Sandra E. Hasmann

Emerging therapies for gait disability and balance impairment: Promises and pitfalls

Therapeutic management of gait and balance impairment during aging and neurodegeneration has long been a neglected topic. This has changed considerably during recent years, for several reasons: (1) an increasing recognition that gait and balance deficits are among the most relevant determinants of an impaired quality of life and increased mortality for affected individuals; (2) the arrival of new technology, which has allowed for new insights into the anatomy and functional (dis)integrity of gait and balance circuits; and (3) based in part on these improved insights, the development of new, more specific treatment strategies in the field of pharmacotherapy, deep brain surgery, and physiotherapy. The initial experience with these emerging treatments is encouraging, although much work remains to be done. The objective of this narrative review is to discuss several promising developments in the field of gait and balance treatment. We also address several pitfalls that can potentially hinder a fast and efficient continuation of this vital progress. Important issues that should be considered in future research include a clear differentiation between gait and balance as two distinctive targets for treatment and recognition of compensatory mechanisms as a separate target for therapeutic intervention.

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.

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.

Instrumented functional reach test differentiates individuals at high risk for Parkinson’s disease from controls

The functional reach (FR) test as a complex measure of balance including limits of stability has been proven to differentiate between patients with Parkinson’s disease (PD) and controls (CO). Recently, it has been shown that the instrumentation of the FR (iFR) with a wearable sensor may increase this diagnostic accuracy. This cross-sectional study aimed at investigating whether the iFR has the potential to differentiate individuals with high risk for PD (HRPD) from CO, as the delineation of such individuals would allow for, e.g., early neuromodulation. Thirteen PD patients, 13 CO, and 31 HRPD were investigated. HRPD was defined by presence of an enlarged area of hyperechogenicity in the mesencephalon on transcranial sonography and either one motor sign or two risk and prodromal markers of PD. All participants were asked to reach with their right arm forward as far as possible and hold this position for 10 s. During this period, sway parameters were assessed with an accelerometer (Dynaport, McRoberts) worn at the lower back. Extracted parameters that differed significantly between PD patients and CO in our cohort [FR distance (shorter in PD), anterior–posterior and mediolateral acceleration (both lower in PD)] as well as JERK, which has been shown to differentiate HRPD from CO and PD in a previous study, were included in a model, which was then used to differentiate HRPD from CO. The model yielded an area under the curve of 0.77, with a specificity of 85%, and a sensitivity of 74%. These results suggest that the iFR can contribute to an assessment panel focusing on the definition of HRPD individuals.

Gait Is Associated with Cognitive Flexibility: A Dual-Tasking Study in Healthy Older People

Objectives: To analyze which gait parameters are primarily influenced by cognitive flexibility, and whether such an effect depends on the walking condition used. Design: Cross-sectional analysis. Setting: Tübingen evaluation of Risk factors for Early detection of Neurodegenerative Disorders. Participants: A total of 661 non-demented individuals (49–80 years). Measurements: A gait assessment with four conditions was performed: a 20 m walk at convenient speed (C), at fast speed (F), at fast speed while checking boxes (FB), and while subtracting serial 7s (FS). Seven gait parameters from a wearable sensor-unit (McRoberts, Netherlands) were compared with delta Trail-Making-Test (dTMT) values, which is a measure of cognitive flexibility. Walking strategies of good and poor dTMT performers were compared by evaluating the patterns of gait parameters across conditions. Results: Five parameters correlated significantly with the dTMT in the FS condition, two parameters in the F and FB condition, and none in the C condition. Overall correlations were relatively weak. Gait speed was the gait parameter that most strongly correlated with the dTMT (r2 = 7.4%). In good, but not poor, dTMT performers differences between FB and FS were significantly different in variability-associated gait parameters. Conclusion: Older individuals need cognitive flexibility to perform difficult walking conditions. This association is best seen in gait speed. New and particularly relevant for recognition and training of deficits is that older individuals with poor cognitive flexibility have obviously fewer resources to adapt to challenging walking conditions. Our findings partially explain gait deficits in older adults with poor cognitive flexibility.

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.

Associations between Early Markers of Parkinson's Disease and Sarcopenia

Introduction: Sarcopenia and Parkinsons disease (PD) are both common age-related syndromes, and there is preliminary evidence that the probability of the co-occurrence of these syndromes within one individual is higher than expected. However, it is unclear to date whether one of the syndromes induces the other, or whether there may be common underlying causes. This pilot study thus aimed at investigating the association of the features of increased risk for PD with early stage sarcopenia (ESS). Method: Two hundred and fifty-five community-dwelling individuals were recruited from the Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study. The following features that are associated with an increased risk for future PD were evaluated: the motor part of the Unified PD Rating Scale (UPDRS-III), hyperechogenicity of the substantia nigra, prevalence of lifetime depression, hyposmia, REM sleep behavior disorder and the recently introduced probability score for prodromal PD. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People, which was adapted to this cohort of healthy adults. Multiple linear regression analysis was used to identify associations of PD-related features with ESS. Results: The UPDRS-III score was significantly associated with ESS. The result remained significant after the adjustment for age, gender and physical activity. No association was found between the other PD-related features and ESS. Conclusion: The significant association of the UPDRS-III score with ESS in this cohort might indicate a common and early pathway in both diseases and supports the existence of an “extended neurodegenerative overlap syndrome.” Moreover, the potential of EES to serve as a prodromal marker of PD should be evaluated in future studies.

Evidence for a Selectively Regulated Prioritization Shift Depending on Walking Situations in Older Adults

Background: Older adults have increased risks of balance issues and falls when walking and performing turns in daily situations. Changes of prioritization during different walking situations associated with dual tasking may contribute to these deficits. The objective of this study was therefore to investigate whether older adults demonstrate changes of prioritization during different walking paths. Methods: In total, 1,054 subjects with an age range from 50 to 83 years were selected from the first follow-up visit of the TREND (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders) study. They were classified according to their performance on the Trail Making Test (TMT) into good and poor TMT performers (based on recent results showing that cognitive flexibility affects prioritization strategies during straight walking). Absolute dual-task performance and relative dual-task costs (DTC, relative performance under dual-task conditions compared with single-task conditions) were assessed in two paradigms: walking while subtracting serial 7 s and walking while checking boxes on a clipboard. Both tasks were performed on straight and curved paths. Results: Overall, the poor TMT performers group performed worse in all single and dual tasks. Interestingly, the relative change in performance measured by dual-task costs differed in the groups between the two walking paths. On straight paths, poor TMT performers had a similar DTC of walking to that of good performers (p = 0.10) but had a significantly lower DTC of subtracting (p = 0.02). On curved paths, poor performers had a similar DTC of subtracting (p = 0.10), but their DTC of walking was significantly higher (p < 0.0001). Conclusion: Given that walking on curved paths is considered more difficult than that on straight paths and that the serial subtracting dual task is more difficult than the box checking dual task, this study in older adults provides evidence for the existence of a (walking) situation-dependent change of prioritization. If confirmed in other studies, situation-dependent change of prioritization should be included as a potential factor contributing to gait and balance impairments, and increased fall risk in older adults.

Dual Tasking for the Differentiation between Depression and Mild Cognitive Impairment

Differentiation of mild cognitive impairment from depression in elderly adults is a clinically relevant issue which is not sufficiently solved. Gait and dual task (DT) parameters may have the potential to complement current diagnostic work-up, as both dementia and depression are associated with changes of gait and DT parameters. Methods: Seven hundred and four participants of the TREND study (Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration) aged 50–80 years were assessed using the Consortium to Establish a Registry for Alzheimers Disease Plus test battery for testing cognition and Becks Depression Inventory for evaluation of depression. Based on these results, four groups were defined: acute depressed (N = 53), cognitively mildly impaired (N = 97), acute depressed, and cognitively mildly impaired (N = 15), and controls (N = 536). Participants underwent a 20 m walk and checking boxes task under single (ST) and DT conditions. ST and DT performance and dual task costs (DTC) were calculated. Due to the typical age of increasing incidence of depressive and also cognitive symptoms, the 7th decade was calculated separately. Results: ST speeds of gait and checking boxes, DT walking speed, and walking DTC were significantly different between groups. Healthy controls were the fastest in all paradigms and cognitively mildly impaired had higher DTC than depressed individuals. Additionally, we constructed a multivariate predictive model differentiating the groups on a single-subject level. Conclusion: DT parameters are simply and comfortably measureable, and DTC can easily be determined. The combination of these parameters allows a differentiation of depressed and cognitively mildly impaired elderly adults.

P171. The relationship between quantitative parameters of the Timed-up-and-Go phases, and health-related quality of life in Parkinson’s disease

Introduction Health related quality of life (HRQoL) is widely accepted as the most important factor for patients living with chronic diseases, and therefore as the most important factor to evaluate (success of) treatment. The downside of the parameter is that evaluation is qualitative, imprecise and prone to bias. To overcome these shortcomings, quantitative and objective assessment tools may be useful that have some potential to serve as a kind of “surrogate marker” for HRQoL. The Timed-Up-and-Go-Test (TUG) is a short test which provides information about important movement patterns, i.e. transfer (sit-to-walk, walk-to-sit), walking and turning. The total time needed to perform the TUG has already been shown to be associated with lower HRQoL in a chronic disease (Parkinson’s disease, PD) however, to the best of our knowledge, no study is currently available which investigated sub-phases of the TUG based on quantitative wearable sensors, and their association with HRQoL in a chronic disease. Objective To identify TUG sub-phases quantitatively that are associated with HRQoL. Methods Thirty-seven PD participants (H&Y stage I-III, ‘off’ state) performed an instrumented TUG (Dynaport®, McRoberts BV, The Netherlands) in four conditions (convenient and fast speed, turning to the left and to the right). The PD Questionnaire 39 (PDQ-39) was used to assess HRQoL. Pearson’s correlation analyses were performed to identify correlations between TUG sub-phases and HRQoL. Results TUG total time correlated well with the PDQ-39 measures. This observation was largely independent of different assessment conditions. From all sub-phases investigated, the walking forth time had the strongest association with the HRQoL questionnaire, followed by the turning phases. Again, these associations were widely independent of the assessment condition. Transfer times did only weakly or even not correlate with the HRQoL measures. Details are provided in Table 1 . Discussion, conclusion Our data confirm previous findings of a relatively strong association of TUG total time with HRQoL in PD. The duration of sub-phases seem not relevantly add to this finding. Interestingly, the sit-to-walk and walk-to-sit times correlated least with the PDQ-39. As the proper execution of transfers is a relevant prerequisite for performing daily activities, this result needs further investigation. Future work – also in our group – will therefore focus on more detailed analysis of sub-phases, considering qualitative aspects of the specific movements.