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BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

Essential tremor (ET) affects approximately 7 million people in the USA, yet public recognition of the disease and its impact remain low.A retrospective observational study examined US claims data from 2015 to 2019 using the Compile database. ET diagnoses were captured using longitudinal data from 2015 to 2019 and for the year 2019, with diagnosis estimates extrapolated to the general US population. Confirmed ET was identified by an ET diagnosis code with at least two relevant prescriptions or by two diagnosis codes for ET and unspecified tremor at least 90 days apart. Comorbidity and treatment use data were extracted, and medication compliance and 2-year treatment persistence were assessed as measures of treatment adherence.A total of 1,336,183 patients with ET diagnoses codes were identified from 2015 through 2019, corresponding to 2,226,971 projected US diagnoses. In 2019, 128,263 patients had a confirmed ET diagnosis, corresponding to 213,772 projected US confirmed diagnoses. Of these, 96% had at least one comorbidity, and 64% received at least one pharmacologic treatment. Propranolol (24%) and primidone (20%) comprised the most common ET prescriptions. Two-year medication discontinuation rates were approximately 40%.Our findings revealed that 1 million people were diagnosed and sought treatment for ET in the USA from 2015 to 2019. Projected population estimates of approximately 2 million people diagnosed suggest a further 1 million remain untreated. Our findings highlight the complexity of patient care in ET, complicated by delayed diagnoses, multiple comorbidities, and lack of effective and tolerable therapies that can mitigate treatment adherence limitations.

Background Available essential tremor (ET) therapies have limitations. Objectives The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. Methods Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. Results The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). Conclusions The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Introduction Patients with Parkinson's disease (PD) are at increased risk for hospitalization and often experience worsening of PD when hospitalized. It is therefore important to identify strategies to prevent hospitalization. Methods Hospital encounter rates in different Parkinson's Foundation Centers of Excellence in United States, Canada, Israel and the Netherlands were analyzed as part of the Parkinson Foundation Parkinson's Outcomes Project (PF-POP). Multivariate logistic regression was used to estimate the odds ratio for hospitalization, adjusted for risk factors. Results Baseline age, disease duration, other relative than spouse/partner as care giver, cancer, arthritis, other comorbidities, falls, use of levodopa, use of dopamine agonist, use of COMT inhibitor, occupational therapy before the baseline visit, PDQ-39, MSCI total score and time between visits were significantly associated with the risk of hospital encounters. After adjustment for these factors, two centers had significantly lower odds for hospitalization admission and ER visit (minimum OR 0.3) and four centers had significantly higher odds (maximum OR 1.5) than the average center. Four centers had significantly lower hazard ratios for time to re-hospitalization compared to the average center. Reducing hospital admission rates in those centers with higher than average rates would reduce overall hospitalizations by 11%. Applied to PD patients over 65 nationwide this represents a potential for cost savings of greater than $1 billion over 48 months. Conclusion Encounter rates vary even across expert centers and suggest that practices carried out in some centers may reduce the risk of hospitalization. Further research will be necessary to identify these practices and implement them more widely to improve care for people with PD.

Background Levodopa is the most efficacious medication in controlling the motor symptoms of Parkinson's disease (PD). There continues to be a controversy as to whether levodopa remains effective after years of therapy. Objective To assess the long-term effectiveness of levodopa in PD patients. Methods The response to levodopa in PD patients undergoing a levodopa challenge for deep brain stimulation (DBS) surgery evaluation from June 1997 through March 2017 were evaluated. The patients were broken into four groups based on disease duration (Group I: 0- 5 years, Group II: 6- 10 years, Group III: 11- 15 years, and Group IV:≥16 years). Levodopa response was calculated based on the changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) scores in the medication ON and OFF states. Results A total of 361 PD patients were included. The mean age in Group I was 59.4 years with a mean disease duration of 3.9 years (n = 29), Group II was 61 years with a mean disease duration of 8.1 years (n = 131), Group III was 64 years with a mean disease duration of 12.8 years (n = 143), and IV was 66.5 years with a mean disease duration of 18.5 years (n = 58). There was a significant improvement in UPDRS motor and ADL scores after the levodopa challenge for all groups. Conclusions In a subgroup of PD patients who were evaluated for DBS surgery, there was a marked improvement in UPDRS motor and ADL scores which did not decrease with disease progression.

Levodopa is the mainstay of treatment in Parkinson's disease (PD). As the disease progresses, variations in plasma levodopa levels lead to motor fluctuations. The common reasons behind variations in the plasma levels include delayed gastric emptying, small intestinal bacterial overgrowth, protein interaction with levodopa absorption, and limited oral bioavailability of levodopa. Efforts to find newer delivery systems for older drugs to avoid the problems associated with oral delivery of medications are continuing. This review aims to provide up-to-date information about the newer delivery options for drugs used for PD and provides a summary of infusion therapy with apomorphine, modifications to other dopamine agonists, various oral formulations of carbidopa/levodopa, inhaled levodopa, intrajejunal infusion of levodopa, and sublingual apomorphine. The advantages, dose, and adverse effects of each treatment modality are reviewed. We also discuss several drugs under investigation, such as the subcutaneous carbidopa/levodopa infusion and subcutaneous rotigotine.

Highlights • 2864 persons from the IETF database responded to the survey. • 28% of respondents were not receiving medical care for their tremor. • In 33% of respondents, tremor was not treated., Introduction Essential tremor (ET) is one of the most common movement disorders; however, many patients are misdiagnosed and do not receive effective treatment. It is important to better understand the diagnosis, symptoms and treatment patterns to improve care for those with ET. Methods Persons in the International Essential Tremor Foundation database were invited to complete an online survey, focusing on symptoms, diagnosis, and treatment of ET. Results The survey was emailed to 19,206 persons, with 2864 (14.9%) respondents. Mean age was 65.4 years, median age of tremor onset was 36–40 years, 61% were women, and 64% had a known family history of tremor. Forty-five percent saw multiple physicians before a diagnosis of ET with 65% being diagnosed by a neurologist. Current care is provided by a neurologist in 42%, a family physician in 26% and 28% do not see a physician for ET. Tremor was most commonly reported in the hands/arms (95%). The most commonly affected daily activities included writing, eating, drinking and carrying. Beta-blockers were the most commonly used treatment (42%); however, 33% had no benefit and 35% discontinued due to side effects. Of note, 33% had never received treatment for their tremor. Conclusion This survey highlights the need for more effective treatments with greater tolerability. Increased awareness among physicians and patients in the diagnosis and treatment of ET is also warranted, with nearly half the respondents seeing multiple physicians before receiving an ET diagnosis and nearly 30% not seeing a physician and/or not receiving treatment for ET.

Dopaminergic mechanisms regulating cognitive and motor control were evaluated comparing visuoperceptual and perceptuomotor functions in Parkinson’s disease (PD). The performance of PD patients (n = 40) was contrasted with healthy controls (n = 42) across two separate visits (on and off dopaminergic medications) on computerized tasks of perception and aiming to a target at variable stimulus lengths (4, 8, 12 cm). Novel visuoperceptual tasks of length equivalence and width interval estimations without motor demands were compared with tasks estimating spatial deviation in movement termination. The findings support the presence of spatial deficits in early PD, more pronounced with increased discrimination difficulty, and with shorter stimulus lengths of 4 cm for both visuoperceptual and perceptumotor functions. Dopaminergic medication had an adverse impact on visuoperceptual accuracy in particular for length equivalence estimations, in contrast with dopaminergic modulation of perceptuomotor functions that reduced angular displacements toward the target. The differential outcomes for spatial accuracy in perception versus movement termination in PD are consistent with involvement of the direct pathway and models of progressive loss of dopamine through corticostriatal loops. Future research should develop validated and sensitive standardized tests of perception and explore dopaminergic selective deficits in PD to optimize medication titration for motor and cognitive symptoms of the disease.

Essential tremor (ET) is one of the most common movement disorders worldwide, yet the size of the pediatric ET population is not well understood. The objective of this review was to identify, evaluate, and synthesize evidence describing the epidemiology of pediatric ET in the United States published between 2010 and 2020.The authors searched MEDLINE, Embase, and the Cochrane Database of Systematic Reviews using terms related to ET, epidemiology, and pediatric patients. Eligibility criteria included observational studies that reported primary data on pediatric prevalence or incidence of ET or age of onset/diagnosis of ET. A total of 562 unique articles were identified for screening.The review did not identify any studies that reported information on pediatric prevalence or incidence of ET, or age of ET diagnosis among nonpediatric patients. A total of 10 samples were identified, all of which described age of ET onset that ranged from 27.0 years to 56.7 years among 9 adult populations (weighted mean of 41.6 years) and 9.7 years in a single pediatric sample. One adult sample reported that 13% of all ET cases reported onset by age 14, and 21.8% of all ET cases reported onset by age 18.There is a notable lack of recent data describing the incidence and prevalence of pediatric ET in the United States. Many children who present with symptoms of ET may not be diagnosed until later in life, and an increased awareness of pediatric ET could allow for early identification and monitoring of these patients.

Background Parkinson’s disease (PD) and essential tremor (ET) are movement disorders that can have similar clinical characteristics including tremor and gait difficulty. These disorders can be misdiagnosed leading to delay in appropriate treatment. The aim of the study was to determine whether balance and gait variables obtained with wearable inertial motion sensors can be utilized to differentiate between PD and ET using machine learning. Additionally, we compared classification performances of several machine learning models. Methods This retrospective study included balance and gait variables collected during the instrumented stand and walk test from people with PD (n = 524) and with ET (n = 43). Performance of several machine learning techniques including neural networks, support vector machine, k-nearest neighbor, decision tree, random forest, and gradient boosting, were compared with a dummy model or logistic regression using F1-scores. Results Machine learning models classified PD and ET based on balance and gait characteristics better than the dummy model (F1-score = 0.48) or logistic regression (F1-score = 0.53). The highest F1-score was 0.61 of neural network, followed by 0.59 of gradient boosting, 0.56 of random forest, 0.55 of support vector machine, 0.53 of decision tree, and 0.49 of k-nearest neighbor. Conclusions This study demonstrated the utility of machine learning models to classify different movement disorders based on balance and gait characteristics collected from wearable sensors. Future studies using a well-balanced data set are needed to confirm the potential clinical utility of machine learning models to discern between PD and ET.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) can effectively control motor complications in Parkinson disease (PD). The outcome of DBS therapy depends on lead placement in the dorsolateral aspect of STN, as well as post-DBS programming. Effective DBS programming requires knowledge of side effects/complications related to stimulation. One of the infrequent complications of STN DBS is stimulation-induced dyskinesia, which can present similar to levodopa-induced dyskinesia with choreiform, ballistic, or dystonic movements. Stimulation-induced dyskinesia can be bothersome and can interfere with effective control of motor symptoms because typically the contact causing dyskinesia is the most effective in improving motor symptoms. This chapter discusses clinical presentation and management strategies in a patient with tremor-predominant PD who developed stimulation-induced dyskinesia. After trying multiple programming parameters, patient tremor and dyskinesia were effectively controlled on interleaved programming settings. The authors conclude that interleaving DBS programming can be a potential option for management of stimulation-induced dyskinesia.

Objective To investigate the reliability and validity of pupillary response during dual-task balance conditions in individuals with Parkinson disease (PD). Design Cross-sectional study. Setting University of Kansas Medical Center Parkinson's Disease and Movement Disorder Center. Participants Participants (N=68) included individuals with PD (n=33) and healthy controls (n=35). Interventions Not applicable. Main Outcome Measures Pupillary response was the main outcome measure that was measured during the following conditions: single-task balance eyes open, single-task balance eyes occluded, dual-task eyes open, and dual-task eyes occluded. After each condition, the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) was administered to assess self-reported cognitive workload. To examine the test-retest reliability of the pupillary response, the conditions were administered twice for each individual within 2 hours. Intraclass correlation coefficients (ICC) were used to analyze the test-retest reliability of pupillary response in each condition for both groups. Pearson’s r correlation was used to assess the convergent validity of pupillary response against the NASA-TLX. Results The test-retest reliability was excellent for both groups in almost all conditions (ICC>0.75). There were no correlations between pupillary response and the NASA-TLX. However, increased mental demand (a subitem of the NASA-TLX) significantly correlated with increased pupillary response in individuals with PD (r=0.38; P=.03). Conclusions Pupillary response showed excellent test-retest reliability and validity during dual-task balance for individuals with PD and healthy controls. Overall, these results suggest that pupillary response represents a stable index of cognitive workload during dual-task balance in individuals with PD.

BACKGROUND: Pupillary response reflects cognitive workload during processing speed, working memory, and arithmetic tasks in Parkinson’s disease (PD). Abstract reasoning, a higher-order cognitive function that relates different objects, events, or thoughts in a similar manner, may also be compromised in PD. The aim of this study was to compare pupillary response as a measure of cognitive workload while completing a verbal abstract reasoning test between patients with PD and age-matched controls. METHODS: Nineteen non-demented individuals with PD (66.6 ± 8.9 years) and 10 healthy controls (65.3 ± 7.3 years) were recruited. A remote eye tracker recorded the pupillary response at 60 Hz, while the participants were performing the Similarities test of Wechsler Adult Intelligence Scale-IV. Outcome measures included pupillary response, evaluated by the Index of Cognitive Activity (ICA), and behavioral responses of the Similarities test. RESULTS: The PD group (scaled scores = 8.9 ± 2.2) did not show impairment in behavioral performance on Similarities test compared with healthy controls (scaled scores = 8.8 ± 2.3; p = .91). However, the PD group (ICA = .32 ± .09) demonstrated significantly greater cognitive workload during the Similarities test compared to controls (ICA = .24 ± .08; p = .03). CONCLUSIONS: Non-demented individuals with PD exerted greater cognitive workload to complete a verbal abstract reasoning task despite similar behavioral performance compared to healthy controls. Clinical utilities of pupillary response to detect and monitor early impairment in higher-order executive function will be the subject of further study in the PD population.

BackgroundWe undertook this study to identify patients with Parkinson disease (PD) with no or rare falls who may progress to frequent falling by their next annual follow-up visit.MethodsWe analyzed data in the National Parkinson Foundation Quality Improvement Initiative database to identify factors predicting which patients with PD with no or rare falls at the baseline visit will report at least monthly falls at the annual follow-up visit. Multivariable models were constructed using logistic regression. Variables were introduced in 4 blocks: in the 1st block, variables present at or before the baseline visit were entered; in the 2nd, baseline visit assessments; in the 3rd, interventions implemented during baseline visit; and, in the 4th block, changes in comorbidities, living situation, and treatment between visits.ResultsOf 3,795 eligible participants, 3,276 (86.3%) reported no or rare falls at baseline visit, and of them, 382 (11.7%) reported at least monthly falls at follow-up visit. Predictors included female sex, ConclusionsThis large-scale analysis identified several predictors of progression to falling in PD. Such identifiers may help target patient subgroups for falls prevention intervention. Some factors are modifiable, offering opportunities for developing such interventions.

Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease on chronic levodopa therapy. The management of LID is important as dyskinesia can be disabling and impair quality of life. Currently, there are limited treatment options for the medical management of LID. Amantadine extended-release capsules (Gocovri™) is the first medication that received US Food and Drug Administration approval for the treatment of LID. The following is a review of the pharmacodynamics, efficacy and safety profile, and current state of treatment of amantadine for LID.

Object We review our experience with Parkinson's disease (PD) patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) and then developed noninfectious, non-hemorrhagic, delayed, symptomatic brain edema associated with a DBS lead. Methods All PD patients who underwent STN DBS lead implantation from 2007 to 2015 were included. The same neurosurgeon performed all surgeries, typically in staged fashion, utilizing single pass microelectrode recordings (MER) within a stereotactic frame. A brain CT was obtained in recovery and subsequently if indicated. Results There were 189 patients who underwent 363 STN lead implantations among which 35 (9.6%) represent re-implantations of removed leads in 28 (14.8%) patients. Among the 363 STN leads implanted, there were 12 (3.3%) cases of delayed symptomatic edema associated with a DBS lead involving 10 (5.3%) of the patients studied. Of the 328 leads representing first-time operations, there were 9 (2.1%) cases of delayed symptomatic edema in 7 (3.7%) patients, one of whom (14.3%) presented with seizures. For lead re-implantations, there were 3 (8.6%) cases of the brain edema in 3 (10.7%) patients; all presenting with seizures. For the 35 re-implantations, the trajectory to target was the same or very similar via the same burr hole as prior surgery in 17 (48.6%); 3 (17.6%) of whom developed edema. There was no case of brain edema in the 18 re-operated cases using a different burr opening. Edema patients were treated with a course of anticonvulsant medication and dexamethasone. Lead-associated edema resolved over generally a 4 to 6-week course. Conclusions Noninfectious, non-hemorrhagic, delayed, symptomatic brain edema occurs in approximately 3% of implanted leads and is more common in re-implantations (9%) compared to new implantations (2%). In re-implantations, the edema is more common when the same trajectory is used (18%) compared to a new trajectory (0%). The edema generally occurs 3 to 8 days after implantation, although immediate post-op CT is normal and seizures are a common presenting feature.

Post-operative, non-hemorrhagic, non-infectious symptomatic delayed edema around the DBS lead is an uncommon complication of DBS surgery. We investigated whether this complication impacts clinical outcomes or has long-term sequelae.All Parkinson's disease (PD) patients with subthalamic nucleus (STN) DBS implantation who developed delayed symptomatic lead edema were identified. UPDRS part III motor, Parkinson's Disease Questionnaire (PDQ-39) total and MoCA scores were analyzed to assess motor outcome, quality of life and cognitive status at 1 year.A total of 260 patients underwent 482 STN lead placements. Of these, 16 patients (20 leads, 4.1% of total 482 leads) developed this delayed complication. None of the patients had edema on immediate post-operative scan. Patients presented with varied symptoms including speech difficulty (n = 8), mild confusion (n = 6), headaches (n = 4), gait difficulty (n = 4) and seizures (n = 3). The mean duration for the diagnosis was 5.8 days after lead implantation and the mean duration for which follow-up CT scans reported complete/near complete resolution or improvement of edema was 4.7 weeks (range 2-10 weeks). At 1-year post-DBS, UPDRS motor scores improved significantly (42.5%, p .001); quality of life improved, but the change was not statistically significant (21.3%, p = .197). There was no decline in cognitive function at 1 year (26.6 vs 26.4, p = .567). No long-term complication related to lead edema occurred in these patients.Symptomatic lead edema after DBS surgery is an uncommon complication which typically resolves over time. In our series, there were no long-term sequelae of this complication and clinical outcomes were comparable to that reported in the literature.

INTRODUCTION Levodopa-induced dyskinesia (LID) is a significant impediment to the long-term use of levodopa for Parkinson's disease (PD). Relatively few studies exist that have described safe and effective therapy for LID. There is thus a significant need for therapy that can control LID to allow for greater sustainability of levodopa therapy. Amantadine extended release (ER) is currently the only FDA-approved medication for the treatment of LID. While other medications have demonstrated efficacy in treating the motor symptoms of PD, amantadine ER is the only one that has been shown, in several clinical trials, to reduce LID and reduce OFF time. Areas Covered: In this review, the authors present the findings of amantadine ER including its efficacy and safety. The authors also provide their expert perspectives on its use and its future prospects. Expert opinion: Several therapies are currently being used and studied for controlling LID, an unmet need in therapy for PD. Amantadine ER has potential to supplement levodopa therapy in PD and improve patient therapeutic outcomes.

The response to levodopa (LR) is important for managing Parkinson&rsquo, s Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson&rsquo, s Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies.

© 2019 International Parkinson and Movement Disorder Society, Background: Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor. Objectives: To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society. Methods: We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee. Results: Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions. Conclusion: Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales.

Parkinson's disease is a neurodegenerative condition secondary to loss of dopaminergic neurons in the substantia nigra pars compacta. Surgical therapy serves as an adjunct when unwanted medication side effects become apparent or additional therapy is needed. Deep brain stimulation emerged into the forefront in the 1990s. Studies have demonstrated improvement in all of the cardinal parkinsonian signs with stimulation. Frameless and ‘mini-frame’ stereotactic systems, improved MRI for anatomic visualization, and intraoperative MRI-guided placement are a few of the surgical advances in deep brain stimulation. Other advances include rechargeable pulse generators, voltage- or current-based stimulation, and enhanced abilities to ‘steer’ stimulation. Work is ongoing investigating closed-loop ‘smart’ stimulation in which stimulation is predicated on neuronal feedback.

Background We aimed at critically appraising the clinimetric properties of existing pain scales or questionnaires and to give recommendations for their use in Parkinson's disease (PD). Methods Clinimetric properties of pain scales used in PD were systematically evaluated. A scale was classified as ‘recommended’ if was used in PD, showed adequate clinimetric properties, and had been used by investigators other than the original developers; as ‘suggested’ if it was used in PD and fulfilled only one other criterion; and as ‘listed’ if it was used in PD but did not meet the other criteria. Only scales rating pain intensity or for syndromic classification were assessed. Results Eleven of the 34 scales initially considered fulfilled inclusion criteria. Among the scales rating pain intensity, the “Brief Pain Inventory short form,” “McGill Pain Questionnaire short and long forms,” “Neuropathic Pain Symptoms Inventory,” “11-point Numeric Rating Scale,” “10-cm Visual Analog Scale,” and “Pain-O-Meter” were “recommended with caution” because of lack of clinimetric data in PD, whereas the “King's PD Pain Scale” was “recommended.” Among scales for pain syndromic classification, the “DN4” was “recommended with caution” because of lack of clinimetric data in PD; the “Leeds Assessment of Neuropathic Symptoms and Signs,” “Pain-DETECT,” and the “King's PD Pain Scale” were “suggested.” Conclusions King's PD pain scale can be recommended for the assessment of pain intensity in PD. Syndromic classification of pain in PD may be achieved by the DN4, but clinimetric data in PD are needed for this scale.

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer-based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet-based measures, vocal acoustic analysis, and several other transducer-based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet-based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer-based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society.

Non-motor symptoms (NMS) including sleep disorders, anxiety, depression, fatigue, and cognitive decline can significantly impact quality of life in people with PD. Qigong exercise is a mind-body exercise that shows a wide range of benefits in various medical conditions. The purpose of this study was to investigate the effect of Qigong exercise on NMS with a focus on sleep quality. Seventeen participants completed a 12-week intervention of Qigong (n = 8) or sham Qigong (n = 9). Disease severity, anxiety and depression levels, fatigue, cognition, quality of life, and other NMS of the participants were evaluated prior to the intervention and at the end of the 12-week intervention. After the intervention, both Qigong and sham-Qigong group showed significant improvement in sleep quality (p < 0.05) and overall NMS (p < 0.05). No significant difference was found between groups. Qigong exercise has the potential as a rehabilitation method for people with PD, specifically alleviating NMS in PD. However, this finding needs to be carefully considered due to the small sample size and potentially low intervention fidelity of this study.

Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD). However, its effect in older patients is not extensively studied, as they are often excluded from DBS surgery due to concerns of complications or reduced benefit. We assessed clinical outcomes after subthalamic nucleus (STN) DBS in older patients (age 75 years) with PD.All PD patients above 75 years who underwent STN-DBS between 1999 and 2015 were included. Unified Parkinson's Disease Rating Scale (UPDRS) scores and Parkinson's Disease Questionnaire (PDQ-39) scores were assessed up to 4 years after surgery. Other measures included were complications/adverse events, levodopa equivalent dose, and cognitive function.A total of 30 patients underwent 52 lead placements. Mean age at surgery was 77.5 years (range 75.0-84.5 years). Post-DBS, motor scores improved by 30.8% after 1-year and 27.3% after a mean of 2.5 years (p .001). All motor sub-scores improved, however axial signs did not change over time. OFF time and dyskinesia duration reduced significantly (p .001), whereas quality of life, activities of daily living and cognitive function did not significantly change. The following adverse events were noted: transient post-operative confusion (36% of patients), gait difficulty (13.3% of patients), hemorrhage (3.8% of leads), personality changes (3.3% of patients), lead revision (1.9% of leads), seizure (1.9% of leads), and infection (1.9% of leads).STN-DBS improves motor outcomes in patients over 75 years of age; however, there was no change in quality of life. Although post-surgical transient confusion was common, there were no serious adverse events and the incidence of other complications was typical for DBS surgery.

OBJECTIVE To evaluate the safety and effectiveness of a wrist-worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in-office session. METHODS This was a randomized controlled study of 77 ET patients who received either treatment stimulation (N = 40) or sham stimulation (N = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40-minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject-rated tasks from the Bain and Findley activities of daily living (ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. RESULTS Subjects who received peripheral nerve stimulation did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject-rated improvements in ADLs were significantly greater with treatment (49% reduction) than with sham (27% reduction; p = 0.001). A greater percentage of ET patients (88%) reported improvement in the stimulation group as compared to the sham group (62%) according to CGI-I ratings (p = 0.019). No significant adverse events were reported; 3% of subjects experienced mild adverse events. CONCLUSIONS Peripheral nerve stimulation in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms.

The purpose of this study is to characterize the base-width neutral step (BNS) as the first step in a compensatory step response in persons with moderate Parkinson's disease (PD), and its effect on balance recovery.Ten PD and 10 healthy controls (HCs) responded to a posterior waist pull. A BNS was defined if the first step was less than 50 mm. The length, height, duration and velocity of the BNS and its effect on balance recovery time and center of mass location at recovery were compared to the first step within other stepping strategies (single step (SS), multiple step (MS)). A linear mixed model was used to compare across strategies.Six of ten persons with PD compared to zero HC used a BNS. The BNS was shorter in length and duration compared to MS responses in HC, and shorter in duration compared to MS responses in PD. The BNS was slower in velocity compared to every other strategy. BNS use resulted in a longer recovery time compared to all strategies in HC and SS responses in PD, and trended toward a longer recovery time compared to MS responses in PD.The BNS as the first step in a MS response may be an unreported strategy for compensatory stepping in PD. This study suggests that the cost of utilizing the BNS may be a longer time for recovery, but further work is necessary to understand the progression of the BNS as PD severity increases.

Parkinson’s disease (PD) is characterized by asymmetric motor symptom onset attributed to greater degeneration of dopamine neurons contralateral to the affected side. However, whether motor asymmetries predict cognitive profiles in PD, and to what extent dopamine influences cognition remains controversial. This study evaluated cognitive variability in PD by measuring differential response to dopamine replacement therapy (DRT) based on hemispheric asymmetries. The influence of DRT on cognition was evaluated in mild PD patients (n=36) with left or right motor onset symptoms. All subjects were evaluated on neuropsychological measures on and off DRT and compared to controls (n=42). PD patients were impaired in executive, memory and motor domains irrespective of side of motor onset, although patients with left hemisphere deficit displayed greater cognitive impairment. Patients with right hemisphere deficit responded to DRT with significant improvement in sensorimotor deficits, and with corresponding improvement in attention and verbal memory functions. Conversely, patients with greater left hemisphere dopamine deficiency did not improve in attentional functions and declined in verbal memory recall following DRT. These findings support the presence of extensive mild cognitive deficits in early PD not fully explained by dopamine depletion alone. The paradoxical effects of levodopa on verbal memory were predicted by extent of fine motor impairment and sensorimotor response to levodopa, which reflects extent of dopamine depletion. The findings are discussed with respect to factors influencing variable cognitive profiles in early PD, including hemispheric asymmetries and differential response to levodopa based on dopamine levels predicting amelioration or overdosing. (JINS, 2015, 21, 259–270)

Oxidative stress is one of the underlying causes of Parkinson’s disease (PD). Because of its antioxidant effect, we hypothesize that green tea consumption (3 cups daily for 3 months) would improve antioxidant status and reduces oxidative damage in Parkinson’s disease. Fifteen subjects who were within the first five years of PD, on stable PD medication, and not regular green tea consumers were recruited. Iron status, oxidative stress and PD status were evaluated before and after 3 months of green tea consumption. Hemoglobin, serum iron, iron saturation and ferritin concentrations were used to assess iron status. Antioxidant enzymes including catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured to determine antioxidant status. Lipid peroxidation and protein carbonyls were measured as oxidative damage markers. There were no changes in total motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS), PDQ-39 total scores and various iron status markers after 3 months. Catalase (p < 0.05) and SOD activities (p < 0.005) were increased significantly indicating an improvement of antioxidant status. Both lipid peroxidation and protein carbonyls decreased by ~52% (p < 0.01) with green tea consumption, indicating less oxidative stress. In conclusion, 3 cups of green tea consumption for 3 months can improve antioxidant status and reduce oxidative damage in PD patients. Further studies are needed to determine if these changes result in slowing the disease progression.

Essential tremor (ET) is the most common cause of tremor. Most studies suggest that the cerebellum is involved in the pathophysiology of ET and that it is an autosomal dominant disorder; however, the actual cause and a gene responsible for the majority of cases have not been identified. The diagnosis of ET is based on evaluation of clinical signs and symptoms. Pharmacological treatment is effective in 30% to 50% of casesm, with primidone and propranolol being first line therapies. Some benefit has also been reported with gabapentin, topiramate, and benzodiazepines. Deep brain stimulation effectively reduces medication-resistant ET in appropriate cases.

Tremor is an involuntary rhythmic, oscillatory movement produced by synchronous or alternating contractions of antagonist muscles. Tremor is the most common movement disorder and one of the most common neurological symptoms. A wide variety of etiologies can cause tremor, with essential tremor being the most common. Parkinson’s disease, multiple sclerosis, and drug-induced tremors are other etiologies commonly seen in clinical practice. The diagnosis of the specific etiology of tremor is based on the clinical characteristics of the tremor as well as associated symptoms. The phenomenology of tremor including whether the tremor is present at rest, with posture or with action, allows classification of tremor. Imaging studies, while not in themselves diagnostic, can help rule out structural etiologies. Dopamine transporter imaging is a recent modality that can help distinguish essential tremor from parkinsonism. The treatment of tremor is based on etiology and, where possible, treatment of the underlying disease state. Deep brain stimulation of the thalamus can be an effective treatment modality in intractable cases of tremor.

Parkinson’s disease (PD) is now thought of as a systemic disorder. Non-motor symptoms such as hyposmia and constipation sometimes precede motor symptoms by years to decades,1–4 and associated α-synuclein pathology in the autonomic and enteric nervous systems may precede development of pathological conditions in the brain.5–8 Some have proposed that PD begins in the gut and moves to the brain by one of several possible mechanisms. These include retrograde axonal transport of a toxic or infectious agent,9–11 neuron-to-neuron transmission of α-synuclein protein aggregates,6,12,13 or a prion-like seeding process.14,15 The gut has the largest mucosal surface of the body and is thus a primary anatomic target for exposure to toxicants and infectious agents. Recent reports suggest that patients with early PD may manifest increased intestinal permeability, bacterial invasion, and high levels of inflammatory cytokines in colonic biopsy specimens.16,17 The gut microbiota, comprising the trillions of organisms that line the length of the gastrointestinal tract, may play a role in PD. Systemic administration of gram-negative bacterial endotoxin (lipopolysaccharide [LPS]) activates microglia in the substantia nigra and induces progressive dopaminergic degeneration in a rodent model of parkinsonism.18 However, little is known about possible effects of other bacterial components. Peptidoglycan is a major structural component of the bacterial cell wall that serves to protect the plasma membrane. Because it is unique to bacteria, it is recognized as foreign and binds pattern recognition receptors, potently triggering an innate immune response.19 Humans have four peptidoglycan recognition proteins (PGRPs), highly conserved innate immunity proteins encoded by PGLYRPs 1–4, which are selectively expressed in a range of tissues and are also secreted into the gut.20 The PGRPs modulate the immune response to advantageous and harmful gut bacteria and play a major role in the development and maintenance of a healthy commensal microbiota,20 and variants in PGLYRP genes have recently been associated with risk of inflammatory bowel disease.21 We hypothesized that variation in PGLYRP genes might affect the risk of PD and tested this hypothesis in two independent study populations.

ObjectiveIPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients.MethodsThis was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39).ResultsAll IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P

The aims of this systematic review were to investigate (1) real-time brain activity during DT gait and balance, (2) whether changes in brain activity correlate with changes in behavioral outcomes in older adults and people with age-related neurodegenerative conditions. PubMed, PsycINFO, and Web of Science were searched from 2009 to 2019 using the keywords dual task, brain activity, gait, balance, aging, neurodegeneration, and other related search terms. A total of 15 articles were included in this review. Functional near-infrared spectroscopy and electroencephalogram measures demonstrated that older adults had higher brain activity, particularly in the prefrontal cortex (PFC), compared to young adults during dual task gait and balance. Similar neurophysiological results were observed in people with age-related neurodegenerative conditions. Few studies demonstrated a relationship between increased brain activity and better behavioral outcomes. This systematic review supports the notion that aging and age-related neurodegenerative conditions are associated with neuronal network changes, resulting in increased brain activity specifically in the PFC. Further studies are warranted to assess the relationship between increased PFC activation during dual task gait and balance and behavioral outcomes to better optimize the rehabilitation interventions.