Grasping premanifest Huntington's disease – Shaping new endpoints for new trials

Department of Neurology, University Clinic Muenster (UKM), Westfaelische Wilhelms University of Muenster, Muenster, Germany.
Movement Disorders (Impact Factor: 5.68). 12/2010; 25(16):2858-62. DOI: 10.1002/mds.23300
Source: PubMed


Future clinical trials in subjects with premanifest Huntington's disease (preHD) may depend on the availability of biomarkers. It was previously shown in symptomatic HD that, the grip force variability coefficient-of-variation (GFV-C) in a grasping paradigm was correlated to the Unified-Huntington's-Disease-Rating-Scale-Total-Motor-Score (UHDRS-TMS) and increased in a 3 year follow-up study. To further elucidate its potential as a biomarker, we investigated whether GFV-C is able to detect a motor phenotype in preHD and is correlated to the genotype assessed by a disease-burden-score. The ability of preHD (n = 15) and symptomatic HD subjects (n = 20) to maintain stable grip forces, while holding an object (250 g and 500 g), was measured and compared with the controls (n = 19). GFV-C was increased in preHD at 500 g, in symptomatic subjects at both weights and was correlated to the disease-burden-score and UHDRS-TMS. GFV-C may be a useful objective and quantitative marker of motor dysfunction across genetically diagnosed premanifest and symptomatic HD subjects.

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    • "The modulation of force output was evaluated using a force transducer with a diameter of 40 mm (Nano-40, ATI Industrial Automation, Apex, NC, USA; 0.025 N resolution) that was attached to a grip instrument mounted on a table top to measure thumb force during precision grip [modified from the 'Q-Motor' grip-force task ('manumotography') (Reilmann et al., 2010, 2013) – see Fig. 1]. Table height was adjusted if required. "
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    ABSTRACT: Background Compelling evidence points at both impaired proprioception and disturbed force control in patients with chronic complex regional pain syndrome (CRPS). Because force modulation at least partly relies on proprioception, we evaluated if impaired sense of force production contributes to disturbances of force control in patients with CRPS. Methods Characteristics of voluntary force modulation were examined in the affected upper extremity in 28 CRPS patients with abnormal postures, in 12 CRPS patients without abnormal postures, and in 32 healthy controls. Isometric grip-force matching was compared between conditions with and without visual feedback to identify potential deficits in the sense of force production in terms of force reproduction errors. ResultsVoluntary force modulation was impaired in CRPS patients, but more so in patients with abnormal postures. In particular, CRPS patients with abnormal postures were characterized by reduced maximum force, reduced ability to increase force output according to task instructions, higher variability of force output and less adequate correction of deviations from the target force. Although effects of visual feedback removal appeared largely similar for the two patient groups and controls, our findings with respect to force reproduction errors suggested that an impaired sense of force production may contribute to the motor dysfunction in CRPS. ConclusionsCRPS patients, in particular those with abnormal postures, showed impaired voluntary force control and an impaired sense of force production. This suggests that therapeutic strategies aimed at restoration of proprioceptive impairments, possibly using online visual feedback, may promote the recovery of motor function in CRPS.
    European journal of pain (London, England) 08/2014; 18(7). DOI:10.1002/j.1532-2149.2013.00446.x · 2.93 Impact Factor
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    • "In this context it seems noteworthy that GFV has evolved as an objective measure of motor dysfunction in Huntington’s disease: GFV was increased and correlated to the UHDRS-total motor score in symptomatic patients [15] and premanifest gene carriers [37]. GFV increased in the course of symptomatic Huntington’s disease in a small 3-year single centre study [38] and this finding was confirmed in a blinded analysis of quantitative motor data from about 120 patients and 120 control subjects across 2 years in the multicentre biomarker study TRACK-HD [40]. "
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    ABSTRACT: Motor disability in MS is commonly assessed by the Expanded Disability Status Scale (EDSS). Categorical rating scales are limited by subjective error and inter-rater variability. Therefore, objective and quantitative measures of motor disability may be useful to supplement the EDSS in the setting of clinical trials. It was previously shown that grip-force-variability (GFV) is increased in MS. We hypothesized that GFV may be an objective measure of motor disability in MS. To investigate whether the increase in GFV in MS is correlated to the clinical disability as assessed by the EDSS and to microstructural changes in the brain as assessed by diffusion tensor imaging, GFV was recorded in a grasping and lifting task in 27 MS patients and 23 controls using a grip-device equipped with a force transducer. The EDSS was assessed by neurologists experienced in MS. Patients underwent diffusion tensor imaging at 3T to assess the fractional anisotropy (FA) of the cerebral white matter as a measure of microstructural brain integrity. GFV was increased in MS and correlated to changes in the FA of white matter in the vicinity of the somatosensory and visual cortex. GFV also correlated with the EDSS. GFV may be a useful objective measure of motor dysfunction in MS linked to disability and structural changes in the brain. Our data suggests that GFV should be further explored as an objective measure of motor dysfunction in MS. It could supplement the EDSS, e.g., in proof of concept studies.
    Journal of Neurology 08/2012; 260(2). DOI:10.1007/s00415-012-6639-7 · 3.38 Impact Factor
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    • "A relapse is defined as de novo development or aggravation or re-occurrence of a preexisting neurological abnormality compatible with MS which lasts a minimum of 24 hours, is separated by at least 30 days from a preceding clinical event and does not occur in the context of fever. Additional secondary endpoints comprise the disease progression as determined by EDSS (evaluated by an independent neurologist), Multiple Sclerosis Functional Composite (MSFC), cognition as determined by the Faces Symbol Test (FST) and the Symbol Digit Modalities Test (SDMT), fatigue and depression as well as quantitative assessment of motor function [31,32]. Additional parameters include retinal nerve fiber layer thickness and macular volume which are increasingly recognized as markers for disease progression in MS [33], visual contrast sensitivity and low contrast visual acuity, 25-hydroxyvitamin D serum levels, and quality of life. "
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    ABSTRACT: Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults. Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D, mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse. We here present the protocol of an interventional clinical phase II study to test the hypothesis, that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects. The EVIDIMS trial is a German multi-center, stratified, randomized, controlled and double-blind clinical phase II pilot study. Eighty patients with the diagnosis of definite multiple sclerosis or clinically isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be randomized to additionally receive either high-dose (average daily dose 10.200 IU) or low-dose (average daily dose 200 IU) cholecalciferol for a total period of 18 months. The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla. Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration, clinical parameters for disease activity, as well as cognition, fatigue, depression, and quality of life. Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters. In light of the discrepancy between existing epidemiological and preclinical data on the one hand and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients. The study design presented here fulfills the criteria of a high-quality clinical phase II trial in MS. Identifier: NCT01440062.
    Trials 02/2012; 13(1):15. DOI:10.1186/1745-6215-13-15 · 1.73 Impact Factor
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Jun 5, 2014

Ralf Reilmann