Background: This evidence-based guideline is an update of the

Abstract-Background: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use. Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence. Results and Conclusions: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.

Summary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson’s disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. Methods A prediction algorithm for global cognitive impairment (defined as Mini Mental State Exam (MMSE) ≤25) was built using data from 1,350 patients with 5,165 longitudinal visits over 12.8 (median, 2.8) years. Age at onset, MMSE, education, motor exam score, gender, depression and GBA mutations, machine selected through stepwise Cox’ hazards analysis and Akaike’s information criterion, were used to compute the multivariable predictor. Independent validation was achieved in another 1,132 patients with 19,127 visits over 8.6 (median, 6.5) years. Findings The cognitive risk score accurately predicted cognitive impairment within ten years of disease onset with an area under the curve (AUC) of >0.85 in both the discovery (95% CI, 0.821–0.902) and validation populations (95% CI, 0.779 – 0.913). 72.6% of patients scoring in the highest quartile were cognitively impaired by ten years vs. 3.7% in the lowest quartile (hazard ratio, 18.4, 95% CI, 9.4 – 36.1). Dementia or disabling cognitive impairment was predicted with an AUC of 0.877 (95% CI 0.788–0.943) and high negative predictive value (0.920, 95% 0.877–0.954) at the predefined cutoff (0.196). Performance was stable in 10,000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson’s. It could improve trials of cognitive interventions and inform on prognosis.

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5–4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249–2470) and for creatine was 2414 (95% CI, 2304–2524). The global statistical test yielded t1865.8 = −0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00449865

Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.

Background: An elevated plasma homocysteine (Hcy) level has been prospectively associated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown.Objective: To determine if hyperhomocysteinemia in patients with PD is associated with depression or with cognitive or physical impairments.Design: Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy level (n=66) and those with hy-perhomocysteinemia (n = 31) (Hcy level, Ͼ1.89 mg/L [Ͼ14 µmol/L]), controlling for age, sex, disease duration, and treatment.Results: Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B 12 and folate. Hyperhomocysteinemic patients were more depressed (P=.02) and had worse cognition (PϽ.01), but the physical measure did not differ.Conclusions: Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD.

Background Neuroprotection for Parkinson Disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson’s Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II-III clinical trials. Methods Utilizing a novel consortium design, the Parkinson’s Disease Biomarker Program is focused on the development of clinical and laboratory-based biomarkers for PD diagnosis, progression, and prognosis. Standardized operating procedures and pooled reference samples were created to allow cross-project comparisons and assessment of batch effects. A web-based Data Management Resource facilitates rapid sharing of data and biosamples across the research community for additional biomarker projects. Results Eleven consortium projects are ongoing, seven of which recruit participants and obtain biosamples. As of October 2014, 1082 participants have enrolled (620 PD, 101 with other causes of parkinsonism, 23 essential tremor, and 338 controls), 1040 of whom have at least one biosample. There are 6898 total biosamples from baseline, 6, 12, and 18-month visits: 1006 DNA, 1661 RNA, 1419 whole blood, 1382 plasma, 1200 serum, and 230 cerebrospinal fluid (CSF). Quality control analysis of plasma, serum, and CSF samples indicates almost all samples are high quality (24 of 2812 samples exceed acceptable hemoglobin levels). Conclusions By making samples and data widely available, using stringent operating procedures based upon existing standards, hypothesis testing for biomarker discovery, and providing a resource which complements existing programs, the Parkinson’s Disease Biomarker Program will accelerate the pace of PD biomarker research.

The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.