Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for ß-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. METHODS: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. DISCUSSION: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Characterization of Parkinsonian Hand Tremor and Validation of a High-Order Tremor Estimator.

Recent progress in wearable technology has made wearable tremor suppression devices (WTSDs) for Parkinson's patients a potentially viable alternative solution for tremor management. So far, in contrast to wrist and elbow tremor, finger tremors have not been studied in depth despite the huge impact that they have on a patient's daily life. In addition, more evidence has been found showing that the performance of current tremor estimators may be limited by their model order due to the multiple harmonics present in tremor. The aim of this paper is to characterize finger and wrist tremor in both the time and frequency domains, and to propose a high-order tremor estimation algorithm. Tremor magnitudes are reported in the forms of linear acceleration, angular velocity, and angular displacement. The activation of forearm flexor and extensor muscles is also investigated. The frequency analysis shows that Parkinsonian tremors produce oscillations of the hand with pronounced harmonics. At last, a high-order weighted-frequency Fourier linear combiner (WFLC)-based Kalman filter is proposed. The percentage estimation accuracy achieved from the proposed estimator is 96.3 ± 1.7%, showing average improvements of 28.5% and 48.9% over its lower-order counterpart and the WFLC. The proposed estimator shows promise for use in a WTSD.

Design and validation of a high-order weighted-frequency fourier linear combiner-based Kalman filter for parkinsonian tremor estimation.

The design of a tremor estimator is an important part of designing mechanical tremor suppression orthoses. A number of tremor estimators have been developed and applied with the assumption that tremor is a mono-frequency signal. However, recent experimental studies have shown that Parkinsonian tremor consists of multiple frequencies, and that the second and third harmonics make a large contribution to the tremor. Thus, the current estimators may have limited performance on estimation of the tremor harmonics. In this paper, a high-order tremor estimation algorithm is proposed and compared with its lower-order counterpart and a widely used estimator, the Weighted-frequency Fourier Linear Combiner (WFLC), using 18 Parkinsonian tremor data sets. The results show that the proposed estimator has better performance than its lower-order counterpart and the WFLC. The percentage estimation accuracy of the proposed estimator is 85±2.9%, an average improvement of 13% over the lower-order counterpart. The proposed algorithm holds promise for use in wearable tremor suppression devices.

An Examination of the Reliability and Factor Structure of the Physical Activity Scale for Individuals With Physical Disabilities (PASIPD) Among Individuals Living With Parkinson's Disease.

Physical activity is generally thought to be beneficial to individuals with Parkinson's disease (PD). There is, however, limited information regarding current rates of physical activity among individuals with PD, possibly due to a lack of well-validated measurement tools. In the current study we sampled 63 individuals (31 women) living with PD between the ages of 52 and 87 (M = 70.97 years, SD = 7.53), and evaluated the amount of physical activity in which they engaged over a 7-day period using a modified form of the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD). The PASIPD was demonstrated to be a reliable measure within this population, with three theoretically defensible factors: (1) housework and home-based outdoor activities; (2) recreational and fitness activities; and (3) occupational activities. These results suggest that the PASIPD may be useful for monitoring physical activity involvement among individuals with PD, particularly within large-scale questionnaire-based studies.

Enhancing the conceptual clarity and utility of the international classification of functioning, disability & health: the potential of a new graphic representation.

PURPOSE: To present a new graphic representation of the international classification of functioning, disability and health (ICF), entitled the ICF-conceptual revision (ICF-CR). The ICF-CR aims to be clearer and more usable tool than the ICF graphic currently used by starting to address criticisms of the ICF raised in the literature, with a focus on positioning quality of life (QoL) in relation to the ICF's other components. METHOD: This is a conceptual paper based on a review of criticisms of the ICF and related literature published on human functioning. RESULTS: In addition to criticisms of the current graphic, four criticisms of the ICF are discussed in relation to the development of the ICF-CR, including: the lack of development of biopsychosocial theory, the lack of clarity between activities and participation, the language used, and the absence of QoL. General systems theory is used to help construct the new graphic in addressing these criticisms and to position QoL. CONCLUSIONS: The ICF-CR is designed to be a more responsive graphic of human functioning; one which enhances the clarity of principles integral to the ICF, including biopsychosocial theory and universalism. It is hoped the ICF-CR will promote continued discussion toward the goal of enhancing the ICF, both visually and conceptually.

The effects of word length, articulation, oral-motor movement, and lexicality on gait: a pilot study.

Previous research has suggested that articulatory demands are important predictors of the impact of dual-task interference on spatial-temporal parameters of gait. In this study, we evaluated the effects of word length, oral-motor movement, articulation, and lexicality, within a verbal task, on a continuous gait task. Fifteen healthy young women participated in a study in which two word lengths (monosyllabic and bisyllabic) were crossed with four levels of secondary task complexity (no dual-task, non-speech movement, spoken non-word, and spoken word). Spatial and temporal parameters of gait were measured using a 23' instrumented carpet. Results indicated a significant multivariate main effect for task type, F(15, 120)=3.07, that explained 71.1% of the demonstrated variability in gait. Univariate analyses of this main effect revealed statistically significant effects for velocity, step time, swing time, and stance time, but no statistically significant effect for step length. Post hoc analyses suggested that dual-task interference produced significant changes in the parameters of gait, but that this interference was not significantly greater with non-words as compared to the non-speech movement condition, nor was it significantly greater with words as compared to non-words. The results of this systematic deconstruction of a simple verbal task suggest that the motor component of a secondary speech task may produce the largest amount of interference within a dual-task interference paradigm.

Upper Extremity Motor Learning among Individuals with Parkinson's Disease: A Meta-Analysis Evaluating Movement Time in Simple Tasks.

Motor learning has been found to occur in the rehabilitation of individuals with Parkinson's disease (PD). Through repetitive structured practice of motor tasks, individuals show improved performance, confirming that motor learning has probably taken place. Although a number of studies have been completed evaluating motor learning in people with PD, the sample sizes were small and the improvements were variable. The purpose of this meta-analysis was to determine the ability of people with PD to learn motor tasks. Studies which measured movement time in upper extremity reaching tasks and met the inclusion criteria were included in the analysis. Results of the meta-analysis indicated that people with PD and neurologically healthy controls both demonstrated motor learning, characterized by a decrease in movement time during upper extremity movements. Movement time improvements were greater in the control group than in individuals with PD. These results support the findings that the practice of upper extremity reaching tasks is beneficial in reducing movement time in persons with PD and has important implications for rehabilitation.

Dual-task interference: the effects of verbal cognitive tasks on upright postural stability in Parkinson's disease.

Although dual-task interference has previously been demonstrated to have a significant effect on postural control among individuals with Parkinson's disease, the impact of speech complexity on postural control has not been demonstrated using quantitative biomechanical measures. The postural stability of twelve participants with idiopathic Parkinson's disease and twelve healthy age-matched controls was evaluated under three conditions: (1) without a secondary task, (2) performing a rote repetition task and (3) generating a monologue. Results suggested a significant effect of cognitive load on biomechanical parameters of postural stability. Although both groups increased their postural excursion, individuals with Parkinson's disease demonstrated significantly reduced excursion as compared with that of healthy age-matched controls. This suggests that participants with Parkinson's disease may be overconstraining their postural adjustments in order to focus attention on the cognitive tasks without losing their balance. Ironically, this overconstraint may place the participant at greater risk for a fall.

Predictive validity of the UPDRS postural stability score and the Functional Reach Test, when compared with ecologically valid reaching tasks.

Balance problems and falls are a common concern among individuals with Parkinson's disease (PD). Falls frequently occur during daily activities such as reaching into cupboards in the kitchen or bathroom. This study compared the correlation among two standard postural stability tests - the postural stability score on the Unified Parkinson's Disease Rating Scale (UPDRS) and the Functional Reach Test (FRT) - and ecologically valid reaching tasks that correspond to reaching at different cupboard heights among 20 individuals with PD and 20 age-matched controls. Both the FRT and the UPDRS postural stability tests are quick measures that can be performed during the clinical examination. The FRT, but not the postural stability score, demonstrated a significant correlation with the ecologically valid reaching tasks, among individuals with PD. Furthermore the FRT scores did not correlate with the UPDRS postural stability scores, indicating that these are measuring different aspects of balance. This study suggests that the FRT score may better predict the risk of postural instability encountered during daily activities among individuals with PD.

Plantar cutaneous sensory stimulation improves single-limb support time, and EMG activation patterns among individuals with Parkinson's disease.

Parkinson's disease is a chronic neurological disorder that results in gait and posture impairment. There is increasing evidence that these motor impairments may be partially due to deficits within the sensory system. In this study, the effects of a facilitatory insole that provides increased plantar sensory stimulation, was evaluated during gait, in a group of individuals with Parkinson's disease in comparison with healthy age-matched controls. Spatial-temporal parameters of gait were evaluated using an instrumented carpet, and muscle activation patterns were evaluated using surface EMG. All participants were tested with both a facilitatory (ribbed) insole and a conventional (flat) insole while walking 20 feet. Results indicated that the use of the facilitatory insole produced a significant increase in single-limb support time. Additionally, the muscle activation sequence of the tibialis anterior was normalized by the facilitatory insole, at the time of initial ground contact. These changes may lead to an overall improvement in gait pattern and stability, and suggest that the use of this type of facilitatory insole may be a useful treatment strategy for improving the gait of individuals with Parkinson's disease. This also provides support for the role of facilitation of the sensory system in improving motor output in individuals with Parkinson's disease.

Teaching evidence-based clinical practice to neurology and neurosurgery residents.

The primary objective of education in evidence-based clinical practice (EBCP) is to provide a resident or student with the requisite skills to satisfactorily solve real everyday clinical problems throughout their careers and to translate those solutions into better care for patients. At the University of Western Ontario in London, Canada, there is a well-developed and highly successful evidence-based neurology curriculum primarily aimed at residents. This article summarizes the current context of EBCP postgraduate training in the neurological sciences and a detailed description of its purpose, learning outcomes, required resources, content, teaching strategies, and assessment tools. In this program, we teach the principles of EBCP through the review of pertinent neurological clinical questions. The summary of each topic is recorded on our website in the form of critically appraised topics (CATs) in electronically accessible CAT banks.

Evaluating a formal evidence-based clinical practice curriculum in a neurology residency program.

BACKGROUND: Since 1998, the University of Western Ontario Evidence-Based Neurology Programme has been fostering life-long self-teaching, self-evaluation, and promoting improvement of the care of neurological patients by teaching neurology residents to practice Evidence-Based Clinical Practice (EBCP). DESIGN/METHODS: Using a questionnaire/survey we evaluated participation during EBCP sessions and the applicability of EBCP to current and future clinical practice. Also, using a rating scale we investigated how likely our residents' and graduates' clinical practice has been influenced by the EBCP knowledge; and, if they were teaching these concepts to residents or medical students. The questionnaire was sent to all neurology residents and neurologists that graduated after implementation of the programme. RESULTS: All residents (100%) returned the survey/questionnaire, indicating that they attended the sessions consistently. Even though all respondents believed that the EBCP concepts were useful during their training, the concepts were infrequently utilized because of time constraints. On a scale of 1 to 10, they rated the influence to include EBCP concepts in their daily clinical practice as high (average: 6.8, S.D. 1.5). They all had frequent contact with medical students and non-neurology residents, but did not teach EBCP concepts to them on a consistent basis, because of time limitations. 10 (77%) out of 13 graduates returned the survey/questionnaire. They also believed the EBCP concepts were useful, but only used them when time allowed. They also rated the influence to include EBCP concepts in their daily clinical practice as high (mean 8.5, S.D. 1.2). Most graduates had frequent contact with trainees, but did not teach EBCP concepts to them on a consistent basis because of time constraints. Finally, all expressed the need to continue having this formal curriculum during residency. CONCLUSION/RELEVANCE: Although EBCP incorporated into the curriculum of a neurology residency programme increased neurologists and neurology trainees' confidence in knowledge of existing evidence, and reinforced the EBCP principles, these concepts were not used in daily clinical practice and were not taught to more junior trainees due to time constraints.

An evaluation of sensorimotor integration during locomotion toward a target in Parkinson's disease.

Recent research suggests that basal ganglia dysfunction may result in problems integrating concurrent vision and proprioception during movement. We evaluated dopaminergic system involvement in this sensorimotor process during locomotion within a large sample of Parkinson's disease (PD) patients while "On" and "Off" their dopaminergic medications (n=25), in conditions that selectively manipulated the availability of proprioception, vision or both. The present experiment focused on two main objectives: i) to examine the relative influence of visual and proprioceptive inputs on locomotion and target accuracy in patients with PD; and ii) to examine the influence of dopamine replacement therapy on sensorimotor integration while moving toward the target. All participants walked at a self-selected pace on a GAITRite carpet in two baseline conditions (light and dark), as well as four experimental darkness conditions: a) to a remembered target (i.e. proprioception only), b) to a remembered target with light on chest for body position awareness (proprioception plus), c) with vision of a lit target, also with light on chest (vision and proprioception), d) pushed in wheelchair to remembered target (no proprioception or vision). Final position was measured by 2-D radial error, and revealed a group by condition interaction, suggesting that PD patients "Off" their medications move to targets with less accuracy, but approach the accuracy of healthy participants when in the "On" state. Both PD and healthy improved their accuracy with availability of concurrent vision and proprioception (condition c). Interestingly, our results demonstrate that PD "Off" performed the task with greater difficulty than when "On" medication, but only when proprioception was the sole source of feedback. Since PD, whether medicated or unmedicated were even more affected when proprioception was removed (wheelchair), a memory-related explanation can be ruled out. Our results suggest that the basal ganglia are not specifically involved in visuoproprioceptive integration; however, assimilation of proprioceptive feedback to guide an ongoing movement may be a critical function of the basal ganglia.

A prospective analysis of serum vitamin K in severely burned pediatric patients.

Patients with burn injuries exhibit multiple risk factors for the development of vitamin K deficiency, including malabsorption, limited enteral intake, antibiotic therapy, and multiple surgical procedures. A prospective evaluation of 48 children was conducted to evaluate serum vitamin K values during the first 4 postburn weeks. Serum levels were analyzed in relation to clinical course. Days of antibiotic (p < 0.02) and albumin therapy (p < 0.003), percentage body surface area excised (p < 0.006), and the administration of blood products (p < 0.05) were significantly correlated with serum vitamin K levels, and days of diarrhea approached statistical significance (p < 0.06). No relationship was found between serum values and prothrombin time, activated partial thromboplastin time, or serum albumin. Ninety-one percent of the children demonstrated serum values below expected norms. These data suggest a relationship between coagulopathy and an intact functioning gastrointestinal tract. However, the relative importance of dietary versus endogenous vitamin K produced by intestinal bacteria remains to be elucidated.

Outpatient burn management.

The outpatient environment is appropriate for the management of many minor or moderate burn injuries. Ambulatory care moves across the continuum of recovery from treatment of the acute insult, through the rehabilitative phase of care, to surgical reconstruction. The patient and family actively participate with the multidisciplinary team in the design of a holistic plan of care. Ongoing evaluation of progress is provided to achieve optimal outcomes based on standards of care and standards of practice.

Evidence that heat and ultraviolet radiation activate a common stress-response program in plants that is altered in the uvh6 mutant of Arabidopsis thaliana.

The uvh6 mutant of Arabidopsis was previously isolated in a screen for increased sensitivity to ultraviolet (UV) radiation. uvh6 mutant plants were killed by incubation at 37 degrees C for 4 d, a treatment not lethal to wild-type plants. Furthermore, under permissive conditions, uvh6 plants were yellow-green with an approximately one-third lower chlorophyll content. Genetic analysis of the uvh6 mutant strongly suggested that all three mutant phenotypes were due to mutation at the same genetic locus. To understand UVH6 function more fully, the response of wild-type plants to growth at elevated temperatures and exposure to UV radiation was analyzed. Wild-type plants grown at 30 degrees C were as UV-hypersensitive and yellow-green as uvh6 mutant plants grown at 24 degrees C. Mutant uvh6 plants induced heat-shock protein HSP21 at a lower threshold temperature than wild-type plants, indicating that the uvh6 mutant was exhibiting signs of heat stress at a 4 to 5 degrees C lower temperature than wild-type plants. We propose the UV damage and heat induce a common stress response in plants that leads to tissue death and reduced chloroplast function, and that the UVH6 product is a negative regulator of this response.