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Objectives: Our goal was to provide a detailed analysis of neurons' electrophysiological activity recorded in sub-territories of Globus pallidus internus (GPi) used as Deep Brain Stimulation (DBS) targets for these clinical conditions to potentially assist electrode targeting., Methods: We used intra-operative microelectrode recording during stereotactic neurosurgery to guide implantation of DBS lead., Results: Units in the medial anterior part of GPi of 7 Tourette's syndrome patients under general anesthesia were firing at mean and median rate of 32.1 and 21 Hz respectively (n = 101), with 45% of spikes fired during bursts and 21.3 bursts per minute. In the latero-posterior part of GPi of 7 dystonic patients under local anesthesia the mean and median activity were 46.1 and 30.6 Hz respectively (n = 27), and a mean of 21.7 bursts per minute was observed, with 30% of all spikes occurring during these bursts., Conclusion: Units activity pattern - slow-regular, fast-irregular or fast-regular were present in different proportions between the two targets., Significance: The electrophysiological characteristics of the medial-anterior part of GPi and its latero-posterior portion can be used to assist DBS electrode targeting and also support the refinement of pathophysiological models of Tourette's syndrome and Dystonia., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Emotional and cognitive disturbances are common complications in Parkinson's disease (PD). N400 is an event related potential (ERP) strongly linked to lexical-semantic processing and has demonstrated alterations in amplitude and latency when PD patients performed semantic priming tasks. The present study investigated the role of N400 in an automatic affective priming paradigm in PD. Other ERP components relevant to emotion processing were also examined., Method: Twenty-two PD patients and 17 healthy adults performed an automatic affective priming task while ERPs were recorded using 128 channels. Prime-target word pairs of negative or neutral valence were presented at a stimulus onset asynchrony of 250 ms. Participants were asked to evaluate the valence of the target word by button press., Results: A larger N400 amplitude for incongruent compared with congruent neutral targets was observed at right central and parietal regions and did not differ between PD and controls. PD and controls also displayed larger P300 and late positive potential (LPP) amplitudes for negative compared with neutral targets at central parietal and right frontal regions. In contrast, whereas controls showed a larger slow negative wave (SNW) for negative targets compared with neutral targets at left frontal and left central regions, PD group demonstrated a significant reduction in SNW amplitude difference at the left central region., Conclusion: N400 is intact in PD when processing evaluative judgments of emotional words. P300 and LPP were also intact in PD. The altered left central SNW in PD suggests an ERP marker for emotional dysfunction in PD. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Event-related potentials (ERPs) were recorded to investigate lexical ambiguity resolution during sentence processing in 16 people with Parkinson's disease (PD) and 16 healthy controls. Sentences were presented word-by-word on computer screen, and participants were required to decide if a subsequent target word was related to the meaning of the sentence. The task consisted of related, unrelated and ambiguous trials. For the ambiguous trials, the sentence ended with an ambiguous word and the target was related to one of the meanings of that word, but not the one captured by the sentence context (e.g., 'He dug with the spade', Target 'ACE'). Both groups demonstrated slower reaction times and lower accuracy for the ambiguous condition relative to the unrelated condition, however accuracy was impacted by the ambiguous condition to a larger extent in the PD group. These results suggested that PD patients experience increased difficulties with contextual ambiguity resolution. The ERP results did not reflect increased ambiguity resolution difficulties in PD, as a similar N400 effect was evident for the unrelated and ambiguous condition in both groups. However, the magnitude of the N400 for these conditions was correlated with a measure of inhibition in the PD group, but not the control group. The ERP results suggest that semantic processing may be more compromised in PD patients with increased response inhibition deficits.

Objective: To evaluate the effect of imposed faster and slower walking speeds on postural stability in people with Parkinson disease (PD)., Design: Cross-sectional cohort study., Setting: General community., Participants: Patients with PD (n=84; 51 with a falls history; 33 without) and age-matched controls (n=82) were invited to participate via neurology clinics and preexisting databases. Of those contacted, 99 did not respond (PD=36; controls=63) and 27 were not interested (PD=18; controls=9). After screening, a further 10 patients were excluded; 5 had deep brain stimulation surgery and 5 could not accommodate to the treadmill. The remaining patients (N=30) completed all assessments and were subdivided into PD fallers (n=10), PD nonfallers (n=10), and age-matched controls (n=10) based on falls history., Interventions: Not applicable., Main Outcome Measures: Three-dimensional accelerometers assessed head and trunk accelerations and allowed calculation of harmonic ratios and root mean square (RMS) accelerations to assess segment control and movement amplitude., Results: Symptom severity, balance confidence, and medical history were established before participants walked on a treadmill at 70%, 100%, and 130% of their preferred speed. Head and trunk control was lower for PD fallers than PD nonfallers and older adults. Significant interactions indicated head and trunk control increased with speed for PD nonfallers and older adults, but did not improve at faster speeds for PD fallers. Vertical head and trunk accelerations increased with walking speed for PD nonfallers and older adults, while the PD fallers demonstrated greater anteroposterior RMS accelerations compared with both other groups., Conclusions: The results suggest that improved gait dynamics do not necessarily represent improved walking stability, and this must be respected when rehabilitating gait in patients with PD., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Stair ambulation is a challenging activity of daily life that requires larger joint moments than walking. Stabilisation of the body and prevention of lower limb collapse during this task depends upon adequately-sized hip, knee and ankle extensor moments. However, people with Parkinson's disease (PD) often present with strength deficits that may impair their capacity to control the lower limbs and ultimately increase their falls risk., Objective: To investigate hip, knee and ankle joint moments during stair ascent and descent and determine the contribution of these joints to the body's support in people with PD., Methods: Twelve PD patients and twelve age-matched controls performed stair ascent and descent trials. Data from an instrumented staircase and a three-dimensional motion analysis system were used to derive sagittal hip, knee and ankle moments. Support moment impulses were calculated by summing all extensor moment impulses and the relative contribution of each joint was calculated., Results: Linear mixed model analyses indicated that PD patients walked slower and had a reduced cadence relative to controls. Although support moment impulses were typically not different between groups during stair ascent or descent, a reduced contribution by the ankle joint required an increased knee joint contribution for the PD patients., Conclusions: Despite having poorer knee extensor strength, people with PD rely more heavily on these muscles during stair walking. This adaptation could possibly be driven by the somewhat restricted mobility of this joint, which may provide these individuals with an increased sense of stability during these tasks., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In this paper we present an efficient model of microelectrode recordings (MER) from the subthalamic nucleus acquired during deep brain stimulation (DBS) surgery. The model shows how changes in the "noise" relate to the neuronal spike time statistics. A top-down approach is used with analysis-by-synthesis of the MER power spectra. The model is built around a sum of filtered point processes consisting of thousands of neurons and including extracellular filtering. The quality of the model is demonstrated through comparisons to recordings from eight individuals (both hemispheres in six) who have undergone DBS implantation for the treatment of Parkinson's disease. The simulated recordings were compared using their voltage amplitude distributions, power spectral density estimates and phase synchrony while varying only one free parameter (the shape of the inter-spike interval distribution). Through this simple model, we show that the noise present in a DBS MER contains properties that match that of patient recordings when a Weibull distribution with shape parameter of 0.8 is used for the inter-spike interval.

Background The trunk plays a critical role in attenuating movement-related forces that threaten to challenge the body's postural control system. For people with Parkinson's disease (PD), disease progression often leads to dopamine-resistant axial symptoms, which impair trunk control and increase falls risk. Objective This prospective study aimed to evaluate the relationship between impaired trunk muscle function, segmental coordination, and future falls in people with PD. Methods Seventy-nine PD patients and 82 age-matched controls completed clinical assessments and questionnaires to establish their medical history, symptom severity, balance confidence, and falls history. Gait characteristics and trunk muscle activity were assessed using 3-dimensional motion analysis and surface electromyography. The incidence, cause, and consequence of any falls experienced over the next 12 months were recorded and indicated that 48 PD and 29 control participants fell at least once during this time. Results PD fallers had greater peak and baseline lumbar multifidus (LMF) and thoracic erector spinae (TES) activations than control fallers and nonfallers. Analysis of covariance indicated that the higher LMF activity was attributable to the stooped posture adopted by PD fallers, but TES activity was independent of medication use, symptom severity, and trunk orientation. Furthermore, greater LMF and TES baseline activity contributed to increasing lateral head, trunk, and pelvis movements in PD fallers but not nonfallers or controls. Conclusions The results provide evidence of neuromuscular deficits for PD fallers that are independent of medications, symptom severity, and posture and contribute to impaired head, trunk, and pelvis control associated with falls in this population., (© The Author(s) 2016.)

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: Cognitive-linguistic impairments in Parkinson's disease (PD) have been well documented; however, few studies have explored the neurophysiological underpinnings of semantic deficits in PD. This study investigated semantic function in PD using event-related potentials., Methods: Eighteen people with PD and 18 healthy controls performed a semantic judgement task on written word pairs that were either congruent or incongruent., Results: The mean amplitude of the N400 for new incongruent word pairs was similar for both groups, however the onset latency was delayed in the PD group. Further analysis of the data revealed that both groups demonstrated attenuation of the N400 for repeated incongruent trials, as well as attenuation of the P600 component for repeated congruent trials., Conclusions: The presence of N400 congruity and N400 repetition effects in the PD group suggests that semantic processing is generally intact, but with a slower time course as evidenced by the delayed N400. Additional research will be required to determine whether N400 and P600 repetition effects are sensitive to further cognitive decline in PD. (JINS, 2017, 23, 78-89).

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

This cross-sectional study aimed to investigate the relationship between accelerometer-derived measures of movement rhythmicity and clinical measures of mobility, balance confidence and gait difficulty in people with Parkinson's disease (PD). Twenty-nine independently-living PD patients (Hoehn & Yahr Stages 1-3) with no history of significant injury or orthopaedic/deep brain stimulation surgery were recruited from a database of patients who had expressed an interest to participate in research. Participants completed clinical assessments of mobility, postural stability, balance confidence and symptom severity, while head and trunk rhythmicity was evaluated during gait using accelerometers. Following data collection, patients were stratified based on disease stage into either a Mild (Hoehn & Yahr Stage 1) or Moderate (Hoehn & Yahr Stages 2-3) PD group. The results highlighted that the Moderate PD group had poorer quality of life, reduced balance confidence and increased gait and falls difficulty. Furthermore, for these patients, gait disability and the number of previous falls were both negatively correlated with multiple components of head and trunk rhythmicity. For the Mild PD group, six-meter walk time was positively correlated with ML head rhythmicity and linear regression highlighted a significant predictive relationship between these outcomes. For the Mild and Moderate PD groups, balance confidence respectively predicted anterior-posterior trunk rhythmicity and vertical head rhythmicity. While these findings demonstrate that falls history and the Gait and Falls questionnaire provide moderate insight into head and trunk rhythmicity in Moderate PD patients, objective and clinically-feasible measures of postural instability would assist with the management of these symptoms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (P NGRC  =   3E-8, P Replication  =   2E-5, P NGRC + Replication  =   1E-11), the second mapped to TPM1 on 15q22.2 (P NGRC  =   8E-9, P Replication  =   2E-4, P NGRC + Replication  =   9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene., (© The Author 2016. Published by Oxford University Press.)

Background: Symptoms of anxiety relating to Parkinson's disease (PD) occur commonly and include symptomatology associated with motor disability and complications arising from PD medication. However, there have been relatively few attempts to profile such disease-specific anxiety symptoms in PD. Consequently, anxiety in PD is underdiagnosed and undertreated. The present study characterizes PD-related anxiety symptoms to assist with the more accurate assessment and treatment of anxiety in PD., Methods: Ninety non-demented PD patients underwent a semi-structured diagnostic assessment targeting anxiety symptoms using relevant sections of the Mini International Neuropsychiatric Interview (MINI-plus). In addition, they were assessed for the presence of 30 PD-related anxiety symptoms derived from the literature, the clinical experience of an expert panel and the PD Anxiety-Motor Complications Questionnaire (PDAMCQ). The onset of anxiety in relation to the diagnosis of PD was determined., Results: Frequent (>25%) PD-specific anxiety symptoms included distress, worry, fear, agitation, embarrassment, and social withdrawal due to motor symptoms and PD medication complications, and were experienced more commonly in patients meeting DSM-IV criteria for an anxiety disorder. The onset of common anxiety disorders was observed equally before and after a diagnosis of PD. Patients in a residual group of Anxiety Not Otherwise Specified had an onset of anxiety after a diagnosis of PD., Conclusion: Careful characterization of PD-specific anxiety symptomatology provides a basis for conceptualizing anxiety and assists with the development of a new PD-specific measure to accurately assess anxiety in PD.

This paper presents the Brisbane experience of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) in Parkinson's disease (PD). Clinical outcomes along with studies of the mechanisms and neurophysiology of PPN in PD patients with severe freezing of gait (FoG) and postural imbalance (PI) are summarised and presented. Our results indicate that PPN DBS improves FoG and falls in the relatively uncommon group of PD patients who respond well to medication other than for continuing on time FoG and falls. Our studies indicate that bilateral DBS is more beneficial than unilateral DBS, and that the more caudal region of the PPN seems preferable for stimulation. There is evidence that rapid-release programs for initiation and correction of gait and posture are modulated by the PPN, possibly to some extent independently of the cerebral cortex. These functions were found to be impaired in PD patients with severe FoG/PI, but to some extent corrected by bilateral PPN DBS.

Neurochemical microstimulation in different parts of the midbrain periaqueductal gray (PAG) in the cat generates four different types of vocalization, mews, howls, cries, and hisses. Mews signify positive vocal expression, whereas howls, hisses, and cries signify negative vocal communications. Mews were generated in the lateral column of the intermediate PAG and howls and hisses in the ventrolateral column of the intermediate PAG. Cries were generated in two regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. To define the specific motor patterns belonging to mews, howls, and cries, the following muscles were recorded during these vocalizations: larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration (diaphragm, internal intercostal, external abdominal oblique, and internal abdominal oblique) muscles. Furthermore, the frequency, intensity, activation cascades, and turns and amplitude analyses of the electromyograms (EMGs) during these vocalizations were analyzed. The results show that each type of vocalization consists of a specific, circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla serves as the final premotor interneuronal output system for vocalization. NRA neurochemical microstimulation also generated vocalizations (guttural sounds). Analysis of the EMGs demonstrated that these vocalizations consist of only small parts of the emotional voalizations generated by neurochemical stimulation in the PAG. These results demonstrate that motor organization of positive and negative emotional vocal expressions are segregated in the PAG and that the PAG uses the NRA as a tool to gain access to the motoneurons generating vocalization., (© 2015 Wiley Periodicals, Inc.)

The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS., (© 2016 S. Karger AG, Basel.)

Objectives: To assess whether the 16-item Activities-specific Balance Confidence scale (ABC-16) and short-form 6-item Activities-specific Balance Confidence scale (ABC-6) could predict future recurrent falls in people with Parkinson disease (PD) and to validate the robustness of their predictive capacities., Design: Twelve-month prospective cohort study., Setting: General community., Participants: People with idiopathic PD (N=79)., Interventions: Clinical tests were conducted to assess symptom severity, balance confidence, and medical history. Over the subsequent 12 months, participants recorded any falls on daily fall calendars, which they returned monthly by reply paid post., Main Outcome Measures: Logistic regression and receiver operating characteristic analyses estimated the sensitivities and specificities of the ABC-16 and ABC-6 for predicting future recurrent falls in this cohort, and "leave-one-out" validation was used to assess their robustness., Results: Of the 79 patients who completed follow-up, 28 (35.4%) fell more than once during the 12-month period. Both the ABC-16 and ABC-6 were significant predictors of future recurrent falls, and moderate sensitivities (ABC-16: 75.0%; ABC-6: 71.4%) and specificities (ABC-16: 76.5%; ABC-6: 74.5%) were reported for each tool for a cutoff score of 77.5 and 65.8, respectively., Conclusions: The results have significant implications and demonstrate that the ABC-16 and ABC-6 independently identify patients with PD at risk of future recurrent falls., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation (DBS) has become the standard treatment for advanced stages of Parkinson's disease (PD) and other motor disorders. Although the surgical procedure has improved in accuracy over the years thanks to imaging and microelectrode recordings, the underlying principles that render DBS effective are still debated today. The aim of this paper is to present initial findings around a new biomarker that is capable of assessing the efficacy of DBS treatment for PD which could be used both as a research tool, as well as in the context of a closed-loop stimulator., Approach: We have used a novel multi-channel stimulator and recording device capable of measuring the response of nervous tissue to stimulation very close to the stimulus site with minimal latency, rejecting most of the stimulus artefact usually found with commercial devices. We have recorded and analyzed the responses obtained intraoperatively in two patients undergoing DBS surgery in the subthalamic nucleus (STN) for advanced PD., Main Results: We have identified a biomarker in the responses of the STN to DBS. The responses can be analyzed in two parts, an initial evoked compound action potential arising directly after the stimulus onset, and late responses (LRs), taking the form of positive peaks, that follow the initial response. We have observed a morphological change in the LRs coinciding with a decrease in the rigidity of the patients., Significance: These initial results could lead to a better characterization of the DBS therapy, and the design of adaptive DBS algorithms that could significantly improve existing therapies and help us gain insights into the functioning of the basal ganglia and DBS.

Objectives: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD)., Methods: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations., Results: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci., Conclusions: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD., (© 2015 American Academy of Neurology.)

Parkinson's disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene, NFE2L2, and PD. In this study, we comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening in hONS cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between NFE2L2 SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900), P = 0.014). In addition, we were able to identify some age-at-onset modifying SNPs and replicate an 'early-onset' haplotype that contains a previously identified 'functional promoter' SNP (rs6721961). Our results suggest a role of NFE2L2 genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD.

Background: Postural instability and gait disability threaten the independence and well-being of people with Parkinson's disease and increase the risk of falls and fall-related injuries. Prospective research has shown that commonly-used clinical assessments of balance and walking lack the sensitivity to accurately and consistently identify those people with Parkinson's disease who are at a higher risk of falling. Wearable sensors provide a portable and affordable alternative for researchers and clinicians who are seeking to objectively assess movements and falls risk in the clinical setting. However, no consensus currently exists on the optimal placements for sensors and the best outcome measures to use for assessing standing balance and walking stability in Parkinson's disease patients. Hence, this systematic review aimed to examine the available literature to establish the best sensor types, locations and outcomes to assess standing balance and walking stability in this population., Methods: Papers listed in three electronic databases were searched by title and abstract to identify articles measuring standing balance or walking stability with any kind of wearable sensor among adults diagnosed with PD. To be eligible for inclusion, papers were required to be full-text articles published in English between January 1994 and December 2014 that assessed measures of standing balance or walking stability with wearable sensors in people with PD. Articles were excluded if they; i) did not use any form of wearable sensor to measure variables associated with standing balance or walking stability; ii) did not include a control group or control condition; iii) were an abstract and/or included in the proceedings of a conference; or iv) were a review article or case study. The targeted search of the three electronic databases identified 340 articles that were potentially eligible for inclusion, but following title, abstract and full-text review only 26 articles were deemed to meet the inclusion criteria. Included articles were assessed for methodological quality and relevant data from the papers were extracted and synthesized., Results: Quality assessment of these included articles indicated that 31% were of low methodological quality, while 58% were of moderate methodological quality and 11% were of high methodological quality. All studies adopted a cross-sectional design and used a variety of sensor types and outcome measures to assess standing balance or walking stability in people with Parkinson's disease. Despite the typically low to moderate methodological quality, 81% of the studies reported differences in sensor-based measures of standing balance or walking stability between different groups of Parkinson's disease patients and/or healthy controls., Conclusion: These data support the use of wearable sensors for detecting differences in standing balance and walking stability between people with PD and controls. Further high-quality research is needed to better understand the utility of wearable sensors for the early identification of Parkinson's disease symptoms and for assessing falls risk in this population., Prospero Registration: CRD42014010838.

Background: Anxiety disorders are common in Parkinson's disease (PD) and are undertreated. The current study investigates demographic and PD-specific factors associated with Diagnostic and Statistical Manual (DSM-IV) anxiety disorders and subsyndromal anxiety in PD. It also examines the use of pharmacological and nonpharmacological treatments for anxiety in PD. Methods: Ninety nondemented PD patients completed a semistructured interview. Logistic regression models were constructed examining associations between several demographic, disease-specific, and treatment factors, as well as both current syndromal, DSM-IV anxiety disorders, and subsyndromal anxiety. Results: Associations were found between current DSM-IV anxiety disorder, as well as female gender, younger age, more severe stages of PD, and poor activities of daily living. Subsyndromal anxiety was related to a younger onset age of PD. Relationships were also found between both anxiety groups and more complications of PD therapy, as well as higher depression scores. There were no associations between anxiety and levodopa equivalent daily dosage, motor disability, and cognition. In our sample, 57% of patients with current DSM-IV anxiety disorders or subsyndromal anxiety were not currently treated with pharmacotherapy. Of those who currently received such treatment, 83% still experienced current anxiety disorders. Results suggest that anxiety is poorly recognized and treated in PD. Conclusions: Clinical trials investigating the efficacy of pharmacotherapy, tailored psychotherapy, and combination therapy primarily focusing on anxiety are much needed, with the aim of establishing novel targeted treatment protocols for the management of subtypes of anxiety disorders in PD.

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients., (© 2014 International Parkinson and Movement Disorder Society.)

There is currently no cure for Parkinson disease (PD). Disease management is directed primarily at motor symptom relief, but the impact of non-motor symptoms associated with PD should not be underestimated. Medical and surgical treatment options aim to increase functional independence and quality of life. Deep brain stimulation (DBS) has proven to be a safe, effective and cost-efficient surgical treatment option. In 2009, the Australian referral guidelines, developed to provide a synopsis of DBS therapy for PD, were introduced, and since then novel findings have been reported regarding the timing of intervention, target selection and symptom management. Our aim is to provide an update of DBS for PD in Australia. Intervention at earlier stages of the disease can potentially improve quality of life over a longer period with greater possibilities for meaningful social and professional contributions. For less responsive motor symptoms (e.g. freezing of gait, postural instability), the pedunculopontine nucleus has emerged as a promising new surgical target. Traditional PD treatment is focused on improvement of motor symptoms, but the disorder is also characterised by non-motor symptoms, often undiagnosed or undisclosed, that have the potential to impact quality of life to a greater extent than motor symptoms. It is essential to identify and routinely monitor for non-motor symptoms as they can emerge at all stages of the disease or can result from treatment. Many of these current advances require long-term monitoring of treatment outcomes to improve future clinical practice, refine patient selection and ensure best patient outcomes., (© 2015 Royal Australasian College of Physicians.)

Background: Deep brain stimulation (DBS) at the subthalamic nucleus (STN) or globus pallidus internus (GPi) can effectively treat the motor symptoms of Parkinson's disease, but dual implantation is rare. We report the first cases of additional GPi stimulation as rescue therapy for disabling dyskinesias following successful STN stimulation., Methods: Two patients, initially treated with bilateral STN DBS, underwent subsequent bilateral GPi DBS after the development of refractory dyskinesias within 1 and 6 years of STN surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgeries for STN and GPi DBS., Results: GPi DBS effectively suppressed dyskinesias in these patients and improved their quality of life, as demonstrated by their videos and UPDRS scores., Conclusions: Additional bilateral GPi DBS may be considered in the rare instance of patients who develop refractory dyskinesias early or late after bilateral STN DBS., (© 2015 S. Karger AG, Basel.)

Introduction: Exercise has been shown to improve clinical measures of strength, balance and mobility, and in some cases, has improved symptoms of tremor and rigidity in people with Parkinson's disease (PD). However, to date, no research has examined whether improvements in trunk control can remedy deficits in dynamic postural stability in this population. The proposed randomised controlled trial aims to establish whether a 12-week exercise programme aimed at improving dynamic postural stability in people with PD; (1) is more effective than education; (2) is more effective when training frequency is increased; and (3) provides greater long-term benefits than education., Methods/design: Forty-five community-dwelling individuals diagnosed with idiopathic PD with a falls history will be recruited. Participants will complete baseline assessments including tests of cognition, vision, disease severity, fear of falling, mobility and quality of life. Additionally, participants will complete a series of standing balance tasks to evaluate static postural stability, while dynamic postural control will be measured during walking using head and trunk-mounted three-dimensional accelerometers. Following baseline testing, participants will be randomly-assigned to one of three intervention groups, who will receive either exercise once per week, exercise 3 days/week, or education. Participants will repeat the same battery of tests conducted at baseline after the 12-week intervention and again following a further 12-week sustainability period., Discussion: This study has the potential to show that low-intensity and progressive trunk exercises can provide a non-invasive and effective means for maintaining or improving postural stability for people with PD. Importantly, if the programme is noted to be effective, it could be easily performed by patients within their home environment or under the guidance of available allied health professionals., Trial Registration Number: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613001175763)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

It is currently hypothesised that a combination of genetic and environmental factors underlies the development of idiopathic isolated dystonia (IID). In this study, we examined several possible environmental or other non-genetic factors that may influence the risk for IID in Queensland, Australia. We surveyed several environmental exposures, lifestyle factors, medical and family histories to investigate potential risk factors for IID. Associations between putative risk factors and IID were assessed using a total of 184 dystonia patients and 1048 neurologically-normal control subjects sampled from Queensland between 2005 and 2012. Our analyses revealed that anxiety disorders, depression, tremor, cigarette smoking and head injuries with a loss of consciousness were associated with increased risk for IID (p<0.05), all of which remained statistically significant following an adjustment for multiple hypothesis testing except for depression. We also observed that the risk for dystonia increased with higher cigarette smoking pack-year quartiles in our analyses. Our results suggest possible environmental factors that influence the development of IID and complement the findings of similar dystonia risk factor studies. Further investigation defining the environmental and other non-genetic risk factors for IID may provide insight into the development of the disorder in genetically-susceptible individuals., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort., Methods: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia., Results: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low., Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease., (© 2014 American Academy of Neurology.)

Background: Quality of life is poorer in Parkinson's disease than in other conditions and in the general population without Parkinson's disease. Malnutrition also results in poorer quality of life. This study aimed at determining the relationship between quality of life and nutritional status., Methods: Community-dwelling people with Parkinson's disease >18 years old were recruited. The Patient-Generated Subjective Global Assessment (PG-SGA) assessed nutritional status. The Parkinson's Disease Questionnaire 39 (PDQ-39) measured quality of life. Phase I was cross-sectional. The malnourished in Phase I were eligible for a nutrition intervention phase, randomised into 2 groups: standard care (SC) with provision of nutrition education materials only and intervention (INT) with individualised dietetic advice and regular weekly follow-up. Data were collected at baseline, 6 weeks, and 12 weeks., Results: Phase I consisted of 120 people who completed the PDQ-39. Phase II consisted of 9 in the SC group and 10 in the INT group. In Phase I, quality of life was poorer in the malnourished, particularly for mobility and activities of daily living domains. There was a significant correlation between PG-SGA and PDQ-39 scores (Phase I, rs = 0.445, p = .000; Phase II, rs = .426, p = .002). In Phase II, no significant difference in the PDQ-39 total or sub-scores was observed between the INT and SC groups; however, there was significant improvement in the emotional well-being domain for the entire group, X2(2) = 8.84, p = .012., Conclusions: Malnourished people with Parkinson's disease had poorer quality of life than the well-nourished, and improvements in nutritional status resulted in quality of life improvements. Attention to nutritional status is an important component of quality of life and therefore the total care of people with Parkinson's disease., Trial Registration: ACTRN12610000819022.

Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite-treated DNA in a leukocyte cohort (358 PD patients and 1084 controls) and in two brain cohorts (Brain1, comprising 69 cerebellum controls; and Brain2, comprising 3 brain regions from 28 PD patients and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. In normal leukocytes, the MAPT H1/H2 diplotype and sex were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed that the H1 haplotype had higher methylation than the H2 haplotype in normal leukocytes and brain tissues. MAPT methylation was negatively associated with MAPT expression in the Brain1 cohort and in transfected cells. Methylation levels differed between three normal brain regions (Brain2 cohort, putamen < cerebellum < anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood vitamin E levels, and the effect was more significant in H2 haplotype carriers; this result was confirmed in cells that were exposed to 100 μM vitamin E. The significant effects of sex, diplotype, and brain region suggest that hypermethylation of the MAPT gene is neuroprotective by reducing MAPT expression. The effect of vitamin E on MAPT represents a possible gene-environment interaction., (© 2013 International Parkinson and Movement Disorder Society.)

Background: We have previously reported the results of Deep Brain Stimulation (DBS) of the antero-medial globus pallidus interna (GPi) for severe Tourette Syndrome (TS) in 11 patients. We extend this case series to 17 patients and a longer follow-up to a maximum of 46 months., Methods: 17 patients (14 male; mean age 29.1 years, range 17-51 years) with severe and medically intractable TS were implanted with Medtronic quadripolar electrodes bilaterally in the antero-medial GPi. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS). Secondary outcome measures included the Yale-Brown Obsessive Compulsive Scale, Hamilton Depression Rating Scale, Gilles de la Tourette Quality of Life Scale and Global Assessment of Functioning. Follow up was at one month, three months and finally at a mean 24.1 months (range 8-46 months) following surgery., Results: Overall, there was a 48.3% reduction in motor tics and a 41.3% reduction in phonic tics at one month, and this improvement was maintained at final follow-up. 12 out of 17 (70.6%) patients had a>50% reduction in YGTSS score at final follow up. Only 8 patients required ongoing pharmacotherapy for tics post-surgery. Patients improved significantly on all secondary measures. Adverse consequences included lead breakage in 4 patients, infection (1), transient anxiety (2), dizziness (1), poor balance (1) and worsening of stuttering (1)., Conclusions: This case series provides further support that antero-medial GPi DBS is an effective and well tolerated treatment for a subgroup of severe TS, with benefits sustained up to 4 years.

Background: Lifespace is a multidimensional construct that describes the geographic area in which a person lives and conducts their activities, and reflects mobility, health, and well-being. Traditionally, it has been measured by asking older people to self-report the length and frequency of trips taken and assistance required. Global Positioning System (GPS) sensors on smartphones have been used to measure Lifespace of older people, but not with people with Parkinson's disease (PD)., Objective: The objective of this study was to investigate whether GPS data collected via smartphones could be used to indicate the Lifespace of people with PD., Methods: The dataset was supplied via the Michael J Fox Foundation Data Challenge and included 9 people with PD and 7 approximately matched controls. Participants carried smartphones with GPS sensors over two months. Data analysis compared the PD group and the control group. The impact of symptom severity on Lifespace was also investigated., Results: Visualization methods for comparing Lifespace were developed including scatterplots and heatmaps. Lifespace metrics for comparison included average daily distance, percentage of time spent at home, and number of trips into the community. There were no significant differences between the PD and the control groups on Lifespace metrics. Visual representations of Lifespace were organized based on the self-reported severity of symptoms, suggesting a trend of decreasing Lifespace with increasing PD symptoms., Conclusions: Lifespace measured by GPS-enabled smartphones may be a useful concept to measure the progression of PD and the impact of various therapies and rehabilitation programs. Directions for future use of GPS-based Lifespace are provided.

The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN.

The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with protein trafficking within endosomes. Recently, a pathogenic point mutation within the Vps35 subunit (D620N) was linked to the manifestation of Parkinson's disease (PD). Here, we investigated details underlying the molecular mechanism by which the D620N mutation in Vps35 modulates retromer function, including examination of retromer's subcellular localization and its capacity to sort cargo. We show that expression of the PD-linked Vps35 D620N mutant redistributes retromer-positive endosomes to a perinuclear subcellular localization and that these endosomes are enlarged in both model cell lines and fibroblasts isolated from a PD patient. Vps35 D620N is correctly folded and binds Vps29 and Vps26A with the same affinity as wild-type Vps35. While PD-linked point mutant Vps35 D620N interacts with the cation-independent mannose-6-phosphate receptor (CI-M6PR), a known retromer cargo, we find that its expression disrupts the trafficking of cathepsin D, a CI-M6PR ligand and protease responsible for degradation of α-synuclein, a causative agent of PD. In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The specific aspects of cognition contributing to balance and gait have not been clarified in people with Parkinson's disease (PD). Twenty PD participants and twenty age- and gender-matched healthy controls were assessed on cognition and clinical mobility tests. General cognition was assessed with the Mini Mental State Exam and Addenbrooke's Cognitive Exam. Executive function was evaluated using the Trail Making Tests (TMT-A and TMT-B) and a computerized cognitive battery which included a series of choice reaction time (CRT) tests. Clinical gait and balance measures included the Tinetti, Timed Up & Go, Berg Balance, and Functional Reach tests. PD participants performed significantly worse than the controls on the tests of cognitive and executive function, balance, and gait. PD participants took longer on Trail Making Tests, CRT-Location, and CRT-Colour (inhibition response). Furthermore, executive function, particularly longer times on CRT-Distracter and greater errors on the TMT-B, was associated with worse balance and gait performance in the PD group. Measures of general cognition were not associated with balance and gait measures in either group. For PD participants, attention and executive function were impaired. Components of executive function, particularly those involving inhibition response and distracters, were associated with poorer balance and gait performance in PD.

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Degradation of the somatosensory system has been implicated in postural instability and increased falls risk for older people and Parkinson's disease (PD) patients. Here we demonstrate that textured insoles provide a passive intervention that is an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet., Methods: 20 healthy older adults (controls) and 20 participants with PD were recruited for the study. We evaluated effects of manipulating somatosensory information from the plantar surface of the feet using textured insoles. Participants performed standing tests, on two different surfaces (firm and foam), under three footwear conditions: 1) barefoot; 2) smooth insoles; and 3) textured insoles. Standing balance was evaluated using a force plate yielding data on the range of anterior-posterior and medial-lateral sway, as well as standard deviations for anterior-posterior and medial-lateral sway., Results: On the firm surface with eyes open both the smooth and textured insoles reduced medial-lateral sway in the PD group to a similar level as the controls. Only the textured insole decreased medial-lateral sway and medial-lateral sway standard deviation in the PD group on both surfaces, with and without visual input. Greatest benefits were observed in the PD group while wearing the textured insoles, and when standing on the foam surface with eyes closed., Conclusions: Data suggested that textured insoles may provide a low-cost means of improving postural stability in high falls-risk groups, such as people with PD.

Background: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease., Methods: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries., Results: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups., Conclusions: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies., (© 2013 Movement Disorder Society.)

A characteristic of Parkinson's disease (PD) is the development of tremor within the 4-6Hz range. One method used to better understand pathological tremor is to compare the responses to tremor-type actions generated intentionally in healthy adults. This study was designed to investigate the similarities and differences between voluntarily generated 4-6Hz tremor and PD tremor in regards to their amplitude, frequency and coupling characteristics. Tremor responses for 8 PD individuals (on- and off-medication) and 12 healthy adults were assessed under postural and resting conditions. Results showed that the voluntary and PD tremor were essentially identical with regards to the amplitude and peak frequency. However, differences between the groups were found for the variability (SD of peak frequency, proportional power) and regularity (Approximate Entropy, ApEn) of the tremor signal. Additionally, coherence analysis revealed strong inter-limb coupling during voluntary conditions while no bilateral coupling was seen for the PD persons. Overall, healthy participants were able to produce a 5Hz tremulous motion indistinguishable to that of PD patients in terms of peak frequency and amplitude. However, differences in the structure of variability and level of inter-limb coupling were found for the tremor responses of the PD and healthy adults. These differences were preserved irrespective of the medication state of the PD persons. The results illustrate the importance of assessing the pattern of signal structure/variability to discriminate between different tremor forms, especially where no differences emerge in standard measures of mean amplitude as traditionally defined., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: People with Parkinson's disease (PD) are at higher risk of malnutrition due to PD symptoms and pharmacotherapy side effects. When pharmacotherapy is no longer effective for symptom control, deep-brain stimulation (DBS) surgery may be considered. The aim of this study was to assess the nutritional status of people with PD who may be at higher risk of malnutrition related to unsatisfactory symptom management with optimised medical therapy., Design: This was an observational study using a convenience sample., Setting: Participants were seen during their hospital admission for their deep brain stimulation surgery., Participants: People with PD scheduled for DBS surgery were recruited from a Brisbane neurological clinic (n=15)., Measurements: The Patient-Generated Subjective Global Assessment (PG-SGA), weight, height and body composition were assessed to determine nutritional status., Results: Six participants (40%) were classified as moderately malnourished (SGA-B). Eight participants (53%) reported previous unintentional weight loss (average loss of 13%). On average, participants classified as well-nourished (SGA-A) were younger, had shorter disease durations, lower PG-SGA scores, higher body mass (BMI) and fat free mass indices (FFMI) when compared to malnourished participants (SGA-B). Five participants had previously received dietetic advice but only one in relation to unintentional weight loss., Conclusion: Malnutrition remains unrecognised and untreated in this group despite unintentional weight loss and presence of nutrition impact symptoms. Improving nutritional status prior to surgery may improve surgical outcomes.

Objective: In Parkinson's disease (PD), commonly reported risk factors for malnutrition in other populations commonly occur. Few studies have explored which of these factors are of particular importance in malnutrition in PD. The aim was to identify the determinants of nutritional status in people with Parkinson's disease (PWP)., Methods: Community-dwelling PWP (>18 years) were recruited (n = 125; 73M/52F; Mdn 70 years). Self-report assessments included Beck's Depression Inventory (BDI), Spielberger Trait Anxiety Inventory (STAI), Scales for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), Modified Constipation Assessment Scale (MCAS) and Freezing of Gait Questionnaire (FOG-Q). Information about age, PD duration, medications, co-morbid conditions and living situation was obtained. Addenbrooke's Cognitive Examination (ACE-R), Unified Parkinson's Disease Rating Scale (UPDRS) II and UPDRS III were performed. Nutritional status was assessed using the Subjective Global Assessment (SGA) as part of the scored Patient-Generated Subjective Global Assessment (PG-SGA)., Results: Nineteen (15%) were malnourished (SGA-B). Median PG-SGA score was 3. More of the malnourished were elderly (84% vs. 71%) and had more severe disease (H&Y: 21% vs. 5%). UPDRS II and UPDRS III scores and levodopa equivalent daily dose (LEDD)/body weight (mg/kg) were significantly higher in the malnourished (Mdn 18 vs. 15; 20 vs. 15; 10.1 vs. 7.6 respectively). Regression analyses revealed older age at diagnosis, higher LEDD/body weight (mg/kg), greater UPDRS III score, lower STAI score and higher BDI score as significant predictors of malnutrition (SGA-B). Living alone and higher BDI and UPDRS III scores were significant predictors of a higher log-adjusted PG-SGA score., Conclusions: In this sample of PWP, the rate of malnutrition was higher than that previously reported in the general community. Nutrition screening should occur regularly in those with more severe disease and depression. Community support should be provided to PWP living alone. Dopaminergic medication should be reviewed with body weight changes.

Objective: Malnutrition results in poor health outcomes, and people with Parkinson's disease may be more at risk of malnutrition. However, the prevalence of malnutrition in Parkinson's disease is not yet well defined. The aim of this study is to provide an estimate of the extent of malnutrition in community-dwelling people with Parkinson's disease., Methods: This is a cross-sectional study of people with Parkinson's disease residing within a 2 hour driving radius of Brisbane, Australia. The Subjective Global Assessment (SGA) and scored Patient Generated Subjective Global Assessment (PG-SGA) were used to assess nutritional status. Body weight, standing or knee height, mid-arm circumference and waist circumference were measured., Results: Nineteen (15%) of the participants were moderately malnourished (SGA-B). The median PG-SGA score of the SGA-B group was 8 (4-15), significantly higher than the SGA-A group, U = 1860.5, p<.05. The symptoms most influencing intake were loss of appetite, constipation, early satiety and problems swallowing., Conclusions: As with other populations, malnutrition remains under-recognised and undiagnosed in people with Parkinson's disease. Regular screening of nutritional status in people with Parkinson's disease by health professionals with whom they have regular contact should occur to identify those who may benefit from further nutrition assessment and intervention.

Background: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive., Methods and Results: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort., Conclusions: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown., Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry., Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD., Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.

Aim: To examine the psychometric properties of a novel anxiety rating scale, the Geriatric Anxiety Inventory (GAI) in Parkinson's disease (PD)., Method: The predictive validity of the GAI was tested against the presence of any DSM-IV anxiety disorders in 58 PD patients using receiver operating curve analysis. The concurrent validity of this scale was also studied against the state half of the Spielberger State Trait Anxiety Inventory (STAI). The internal consistency and test-retest reliability of the GAI were also examined., Results: The GAI displayed good concurrent validity against the STAI and the DSM-IV. It also showed good internal consistency and test-retest reliability., Conclusions: This study suggested that the GAI is an appropriate scale to use in non-demented PD patients., (© 2010 The Authors. Australasian Journal on Ageing © 2010 ACOTA.)