVE: To determine if cardiac valve regurgitation occurs more commonly in patients with Parkinson disease (PD) treated with pergolide than in those treated with nonergot agonists at a comparable dose. DESIGN: A case-control study of echocardiographic findings of valve function in patients receiving dopamine agonists for PD. SETTING: University-based referral center. Patients Thirty-six patients with idiopathic PD taking pergolide were compared with a matched control group of patients taking nonergot agonists with regard to the frequency and severity of cardiac valve regurgitation. Main Outcome Measure Valve scores (1 indicates trace; 2, mild; 3, moderate; and 4, severe) for the pergolide group were compared with those for the nonergot agonist control group. RESULTS: The mean +/- SD valve regurgitation scores in the matched pergolide group compared with the nonergot group were as follows: aortic, 0.83 +/- 1.23 vs 0.19 +/- 0.53 (P = .01); mitral, 1.42 +/- 1.0 vs 0.39 +/- 0.65 (P<.001); and tricuspid, 1.43 +/- 1.0 vs 0.19 +/- 0.53 (P<.001). Lifetime exposure to a dopamine agonist was not statistically different between the pergolide and nonergot agonist groups (P = .18). CONCLUSIONS: These data strengthen the conclusion that pergolide contributes to cardiac valve regurgitation when used in the long term as a treatment for PD. There appears to be low risk of cardiac valve regurgitation when using non-ergot-derived dopamine agonists.

Clinical course in Parkinson's disease with elevated homocysteine.

Elevated homocysteine (Hcy), prevalent in Parkinson's disease (PD), is potentially a modifiable risk factor for neurologic deterioration. We measured cognitive, affective and motor changes over 2 years in a cohort of people with early PD. Subjects whose Hcy had been elevated (>14 micromol/L, n = 31) at baseline were compared with the rest (n = 66). Overall progression in 2 years did not significantly differ (p = 0.20). Four subjects with elevated and one with normal Hcy had died (p = 0.03). We conclude that hyperhomocysteinemia does not predict significantly worse progression over 2 years in early PD. The data raised the possibility of higher mortality, but the number of deaths was small.

Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease.

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) micromol/L increased to 10.1 (3.1) micromol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L-dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 micromol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined.