Quantitative assessment of movement impairment in Huntington’s disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.
Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.
The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n = 64) and healthy controls (n = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.
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