Longitudinal Change in Gait and Motor Function in Pre-manifest Huntington’s Disease

Abstract

The purpose of this study was to examine longitudinal change in gait and motor function in pre-manifest Huntington’s disease (HD).We examined ten pre-manifest subjects at baseline, one and five years. Quantitative gait data were collected with an electronic mat (GAITRite®). We analyzed measures related to speed (velocity, step length, cadence), asymmetry (step length difference), dynamic balance (percent time in double support, support base) and variability in stride length and swing time. Motor function was assessed with the motor component of the Unified Huntington’s Disease Rating Scale.Gait velocity decreased (p=0.001), whereas step length difference (p=0.006), stride length variability (p=0.0001) and swing time variability increased (p=0.0001) from baseline to year five. Step length difference (p<0.05) and swing time variability (p<0.05) increased marginally in one year from baseline. UHDRS Total motor score increased over five years (p=0.003), though the increase in one year was not significant (p=0.053). Of the individual motor domain scores (eye, hand movements, gait and balance, chorea) only dystonia worsened over five years (p=0.02). Total motor score (r2= 0.49, p<0.001) and swing time variability (r2= 0.22, p<0.009) were correlated with estimated years to diagnosis.Our results present the longest longitudinal follow up of gait in pre-manifest HD thus far. Despite the small sample size, quantitative gait analysis was able to detect changes in gait speed, symmetry and variability. Swing time variability was particularly important because it increased in one year from baseline and was correlated with estimated time to diagnosis. Our results highlight the importance of predictive outcomes such as gait variability using quantitative analysis.

Behavioral phenotyping of minipigs transgenic for the Huntington gene

“…Selection of the tests was partly driven by availability of data from human HD studies Tabrizi et al, 2009Tabrizi et al, , 2012Tabrizi et al, , 2013, which may facilitate the translation of findings from preclinical to clinical studies in humans. Motor assessments, such as the GAITRite based automated gait analysis have been successfully used in the assessment of clinical HD patients (Bohlen et al, 2012;Rao et al, 2011Rao et al, , 2008Tabrizi et al, 2009Tabrizi et al, , 2011 and were amenable for direct translation to minipigs. Assessment of gait coordination under challenging conditions as assessed in the Unified-Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) tandem walking subitem (Huntington Study Group, 1996) may be related to the "Hurdle Test" for the minipigs introduced here; assessment of tongue motor coordination routinely performed in the UHDRS-TMS was translated to the Q-Motor "glossomotography" assessment (Reilmann et al, 2010), which has been applied in biomarker studies (Tabrizi et al, 2009) and clinical trials (Reilmann et al, 2015) and now translated to the "Tongue Test" for minpigs.…”

“…In addition, a camera is connected to the computer and the software, to allow for independent scoring and internal quality control. GAITRite ® measures were shown to detect deficits in both manifest and premanifest carriers of the Huntington gene in cross sectional and longitudinal studies (Rao et al, 2011;Rao et al, 2008;Tabrizi et al, 2009) and some correlation of gait disturbances with changes in volumetric imaging was reported. While the GAITRite ® has widely been used to assess gait patterns of humans, its capability has only recently been extended to assess gait patters of quadrupeds using the "GAITfour ® " software (further information about the veterinary use of the GAITRite ® can be found at http://www.gaitrite.com).…”

First use of creatine hydrochloride in premanifest Huntington disease

“…Implementation of a targeted multidisciplinary rehabilitation program into the Huntington's disease population is anticipated to reduce dependence on the health system due to a reduction in the utilisation of health services as a result of a reduction in fall-related injuries, and may delay placement into residential and end-stage facilities by encouraging and maintaining patient independence. Huntington's disease is characterised by progressive cognitive, affective and motor deterioration over a 15-25 year period, together with a spectrum of associated physical deficits including postural instability [6][7][8][9][10] , gait impairments [11][12][13][14][15][16] and lean and fat tissue loss 17,18 .…”

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…The CAG triplets result in an elongated stretch of glutamines in the N-terminal portion of HTT. Motor disorders -including involuntary movements, muscle rigidity (2), impaired balance and coordination (3)(4)(5)(6), and impaired motor skill learning (7,8) -are a prominent feature of behavioral symptoms of HD. The disease usually manifests in midlife and is fatal 10-15 years from the onset of symptoms (9,10).…”