Do Antibiotic-Impregnated Envelopes Prevent Deep Brain Stimulation Implantable Pulse Generator Infections? A Prospective Cohort Study.

INTRODUCTION: Infection after deep brain stimulation (DBS) implanted pulse generator (IPG) replacement is uncommon but when it occurs can cause significant clinical morbidity, often resulting in partial or complete DBS system removal. An antibiotic absorbable envelope developed for cardiac implantable electronic devices (IEDs), which releases minocycline and rifampicin for a minimum of 7 days, was shown in the WRAP-IT study to reduce cardiac IED infections for high-risk cardiac patients. We aimed to assess whether placing an IPG in the same antibiotic envelope at the time of IPG replacement reduced the IPG infection rate. METHODS: Following institutional ethics approval (UnitingCare HREC), patients scheduled for IPG change due to impending battery depletion were prospectively randomised to receive IPG replacement with or without an antibiotic envelope. Patients with a past history of DBS system infection were excluded. Patients underwent surgery with standard aseptic neurosurgical technique [J Neurol Sci. 2017;383:135-41]. Subsequent infection requiring antibiotic therapy and/or IPG removal or revision was recorded. RESULTS: A total of 427 consecutive patients were randomised from 2018 to 2021 and followed for a minimum of 12 months. No patients were lost to follow-up. At the time of IPG replacement, 200 patients received antibiotic envelope (54 female, 146 male, mean age 72 years), and 227 did not (43 female, 184 male, mean age 71 years). The two groups were homogenous for risk factors of infection. The IPG replacement infection rate was 2.1% (9/427). There were six infections, which required antibiotic therapy and/or IPG removal, in the antibiotic envelope group (6/200) and three in the non-envelope group (3/227) (p = 0.66). CONCLUSION: This prospective randomised study did not find that an antibiotic envelope reduced the IPG infection rate in our 427 patients undergoing routine DBS IPG replacement. Further research to reduce IPG revisions and infections in a cost-effective manner is required.

A Pilot Trial of Cognitive Behavioral Therapy for Caregivers After Deep Brain Stimulation for Parkinson's Disease.

Subthalamic deep brain stimulation for Parkinson's disease may not ameliorate burden among caregivers. An 8-session, manualized program of cognitive-behavioral therapy (CBT) was delivered to a pilot sample of 10 caregivers (6 females, mean age: 60, age range: 34-79). Primary outcome measures were caregiver burden (Zarit Burden Interview) and caregiver quality of life (Parkinson's Disease Questionnaire-Carer). Secondary outcome measures comprised ratings of depression and anxiety in the caregiver, in addition to relationship quality. Caregiver burden (t = 2.91 P = .017) and caregiver anxiety (t = 2.82 P = .020) symptoms were significantly reduced at completion of the program, and these benefits were maintained 3 months later. Caregiver quality of life had significantly improved by the end of the intervention (t = 3.02 P = .015), but this effect was not sustained after 3 months. The longitudinal influence of participation in the program on caregiver burden was confirmed in a linear, mixed-effects model, χ2 (3) = 15.1, P = .0017). The intervention was well received by participants, and qualitative feedback was obtained. These results indicate that caregiver burden is modifiable in this cohort with a short course of CBT, that benefits are maintained after termination of the program, and that psychological treatment is acceptable to participants. Larger, controlled trials are justified.

The structural connectivity of subthalamic deep brain stimulation correlates with impulsivity in Parkinson's disease.

Subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease treats motor symptoms and improves quality of life, but can be complicated by adverse neuropsychiatric side-effects, including impulsivity. Several clinically important questions remain unclear: can 'at-risk' patients be identified prior to DBS; do neuropsychiatric symptoms relate to the distribution of the stimulation field; and which brain networks are responsible for the evolution of these symptoms? Using a comprehensive neuropsychiatric battery and a virtual casino to assess impulsive behaviour in a naturalistic fashion, 55 patients with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) were assessed prior to STN-DBS and 3 months postoperatively. Reward evaluation and response inhibition networks were reconstructed with probabilistic tractography using the participant-specific subthalamic volume of activated tissue as a seed. We found that greater connectivity of the stimulation site with these frontostriatal networks was related to greater postoperative impulsiveness and disinhibition as assessed by the neuropsychiatric instruments. Larger bet sizes in the virtual casino postoperatively were associated with greater connectivity of the stimulation site with right and left orbitofrontal cortex, right ventromedial prefrontal cortex and left ventral striatum. For all assessments, the baseline connectivity of reward evaluation and response inhibition networks prior to STN-DBS was not associated with postoperative impulsivity; rather, these relationships were only observed when the stimulation field was incorporated. This suggests that the site and distribution of stimulation is a more important determinant of postoperative neuropsychiatric outcomes than preoperative brain structure and that stimulation acts to mediate impulsivity through differential recruitment of frontostriatal networks. Notably, a distinction could be made amongst participants with clinically-significant, harmful changes in mood and behaviour attributable to DBS, based upon an analysis of connectivity and its relationship with gambling behaviour. Additional analyses suggested that this distinction may be mediated by the differential involvement of fibres connecting ventromedial subthalamic nucleus and orbitofrontal cortex. These findings identify a mechanistic substrate of neuropsychiatric impairment after STN-DBS and suggest that tractography could be used to predict the incidence of adverse neuropsychiatric effects. Clinically, these results highlight the importance of accurate electrode placement and careful stimulation titration in the prevention of neuropsychiatric side-effects after STN-DBS.

Low-frequency STN-DBS provides acute gait improvements in Parkinson's disease: a double-blinded randomised cross-over feasibility trial.

BACKGROUND: Some people with Parkinson's disease (PD) report poorer dynamic postural stability following high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS), which may contribute to an increased falls risk. However, some studies have shown low-frequency (60 Hz) STN-DBS improves clinical measures of postural stability, potentially providing support for this treatment. This double-blind randomised crossover study aimed to investigate the effects of low-frequency STN-DBS compared to high-frequency stimulation on objective measures of gait rhythmicity in people with PD. METHODS: During high- and low-frequency STN-DBS and while off-medication, participants completed assessments of symptom severity and walking (e.g., Timed Up-and-Go). During comfortable walking, the harmonic ratio, an objective measures of gait rhythmicity, was derived from head- and trunk-mounted accelerometers to provide insight in dynamic postural stability. Lower harmonic ratios represent less rhythmic walking and have discriminated people with PD who experience falls. Linear mixed model analyses were performed on fourteen participants. RESULTS: Low-frequency STN-DBS significantly improved medial-lateral and vertical trunk rhythmicity compared to high-frequency. Improvements were independent of electrode location and total electrical energy delivered. No differences were noted between stimulation conditions for temporal gait measures, clinical mobility measures, motor symptom severity or the presence of gait retropulsion. CONCLUSIONS: This study provides evidence for the acute benefits of low-frequency stimulation for gait outcomes in STN-DBS PD patients, independent of electrode location. However, the perceived benefits of this therapy may be diminished for people who experienced significant tremor pre-operatively, as lower frequencies may cause these symptoms to re-emerge. TRIAL REGISTRATION: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry on 5 June 2018 (ACTRN12618000944235).

Subthalamic deep brain stimulation identifies frontal networks supporting initiation, inhibition and strategy use in Parkinson's disease.

Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS.

The structural connectivity of discrete networks underlies impulsivity and gambling in Parkinson's disease.

Impulsivity in Parkinson's disease may be mediated by faulty evaluation of rewards or the failure to inhibit inappropriate choices. Despite prior work suggesting that distinct neural networks underlie these cognitive operations, there has been little study of these networks in Parkinson's disease, and their relationship to inter-individual differences in impulsivity. High-resolution diffusion MRI data were acquired from 57 individuals with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) prior to surgery for deep brain stimulation. Reward evaluation and response inhibition networks were reconstructed with seed-based probabilistic tractography. Impulsivity was evaluated using two approaches: (i) neuropsychiatric instruments were used to assess latent constructs of impulsivity, including trait impulsiveness and compulsivity, disinhibition, and also impatience; and (ii) participants gambled in an ecologically-valid virtual casino to obtain a behavioural read-out of explorative, risk-taking, impulsive behaviour. Multivariate analyses revealed that different components of impulsivity were associated with distinct variations in structural connectivity, implicating both reward evaluation and response inhibition networks. Larger bet sizes in the virtual casino were associated with greater connectivity of the reward evaluation network, particularly bilateral fibre tracts between the ventral striatum and ventromedial prefrontal cortex. In contrast, weaker connectivity of the response inhibition network was associated with increased exploration of alternative slot machines in the virtual casino, with right-hemispheric tracts between the subthalamic nucleus and the pre-supplementary motor area contributing most strongly. Further, reduced connectivity of the reward evaluation network was associated with more 'double or nothing' gambles, weighted by connections between the subthalamic nucleus and ventromedial prefrontal cortex. Notably, the variance explained by structural connectivity was higher for behavioural indices of impulsivity, derived from clinician-administered tasks and the gambling paradigm, as compared to questionnaire data. Lastly, a clinically-meaningful distinction could be made amongst participants with a history of impulse control behaviours based on the interaction of their network connectivity with medication dosage and gambling behaviour. In summary, we report structural brain-behaviour covariation in Parkinson's disease with distinct reward evaluation and response inhibition networks that underlie dissociable aspects of impulsivity (cf. choosing and stopping). More broadly, our findings demonstrate the potential of using naturalistic paradigms and neuroimaging techniques in clinical settings to assist in the identification of those susceptible to harmful behaviours.

Comparing Current Steering Technologies for Directional Deep Brain Stimulation Using a Computational Model That Incorporates Heterogeneous Tissue Properties.

OBJECTIVE: A computational model that accounts for heterogeneous tissue properties was used to compare multiple independent current control (MICC), multi-stim set (MSS), and concurrent activation (co-activation) current steering technologies utilized in deep brain stimulation (DBS) on volume of tissue activated (VTA) and power consumption. METHODS: A computational model was implemented in Sim4Life v4.0 with the multimodal image-based detailed anatomical (MIDA) model, which accounts for heterogeneous tissue properties. A segmented DBS lead placed in the subthalamic nucleus (STN). Three milliamperes of current (with a 90 µs pseudo-biphasic waveform) was distributed between two electrodes with various current splits. The laterality, directional accuracy, volume, and shape of the VTAs using MICC, MSS and co-activation, and their power consumption were computed and compared. RESULTS: MICC, MSS, and coactivation resulted in less laterality of steering than single-segment activation. Both MICC and MSS show directional inaccuracy (more pronounced with MSS) during radial current steering. Co-activation showed greater directional accuracy than MICC and MSS at centerline between the two activated electrodes. MSS VTA volume was smaller and more compact with less current spread outside the active electrode plane than MICC VTA. There was no consistent pattern of power drain between MSS and MICC, but electrode co-activation always used less power than either fractionating paradigm. CONCLUSION: While current fractionalization technologies can achieve current steering between two segmented electrodes, this study shows that there are important limitations in accuracy and focus of tissue activation when tissue heterogeneity is accounted for.

Balance control systems in Parkinson's disease and the impact of pedunculopontine area stimulation.

Impaired balance is a major contributor to falls and diminished quality of life in Parkinson's disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson's disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson's disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional-integral-derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the 'pull test' to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson's disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = - 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson's disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation.

Trunk Exercises Improve Balance in Parkinson Disease: A Phase II Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Trunk control is important for maintaining balance; hence, deficient trunk control may contribute to balance problems in people with Parkinson disease (PD). Unfortunately, this deficit is poorly managed with pharmacological therapies, emphasizing the need for alternative therapies for these patients. This randomized controlled trial sought to examine the effects of a 12-week trunk-specific exercise-based intervention on balance in people with PD. METHODS: Twenty-four people with PD and with a history of falls completed assessments of motor symptom severity, balance confidence, mobility, quality of life, and quiet-standing balance. Participants were then randomized to receive either 12 weeks of exercise or education and reassessed after 12 and 24 weeks. RESULTS: Linear mixed-models analyses showed no significant changes in clinical outcomes following the intervention. However, during quiet standing, sway area on a foam surface without vision was reduced for the exercise group at 12 (-6.9 ± 3.1 cm; 95% confidence interval [CI] = -13.1 to -0.7; P = 0.029; d = 0.66) and 24 weeks (-7.9 ± 3.1 cm; 95% CI = -14.1 to -1.7; P = 0.013; d = 0.76). Furthermore, the exercise group demonstrated reduced sway variability at 12 (-0.2 ± 0.1 cm; 95% CI = -0.4 to 0.0; P = 0.042; d = 0.62) and 24 weeks in the medial-lateral direction (-0.2 ± 0.1 cm; 95% CI = -0.4 to 0.0; P = 0.043; d = 0.62). No changes in quiet standing balance were recorded for the education group. DISCUSSION AND CONCLUSIONS: The results of this study suggest that exercise-based interventions targeting trunk strength, endurance, and mobility may be effective for improving quiet-standing balance in people with PD. However, additional research is needed to determine whether these improvements are sufficient to reduce falls risk.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A254).

Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation.

PURPOSE: Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. METHODS: To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. RESULTS: The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean - 8.3% versus - 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). CONCLUSION: PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

Identification of genetic modifiers of age-at-onset for familial Parkinson's disease.

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 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + 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.

How Well Do Caregivers Detect Depression and Anxiety in Patients With Parkinson Disease?

Depression and anxiety are prevalent in Parkinson disease (PD) yet underrecognized in clinical practice. Caregiver reports are frequently utilized to aid in the assessment of neuropsychiatric symptoms but little is known about caregivers' ability to recognize them in patients with PD. This study sought to examine the accuracy of caregiver reports. Eighty patient-caregiver dyads were involved. Accuracy of caregiver recognition was assessed by examining the level of agreement between caregiver ratings on the Neuropsychiatric Inventory and patients' diagnosis of depression and anxiety on the Mini-International Neuropsychiatric Interview (MINI)-Plus. The agreement between caregiver report and MINI-Plus diagnosis was low for both depression (6.3%) and anxiety (17.5%). The presence of depression was overreported, while anxiety was largely underestimated by caregivers. Caregiver distress significantly predicted inaccurate caregiver identification of depression ( R2 = .51, P < .001) and anxiety ( R2 = .08, P < .05). Results indicate that caregivers may be poor at recognizing depression and anxiety in patients with PD. Utilization of caregiver report should take into account potential biases that affect caregiver judgment.

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

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.

Understanding the lived experiences of Parkinson's disease and deep brain stimulation (DBS) through occupational changes.

BACKGROUND: Deep brain stimulation (DBS), a surgically based treatment for people living with Parkinson's disease (PD), can result in a significant improvement of motor symptoms. However, the broader impact of DBS and the changes it creates are not well understood. Greater understanding of the experiences and needs related to DBS would enable development of relevant outcome measures and supports. OBJECTIVES: To explore the lived experiences of people undergoing DBS for Parkinson's disease. METHODS: A descriptive phenomenological study was undertaken exploring experiences, perspectives and outcomes with key stakeholders. Semi-structured, audiotaped interviews were undertaken with people with PD who have had DBS, their family members and health professionals across four states and territories in Australia. RESULTS: Perspectives and experiences of 14 people with PD undergoing DBS, 10 family members and 11 health professionals were analysed. Occupations emerged as a key aspect throughout the DBS experience. Two major themes captured the role of occupation in relation to DBS: Occupations as a barometer, where occupational experiences and performances shaped people's understanding of their condition, the impact of treatments and their overall adjustment; and Shifting occupational identity where the life transition of DBS altered the occupational experiences of relationships, volition, roles and responsibilities of people with PD and their family members. CONCLUSION: Occupational experiences and changes served as an important way for people with PD and their families to understand and communicate their experiences of PD and related treatments. There is an identified need for outcome measures and clinical education and interventions to reflect this.

A Neurophysiological Study of Semantic Processing in Parkinson's Disease.

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).

Imposed Faster and Slower Walking Speeds Influence Gait Stability Differently in Parkinson Fallers.

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.

Can smartphones measure momentary quality of life and participation? A proof of concept using experience sampling surveys with university students.

BACKGROUND: Understanding quality of life and participation is a key aspect of occupational therapy research. The use of smartphones to deliver experience-sampling surveys may provide an accessible way to monitor these outcomes. This study used smartphone-based experience sampling methods (ESM) to investigate factors influencing momentary quality of life (mQOL) of university students. METHODS: A convenience sample of students at an Australian university participated. Using a custom smartphone application, ESM surveys were sent six to eight times, every second day, over a week. Participants indicated their mQOL, occupational participation, occupational enjoyment, social context and location via surveys and provided demographic and health information in a single self-report questionnaire. The relationship between mQOL and variables was analysed at the survey level using logistic regression. RESULTS: Forty students completed 391 surveys. Higher mQOL was significantly related to participation in productive occupations (z = 3.48; P = 0.001), moderate (z = 4.00; P < 0.001) or high occupational enjoyment (z = 7.06; P < 0.001), being with someone (z = 2.15, P = 0.031), being at home (z = 2.49; P = 0.013) and an excellent self-rated health status (z = 2.35; P = 0.019). The magnitude of differences in mQOL was small. CONCLUSION: This study suggests that mQOL amongst university students relates to personal, environmental and occupational factors. The use of smartphone-based ESM appears to be a practical approach for investigating participation and QOL. Further research utilising a more diverse sample, analysing at the individual level, and using ESM in conjunction with other methodologies is recommended.

The Vps35 D620N mutation linked to Parkinson's disease disrupts the cargo sorting function of retromer.

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.

Understanding the human pedunculopontine nucleus in Parkinson's disease.

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.

Use of a Short-Form Balance Confidence Scale to Predict Future Recurrent Falls in People With Parkinson Disease.

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.