Time- and frequency-domain parameters of heart rate variability and sympathetic skin response in Parkinson's disease.

The autonomic nervous system (ANS) is regularly affected in Parkinson's disease (PD). Information on autonomic dysfunction can be derived from e.g. altered heart rate variability (HRV) and sympathetic skin response (SSR). Such parameters can be quantified easily and measured repeatedly which might be helpful for evaluating disease progression and therapeutic outcome. In this 2-center study, HRV and SSR of 45 PD patients and 26 controls were recorded. HRV was measured during supine metronomic breathing and analyzed in time- and frequency-domains. SSR was evoked by repetitive auditory stimulation. Various ANS parameters were compared (1) between patients and healthy controls, (2) to clinical scales (Unified Parkinson's disease rating scale, Mini-Mental State Examination, Becks Depression Inventory), and (3) to disease duration. Root mean square of successive differences (RMSSD) and low frequency/high frequency (LF/HF) ratio differed significantly between PD and controls. Both, HRV and SSR parameters showed low or no association with clinical scores. Time-domain parameters tended to be affected already at early PD stages but did not consistently change with longer disease duration. In contrast, frequency-domain parameters were not altered in early PD phases but tended to be lower (LF, LF/HF ratio), respectively higher (HF) with increasing disease duration. This report confirms previous results of altered ANS parameters in PD. In addition, it suggests that (1) these ANS parameters are not relevantly associated with motor, behavioral, and cognitive changes in PD, (2) time-domain parameters are useful for the assessment of early PD, and (3) frequency-domain parameters are more closely associated with disease duration.

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.

Potential Markers of Progression in Idiopathic Parkinson's Disease Derived From Assessment of Circular Gait With a Single Body-Fixed-Sensor: A 5 Year Longitudinal Study.

Background and Aim: Development of objective, reliable and easy-to-use methods to obtain progression markers of Parkinson's disease (PD) is required to evaluate interventions and to advance research in PD. This study aimed to provide quantitative markers of progression in idiopathic PD from the assessment of circular gait (walking in circles) with a single body-fixed inertial sensor placed on the lower back. Methods: The assessments were performed every 6 months over a (up to) 5 years period for 22 patients in early-stage PD, 27 patients in middle-stage PD and 25 healthy controls (HC). Longitudinal changes of 24 gait features extracted from accelerometry were compared between PD groups and HCs with generalized estimating equations (GEE) analysis, accounting for gait speed, age and levodopa medication state confounders when required. Results: Five gait features indicated progressive worsening in early stages of PD: number of steps, total duration and harmonic ratios calculated from vertical (VT), medio-lateral (ML), and anterior-posterior (AP) accelerations. For middle stages of PD, three gait features were identified as potential progression markers: stride time variability, and stride regularity from VT and AP acceleration. Conclusion: Faster progressive worsening of gait features in early and middle stages of PD relative to healthy controls over 5 years confirmed the potential of accelerometry-based assessments as quantitative progression markers in early and middle stages of the disease. The difference in significant parameters between both PD groups suggests that distinct domains of gait deteriorate in these PD stages. We conclude that instrumented circular walking assessment is a practical and useful tool in the assessment of PD progression that may have relevant potential to be implemented in clinical trials and even clinical routine, particularly in a developing digital era.

Dual vs. Single Tasking During Circular Walking: What Better Reflects Progression in Parkinson's Disease?

Background and Aim: Reliable, valid and sensitive measures of dual-task-associated impairments in patients with Parkinson's disease (PD) may reveal progressive deficits unnoticed under single-task walking. The aim of this study was to quantitatively identify markers of progressive gait deficits in idiopathic PD while walking over a circular trajectory condition in single-task walking and in different dual-task conditions: (1) circular walking while checking boxes on a paper sheet as fast as possible and (2) circular walking while performing subtraction of 7 as fast as possible. In addition, we aimed to study the added value of dual-tasking assessment over single (circular) walking task assessment in the study of PD progression. Methods: The assessments were performed every 6 months over a (up to) 5 years period for 22 patients in early-stage PD, 27 patients in middle-stage PD and 25 healthy controls (HC). Longitudinal changes of 27 gait features extracted from accelerometry were compared between PD groups and HCs using generalized estimating equations analysis, accounting for gait speed, age, and levodopa medication state confounders when required. In addition, dual-task-interference with gait and cognitive performance was assessed, as well as their combination. Results: The results support the validity and robustness of some of the gait features already identified in our previous work as progression markers of the disease in single-task circular walking. However, fewer gait features from dual-task than from single-task assessments were identified as markers of progression in PD. Moreover, we did not clearly identify progressive worsening of dual-task-interference in patients with PD, although some group differences between early and middle stages of PD vs. the control group were observed for dual-task interference with the gait task and with the concurrent tasks. Conclusions: Overall, the results showed that dual-tasking did not have added value in the study of PD progression from circular gait assessments. Our analyses suggest that, while single-task walking might be sensitive enough, dual-tasking may introduce additional (error) variance to the data and may represent complex composite measures of cognitive and motor performance.

Algorithm for Turning Detection and Analysis Validated under Home-Like Conditions in Patients with Parkinson's Disease and Older Adults using a 6 Degree-of-Freedom Inertial Measurement Unit at the Lower Back.

INTRODUCTION: Aging and age-associated disorders such as Parkinson's disease (PD) are often associated with turning difficulties, which can lead to falls and fractures. Valid assessment of turning and turning deficits specifically in non-standardized environments may foster specific treatment and prevention of consequences. METHODS: Relative orientation, obtained from 3D-accelerometer and 3D-gyroscope data of a sensor worn at the lower back, was used to develop an algorithm for turning detection and qualitative analysis in PD patients and controls in non-standardized environments. The algorithm was validated with a total of 2,304 turns ≥90° extracted from an independent dataset of 20 PD patients during medication ON- and OFF-conditions and 13 older adults. Video observation by two independent clinical observers served as gold standard. RESULTS: In PD patients under medication OFF, the algorithm detected turns with a sensitivity of 0.92, a specificity of 0.89, and an accuracy of 0.92. During medication ON, values were 0.92, 0.78, and 0.83. In older adults, the algorithm reached validation values of 0.94, 0.89, and 0.92. Turning magnitude (difference, 0.06°; SEM, 0.14°) and duration (difference, 0.004 s; SEM, 0.005 s) yielded high correlation values with gold standard. Overall accuracy for direction of turning was 0.995. Intra class correlation of the clinical observers was 0.92. CONCLUSION: This wearable sensor- and relative orientation-based algorithm yields very high agreement with clinical observation for the detection and evaluation of ≥90° turns under non-standardized conditions in PD patients and older adults. It can be suggested for the assessment of turning in daily life.

Validation of a Step Detection Algorithm during Straight Walking and Turning in Patients with Parkinson's Disease and Older Adults Using an Inertial Measurement Unit at the Lower Back.

INTRODUCTION: Inertial measurement units (IMUs) positioned on various body locations allow detailed gait analysis even under unconstrained conditions. From a medical perspective, the assessment of vulnerable populations is of particular relevance, especially in the daily-life environment. Gait analysis algorithms need thorough validation, as many chronic diseases show specific and even unique gait patterns. The aim of this study was therefore to validate an acceleration-based step detection algorithm for patients with Parkinson's disease (PD) and older adults in both a lab-based and home-like environment. METHODS: In this prospective observational study, data were captured from a single 6-degrees of freedom IMU (APDM) (3DOF accelerometer and 3DOF gyroscope) worn on the lower back. Detection of heel strike (HS) and toe off (TO) on a treadmill was validated against an optoelectronic system (Vicon) (11 PD patients and 12 older adults). A second independent validation study in the home-like environment was performed against video observation (20 PD patients and 12 older adults) and included step counting during turning and non-turning, defined with a previously published algorithm. RESULTS: A continuous wavelet transform (cwt)-based algorithm was developed for step detection with very high agreement with the optoelectronic system. HS detection in PD patients/older adults, respectively, reached 99/99% accuracy. Similar results were obtained for TO (99/100%). In HS detection, Bland-Altman plots showed a mean difference of 0.002 s [95% confidence interval (CI) -0.09 to 0.10] between the algorithm and the optoelectronic system. The Bland-Altman plot for TO detection showed mean differences of 0.00 s (95% CI -0.12 to 0.12). In the home-like assessment, the algorithm for detection of occurrence of steps during turning reached 90% (PD patients)/90% (older adults) sensitivity, 83/88% specificity, and 88/89% accuracy. The detection of steps during non-turning phases reached 91/91% sensitivity, 90/90% specificity, and 91/91% accuracy. CONCLUSION: This cwt-based algorithm for step detection measured at the lower back is in high agreement with the optoelectronic system in both PD patients and older adults. This approach and algorithm thus could provide a valuable tool for future research on home-based gait analysis in these vulnerable cohorts.

Motor dual-tasking deficits predict falls in Parkinson's disease: A prospective study.

INTRODUCTION: Falls severely affect lives of Parkinson's disease (PD) patients. Cognitive impairment including dual-tasking deficits contribute to fall risk in PD. However, types of dual-tasking deficits preceding falls in PD are still unclear. METHODS: Walking velocities during box-checking and subtracting serial 7s were assessed twice a year in 40 PD patients over 2.8 ± 1.0 years. Fourteen patients reported a fall within this period (4 excluded fallers already reported falls at baseline). Their dual-task costs (DTC; mean ± standard deviation) 4.2 ± 2.2 months before the first fall were compared with 22 patients never reporting falls. ROC analyses and logistic regressions accounting for DTC, UPDRS-III and disease duration were used for faller classification and prediction. RESULTS: Only walking/box-checking predicted fallers. Fallers showed higher DTC for walking while box-checking, p = 0.029, but not for box-checking while walking, p = 0.178 (combined motor DTC, p = 0.022), than non-fallers. Combined motor DTC classified fallers and non-fallers (area under curve: 0.75; 95% confidence interval, CI: 0.60-0.91) with 71.4% sensitivity (95%CI: 41.9%-91.6%) and 77.3% specificity (54.6%-92.2%), and significantly predicted future fallers (p = 0.023). Here, 20.4%-points higher combined motor DTC (i.e. the mean difference between fallers and non-fallers) was associated with a 2.6 (1.1-6.0) times higher odds to be a future faller. CONCLUSION: Motor dual-tasking is a potentially valuable predictor of falls in PD, suggesting that avoiding dual task situations as well as specific motor dual-task training might help to prevent falls in PD. These findings and their therapeutic relevance need to be further validated in PD patients without fall history, in early PD stages, and with various motor-motor dual-task challenges.

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors.

INTRODUCTION: Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). MATERIALS AND METHODS: IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. RESULTS: PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. DISCUSSION: Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.

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 standardized ST and dual tasks as fast as possible for 1 min 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.

Continuous leg dyskinesia assessment in Parkinson's disease -clinical validity and ecological effect.

INTRODUCTION: Dyskinesias in Parkinson's disease (PD) patients are a common side effect of long-term dopaminergic therapy and are associated with motor dysfunctions, including gait and balance deficits. Although promising compounds have been developed to treat these symptoms, clinical trials have failed. This failure may, at least partly, be explained by the lack of objective and continuous assessment strategies. This study tested the clinical validity and ecological effect of an algorithm that detects and quantifies dyskinesias of the legs using a single ankle-worn sensor. METHODS: Twenty-three PD patients (seven with leg dyskinesias) and 13 control subjects were investigated in the lab. Participants performed purposeful daily activity-like tasks while being video-taped. Clinical evaluation was performed using the leg dyskinesia item of the Unified Dyskinesia Rating Scale. The ecological effect of the developed algorithm was investigated in a multi-center, 12-week, home-based sub-study that included three patients with and seven without dyskinesias. RESULTS: In the lab-based sub-study, the sensor-based algorithm exhibited a specificity of 98%, a sensitivity of 85%, and an accuracy of 0.96 for the detection of dyskinesias and a correlation level of 0.61 (p < 0.001) with the clinical severity score. In the home-based sub-study, all patients could be correctly classified regarding the presence or absence of leg dyskinesias, supporting the ecological relevance of the algorithm. CONCLUSION: This study provides evidence of clinical validity and ecological effect of an algorithm derived from a single sensor on the ankle for detecting leg dyskinesias in PD patients. These results should motivate the investigation of leg dyskinesias in larger studies using wearable sensors.

Quantitative Timed-Up-and-Go Parameters in Relation to Cognitive Parameters and Health-Related Quality of Life in Mild-to-Moderate Parkinson's Disease.

INTRODUCTION: The instrumented-Timed-Up-and-Go test (iTUG) provides detailed information about the following movement patterns: sit-to-walk (siwa), straight walking, turning and walk-to-sit (wasi). We were interested in the relative contributions of respective iTUG sub-phases to specific clinical deficits most relevant for daily life in Parkinson's disease (PD). More specifically, we investigated which condition-fast speed (FS) or convenient speed (CS)-differentiates best between mild- to moderate-stage PD patients and controls, which parameters of the iTUG sub-phases are significantly different between PD patients and controls, and how the iTUG parameters associate with cognitive parameters (with particular focus on cognitive flexibility and working memory) and Health-Related-Quality of Life (HRQoL). METHODS: Twenty-eight PD participants (65.1 ± 7.1 years, H&Y stage 1-3, medication OFF state) and 20 controls (66.1 ± 7.5 years) performed an iTUG (DynaPort®, McRoberts BV, The Netherlands) under CS and FS conditions. The PD Questionnaire 39 (PDQ-39) was employed to assess HRQoL. General cognitive and executive functions were assessed using the Montreal Cognitive Assessment and the Trail Making Test. RESULTS: The total iTUG duration and sub-phases durations under FS condition differentiated PD patients slightly better from controls, compared to the CS condition. The following sub-phases were responsible for the observed longer total duration PD patients needed to perform the iTUG: siwa, turn and wasi. None of the iTUG parameters correlated relevantly with general cognitive function. Turning duration and wasi maximum flexion velocity correlated strongest with executive function. Walking back duration correlated strongest with HRQoL. DISCUSSION: This study confirms that mild- to moderate-stage PD patients need more time to perform the iTUG than controls, and adds the following aspects to current literature: FS may be more powerful than CS to delineate subtle movement deficits in mild- to moderate-stage PD patients; correlation levels of intra-individual siwa and wasi parameters may be interesting surrogate markers for the level of automaticity of performed movements; and sub-phases and kinematic parameters of the iTUG may have the potential to reflect executive functioning and HRQoL aspects of PD patients.

Digitomotography in Parkinson's disease: a cross-sectional and longitudinal study.

Motor symptoms in Parkinson's disease (PD) are usually assessed with semi-quantitative tests such as the Unified PD Rating Scale (UPDRS) which are limited by subjectivity, categorical design, and low sensitivity. Particularly bradykinesia as assessed e.g. with speeded index finger tapping exhibits low validity measures. This exploratory study set out to (i) assess whether force transducer-based objective and quantitative analysis of motor coordination in index finger tapping is able to distinguish between PD patients and controls, and (ii) assess longitudinal changes. Sixteen early-stage and 17 mid-stage PD patients as well as 18 controls were included in the cross-sectional part of the study; thirteen, 16 and 16 individuals of the respective groups agreed in a reassessment 12 months later. Frequency, force, rhythmicity, regularity and laterality of speeded and metronome paced tapping were recorded by digitomotography using a quantitative motor system ("Q-Motor"). Analysis of cross-sectional data revealed most consistent differences between PD patients and controls in variability of tap performance across modalities assessed. Among PD patients, variability of taps and the ability to keep a given rhythm were associated with UPDRS motor and finger tapping scores. After 12 months, laterality parameters were reduced but no other parameters changed significantly. This data suggests that digitomotography provides quantitative and objective measures capable to differentiate PD from non-PD in a small cohort, however, the value of the assessment to track PD progression has to be further evaluated in larger cohorts of patients.

Neurodegenerative CSF markers in genetic and sporadic PD: Classification and prediction in a longitudinal study.

BACKGROUND: Parkinson's disease (PD) patients show a large phenotypic variability probably reflecting inter-individual pathologic heterogeneity. Next to typical Lewy-body pathology, ß-amyloid (Aß) and tau pathology have been found at autopsy and several studies have reported altered CSF levels of Aß1-42, total-Tau (t-Tau) and phosphorylated-Tau (p-Tau). OBJECTIVES: To evaluate whether CSF levels of neurodegenerative markers are influenced by genetics and whether specific subgroups of PD are more prone to a concomitant pathology possibly reflecting aspects of disease progression. METHODS: In an explorative study we assessed CSF profiles of Aß1-42, t-Tau, and p-Tau longitudinally in PD patients carrying LRRK2 (n = 5) or GBA mutations (n = 12), sporadic PD patients (n = 30) and healthy controls (n = 16). RESULTS: Compared to healthy controls, all three PD cohorts showed lower levels of Aß1-42. Moreover, sporadic PD and GBA-PD patients presented with lower levels of t-Tau and p-Tau whereas this phenomenon was not seen in LRRK2-PD patients. Regression analyses revealed an association between higher levels of Baseline p-Tau with more accelerated cognitive deterioration over time in LRRK2-PD and GBA-PD patients, but not in sporadic PD. CONCLUSION: PD patients present with disease-specific CSF profiles of Aß1-42, t-Tau and p-Tau arguing in favor of an involvement of these proteins in PD pathogenesis in both sporadic and genetic forms. Moreover, we found first hints for differences in these CSF profiles between genetically determined PD cohorts but that CSF constellations which tend to predict aspects of disease progression such as cognitive decline seem similar across subgroups of PD.