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.
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.
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.
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.
CRD42014010838.
DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration ...residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association.
In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues.
We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor.
This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.
An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We ...present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
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.
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.
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.
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).
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.
A genetic mutation in the Vps35 subunit of retromer has recently been linked to late onset Parkinson's disease. We observed that the distribution and maturation of Vps35 D620N positive endosomes are ...altered. While Vps35 D620N containing retromer still binds CI‐M6PR, its trafficking is perturbed as shown by secretion of its ligand cathepsin D. As cathepsin D is involved in processing of α‐synuclein, a well‐established causative agent of Parkinson's disease, its altered trafficking may therefore represent the underlying cause of disease.
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.
Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, nine participants (four females, mean age 47.9 ± 10.7 years) were ...implanted with DBS electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). Following a one-month postoperative recovery phase, participants entered a three-month randomised, double-blind, sham-controlled phase before a twelve-month period of open-label stimulation incorporating a course of cognitive behavioural therapy (CBT). The primary outcome measure was OCD symptoms as rated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the blinded phase, there was a significant benefit of active stimulation over sham (p = 0.025, mean difference 4.9 points). After the open phase, the mean reduction in YBOCS was 16.6 ± 1.9 points (χ
(11) = 39.8, p = 3.8 × 10
), with seven participants classified as responders. CBT resulted in an additive YBOCS reduction of 4.8 ± 3.9 points (p = 0.011). There were two serious adverse events related to the DBS device, the most severe of which was an infection during the open phase necessitating device explantation. There were no serious psychiatric adverse events related to stimulation. An analysis of the structural connectivity of each participant's individualised stimulation field isolated right-hemispheric fibres associated with YBOCS reduction. These included subcortical tracts incorporating the amygdala, hippocampus and stria terminalis, in addition to cortical regions in the ventrolateral and ventromedial prefrontal cortex, parahippocampal, parietal and extrastriate visual cortex. In conclusion, this study provides further evidence supporting the efficacy and tolerability of DBS in the region of the BNST for individuals with otherwise treatment-refractory OCD and identifies a connectivity fingerprint associated with clinical benefit.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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