Showing papers by "Anat Mirelman published in 2019"

Gait impairments in Parkinson's disease.

Abstract: Summary Gait impairments are among the most common and disabling symptoms of Parkinson's disease. Nonetheless, gait is not routinely assessed quantitatively but is described in general terms that are not sensitive to changes ensuing with disease progression. Quantifying multiple gait features (eg, speed, variability, and asymmetry) under natural and more challenging conditions (eg, dual-tasking, turning, and daily living) enhanced sensitivity of gait quantification. Studies of neural connectivity and structural network topology have provided information on the mechanisms of gait impairment. Advances in the understanding of the multifactorial origins of gait changes in patients with Parkinson's disease promoted the development of new intervention strategies, such as neurostimulation and virtual reality, aimed at alleviating gait impairments and enhancing functional mobility. For clinical applicability, it is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.

Is every-day walking in older adults more analogous to dual-task walking or to usual walking? Elucidating the gaps between gait performance in the lab and during 24/7 monitoring.

Abstract: The traditional evaluation of gait in the laboratory during structured testing has provided important insights, but is limited by its “snapshot” character and observation in an unnatural environment. Wearables enable monitoring of gait in real-world environments over a week. Initial findings show that in-lab and real-world measures differ. As a step towards better understanding these gaps, we directly compared in-lab usual-walking (UW) and dual-task walking (DTW) to daily-living measures of gait. In-lab gait features (e.g., gait speed, step regularity, and stride regularity) derived from UW and DTW were compared to the same gait features during daily-living in 150 elderly fallers (age: 76.5 ± 6.3 years, 37.6% men). In both settings, features were extracted from a lower-back accelerometer. In the real-world setting, subjects were asked to wear the device for 1 week and pre-processing detected 30-s daily-living walking bouts. A histogram of all walking bouts was determined for each walking feature for each subject and then each subject’s typical (percentile 50, median), worst (percentile 10) and the best (percentile 90) values over the week were determined for each feature. Statistics of reliability were assessed using Intra-Class correlations and Bland-Altman plots. As expected, in-lab gait speed, step regularity, and stride regularity were worse during DTW, compared to UW. In-lab gait speed, step regularity, and stride regularity during UW were significantly higher (i.e., better) than the typical daily-living values (p < 0.001) and different (p < 0.001) from the worst and best values. DTW values tended to be similar to typical daily-living values (p = 0.205, p = 0.053, p = 0.013 respectively). ICC assessment and Bland-Altman plots indicated that in-lab values do not reliably reflect the daily-walking values. Gait values measured during relatively long (30-s) daily-living walking bouts are more similar to the corresponding values obtained in the lab during dual-task walking, as compared to usual walking. Still, gait performance during most daily-living walking bouts is worse than that measured during usual and dual-tasking in the lab. The values measured in the lab do not reliably reflect daily-living measures. That is, an older adult’s typical daily-living gait cannot be estimated by simply measuring walking in a structured, laboratory setting.

Analysis of Free-Living Gait in Older Adults With and Without Parkinson's Disease and With and Without a History of Falls: Identifying Generic and Disease-Specific Characteristics.

Abstract: Background - Falls are associated with gait impairments in older adults (OA) and Parkinson’s disease (PD). Current approaches for evaluating falls risk are based on self-report or one-time assessment and may be suboptimal. Wearable technology allows gait to be measured continuously in free-living conditions. The aim of this study was to explore generic and specific associations in free-living gait in fallers and nonfallers with and without PD. Methods - Two hundred and seventy-seven fallers (155 PD, 122 OA) who fell twice or more in the previous 6 months and 65 nonfallers (15 PD, 50 OA) were tested. Free-living gait was characterized as the volume, pattern, and variability of ambulatory bouts (Macro), and 14 discrete gait characteristics (Micro). Macro and Micro variables were quantified from free-living data collected using an accelerometer positioned on the low back for one week. Results - Macro variables showed that fallers walked with shorter and less variable ambulatory bouts than nonfallers, independent of pathology. Micro variables within ambulatory bouts showed fallers walked with slower, shorter and less variable steps than nonfallers. Significant interactions showed disease specific differences in variability with PD fallers demonstrating greater variability (step length) and OA fallers less variability (step velocity) than their nonfaller counterparts (p < 0.004). Conclusions - Common and disease-specific changes in free-living Macro and Micro gait highlight generic and selective targets for intervention depending on type of faller (OA-PD). Our findings support free-living monitoring to enhance assessment. Future work is needed to confirm the optimal battery of measures, sensitivity to change and value for fall prediction.

Home monitoring of sleep with a temporary-tattoo EEG, EOG and EMG electrode array: a feasibility study

Abstract: Objective Circadian and sleep dysfunction have long been symptomatic hallmarks of a variety of devastating neurodegenerative conditions. The gold standard for sleep monitoring is overnight sleep in a polysomnography (PSG) laboratory. However, this method has several limitations such as availability, cost and being labour-intensive. In recent years there has been a heightened interest in home-based sleep monitoring via wearable sensors. Our objective was to demonstrate the use of printed electrode technology as a novel platform for sleep monitoring. Approach Printed electrode arrays offer exciting opportunities in the realm of wearable electrophysiology. In particular, soft electrodes can conform neatly to the wearer's skin, allowing user convenience and stable recordings. As such, soft skin-adhesive non-gel-based electrodes offer a unique opportunity to combine electroencephalography (EEG), electromyography (EMG), electrooculography (EOG) and facial EMG capabilities to capture neural and motor functions in comfortable non-laboratory settings. In this investigation temporary-tattoo dry electrode system for sleep staging analysis was designed, implemented and tested. Main results EMG, EOG and EEG were successfully recorded using a wireless system. Stable recordings were achieved both at a hospital environment and a home setting. Sleep monitoring during a 6 h session shows clear differentiation of sleep stages. Significance The new system has great potential in monitoring sleep disorders in the home environment. Specifically, it may allow the identification of disorders associated with neurological disorders such as rapid eye movement (REM) sleep behavior disorder.

Virtual reality training to enhance behavior and cognitive function among children with attention-deficit/hyperactivity disorder: brief report

Abstract: Purpose: To examine the feasibility and efficacy of a combined motor-cognitive training using virtual reality to enhance behavior, cognitive function and dual-tasking in children with Atten...

Deterioration of specific aspects of gait during the instrumented 6-min walk test among people with multiple sclerosis.

Abstract: Prolonged walking is typically impaired among people with multiple sclerosis (pwMS), however, it is unclear what the contributing factors are or how to evaluate this deterioration. We aimed to determine which gait features become worse during sustained walking and to examine the clinical correlates of gait fatigability in pwMS. Fifty-eight pwMS performed the 6-min walk test while wearing body-fixed sensors. Multiple gait domains (e.g., pace, rhythm, variability, asymmetry and complexity) were compared across each minute of the test and between mild- and moderate-disability patient groups. Associations between the decline in gait performance (i.e., gait fatigability) and patient-reported gait disability, fatigue and falls were also determined. Cadence, stride time variability, stride regularity, step regularity and gait complexity significantly deteriorated during the test. In contrast, somewhat surprisingly, gait speed and swing time asymmetry did not change. As expected, subjects with moderate disability (n = 24) walked more poorly in most gait domains compared to the mild-disability group (n = 34). Interestingly, a group × fatigue interaction effect was observed for cadence and gait complexity; these measures decreased over time in the moderate-disability group, but not in the mild group. Gait fatigability rate was significantly correlated with physical fatigue, gait disability, and fall history. These findings suggest that sustained walking affects specific aspects of gait, which can be used as markers for fatigability in MS. This effect on gait depends on the degree of disability, and may increase fall risk in pwMS. To more fully understand and monitor correlates that reflect everyday walking in pwMS, multiple domains of gait should be quantified.

Using wearables to assess bradykinesia and rigidity in patients with Parkinson’s disease: a focused, narrative review of the literature

Abstract: The potential of using wearable technologies for the objective assessment of motor symptoms in Parkinson's disease (PD) has gained prominence recently. Nonetheless, compared to tremor and gait impairment, less emphasis has been placed on the quantification of bradykinesia and rigidity. This review aimed to consolidate the existing research on objective measurement of bradykinesia and rigidity in PD through the use of wearables, focusing on the continuous monitoring of these two symptoms in free-living environments. A search of PubMed was conducted through a combination of keyword and MeSH searches. We also searched the IEEE, Google Scholar, Embase, and Scopus databases to ensure thorough results and to minimize the chances of missing relevant studies. Papers published after the year 2000 with sample sizes greater than five were included. Studies were assessed for quality and information was extracted regarding the devices used and their location on the body, the setting and duration of the study, the "gold standard" used as a reference for validation, the metrics used, and the results of each paper. Thirty-one and eight studies met the search criteria and evaluated bradykinesia and rigidity, respectively. Several studies reported strong associations between wearable-based measures and the gold-standard references for bradykinesia, and, to a lesser extent, rigidity. Only a few, pilot studies investigated the measurement of bradykinesia and rigidity in the home and free-living settings. While the current results are promising for the future of wearables, additional work is needed on their validation and adaptation in ecological, free-living settings. Doing so has the potential to improve the assessment and treatment of motor fluctuations and symptoms of PD more generally through real-time objective monitoring of bradykinesia and rigidity.

Differential Associations Between Distinct Components of Cognitive Function and Mobility: Implications for Understanding Aging, Turning and Dual-Task Walking.

Abstract: Objective: Cognition and mobility are interrelated. However, this association can be impacted by the specific facets of cognition and mobility that are measured, and further by the different task conditions, single- versus dual-task walking, under which these associations are evaluated. Systematically studying the multiple facets of cognitive-mobility associations under both the task conditions is critical because both cognition and mobility change with age and pose significant risks associated with falls, morbidity, and disability. Methods: Using a cross-sectional, prospective study design, data from 124 healthy adults (mean age (SD) = 61.51 (11.90); mean education (SD) = 15.94 (2.18)) was collected. A comprehensive battery of cognitive tests was administered, and gait was assessed using a small, lightweight, three-axis accelerometer with a gyroscope. Analytical Plan: Data was transformed, and only relatively strong relationships survived after strict statistical criteria adjusting for multiple comparisons was applied. Spearman rho correlation coefficients were used to examine the matrix of correlations between the cognitive-motor variables while adjusting for age and gender. Results: Executive functions, processing speed, and language were associated with distinct facets of variability, pace, asymmetry, especially under the dual-task walking condition. Both turns and transitions were also associated with cognition during the Timed Up and Go task. Conclusion: Our results extend converging evidence for the involvement of executive functions and processing speed in specific aspects of mobility, along with the role of language. The study has important implications for aging in terms of both assessment and rehabilitation of cognition and gait as well as for the emerging dual-tasking theories and the role of the neural pathways involved in mobility.

A Multimodal Training Modulates Short Afferent Inhibition and Improves Complex Walking in a Cohort of Faller Older Adults With an Increased Prevalence of Parkinson's Disease.

Abstract: BACKGROUND Falls are frequent in Parkinson's disease and aging. Impairments in the cholinergic-mediated attentional supervision of gait may contribute to increased fall risk, especially when obstacles challenge gait. Interventions combining motor-cognitive approaches have been shown to improve motor performance, cognitive skills, and falls number. Here, we hypothesized that an intervention simulating an attention-demanding walking condition could affect not only complex gait performance and fall risk but also short-latency afferent inhibition (SAI), as a marker of cholinergic activity. METHODS Thirty-nine participants at falls risk (24 Parkinson's disease participants and 15 older adults) were recruited in a randomized controlled trial. Participants were assigned to treadmill training or treadmill training with non-immersive virtual reality intervention and trained three times a week for 6 weeks. SAI, a transcranial magnetic stimulation paradigm, was used to assess cholinergic activity. Gait kinematics was measured during usual walking and while negotiating physical obstacles. Transcranial magnetic stimulation and gait assessments were performed pre, post, and 6 months post-intervention. RESULTS Treadmill training combined with non-immersive virtual reality induced an increase in inhibition of the SAI protocol on cortical excitability, improved obstacle negotiation performance, and induced a reduction of the number of falls compared with treadmill training. Furthermore, the more SAI increased after training, the more the obstacle negotiation performance improved and fall rate decreased. CONCLUSIONS We provide evidence that an innovative rehabilitation approach targeting cognitive components of complex motor actions can induce changes in cortical cholinergic activity, as indexed by SAI, thereby enabling functional gait improvements.

Altered reward-related neural responses in non-manifesting carriers of the Parkinson disease related LRRK2 mutation.

Abstract: Disturbances in reward processing occur in Parkinson’s disease (PD) however it is unclear whether these are solely drug-related. We applied an event-related fMRI gambling task to a group of non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene, in order to assess the reward network in an “at risk” population for future development of PD. Sixty-eight non-manifesting participants, 32 of which were non-manifesting non-carriers (NMNC), performed a gambling task which included defined intervals of anticipation and response to both reward and punishment in an fMRI setup. Behavior and cerebral activations were measured using both hypothesis driven and whole brain analysis. NMC demonstrated higher trait anxiety scores (p = 0.04) compared to NMNC. Lower activations were detected among NMC during risky anticipation in the left nucleus accumbens (NAcc) (p = 0.05) and during response to punishment in the right insula (p = 0.02), with higher activations among NMC during safe anticipation in the right insula (p = 0.02). Psycho-Physiological Interaction (PPI) analysis from the NAcc and insula revealed differential connectivity patterns. Whole brain analysis demonstrated divergent between-group activations in distributed cortical regions, bilateral caudate, left midbrain, when participants were required to press the response button upon making their next chosen move. Abnormal neural activity in both the reward and motor networks were detected in NMC indicating involvement of the ventral striatum regardless of medication use in “at risk” individuals for future development of PD.

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

Abstract: BACKGROUND Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

Network abnormalities among non-manifesting Parkinson disease related LRRK2 mutation carriers

Abstract: Non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an "at risk" group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting-state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (DEP NA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty-four NMC and 41 non-manifesting non-carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non-motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non-motor cerebral changes among populations "at risk" for future development of PD.

Hierarchical Data-Driven Analysis of Clinical Symptoms Among Patients With Parkinson's Disease.

Abstract: Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; p-values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.

Pace of movement: the role of single neurons in the subthalamic nucleus

Abstract: OBJECTIVEThe ability to modulate the pace of movement is a critical factor in the smooth operation of the motor system. The authors recently described distinct and overlapping representations of movement kinematics in the subthalamic nucleus (STN), but it is still unclear how movement pace is modulated according to the demands of the task at the neuronal level in this area. The goal of this study was to clarify how different movement paces are being controlled by neurons in the STN.METHODSThe authors performed direct recording of the electrical activity of single neurons in the STN of neurosurgical patients with Parkinson’s disease undergoing implantation of a deep brain stimulator under local anesthesia while the patients performed repetitive foot and hand movements intraoperatively at multiple paces.RESULTSA change was observed in the neuronal population controlling the movement for each pace. The mechanism for switching between these controlling populations differs for hand and foot movements.CONCLUSIO...

Distinguishing Dementia With Lewy Bodies From Alzheimer Disease: What is the Influence of the GBA Genotype in Ashkenazi Jews?

Abstract: Cognitive deficits beyond memory impairment, such as those affecting language production or executive functioning, can be useful in clinically distinguishing between dementia syndromes. We tested the hypothesis that Ashkenazi Jewish (AJ) patients who have dementia with Lewy bodies (DLB) and carry glucocerebrosidase (GBA) mutations will have verbal fluency deficits different from those found in Alzheimer disease (AD), whereas AJ patients with DLB who have no GBA mutations will have similar deficits in verbal fluency to those found in AD. We compared performance in phonemic and semantic verbal fluency tasks in 44 AJ patients with DLB and 20 patients with AD, matched for age, education, and age of immigration. All groups were found to have a deficit in semantic verbal fluency. On conducting the phonemic task, patients with DLB who carried GBA mutations scored more poorly than patients with AD, whereas DLB-noncarriers performed similarly to patients with AD. We suggest that verbal fluency tasks could serve as a possible clinical marker to subtype patients with DLB, with phonemic fluency being a marker for GBA-associated DLB.

Automatic quantification of tandem walking using a wearable device: validity of the instrumented tandem walk

Abstract: Abstract Tandem walk (TW) is typically assessed by the time to complete the task and the number of missteps, however, these measures suffer from limitations and may not fully capture the range of performance in this task. We developed metrics of TW by using a body-fixed, wearable sensor in young and older adults. Healthy young men (n=40) and older adult men (n=362) were studied. While wearing a 3D accelerometer on their lower back, subjects performed three different tasks: TW, usual-walking, and quiet standing. The extracted measures for TW were: High-to-Low frequency band ratio from the power spectral density from the ML axis [nu], signal vector magnitude[g], step duration[s], sample entropy from ML, AP axis[nu] and CV[%]. All of the TW metrics were significantly different in the young and older men (p<0.001). Older men completed the TW with higher CV, suggesting greater stride-to-stride variability and they walked more slowly, as seen by their step duration. Additionally, the frequency ratio measure suggests that the older adults displayed less complex corrective movements in the ML axis. TW measures were modestly correlated with usual-walking (e.g., average stride time with TW step time, r=0.3; p<0.001) and with quiet standing postural control (e.g., acceleration path length in the ML and AP axis with TW sample entropy in the ML axis, r=0.13; p=0.014). Metrics derived from a wearable device complement conventional TW measures and vary with age. Further work is needed to determine if TW, gait and posture metrics are differentially associated with distinct adverse health outcomes.

Evidence for increased completed suicide in first-degree relatives of LRRK2 G2019S mutation Parkinson's disease.

Abstract: Mutations in the l eucine-rich repeat kinase 2 ( LRRK2 ) gene are an important monogenic cause of Parkinson’s disease (PD). Reported non-motor features of LRRK2 PD include depression, anxiety and bipolar disorder,1 but suicide has not been systematically investigated. As part of our LRRK2 Ashkenazi Jewish Consortium study we assessed the history of death by suicide in probands and first-degree relatives with and without LRRK2 G2019S mutations. The sample comprised participants from the Ashkenazi Jewish LRRK2 Consortium study sites in Tel Aviv (Tel Aviv Medical Center) and New York (Columbia University Irving Medical Center and Mount Sinai Beth Israel).2 PD probands were screened for the LRRK2 G2019S mutation.3 Genetic status of the first-degree relatives was not known. Questionnaire and pedigree information was systematically collected on LRRK2 PD and non- LRRK2 mutation, idiopathic PD (IPD) probands, and evaluated for suicide as cause of death among first-degree relatives. The odds of suicide among first-degree relatives was compared using a logistic generalised estimating equation, accounting for family membership, site and sex using Stata V.14 (StataCorp, 2015, Stata Statistical Software: Release 14. College Station, TX). No LRRK2 PD or IPD was known to commit suicide during the course of the study. (Study follow-up ranged from 0 to 5 years, and the mean duration among those with at least one follow-up visit was 3.4 years). LRRK2 PD probands were more likely to report a death in a first-degree …