Evaluation of walking activity and gait to identify physical and mental fatigue in neurodegenerative and immune disorders: preliminary insights from the IDEA-FAST feasibility study.

BACKGROUND: Many individuals with neurodegenerative (NDD) and immune-mediated inflammatory disorders (IMID) experience debilitating fatigue. Currently, assessments of fatigue rely on patient reported outcomes (PROs), which are subjective and prone to recall biases. Wearable devices, however, provide objective and reliable estimates of gait, an essential component of health, and may present objective evidence of fatigue. This study explored the relationships between gait characteristics derived from an inertial measurement unit (IMU) and patient-reported fatigue in the IDEA-FAST feasibility study. METHODS: Participants with IMIDs and NDDs (Parkinson's disease (PD), Huntington's disease (HD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (PSS), and inflammatory bowel disease (IBD)) wore a lower-back IMU continuously for up to 10 days at home. Concurrently, participants completed PROs (physical fatigue (PF) and mental fatigue (MF)) up to four times a day. Macro (volume, variability, pattern, and acceleration vector magnitude) and micro (pace, rhythm, variability, asymmetry, and postural control) gait characteristics were extracted from the accelerometer data. The associations of these measures with the PROs were evaluated using a generalised linear mixed-effects model (GLMM) and binary classification with machine learning. RESULTS: Data were recorded from 72 participants: PD = 13, HD = 9, RA = 12, SLE = 9, PSS = 14, IBD = 15. For the GLMM, the variability of the non-walking bouts length (in seconds) with PF returned the highest conditional R2, 0.165, and with MF the highest marginal R2, 0.0018. For the machine learning classifiers, the highest accuracy of the current analysis was returned by the micro gait characteristics with an intrasubject cross validation method and MF as 56.90% (precision = 43.9%, recall = 51.4%). Overall, the acceleration vector magnitude, bout length variation, postural control, and gait rhythm were the most interesting characteristics for future analysis. CONCLUSIONS: Counterintuitively, the outcomes indicate that there is a weak relationship between typical gait measures and abnormal fatigue. However, factors such as the COVID-19 pandemic may have impacted gait behaviours. Therefore, further investigations with a larger cohort are required to fully understand the relationship between gait and abnormal fatigue.

A roadmap for implementation of patient-centered digital outcome measures in Parkinson's disease obtained using mobile health technologies.

Obtaining reliable longitudinal information about everyday functioning from individuals with Parkinson's disease (PD) in natural environments is critical for clinical care and research. Despite advances in mobile health technologies, the implementation of digital outcome measures is hindered by a lack of consensus on the type and scope of measures, the most appropriate approach for data capture (eg, in clinic or at home), and the extraction of timely information that meets the needs of patients, clinicians, caregivers, and health care regulators. The Movement Disorder Society Task Force on Technology proposes the following objectives to facilitate the adoption of mobile health technologies: (1) identification of patient-centered and clinically relevant digital outcomes; (2) selection criteria for device combinations that offer an acceptable benefit-to-burden ratio to patients and that deliver reliable, clinically relevant insights; (3) development of an accessible, scalable, and secure platform for data integration and data analytics; and (4) agreement on a pathway for approval by regulators, adoption into e-health systems and implementation by health care organizations. We have developed a tentative roadmap that addresses these needs by providing the following deliverables: (1) results and interpretation of an online survey to define patient-relevant endpoints, (2) agreement on the selection criteria for use of device combinations, (3) an example of an open-source platform for integrating mobile health technology output, and (4) recommendations for assessing readiness for deployment of promising devices and algorithms suitable for regulatory approval. This concrete implementation guidance, harmonizing the collaborative endeavor among stakeholders, can improve assessments of individuals with PD, tailor symptomatic therapy, and enhance health care outcomes. © 2019 International Parkinson and Movement Disorder Society.

Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures.

Friedreich's ataxia (FRDA) is a rare autosomal-recessive slowly progressive neurodegenerative disorder. As common clinical measures for this devastating disease lack sensitivity, we explored whether (a) the quantitative motor assessments of the Q-Motor battery can enhance clinical characterisation of FRDA; (b) clinical measures can predict Q-Motor outcomes and (c) Q-Motor is sensitive to longitudinal change. At baseline 29 patients and 23 controls and in a 1-year follow-up 14 patients and 6 controls were included. The Q-Motor included lift (manumotography), finger tapping (digitomotography) and pronate/supinate (dysdiadochomotography) tasks. To model responses, a search of generalised linear models was conducted, selecting best fitting models, using demographic and clinical data as predictors. Predictors from selected models were used in linear mixed models to investigate longitudinal changes. Patients with FRDA performed worse than controls on most measures. Modelling of the pronate/supinate task was dominated by SCAFI (SCA functional index) subtasks, while tapping task and lift task models suggested a complex relationship with clinical measures. Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients. Further longitudinal research is warranted to fully characterise its relation to routinely used measures and scales for FRDA.

Quantitative grip force assessment of muscular weakness in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: In patients suffering from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) disease severity is assessed by Medical Research Counsil (MRC) Scale or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. However, none of these methods is appropriate to objectively assess muscle weakness or to detect very small subclinical changes. More objective and quantitative measures are needed in order to evaluate treatment efficiency or to detect subclinical affection of upper limps for early diagnosis. The goal of our study was to objectively quantify muscular weakness in CIDP patients with the non-invasive Quantitative Motor (Q-Motor) test of Grip Force Assessment (QGFA) as well as the Involuntary Movement Assessment (QIMA) and to search for differences between typical and atypical CIDP variants. In addition, we hypothesized that Q-Motor findings correlate with disease severity scales such as MRC or INCAT score. METHODS: In this cross-sectional exploratory proof-of-concept study subjects with confirmed diagnosis of typical or atypical CIDP were examined and compared to healthy controls (HC). For Q-Motor tests all subjects had to lift a device (250 g and 500 g) equipped with an electromagnetic sensor that measured grip force (GF) and three-dimensional changes in position and orientation. The measures "grip force variability" (GFV), "position index" (PI) and "orientation index" (OI) were provided to assess involuntary movements due to muscular weakness. RESULTS: 33 patients with CIDP and 28 HC were included. All measures were significantly elevated in CIDP patients for both devices in the right and left hand compared to healthy controls. Subgroup analysis revealed no differences between typical and atypical CIDP variants. INCAT score only weakly correlated with OI and PI. However, there was a stronger correlation between MRC and QIMA parameters in both hands. CONCLUSION: Q-Motor assessments were capable to objectively assess muscular weakness in CIDP. In particular, QIMA measures detected subclinical generalized muscle weakness even in patients with milder disability. Sensitivity and rater-independence of Q-Motor assessments support a further exploration of QIMA measures as potential endpoints for future clinical trials in CIDP.

Stimulating neural plasticity with real-time fMRI neurofeedback in Huntington's disease: A proof of concept study.

Novel methods that stimulate neuroplasticity are increasingly being studied to treat neurological and psychiatric conditions. We sought to determine whether real-time fMRI neurofeedback training is feasible in Huntington's disease (HD), and assess any factors that contribute to its effectiveness. In this proof-of-concept study, we used this technique to train 10 patients with HD to volitionally regulate the activity of their supplementary motor area (SMA). We collected detailed behavioral and neuroimaging data before and after training to examine changes of brain function and structure, and cognitive and motor performance. We found that patients overall learned to increase activity of the target region during training with variable effects on cognitive and motor behavior. Improved cognitive and motor performance after training predicted increases in pre-SMA grey matter volume, fMRI activity in the left putamen, and increased SMA-left putamen functional connectivity. Although we did not directly target the putamen and corticostriatal connectivity during neurofeedback training, our results suggest that training the SMA can lead to regulation of associated networks with beneficial effects in behavior. We conclude that neurofeedback training can induce plasticity in patients with Huntington's disease despite the presence of neurodegeneration, and the effects of training a single region may engage other regions and circuits implicated in disease pathology.

Huntington's disease: Current and future therapeutic prospects.

Huntington's disease is a progressive neurodegenerative disorder for which therapies are woefully inadequate and do not prevent inevitable progression. Currently approved therapies are primarily aimed at treating chorea, but do not address the more clinically meaningful motor, behavioral, and cognitive features of the disease. However, there are a number of promising new therapies that are currently being studied in the laboratory, and in the clinic. This article will review the wide variety of therapies currently being tested, the advances in clinical trials and end points, and the many potentially relevant new targets. © 2018 International Parkinson and Movement Disorder Society.

Quantitative Measurements of Motor Function in Alzheimer's Disease, Frontotemporal Dementia, and Dementia with Lewy Bodies: A Proof-of-Concept Study.

BACKGROUND: This study examines the efficacy of using quantitative measurements of motor dysfunction, compared to clinical ratings, in Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: In this cross-sectional study, 49 patients with a diagnosis of AD (n = 17), FTD (n = 19), or DLB (n = 13) were included and underwent cognitive testing, clinical motor evaluation, and quantitative motor tests: pronation/supination hand tapping, grasping and lifting, and finger and foot tapping. RESULTS: Our results revealed significantly higher Q-Motor values in pronation/supination and in grip lift force assessment in AD, FTD, and DLB compared to healthy controls (HC). Q-Motor values detected significant differences between AD and HC, while clinical ratings did not. CONCLUSION: Our results suggest that quantitative measurements provide more objective and sensitive measurements of motor dysfunction in dementia.

Design optimization for clinical trials in early-stage manifest Huntington's disease.

OBJECTIVES: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. METHODS: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. RESULTS: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. DISCUSSION: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society.

Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.

While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc.

Technology in Parkinson's disease: Challenges and opportunities.

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease.

BACKGROUND: This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). METHODS: This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. RESULTS: Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. CONCLUSIONS: AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.

A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers.

Putaminal metabolites examined using cross-sectional magnetic resonance spectroscopy (MRS) can distinguish pre-manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty-four participants (30 controls, 25 pre-manifest HD, 29 early HD) recruited as part of TRACK-HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK-HD motor assessment. Statistical analyses included linear regression and one-way analysis of variance (ANOVA). At all time-points N-acetyl aspartate and total N-acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre-manifest HD than in controls, whereas the gliosis marker myo-inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross-sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD-affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi-site assessments in large, pathologically diverse cohorts.

Quantitative motor assessment of dyskinesias in Parkinson's disease.

Although Levodopa-induced dyskinesias (LID) are one of the most compromising complications of dopaminergic treatment in Parkinson's disease (PD), there is no widely accepted assessment tool available that evaluates LID quantitatively. This is of relevance as objective assessment may help to facilitate proof-of-concept studies with novel treatments and thus eventually contribute to better patient care. PD patients were asked to perform a grip-lift task as well as tapping tasks assessed with the "Q-Motor" system. PD patients were separated into three groups according to their modified abnormal involuntary movement scale (M-AIMS)-score: PD patients without dyskinesias (PD(LID-) n = 17), with slight dyskinesias (PD(LID+) n = 15) and with severe dyskinesias (PD(LID++) n = 15). An explorative analysis to identify measures detecting LID was performed with 5 PD(LID-) and 5 PD(LID++) patients; these measures were then used in the remaining patients to assess the accuracy of the system to differentiate LID. The measures "Orientation-Index" and "Position-Index" of the grip-lift task differed significantly between the explorative cohorts. Using these two parameters for the differentiation of the remaining cohorts, the area under the ROC curve (AUC) yielded 0.809 for the differentiation of PD(LID-) vs. PD(LID++), 0.852 for the differentiation of PD(LID-) vs. PD(LID+) patients, and 0.830 for the differentiation of PD(LID+) and PD(LID++). The "Orientation-Index" and "Position-Index" of the Q-Motor assessment are sensitive, easy to apply and non-invasive measures for the objective assessment of manifestation and severity of LID.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

BACKGROUND: Deterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage. METHODS: We employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed. RESULTS: MS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001). CONCLUSIONS: Changes in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Quantitative motor assessment of muscular weakness in myasthenia gravis: a pilot study.

BACKGROUND: Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG. METHODS: This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three-dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness. RESULTS: Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand. CONCLUSION: Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG.

Clinical trials in Huntington's disease: Interventions in early clinical development and newer methodological approaches.

Since the identification of the Huntington's disease (HD) gene, knowledge has accumulated about mechanisms directly or indirectly affected by the mutated Huntingtin protein. Transgenic and knock-in animal models of HD facilitate the preclinical evaluation of these targets. Several treatment approaches with varying, but growing, preclinical evidence have been translated into clinical trials. We review major landmarks in clinical development and report on the main clinical trials that are ongoing or have been recently completed. We also review clinical trial settings and designs that influence drug-development decisions, particularly given that HD is an orphan disease. In addition, we provide a critical analysis of the evolution of the methodology of HD clinical trials to identify trends toward new processes and endpoints. Biomarker studies, such as TRACK-HD and PREDICT-HD, have generated evidence for the potential usefulness of novel outcome measures for HD clinical trials, such as volumetric imaging, quantitative motor (Q-Motor) measures, and novel cognitive endpoints. All of these endpoints are currently applied in ongoing clinical trials, which will provide insight into their reliability, sensitivity, and validity, and their use may expedite proof-of-concept studies. We also outline the specific opportunities that could provide a framework for a successful avenue toward identifying and efficiently testing and translating novel mechanisms of action in the HD field.

Diagnostic criteria for Huntington's disease based on natural history.

Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset. Furthermore, subtle motor dysfunction, cognitive changes, and behavioral alterations are often seen before diagnosis made according to the current criteria. As disease-modifying treatments are developed, likely beginning therapy early will be desirable. We therefore suggest that expanded diagnostic criteria for HD should be adapted to better reflect the natural history of the disease, to enable the conduct of clinical trials in premanifest subjects targeting prevention of neurodegeneration, and to facilitate earlier symptomatic treatment. We propose a new set of criteria for HD diagnostic categories in the International Classification of Diseases that reflect our current understanding of HD natural history and pathogenesis. Based on defined criteria, for example, the Diagnostic Confidence Level and the Total Functional Capacity scales of the Unified Huntington's Disease Rating Scale, HD should be divided in the categories "genetically confirmed" with the subcategories "presymptomatic," "prodromal," and "manifest" and "not genetically confirmed" subdivided into "clinically at risk," "clinically prodromal," and "clinically manifest."