Motor abnormalities in premanifest persons with Huntington's disease: The PREDICT-HD study

University of Rochester, Rochester, New York, USA.
Movement Disorders (Impact Factor: 5.68). 09/2009; 24(12):1763-72. DOI: 10.1002/mds.22601
Source: PubMed


The PREDICT-HD study seeks to identify clinical and biological markers of Huntington's disease in premanifest individuals who have undergone predictive genetic testing. We compared baseline motor data between gene-expansion carriers (cases) and nongene-expansion carriers (controls) using t-tests and Chi-square. Cases were categorized as near, mid, or far from diagnosis using a CAG-based formula. Striatal volumes were calculated using volumetric magnetic resonance imaging measurements. Multiple linear regression associated total motor score, motor domains, and individual motor items with estimated diagnosis and striatal volumes. Elevated total motor scores at baseline were associated with higher genetic probability of disease diagnosis in the near future (partial R(2) 0.14, P < 0.0001) and smaller striatal volumes (partial R(2) 0.15, P < 0.0001). Nearly all motor domain scores showed greater abnormality with increasing proximity to diagnosis, although bradykinesia and chorea were most highly associated with diagnostic immediacy. Among individual motor items, worse scores on finger tapping, tandem gait, Luria, saccade initiation, and chorea show unique association with diagnosis probability. Even in this premanifest population, subtle motor abnormalities were associated with a higher probability of disease diagnosis and smaller striatal volumes. Longitudinal assessment will help inform whether motor items will be useful measures in preventive clinical trials.

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Available from: Kevin Biglan, Mar 10, 2014
    • "Specifically, working memory is among the first cognitive domains to be affected and dysfunctions are characterized by reduced connectivity in frontostriatal and frontoparietal networks in mHD [Wolf et al., 2008a, 2008b], as well as by volume loss in anterior cingulate cortex, parietal lobe, and striatum [Rosas et al., 2008; Tabrizi et al., 2009]. Also, deficits in executive functions, including motor control [Biglan et al., 2009; Kl€ oppel et al., 2009a], cognitive flexibility [Hanes et al., 1995; O'Rourke et al., 2011; Paulsen et al., 1995], and inhibitory control mechanisms [Georgiou-Karistianis et al., 2007, 2014; Kl€ oppel et al., 2008; Rao et al., 2014], have been confirmed for both pre-HD and mHD and are possibly the result of striatal atrophy, as well as of volume loss in prefrontal regions [Lawrence, 1998; Rosas et al., 2003]. Moreover , impairments in striatum, amygdala, pallidum, and insula [Henley et al., 2012; Thieben et al., 2002], all considered to be part of the limbic loop [Douaud et al., 2006], may account for the deficits in emotion recognition that are observed in pre-HD and mHD [Gray et al., 1997; Henley et al., 2012; Hennenlotter et al., 2004; Milders et al., 2003; Sprengelmeyer et al., 1996, 2006]. "
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    ABSTRACT: Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel-based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre-specified motor, working memory, cognitive flexibility, and social-affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre-HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre-HD were observed, but increased positive correlations were evident for mHD, relative to pre-HD and HC. These findings could be explained by a HD-related neuronal loss heterogeneously affecting the examined network at the pre-HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow-up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 10/2015; DOI:10.1002/hbm.23014 · 5.97 Impact Factor
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    • "and PREDICT-HD Investigators and Coordinators of the Huntington Study Group 2006 , 2008 ; Duff et al . , 2007 ; Biglan et al . , 2009"
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    ABSTRACT: There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.
    Frontiers in Aging Neuroscience 04/2014; 6:78. DOI:10.3389/fnagi.2014.00078 · 4.00 Impact Factor
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    • "The performance of prHD subjects provided an opportunity to assess whether subtle deficits in motor skill learning emerge prior to the time of clinical diagnosis. Previous studies have described abnormalities of movement execution (De Boo et al., 1997; Kirkwood et al., 1999, 2000; Smith et al., 2000; Farrow et al., 2006; Rao et al., 2008; Biglan et al., 2009; Tabrizi et al., 2009), dual-task motor control (Mazzoni and Wexler, 2009), and sequence learning (Ghilardi et al., 2008). At the group level, we found that prHD subjects performed similarly to CTL subjects in motor execution and skill learning. "
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    ABSTRACT: The basal ganglia are known to play a crucial role in movement execution, but their importance for motor skill learning remains unclear. Obstacles to our understanding include the lack of a universally accepted definition of motor skill learning (definition confound), and difficulties in distinguishing learning deficits from execution impairments (performance confound). We studied how healthy subjects and subjects with a basal ganglia disorder learn fast accurate reaching movements. We addressed the definition and performance confounds by: (1) focusing on an operationally defined core element of motor skill learning (speed-accuracy learning), and (2) using normal variation in initial performance to separate movement execution impairment from motor learning abnormalities. We measured motor skill learning as performance improvement in a reaching task with a speed-accuracy trade-off. We compared the performance of subjects with Huntington's disease (HD), a neurodegenerative basal ganglia disorder, to that of premanifest carriers of the HD mutation and of control subjects. The initial movements of HD subjects were less skilled (slower and/or less accurate) than those of control subjects. To factor out these differences in initial execution, we modeled the relationship between learning and baseline performance in control subjects. Subjects with HD exhibited a clear learning impairment that was not explained by differences in initial performance. These results support a role for the basal ganglia in both movement execution and motor skill learning.
    Frontiers in Human Neuroscience 11/2013; 7:752. DOI:10.3389/fnhum.2013.00752 · 3.63 Impact Factor
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