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.
    Full-text · Article · Aug 2014 · European journal of pain (London, England)
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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: 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.
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