Progressive Gait Deficits in Parkinson’s Disease: A Wearable-Based Biannual 5-Year Prospective Study

Background: Gait changes occur during all Parkinson’s disease (PD) stages and wearable sensor-derived gait parameters may quantify PD progression. However, key aspects that may qualify quantitative gait parameters as progression markers in PD remain elusive.Objectives: Longitudinal changes in gait parameters from a lower-back sensor under convenient and challenging walking conditions in early- and mid-stage PD patients (E-PD, M-PD) compared to controls were investigated.Methods: Normal- and fast-pace parameters (step: number, time, velocity, variability) were assessed every 6 months for up to 5 years in 22 E-PD (<4 years baseline disease duration), 18 M-PD (>5 years) and 24 controls. Parameter trajectories and associations with MDS-UPDRS-III were tested using generalized estimating equations.Results: Normal-pace step number (annual change in E-PD: 2.1%, Time∗Group: p = 0.001) and step time variability (8.5%, p < 0.05) longitudinally increased in E-PD compared to controls (0.7%, -12%). For fast pace, no significant progression differences between groups were observed. Longitudinal changes in M-PD did not differ significantly from controls. MDS-UPDRS-III was largely associated with normal-pace parameters in M-PD.Conclusion: Wearables can quantify progressive gait deficits indicated by increasing step number and step time variability in E-PD. In M-PD, and for fast-pace, gait parameters possess limited potential as PD progression markers

Distinct Relationship Between Cognitive Flexibility and White Matter Integrity in Individuals at Risk of Parkinson’s Disease

Background and Objective: Executive dysfunction is the most common cognitive impairment in Parkinson’s disease (PD), occurring even in its early stages. In our study, we applied diffusion tensor imaging (DTI) to investigate white matter integrity and its association with a specific executive function such as cognitive flexibility in individuals with risk factors for PD. Methods: We examined 50 individuals with risk factors for developing PD and 24 healthy controls from the TREND (Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration) study including neuropsychological evaluation and DTI. Cognitive flexibility was assessed using the trail making test (TMT). Tract based spatial statistics (TBSS) were employed to assess white matter abnormalities and their correlation with cognitive flexibility. Results: TMT performance correlated with mean and axial diffusivity in several white matter regions, predominantly in the frontoparietal white matter. These effects were stronger in PD risk persons (PD-RP) than in controls as evidenced by a significant group interaction. White matter integrity and TMT performance did not significantly differ across groups. Conclusion: Based on our results, PD-RP do no exhibit white matter changes or impaired cognitive flexibility. However, specific executive functions in PD-RP are more related to white matter alterations than in healthy older adults

Gait decline while dual-tasking is an early sign of white matter deterioration in middle-aged and older adults

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.e., degeneration of shared brain regions. In this study, we applied diffusion tensor imaging (DTI) and a standardized gait assessment under single- and dual-tasking (DT) conditions (walking and subtracting) in 74 middle-aged and older adults without any significant gait or cognitive impairments to detect subtle WM alterations associated with gait decline under DT conditions. Additionally, the Trail Making Test (TMT) was used to assess EF, classify participants into three groups based on their performance, and examine a possible interaction between gait, EF, and WMI. Gait speed and subtracting speed while dual-tasking correlated significantly with the fractional anisotropy (FA) in the bilateral anterior corona radiata (highest r = 0.51/p < 0.0125 FWE-corrected). Dual-task costs (DTC) of gait speed correlated significantly with FA in widespread pathways, including the corpus callosum, bilateral anterior and superior corona radiata, as well as the left superior longitudinal fasciculus (highest r = −0.47/p < 0.0125 FWE-corrected). EF performance was associated with FA in the left anterior corona radiata (p < 0.05); however, EF did not significantly mediate the effects of WMI on DTC of gait speed. There were no significant correlations between TMT and DTC of gait and subtracting speed, respectively. Our findings indicate that gait decline under DT conditions is associated with widespread WM deterioration even in middle-aged and older adults without any significant gait or cognitive impairments

Mobility Deficits Assessed With Mobile Technology: What Can We Learn From Brain Iron-Altered Animal Models?

Background: Recent developments in mobile technology have enabled the investigation of human movements and mobility under natural conditions, i.e., in the home environment. Iron accumulation in the basal ganglia is deleterious in Parkinson's disease (i.e., iron accumulation with lower striatal level of dopamine). The effect of iron chelation (i.e., re-deployment of iron) in Parkinson's disease patients is currently tested in a large investigator-initiated multicenter study. Conversely, restless legs syndrome (RLS) is associated with iron depletion and higher striatal level of dopamine. To determine from animal models which movement and mobility parameters might be associated with iron content modulation and the potential effect of therapeutic chelation inhuman. Methods: We recapitulated pathophysiological aspects of the association between iron, dopamine, and neuronal dysfunction and deterioration in the basal ganglia, and systematically searched PubMed to identify original articles reporting about quantitatively assessed mobility deficits in animal models of brain iron dyshomeostasis. Results: We found six original studies using murine and fly models fulfilling the inclusion criteria. Especially postural and trunk stability were altered in animal models with iron overload. Animal models with lowered basal ganglia iron suffered from alterations in physical activity, mobility, and sleep fragmentation. Conclusion: From preclinical investigations in the animal model, we can deduce that possibly also in humans with iron accumulation in the basal ganglia undergoing therapeutic chelation may primarily show changes in physical activity (such as daily "motor activity"), postural and trunk stability and sleep fragmentation. These changes can readily be monitored with currently available mobile technology

Limited Effect of Dopaminergic Medication on Straight Walking and Turning in Early-to-Moderate Parkinson’s Disease during Single and Dual Tasking

Background: In Parkinson’s disease (PD), the effects of dopaminergic medication on straight walking and turning were mainly investigated under single tasking (ST) conditions. However, multitasking situations are considered more daily relevant.Methods: Thirty-nine early to moderate PD patients performed the following standarized ST and dual tasks (DT) as fast as possible for one minute during On- and Off-medication while wearing inertial sensors: straight walking and turning, checking boxes, and subtracting serial 7s. Quantitative gait parameters, as well as velocity of the secondary tasks were analyzed.Results: The following parameters improved significantly in On-medication during ST: gait velocity during straight walking (p=0.03); step duration (p=0.048) and peak velocity (p=0.04) during turning; velocity of checking boxes during ST (p=0.04) and DT (p=0.04). Velocity of checking boxes was the only parameter that also improved during DT.Conclusion: These results suggest that dopaminergic medication does not relevantly influence straight walking and turning in early to moderate PD during DT

White Matter Changes-Related Gait and Executive Function Deficits: Associations with Age and Parkinson's Disease

Background: White matter changes (WMC) are a common finding among older adults and patients with Parkinson's disease (PD), and have been associated with, e.g., gait deficits and executive dysfunction. How the factors age and PD influence WMC-related deficits is, to our best knowledge, not investigated to date. We hypothesized that advanced age and presence of PD leads to WMC-related symptoms while practicing tasks with a low complexity level, and low age and absence of PD leads to WMC-related symptoms while practicing tasks with a high complexity level.Methods: Hundred and thirty-eight participants [65 young persons without PD (50–69 years, yPn), 22 young PD patients (50–69 years, yPD), 36 old persons without PD (70–89 years, oPn) and 15 old PD patients (70–89 years, oPD)] were included. Presence and severity of WMC were determined with the modified Fazekas score. Velocity of walking under single and dual tasking conditions and the Trail Making Test (TMT) were used as gait and executive function parameters. Correlations between presence and severity of WMC, and gait and executive function parameters were tested in yPn, yPD, oPn, and oPD using Spearman's rank correlation, and significance between groups was evaluated with Fisher's z-transformed correlation coefficient.Results: yPn and yPD, as well as oPn and oPD did not differ regarding demographic and clinical parameters. Severity of WMC was not significantly different between groups. yPn and yPD displayed significant correlations of WMC with executive function parameters at low levels of task complexity, oPn at intermediate, and oPD at high complexity levels.Conclusion: This study argues for a relevant association of age and PD-related brain pathology with WMC-related gait and executive function deficits

New methods for the assessment of Parkinson’s Disease (2005 to 2015): a systematic review

"BACKGROUND: The past decade has witnessed a highly dynamic and growing expansion of novel methods aimed at improving the assessment of Parkinson's disease with technology (NAM-PD) in laboratory, clinical, and home environments. However, the current state of NAM-PD regarding their maturity, feasibility, and usefulness in assessing the main PD features has not been systematically evaluated. METHODS: A systematic review of articles published in the field from 2005 to 2015 was performed. Of 9,503 publications identified in PubMed and the Web of Science, 848 full papers were evaluated, and 588 original articles were assessed to evaluate the technological, demographic, clinimetric, and technology transfer readiness parameters of NAM-PD. RESULTS: Of the studies, 65% included fewer than 30 patients, < 50% employed a standard methodology to validate diagnostic tests, 8% confirmed their results in a different dataset, and 87% occurred in a clinic or lab. The axial features domain was the most frequently studied, followed by bradykinesia. Rigidity and nonmotor domains were rarely investigated. Only 6% of the systems reached a technology level that justified the hope of being included in clinical assessments in a useful time period. CONCLUSIONS: This systematic evaluation provides an overview of the current options for quantitative assessment of PD and what can be expected in the near future. There is a particular need for standardized and collaborative studies to confirm the results of preliminary initiatives, assess domains that are currently underinvestigated, and better validate the existing and upcoming NAM-PD. © 2016 International Parkinson and Movement Disorder Society."Funding agency: The research leading to these results has received funding from “Consejería de Educación, Juventud y Deporte of Comunidad de Madrid” and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA Grant 291820.info:eu-repo/semantics/acceptedVersio

TUG Test Instrumentation for Parkinson’s disease patients using Inertial Sensors and Dynamic Time Warping

The Timed Up and Go (TUG) test is a clinical tool widely used to evaluate balance and mobility, e.g. in Parkinson’s disease (PD). This test includes a sequence of functional activities, namely: sit-to-stand, 3-meters walk, 180° turning, walk back, and turn-to-sit. The work introduces a new method to instrument the TUG test using a wearable inertial sen-sor unit (DynaPort Hybrid, McRoberts B.V., NL) attached on the lower back of the person. It builds on Dynamic Time Warping (DTW) for detection and duration assessment of associated state transitions. An automatic assessment to sub-stitute a manual evaluation with visual observation and a stopwatch is aimed at to gain objective information about the patients. The algorithm was tested on data of 10 healthy individuals and 20 patients with Parkinson's disease (10 pa-tients for early and late disease phases respectively). The algorithm successfully extracted the time information of the sit-to-stand, turn and turn-to-sit transitions

In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin

Acknowledgements Samples were obtained from the Neuro Biobank of the University of Tuebingen, Germany (http://www.hih-tuebingen.de/nd/biobank/for-researchers/). This biobank is supported by the Hertie Institute and the DZNE. We are grateful to the staff of the Medical Research Facility for their help with the animal care. We thank Dr. Kinnari Sathe for her help with the experiments. We thank Claire A. Walker for assisting with western blot analysis. This study was supported by: Tenovus Scotland, Parkinson's Disease Foundation, Royal Society 2006/R1, NHS Endowment 14-42, and Wellcome Trust WT080782MF.Peer reviewedPublisher PD

Additive Effect of Dopaminergic Medication on Gait Under Single and Dual-Tasking Is Greater Than of Deep Brain Stimulation in Advanced Parkinson Disease With Long-duration Deep Brain Stimulation.

INTRODUCTION: Patients with advanced Parkinson disease (PD) often experience problems with mobility, including walking under single- (ST) and dual-tasking (DT) conditions. The effects of deep brain stimulation in the subthalamic nucleus (DBS) versus dopaminergic medication (Med) on these conditions are not well investigated. MATERIALS AND METHODS: We used two ST and two DT-gait paradigms to evaluate the effect of DBS and dopaminergic medication on gait parameters in 14 PD patients (mean age 66 ± 8 years) under DBS(OFF)/Med(ON), DBS(ON)/Med(OFF), and DBS(ON)/Med(ON) conditions. They performed standardized 20-meter walks with convenient and fast speed. To test DT capabilities, they performed a checking-boxes and a subtraction task during fast-paced walking. Quantitative gait analysis was performed using a tri-axial accelerometer (Dynaport, McRoberts, The Netherlands). Dual-task costs (DTC) of gait parameters and secondary task performance were compared intraindividually between DBS(OFF)/Med(ON) vs DBS(ON)/Med(ON), and DBS(ON)/Med(OFF) vs DBS(ON)/Med(ON) to estimate responsiveness. RESULTS: Dopaminergic medication increased gait speed and cadence at convenient speed. It increased cadence and decreased number of steps at fast speed, and improved DTC of cadence during the checking boxes and DTC of cadence and number of steps during the subtraction tasks. DBS only improved DTC of cadence during the checking boxes and DTC of gait speed during the subtraction task. CONCLUSION: Dopaminergic medication showed larger additional effects on temporal gait parameters under ST and DT conditions in advanced PD than DBS. These results, after confirmation in independent studies, should be considered in the medical management of advanced PD patients with gait and DT deficits