Showing papers by "Anat Mirelman published in 2014"

Increased frontal brain activation during walking while dual tasking: an fNIRS study in healthy young adults

Abstract: Background: Accumulating evidence suggests that gait is influenced by higher order cognitive and cortical control mechanisms. Recently, several studies used functional near infrared spectroscopy (fNIRS) to examine brain activity during walking, demonstrating increased oxygenated hemoglobin (HbO2) levels in the frontal cortex during walking while subjects completed a verbal cognitive task. It is, however, still unclear whether this increase in activation was related to verbalization, if the response was specific to gait, or if it would also be observed during standing, a different motor control task. The aim of this study was to investigate whether an increase in frontal activation is specific to dual tasking during walking. Methods: Twenty-three healthy young adults (mean 30.9 ± 3.7 yrs, 13 females) were assessed using an electronic walkway. Frontal brain activation was assessed using an fNIRS system consisting of two probes placed on the forehead of the subjects. Assessments included: walking in a self-selected speed; walking while counting forward; walking while serially subtracting 7s (Walking+S7); and standing while serially subtracting 7s (Standing+S7). Data was collected from 5 walks of 30 meters in each condition. Twenty seconds of quiet standing before each walk served as baseline frontal lobe activity. Repeated Measures Analysis of Variance (RM ANOVA) tested for differences between the conditions. Results: Significant differences were observed in HbO2 levels between all conditions (p = 0.007). HbO2 levels appeared to be graded; walking alone demonstrated the lowest levels of HbO2 followed by walking+counting condition (p = 0.03) followed by Walking+S7 condition significantly increased compared to the two other walking conditions (p < 0.01). No significant differences in HbO2 levels were observed between usual walking and the standing condition (p = 0.38) or between standing with or without serial subtraction (p = 0.76). Conclusions: This study provides direct evidence that dual tasking during walking is associated with frontal brain activation in healthy young adults. The observed changes are apparently not a response to the verbalization of words and are related to the cognitive load during gait.

Estimation of step-by-step spatio-temporal parameters of normal and impaired gait using shank-mounted magneto-inertial sensors: application to elderly, hemiparetic, parkinsonian and choreic gait

Abstract: Background The step-by-step determination of the spatio-temporal parameters of gait is clinically relevant since it provides an estimation of the variability of specific gait patterns associated with frequent geriatric syndromes. In recent years, several methods, based on the use of magneto-inertial units (MIMUs), have been developed for the step-by-step estimation of the gait temporal parameters. However, most of them were applied to the gait of healthy subjects and/or of a single pathologic population. Moreover, spatial parameters in pathologic populations have been rarely estimated step-by-step using MIMUs. The validity of clinically suitable MIMU-based methods for the estimation of spatio-temporal parameters is therefore still an open issue. The aim of this study was to propose and validate a method for the determination of both temporal and spatial parameters that could be applied to normal and heavily compromised gait patterns.

Association Between Performance on Timed Up and Go Subtasks and Mild Cognitive Impairment: Further Insights into the Links Between Cognitive and Motor Function

Abstract: OBJECTIVES: To assess whether different Timed Up and Go (TUG) subtasks are affected differently in older adults with mild cognitive impairment (MCI) and are specific to different cognitive abilities. DESIGN: Cross-sectional. SETTING: Community and home. PARTICIPANTS: Older adults without dementia (N = 347; mean age 83.6 3.5, 75% female, 19.3% with MCI) participating in the Rush Memory and Aging Project. MEASUREMENTS: Subjects wore a small, light-weight sensor that measured acceleration and angular velocity while they performed the instrumented TUG (iTUG). Measures of iTUG were derived from four subtasks (walking, turning, sit-to-stand, stand-to-sit) and compared between participants with MCI and those with no cognitive impairment. RESULTS: Participants with no cognitive impairment and those with MCI did not differ in age (P = .90), sex (P = .80), years of education (P = .48) or time to complete

Automated detection of missteps during community ambulation in patients with Parkinson’s disease: a new approach for quantifying fall risk in the community setting

Abstract: Background: Falls are a leading cause of morbidity and mortality among older adults and patients with neurological disease like Parkinson’s disease (PD). Self-report of missteps, also referred to as near falls, has been related to fall risk in patients with PD. We developed an objective tool for detecting missteps under real-world, daily life conditions to enhance the evaluation of fall risk and applied this new method to 3 day continuous recordings. Methods: 40 patients with PD (mean age ± SD: 62.2 ± 10.0 yrs, disease duration: 5.3 ± 3.5 yrs) wore a small device that contained accelerometers and gyroscopes on the lower back while participating in a protocol designed to provoke missteps in the laboratory. Afterwards, the subjects wore the sensor for 3 days as they carried out their routine activities of daily living. An algorithm designed to automatically identify missteps was developed based on the laboratory data and was validated on the 3 days recordings. Results: In the laboratory, we recorded 29 missteps and more than 60 hours of data. When applied to this dataset, the algorithm achieved a 93.1% hit ratio and 98.6% specificity. When we applied this algorithm to the 3 days recordings, patients who reported two falls or more in the 6 months prior to the study (i.e., fallers) were significantly more likely to have a detected misstep during the 3 day recordings (p = 0.010) compared to the non-fallers. Conclusions: These findings suggest that this novel approach can be applied to detect missteps during daily life among patients with PD and will likely help in the longitudinal assessment of disease progression and fall risk.

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes

Abstract: The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.

Validation of a method for real time foot position and orientation tracking with Microsoft Kinect technology for use in virtual reality and treadmill based gait training programs.

Abstract: The use of virtual reality for the provision of motor-cognitive gait training has been shown to be effective for a variety of patient populations. The interaction between the user and the virtual environment is achieved by tracking the motion of the body parts and replicating it in the virtual environment in real time. In this paper, we present the validation of a novel method for tracking foot position and orientation in real time, based on the Microsoft Kinect technology, to be used for gait training combined with virtual reality. The validation of the motion tracking method was performed by comparing the tracking performance of the new system against a stereo-photogrammetric system used as gold standard. Foot position errors were in the order of a few millimeters (average RMSD from 4.9 to 12.1 mm in the medio-lateral and vertical directions, from 19.4 to 26.5 mm in the anterior-posterior direction); the foot orientation errors were also small (average %RMSD from 5.6% to 8.8% in the medio-lateral and vertical directions, from 15.5% to 18.6% in the anterior-posterior direction). The results suggest that the proposed method can be effectively used to track feet motion in virtual reality and treadmill-based gait training programs.

Clinical Experience Using a 5-Week Treadmill Training Program With Virtual Reality to Enhance Gait in an Ambulatory Physical Therapy Service

Abstract: Background Current literature views safe gait as a complex task, relying on motor and cognitive resources. The use of virtual reality (VR) in gait training offers a multifactorial approach, showing positive effects on mobility, balance, and fall risk in elderly people and individuals with neurological disorders. This form of training has been described as a viable research tool; however, it has not been applied routinely in clinical practice. Recently, VR was used to develop an adjunct training method for use by physical therapists in an ambulatory clinical setting. Objective The aim of this article is to describe the initial clinical experience of applying a 5-week VR clinical service to improve gait and mobility in people with a history of falls, poor mobility, or postural instability. Design A retrospective data analysis was conducted. Methods The clinical records of the first 60 patients who completed the VR gait training program were examined. Training was provided 3 times per week for 5 weeks, with each session lasting approximately 1 hour and consisting of walking on a treadmill while negotiating virtual obstacles. Main outcome measures were compared across time and included the Timed “Up & Go” Test (TUG), the Two-Minute Walk Test (2MWT), and the Four Square Step Test (FSST). Results After 5 weeks of training, time to complete the TUG decreased by 10.3%, the distance walked during the 2MWT increased by 9.5%, and performance on the FSST improved by 13%. Limitations Limitations of the study include the use of a retrospective analysis with no control group and the lack of objective cognitive assessment. Conclusions Treadmill training with VR appears to be an effective and practical tool that can be applied in an outpatient physical therapy clinic. This training apparently leads to improvements in gait, mobility, and postural control. It, perhaps, also may augment cognitive and functional aspects.

Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker?

Abstract: Objective Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease (PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated. Methods We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers. Results Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: −3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (−12.8, −9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers. Interpretation Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction.

Can cognitive remediation improve mobility in patients with Parkinson's disease? Findings from a 12 week pilot study.

Abstract: Background Patients with Parkinson's disease (PD) suffer from impaired gait and mobility. These changes in motor function have been associated with cognitive deficits that also commonly co-occur in PD, especially executive function (EF) and attention. Objective We hypothesized that a cognitive remediation program would enhance gait and mobility. Methods The 18 PD patients in this study were assessed at baseline and again one and four weeks after completion of a 12 week long, home-based computerized cognitive training program. Subjects were asked to "play" computer games designed to improve EF and attention for 30 minutes a day, three times per week for 12 weeks, while seated. The Timed Up and Go (TUG), gait speed, and stride time variability quantified mobility. A previously validated, computerized neuropsychological battery quantified global cognitive function and its sub-domains. Results Compared to pre-training values, global cognitive scores and time to complete the TUG significantly improved after the training. TUG components of turning speed and duration also improved. Other TUG components, gait speed, and variability did not change after training. Conclusions These initial findings suggest that computerized cognitive training can improve cognitive function and has a beneficial carryover effect to certain aspects of mobility in patients with PD. Additional studies are required to replicate these findings and more fully assess the underlying mechanisms. Nonetheless, the present results underscore the motor-cognitive link in PD and suggest that computerized cognitive training may be applied as a therapeutic option to enhance mobility in patients with PD.

Associations between quantitative mobility measures derived from components of conventional mobility testing and Parkinsonian gait in older adults.

Abstract: Objective To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait. Methods During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS). Results In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor. Interpretation Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults.

The Contribution of Proprioceptive Information to Postural Control in Elderly and Patients with Parkinson’s Disease with a History of Falls

Abstract: Proprioceptive deficits negatively affect postural control but their precise contribution to postural instability in Parkinson’s disease (PD) is unclear. We investigated if proprioceptive manipulations differentially affect balance, measured by force plates, during quiet standing in 13 PD patients and 13 age-matched controls with a history of falls. Perceived limits of stability (LoS) were derived from the differences between maximal center of pressure (CoP) displacement in anterior-posterior (AP) and medio-lateral (ML) direction during a maximal leaning task. Task conditions comprised standing with eyes open (EO) and eyes closed (EC), (1) on a stable surface; (2) an unstable surface and (3) with Achilles tendon vibration. CoP displacements were calculated as a percentage of their respective LoS. Perceived LoS did not differ between groups. PD patients showed greater ML CoP displacement than elderly fallers (EF) across all conditions (p = 0.043) and tended to have higher postural sway in relation to the LoS (p = 0.050). Both groups performed worse on an unstable surface and during tendon vibration compared to standing on a stable surface with EO and even more so with EC. Both PD and EF had more AP sway in all conditions with EC compared to EO (p < 0.001) and showed increased CoP displacements when relying on proprioception only compared to standing with normal sensory input. This implies a similar role of the proprioceptive system in postural control in fallers with and without PD. PD fallers showed higher ML sway after sensory manipulations disturbing postural control, as a result of which these values approached their perceived LoS more closely than in EF. We conclude that despite a similar fall history, PD patients showed more ML instability than EF, irrespective of sensory manipulation, but had a similar reliance on ankle proprioception. Hence, we recommend that rehabilitation and fall prevention for PD should focus on motor rather than on sensory aspects.

A Voxel-Based Morphometry and Diffusion Tensor Imaging Analysis of Asymptomatic Parkinson's Disease-Related G2019S LRRK2 Mutation Carriers

Abstract: Background: Patients with Parkinson’s disease have reduced gray matter volume and fractional anisotropy in both cortical and sub-cortical structures, yet changes in the pre-motor phase of the disease are unknown. Methods: A comprehensive imaging study using voxelbased morphometry and diffusion tensor imaging tract-based spatial statistics analysis was performed on 64 Ashkenazi Jewish asymptomatic first degree relatives of patients with Parkinson’s disease (30 mutation carriers), who carry the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene. Results: No between-group differences in gray matter volume could be noted in either whole-brain or volume-of-interest analysis. Diffusion tensor imaging analysis did not identify group differences in white matter areas, and volume-of-interest analysis identified no differences in diffusivity parameters in Parkinson’s disease-related structures. Conclusions: G2019S carriers do not manifest changes in gray matter volume or diffusivity parameters in Parkinson’s disease-related structures prior to the appearance of motor symptoms. V C 2014 Interna

Gait Disorders in Patients with Cognitive Impairment or Dementia

Abstract: Cognitive impairment and dementia are common in aging. In recent years, there is a growing body of evidence that suggests that gait is reliant on cognitive function and that gait impairments and falls are affected by a wide spectrum of age-associated changes in cognitive function. Several studies have suggested that gait abnormalities can already be present in the early stages of cognitive decline, even before dementia has been diagnosed. In this chapter, we describe the relationship between gait and cognition as a function of the severity of cognitive decline. We begin with a review of the current understanding of age-associated changes in both cognition and motor function and the interrelation between these domains in older adults. We then review reports on gait changes in mild cognitive impairment, dementia, and Alzheimer’s disease dementia, as well as alterations of motor function throughout the course of cognitive decline. Finally, we summarize information on therapeutic interventions designed to improve gait and reduce fall risk based on the interactions between gait and cognitive function.

Virtual Reality Augmented Training for Improving Walking and Reducing Fall Risk in Patients with Neurodegenerative Disease

Abstract: This chapter presents the common impairments in gait that are fundamental to neurodegenerative diseases and provide examples from studies on aging, Parkinson’s disease, a classical neurodegenerative disease, and multiple sclerosis, an inflammatory progressive disease that involves neuronal loss. Factors that contribute to problems in mobility are discussed along with current treatment approaches. The review of these topics leads to the rationale and potential advantages of VR-based methods for improving walking and mobility in patients with neurodegenerative disease.

Age Specific Penetrance of the LRRK2 G2019S Mutation in the Michael J Fox Ashkenazi Jewish (AJ) LRRK2 Consortium (S17.002)

Abstract: OBJECTIVE: To estimate the penetrance of the G2019S mutation in the M.J. Fox Ashkenazi Jewish (AJ) Consortium. BACKGROUND: Estimates of the penetrance of LRRK2 G2019S vary widely (24-100%).We used the kin cohort method to predict penetrance in 983 relatives of 181 AJ PD cases. Lifetime penetrance to age 80 was 0.262 (95% CI 0.16-0.43) in predicted G2019S+ relatives and 0.06 (0.04-0.95) in wildtype (WT) relatives (Clark 2006). DESIGN/METHODS: PD cases completed a validated family history interview (FHI) for PD, age at onset (AAO) of PD, current age, or age at death for each first-degree relative. The kin-cohort method uses the LRRK2 G2019S mutation status in PD cases to infer unobserved genotypes in relatives and combines this with PD AAO to estimate penetrance of G2019S in relatives. RESULTS: 131 G2019S+ PD probands (40 Beth Israel, 39 Columbia U, and 52 Tel Aviv) and 341 G2019S - (WT) PD probands (94 Beth Israel, 107 Columbia U, and 140 Tel Aviv) completed FHI on 563 relatives predicted to be G2019S+ and 1311 predicted WT. 126 relatives met FHI criteria for PD (56 G2019S+, 70 WT). Cumulative risk was 0.263 (95% CI= 0.158-0.359) in predicted G2019S+ and 0.092 (95% CI=0.064-0.116) in predicted WT relatives; RR 2.87 (95%CI= 1.48-4.70) p<0.001. Risk in predicted G2019S+ parents was 0.279 (0.14-43.9) and 31.3(0.07-0.63) in predicted G109S+ siblings. Cumulative risk in predicted G2019S+ female relatives was 0.279 (95%CI=0.139-0.439) and 0.054 (95%CI=0.028-0.089) in predicted WT female relatives; RR 5.12 (1.88-12.60) p<0.0001. Cumulative risk to age 80 in predicted G2019S+ male relatives was 0.242 (95%CI=0.089-0.422) and 0.133 (95%CI=0.093-0.186) in predicted WT male relatives; RR 1.81 (0.58-3.67) p=0.56. CONCLUSIONS: We confirm that the penetrance of LRRK2 G2019S to age 80 is low in AJ. The relative differences in penetrance in female and male relatives may explain the similar frequency of male and female LRRK2 G2019S PD. Study Supported by: Michael J. Fox Foundation, NIH (NS036630, NS080915, NS050487, NS060113, UL1TR000040), Parkinson9s Disease Foundation Disclosure: Dr. Marder has received personal compensation in an editorial capacity for Current Neuroscience. Dr. Marder has received research support from the National Institutes of Health, Michael J Fox Foundation, Parkinson Disease Foundation, CHDI Foundation, and Huntington9s Disease Soceity of America. Dr. Tang has nothing to disclose. Dr. Alcalay has received personal compensation for activities with Genzyme. Dr. Alcalay has received research support from the National Institutes of Health, Brookdale Foundation, Parkinson9s Disease Foundation, Smart Foundation, and the Michael J Fox Foundation. Dr. Mejia-Santana has nothing to disclose. Dr. Raymond has nothing to disclose. Dr. Mirelman has nothing to disclose. Dr. Saunders-Pullman has nothing to disclose. Dr. Clark has nothing to disclose. Dr. Ozelius has received royalty payments from Athena Diagnostics. Dr. Orr-Urtreger has nothing to disclose. Dr Giladi has received personal compensation for activities with Biogen Idec, Teva Lundbeck, Merz & Co. Inc., UCB Pharma, Intec Pharma, Teva Neuroscience, and NeuroDerm Inc. Dr. Bressman has received a royalty, liscense fee or contractual rights payment from Athena Diagnostics.