Fatta B. Nahab

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.

The Neural Processes Underlying Self-Agency

Self-agency (SA) is the individuals perception that an action is the consequence of his/her own intention. The neural networks underlying SA are not well understood. We carried out a novel, ecologically valid, virtual-reality experiment using blood oxygen level-dependent functional magnetic resonance imaging (fMRI) where SA could be modulated in real-time while subjects performed voluntary finger movements. Behavioral testing was also performed to assess the explicit judgment of SA. Twenty healthy volunteers completed the experiment. Results of the behavioral testing demonstrated paradigm validity along with the identification of a bias that led subjects to over- or underestimate the amount of control they had. The fMRI experiment identified 2 discrete networks. These leading and lagging networks likely represent a spatial and temporal flow of information, with the leading network serving the role of mismatch detection and the lagging network receiving this information and mediating its elevation to conscious awareness, giving rise to SA.

Technology in Parkinson's disease: Challenges and opportunities

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinsons disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide‐scale and long‐term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the “big data” acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open‐source and/or open‐hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self‐adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed‐loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico‐pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease‐modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD.

Validation of Digital Spiral Analysis as Outcome Parameter for Clinical Trials in Essential Tremor

Essential tremor, one of the most prevalent movement disorders, is characterized by kinetic and postural tremor affecting activities of daily living. Spiral drawing is commonly used to visually rate tremor intensity, as part of the routine clinical assessment of tremor and as a tool in clinical trials. We present a strategy to quantify tremor severity from spirals drawn on a digitizing tablet. We validate our method against a well‐established visual spiral rating method and compare both methods on their capacity to capture a therapeutic effect, as defined by the change in clinical essential tremor rating scale after an ethanol challenge. Fifty‐four Archimedes spirals were drawn using a digitizing tablet by nine ethanol‐responsive patients with essential tremor before and at five consecutive time points after the administration of ethanol in a standardized treatment intervention. Quantitative spiral tremor severity was estimated from the velocity tremor peak amplitude after numerical derivation and Fourier transformation of pen‐tip positions. In randomly ordered sets, spirals were scored by seven trained raters, using Bain and Findleys 0 to 10 rating scale. Computerized scores correlated with visual ratings (P < 0.0001). The correlation was significant at each time point before and after ethanol (P < 0.005). Quantitative ratings provided better sensitivity than visual rating to capture the effects of an ethanol challenge (P < 0.05). Using a standardized treatment approach, we were able to demonstrate that spirography time‐series analysis is a valid, reliable method to document tremor intensity and a more sensitive measure for small effects than currently available visual spiral rating methods.

C9ORF72 Intermediate Repeat Copies Are a Significant Risk Factor for Parkinson Disease

We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat‐primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fishers exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.

Essential tremor, deceptively simple …

The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.

Whole-brain proton MR spectroscopic imaging in Parkinson's disease.

To examine the distributions of proton magnetic resonance spectroscopy (MRS) observed metabolites in Parkinsons disease (PD) throughout the whole brain.

Octanoic acid in alcohol-responsive essential tremor: A randomized controlled study

Objective: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). Methods: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. Results: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F1,16 = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F1,16 = 6.1, p = 0.025). Conclusions: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. Classification of evidence: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes.

Multi-Modal Hallucinations and Cognitive Function in Parkinson’s Disease

Background/Aims: Hallucinations have been linked to a constellation of cognitive deficits in Parkinson’s disease (PD), but it is not known whether multi-modal hallucinations are associated with greater neuropsychological dysfunction. Methods: 152 idiopathic PD patients were categorized based on the presence or absence of hallucinations and then were further subdivided into visual-only (VHonly; n = 35) or multi-modal (VHplus; n = 12) hallucination groups. All participants underwent detailed neuropsychological assessment. Results: Participants with hallucinations performed more poorly on select neuropsychological measures and exhibited more mood symptoms. There were no differences between VHonly and VHplus groups. Conclusions: PD patients with multi-modal hallucinations are not at greater risk for neuropsychological impairment than those with single-modal hallucinations.

DOUBLE-BLIND, PLACEBO-CONTROLLED, PILOT TRIAL OF BOTULINUM TOXIN A IN RESTLESS LEGS SYNDROME

The hallmarks of restless legs syndrome (RLS) are a desire to move the limbs due to sensory discomfort, motor restlessness, and worsening of symptoms during rest or at night.1 Sensory symptoms cause the greatest discomfort,2 and are commonly localized to muscle. Sensory and motor symptoms can be improved with dopaminergic medications, some anticonvulsants, opioids, and to a lesser extent with GABA-active hypnotics. Botulinum toxin has been suggested as a potential therapy for refractory RLS, based on its ability to reduce peripheral and central sensitization to pain.3 In an unblinded observational study by Rotenberg and colleagues, IM injections of 70–320 mouse units (mU) of botulinum toxin type A (BTX-A; Botox, Irvine, CA) were injected into the legs of three patients with RLS and demonstrated symptom improvement, reduced medication use, and a reduction in daytime sleepiness.4 Based on these findings, we conducted a randomized, placebo-controlled, double-blind, crossover study. ### Methods. #### Patients. We enrolled six patients from June to July 2007 who were age 18 or older, had a diagnosis of primary RLS based on International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria,1 had a minimum score of 11 (at least moderate severity) on the IRLSSG rating scale (IRLS),5 and were stable on medications for greater than 6 weeks prior to enrollment. Patients were excluded for an abnormal neurologic examination, abnormal laboratory test results, a dermatologic disorder precluding leg injections, pregnancy/lactation, incapacity for informed consent, taking medications which could interact with BTX-A, …