Markus A. Hobert

Impaired trunk stability in individuals at high risk for Parkinson's disease

Background The search for disease-modifying treatments for Parkinsons disease advances, however necessary markers for early detection of the disease are still lacking. There is compelling evidence that changes of postural stability occur at very early clinical stages of Parkinsons disease, making it tempting to speculate that changes in sway performance may even occur at a prodromal stage, and may have the potential to serve as a prodromal marker for the disease. Methodology/Principal Findings Balance performance was tested in 20 individuals with an increased risk of Parkinsons disease, 12 Parkinsons disease patients and 14 controls using a cross-sectional approach. All individuals were 50 years or older. Investigated groups were similar with respect to age, gender, and height. An accelerometer at the centre of mass at the lower spine quantified sway during quiet semitandem stance with eyes open and closed, as well as with and without foam. With increasing task difficulty, individuals with an increased risk of Parkinsons disease showed an increased variability of trunk acceleration and a decrease of smoothness of sway, compared to both other groups. These differences reached significance in the most challenging condition, i.e. the eyes closed with foam condition. Conclusions/Significance Individuals with an increased risk of Parkinsons disease have subtle signs of a balance deficit under most challenging conditions. This preliminary finding should motivate further studies on sway performance in individuals with an increased risk of Parkinsons disease, to evaluate the potential of this symptom to serve as a biological marker for prodromal Parkinsons disease.

Poor Trail Making Test Performance Is Directly Associated with Altered Dual Task Prioritization in the Elderly – Baseline Results from the TREND Study

Background Deterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance—which specifically measures cognitive flexibility and working memory—and dual task costs, a measure of prioritization. Methodology and Principal Findings Out of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range −6 to 58%) compared to the good performers (17%; −16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, −1.6%; good performers, +3%; p = 0.035). Conclusion Under most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.

New methods for the assessment of Parkinson's disease (2005 to 2015): A systematic review.

The past decade has witnessed a highly dynamic and growing expansion of novel methods aimed at improving the assessment of Parkinsons 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.

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

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinsons disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.

Accelerometer-based quantitative analysis of axial nocturnal movements differentiates patients with Parkinson's disease, but not high-risk individuals, from controls

Introduction There is a need for prodromal markers to diagnose Parkinson’s disease (PD) as early as possible. Knowing that most patients with overt PD have abnormal nocturnal movement patterns, we hypothesised that such changes might occur already in non-PD individuals with a potentially high risk for future development of the disease. Methods Eleven patients with early PD (Hoehn & Yahr stage ≤2.5), 13 healthy controls and 33 subjects with a high risk of developing PD (HR-PD) were investigated. HR-PD was defined by the occurrence of hyperechogenicity of the substantia nigra in combination with prodromal markers (eg, slight motor signs, olfactory dysfunction). A triaxial accelerometer was used to quantify nocturnal movements during two nights per study participant. Outcome measurements included mean acceleration, and qualitative axial movement parameters, such as duration and speed. Results Mean acceleration of nocturnal movements was lower in patients with PD compared to controls. Frequency and speed of axial movements did not differ between patients with PD and controls, but mean size and duration were lower in PD. The HR-PD group did not significantly differ from the control group in any of the parameters analysed. Conclusions Compared with controls, patients with PD had an overall decreased mean acceleration, as well as smaller and shorter nocturnal axial movements. These changes did not occur in our potential HR-PD individuals, suggesting that relevant axial movement alterations during sleep have either not developed or cannot be detected by the means applied in this at-risk cohort.

Mild Parkinsonian Signs in the Elderly – Is There an Association with PD? Crossectional Findings in 992 Individuals

Background Mild parkinsonian signs (MPS) are common in the elderly population, and have been associated with vascular diseases, mild cognitive impairment and dementia; however their relation to Parkinsons disease (PD) is unclear. Hypothesizing that individuals with MPS may reflect a pre-stage of PD, i.e. a stage in which the nigrostriatal system is already affected although to a milder degree than at the time of PD diagnosis, aim of this study was to evaluate the similarities between MPS and PD. Methods The TREND study is a prospective cross-sectional cohort study in individuals >50 years with biennial assessments designed to identify markers for an earlier diagnosis of Parkinsons and Alzheimers disease. For this substudy 992 individuals were included for analyses (892 controls, 73 MPS individuals, 27 PD patients). Parameters defining risk of PD (sex, age, positive family history), prodromal markers (hyposmia, REM sleep behavior disorder, depression and autonomic failure) as well as quantitative fine motor, axial motor and cognitive parameters were compared between the three cohorts. Results As expected, PD patients differed from controls with regard to 12 of 15 of the assessed parameters. MPS individuals differed significantly from controls in 12 of the PD-associated parameters, but differed from PD only in 5 parameters. Conclusion This study shows that individuals with MPS share many prodromal and clinical markers of PD with PD patients, implying that either a common dynamic process or similar constitutional factors occur in MPS individuals and PD patients.

Intra-rater, inter-rater and test-retest reliability of an instrumented Timed Up and Go (iTUG) test in patients with Parkinson's disease.

Background The “Timed Up and Go” (TUG) is a widely used measure of physical functioning in older people and in neurological populations, including Parkinson’s Disease. When using an inertial sensor measurement system (instrumented TUG [iTUG]), the individual components of the iTUG and the trunk kinematics can be measured separately, which may provide relevant additional information. Objective The aim of this study was to determine intra-rater, inter-rater and test-retest reliability of the iTUG in patients with Parkinson’s Disease. Methods Twenty eight PD patients, aged 50 years or older, were included. For the iTUG the DynaPort Hybrid (McRoberts, The Hague, The Netherlands) was worn at the lower back. The device measured acceleration and angular velocity in three directions at a rate of 100 samples/s. Patients performed the iTUG five times on two consecutive days. Repeated measurements by the same rater on the same day were used to calculate intra-rater reliability. Repeated measurements by different raters on the same day were used to calculate intra-rater and inter-rater reliability. Repeated measurements by the same rater on different days were used to calculate test-retest reliability. Results Nineteen ICC values (15%) were ≥ 0.9 which is considered as excellent reliability. Sixty four ICC values (49%) were ≥ 0.70 and < 0.90 which is considered as good reliability. Thirty one ICC values (24%) were ≥ 0.50 and < 0.70, indicating moderate reliability. Sixteen ICC values (12%) were ≥ 0.30 and < 0.50 indicating poor reliability. Two ICT values (2%) were < 0.30 indicating very poor reliability. Conclusions In conclusion, in patients with Parkinson’s disease the intra-rater, inter-rater, and test-retest reliability of the individual components of the instrumented TUG (iTUG) was excellent to good for total duration and for turning durations, and good to low for the sub durations and for the kinematics of the SiSt and StSi. The results of this fully automated analysis of instrumented TUG movements demonstrate that several reliable TUG parameters can be identified that provide a basis for a more precise, quantitative use of the TUG test, in clinical practice.

Using multi-dimensional dynamic time warping for TUG test instrumentation with inertial sensors

The Timed Up and Go (TUG) is a clinical test used widely to measure balance and mobility, e.g. in Parkinsons disease (PD). The test includes a sequence of functional activities, namely: sit-to-stand, 3-meters walk, 180° turn, walk back, another turn and sit on the chair. Meanwhile the stopwatch is used to score the test by measuring the time which the patients with PD need to perform the test. Here, the work presents an instrumented TUG using a wearable inertial sensor unit attached on the lower back of the person. The approach is used to automate the process of assessment compared with the manual evaluation by using visual observation and a stopwatch. The developed algorithm is based on the Dynamic Time Warping (DTW) for multi-dimensional time series and has been applied with the augmented feature for detection and duration assessment of turn state transitions, while a 1-dimensional DTW is used to detect the sit-to-stand and stand-to-sit phases. The feature set is a 3-dimensional vector which consists of the angular velocity, derived angle and features from Linear Discriminant Analysis (LDA). The algorithm was tested on 10 healthy individuals and 20 patients with PD (10 patients with early and late disease phases respectively). The test demonstrates that the developed technique can successfully extract the time information of the sit-to-stand, both turns and stand-to-sit transitions in the TUG test.

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 Parkinsons 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.

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.