Anat Mirelman

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

BACKGROUND Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gauchers disease, among patients with Parkinsons disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinsons disease. METHODS Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinsons disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinsons disease.

Executive Control Deficits as a Prodrome to Falls in Healthy Older Adults: A Prospective Study Linking Thinking, Walking, and Falling

BACKGROUND Executive function (EF) deficits may increase fall risk, even among older adults with no overt cognitive impairment. Indeed, the effects of dual tasking (DT) on gait, a challenge to executive control, are more exaggerated in persons with a history of falls. Prospective evidence is, however, lacking. METHODS We prospectively evaluated whether EF predicts falls over a 2-year period among 262 community-living, healthy, and well-functioning older adults, focusing on the 201 who reported no falls during the previous year. At baseline, participants completed a computerized cognitive battery that generated an index of EF and other cognitive domains. Gait was assessed using performance-based tests and by quantifying walking during single- and dual-task conditions. RESULTS The 262 participants (mean age: 76.3 ± 4.3 years, 60.3% women) had intact cognitive function on testing, a low comorbidity index, and good mobility. The EF index predicted future falls. Among those who reported no previous falls, participants in the worst EF quartile were three times more likely to fall during the 2 years of follow-up, and they were more likely to transition from nonfaller to faller sooner. DT gait variability also predicted future falls and multiple falls, whereas other measures of cognitive function, gait, and mobility did not. CONCLUSIONS Among healthy older adults, individuals with poorer EF are more prone to falls. Higher-level cognitive functions such as those regulated by the frontal lobes are apparently needed for safe everyday navigation that demands multitasking. Optimal screening, early detection, and treatment of falls should, apparently, also target this cognitive domain.

Effects of Training With a Robot-Virtual Reality System Compared With a Robot Alone on the Gait of Individuals After Stroke

Background and Purpose— Training of the lower extremity (LE) using a robot coupled with virtual environments has shown to transfer to improved overground locomotion. The purpose of this study was to determine whether the transfer of training of LE movements to locomotion was greater using a virtual environment coupled with a robot or with the robot alone. Methods— A single, blind, randomized clinical trial was conducted. Eighteen individuals poststroke participated in a 4-week training protocol. One group trained with the robot virtual reality (VR) system and the other group trained with the robot alone. Outcome measures were temporal features of gait measured in a laboratory setting and the community. Results— Greater changes in velocity and distance walked were demonstrated for the group trained with the robotic device coupled with the VR than training with the robot alone. Similarly, significantly greater improvements in the distance walked and number of steps taken in the community were measured for the group that trained with robot coupled with the VR. These differences were maintained at 3 months’ follow-up. Conclusions— The study is the first to demonstrate that LE training of individuals with chronic hemiparesis using a robotic device coupled with VR improved walking ability in the laboratory and the community better than robot training alone.

Executive Function and Falls in Older Adults: New Findings from a Five-Year Prospective Study Link Fall Risk to Cognition

Background Recent findings suggest that executive function (EF) plays a critical role in the regulation of gait in older adults, especially under complex and challenging conditions, and that EF deficits may, therefore, contribute to fall risk. The objective of this study was to evaluate if reduced EF is a risk factor for future falls over the course of 5 years of follow-up. Secondary objectives were to assess whether single and dual task walking abilities, an alternative window into EF, were associated with fall risk. Methodology/Main Results We longitudinally followed 256 community-living older adults (age: 76.4±4.5 yrs; 61% women) who were dementia free and had good mobility upon entrance into the study. At baseline, a computerized cognitive battery generated an index of EF, attention, a closely related construct, and other cognitive domains. Gait was assessed during single and dual task conditions. Falls data were collected prospectively using monthly calendars. Negative binomial regression quantified risk ratios (RR). After adjusting for age, gender and the number of falls in the year prior to the study, only the EF index (RR: .85; CI: .74–.98, p = .021), the attention index (RR: .84; CI: .75–.94, p = .002) and dual tasking gait variability (RR: 1.11; CI: 1.01–1.23; p = .027) were associated with future fall risk. Other cognitive function measures were not related to falls. Survival analyses indicated that subjects with the lowest EF scores were more likely to fall sooner and more likely to experience multiple falls during the 66 months of follow-up (p<0.02). Conclusions/Significance These findings demonstrate that among community-living older adults, the risk of future falls was predicted by performance on EF and attention tests conducted 5 years earlier. The present results link falls among older adults to cognition, indicating that screening EF will likely enhance fall risk assessment, and that treatment of EF may reduce fall risk.

Virtual Reality for Gait Training: Can It Induce Motor Learning to Enhance Complex Walking and Reduce Fall Risk in Patients With Parkinson's Disease?

BACKGROUND Gait and cognitive disturbances are common in Parkinsons disease (PD). These deficits exacerbate fall risk and difficulties with mobility, especially during complex or dual-task walking. Traditional gait training generally fails to fully address these complex gait activities. Virtual reality (VR) incorporates principles of motor learning while delivering engaging and challenging training in complex environments. We hypothesized that VR may be applied to address the multifaceted deficits associated with fall risk in PD. METHODS Twenty patients received 18 sessions (3 per week) of progressive intensive treadmill training with virtual obstacles (TT + VR). Outcome measures included gait under usual-walking and dual-task conditions and while negotiating physical obstacles. Cognitive function and functional performance were also assessed. RESULTS Patients were 67.1 ± 6.5 years and had a mean disease duration of 9.8 ± 5.6 years. Posttraining, gait speed significantly improved during usual walking, during dual task, and while negotiating overground obstacles. Dual-task gait variability decreased (ie, improved) and Trail Making Test times (parts A and B) improved. Gains in functional performance measures and retention effects, 1 month later, were also observed. CONCLUSIONS To our knowledge, this is the first time that TT + VR has been used for gait training in PD. The results indicate that TT + VR is viable in PD and may significantly improve physical performance, gait during complex challenging conditions, and even certain aspects of cognitive function. These findings have important implications for understanding motor learning in the presence of PD and for treating fall risk in PD, aging, and others who share a heightened risk of falls.

How Does Explicit Prioritization Alter Walking During Dual-Task Performance? Effects of Age and Sex on Gait Speed and Variability

Background Previous studies have demonstrated that the performance of a secondary task during walking alters gait. Objective This study investigated the effects of task prioritization on walking in young and older adults to evaluate the “default” prioritization scheme used, the flexibility to alter prioritization and cortical resources allocated to gait and a secondary cognitive task, and any age-associated changes in these abilities. Design A cross-sectional study that explicitly altered the focus of attention was used to investigate the effects of prioritization in young and older adults who were healthy. Methods Gait speed and gait variability were evaluated in young adults (n=40) and older adults (n=17) who were healthy, both during usual walking and under 3 dual-task conditions: (1) no specific prioritization instructions, (2) prioritization of gait, and (3) prioritization of the cognitive task. Results Young adults significantly increased gait speed in the gait prioritization condition compared with gait speed in the no-instruction condition; a similar tendency was seen in the older adults. Gait speed was reduced when priority was given to the cognitive task in both age groups; however, this effect was less dramatic in the older adults. In the young adults, prioritization of gait tended to have different effects on gait speed among both men and women. In the older adults, but not in the young adults, all dual-task conditions produced increased gait variability, whereas prioritization did not alter this gait feature. Limitations The sample size and the relative homogeneity of the older adults could be considered as possible limitations of the study. Conclusions Even among young adults, the effects of secondary, cognitive tasks on gait speed are strongly influenced by prioritization. This finding was less significant in the older adults, suggesting that there is an age-associated decline in the ability to flexibly allocate attention to gait. Somewhat surprisingly, when prioritization was not explicitly instructed, gait speed in both young and older adults most closely resembled that of the condition when they were instructed to focus attention on the cognitive task.

The interplay between gait, falls and cognition: can cognitive therapy reduce fall risk?

In this article, we briefly summarize the incidence and significant consequences of falls among older adults, the insufficient effectiveness of commonly used multifactorial interventions and the evidence linking falls and cognitive function. Recent pharmacologic and nonpharmacologic studies that evaluated the effects of cognitive therapy on fall risk are reviewed. The results of this article illustrate the potential utility of multiple, diverse forms of cognitive therapy for reducing fall risk. The article also indicates that large-scale, randomized controlled trials are warranted and that additional research is needed to better understand the pathophysiologic mechanisms underlying the interplay between human mobility, fall risk and cognitive function. Nonetheless, we suggest that multimodality interventions that combine motor and cognitive therapy should, eventually, be incorporated into clinical practice to enable older adults and patients to move safer and with a reduced fall risk.

Effects of virtual reality training on gait biomechanics of individuals post-stroke.

OBJECTIVE To evaluate gait biomechanics after training with a virtual reality (VR) system and to elucidate underlying mechanisms that contributed to the observed functional improvement in gait speed and distance. DESIGN A single blind randomized control study. SETTING Gait analysis laboratory in a rehabilitation hospital and the community. PARTICIPANTS Fifteen men and three women with hemiparesis caused by stroke. INTERVENTIONS Subjects trained on a six-degree of freedom force-feedback robot interfaced with a VR simulation. Subjects were randomized to either a VR group (n=9) or non-VR group (NVR, n=9). Training was performed three times a week for 4 weeks for approximately 1h each visit. MAIN OUTCOME MEASURES Kinematic and kinetic gait parameters. RESULTS Subjects in the VR group demonstrated a significantly larger increase in ankle power generation at push-off as a result of training (p=0.036). The VR group had greater change in ankle ROM post-training (19.5%) as compared to the NVR group (3.3%). Significant differences were found in knee ROM on the affected side during stance and swing, with greater change in the VR group. No significant changes were observed in kinematics or kinetics of the hip post-training. CONCLUSIONS These findings are encouraging because they support the potential for recovery of force and power of the lower extremity for individuals with chronic hemiparesis. It is likely that the effects of training included improved motor control at the ankle, which enabled the cascade of changes that produced the functional improvements seen after training.

Gait alterations in healthy carriers of the LRRK2 G2019S mutation

To test for an association between the LRRK2‐G2019S mutation and gait, we studied 52 first‐degree relatives of patients with Parkinsons disease (PD) who carry this mutation. An accelerometer quantified gait during usual‐walking, fast‐walking, and dual‐tasking. Noncarriers (n = 27) and carriers (n = 25) were similar with respect to age, gender, height, and gait speed during all conditions. During dual‐tasking and fast‐walking, gait variability and the amplitude of the dominant peak of the accelerometer signal were significantly altered among the carriers. These findings support the possibility of previously unidentified, presymptomatic motor changes among relatives who have an increased risk of developing PD. Ann Neurol 2010

When does walking alter thinking? Age and task associated findings

Age-associated changes in gait are exacerbated when another task is performed simultaneously. We quantified the converse, i.e., the effects of walking on cognitive abilities, and determined the role of aging and executive function (EF) in any observed changes. 276 healthy older adults and 52 healthy young adults performed three cognitive tasks, i.e., serial 7 and 3 subtractions and phoneme-monitoring, while sitting and again while walking. Among the elderly, walking decreased performance on serial 3 and 7 subtractions and the number of phonemes counted (p<0.0001), but enhanced content recall. In contrast, for the young adults, walking did not alter serial 3 subtractions, phoneme-monitoring or content recall, while serial 7 subtraction performance decreased during walking (p=0.047). Measures of EF explained the age-associated changes in performance of the cognitive task during walking. Findings in both young and old subjects underscore the idea that gait is attention-demanding and is not a purely motor task. Even young, healthy adults demonstrate decreased cognitive performance while walking, when the cognitive task is sufficiently difficult. Age-associated declines in EF apparently contribute to the difference in dual tasking abilities during walking between young and older adults.