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
    • "Chorea and oculomotor impairment are among the first signs that discriminate individuals with CAG expansions in the prodromal phase from non-gene-expanded individuals (Biglan et al., 2009; Paulsen, 2010). Oculomotor functions are classified into several different categories (Leigh & Zee, 1999) and typically include ocular pursuit and saccades, both of which are commonly affected in prodromal and early HD patients. "
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    ABSTRACT: Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.
    No preview · Article · Feb 2016 · Journal of Clinical and Experimental Neuropsychology
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    • "HD disease-specific effects have been observed in fronto-striatal and fronto-parietal networks (Klöppel et al., 2008, 2010; Rosas et al., 2008; Wolf et al., 2008, 2011, 2012; Tabrizi et al., 2009), affecting essential cognitive, motor and executive domains. Specifically, deficits in motor functioning are a clinical hallmark of HD, as indicated by previous functional magnetic resonance imaging (fMRI) studies (Biglan et al., 2009; Klöppel et al., 2009), and are possibly caused by striatal atrophy as well as volume loss in prefrontal areas (Lawrence, 1998; Rosas et al., 2003). Furthermore, diffusion tensor imaging (DTI) studies have indicated disease-specific changes in overall white matter diffusivity, correlated with caudate and white matter volume loss (Novak et al., 2014), as well as alterations in striatal projection pathways and their associations with clinical motor data (Poudel et al., 2014) in earlyHD and to varying extent in preHD. "
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    ABSTRACT: Deficits in motor functioning are one of the hallmarks of Huntington's disease (HD), a genetically caused neurodegenerative disorder. We applied functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to assess changes that occur with disease progression in the neural circuitry of key areas associated with executive and cognitive aspects of motor control. Seventy-seven healthy controls, 62 pre-symptomatic HD gene carriers (preHD), and 16 patients with manifest HD symptoms (earlyHD) performed a motor finger-tapping fMRI task with systematically varying speed and complexity. DCM was used to assess the causal interactions among seven pre-defined regions of interest, comprising primary motor cortex, supplementary motor area (SMA), dorsal premotor cortex, and superior parietal cortex. To capture heterogeneity among HD gene carriers, DCM parameters were entered into a hierarchical cluster analysis using Ward's method and squared Euclidian distance as a measure of similarity. After applying Bonferroni correction for the number of tests, DCM analysis revealed a group difference that was not present in the conventional fMRI analysis. We found an inhibitory effect of complexity on the connection from parietal to premotor areas in preHD, which became excitatory in earlyHD and correlated with putamen atrophy. While speed of finger movements did not modulate the connection from caudal to pre-SMA in controls and preHD, this connection became strongly negative in earlyHD. This second effect did not survive correction for multiple comparisons. Hierarchical clustering separated the gene mutation carriers into three clusters that also differed significantly between these two connections and thereby confirmed their relevance. DCM proved useful in identifying group differences that would have remained undetected by standard analyses and may aid in the investigation of between-subject heterogeneity.
    Full-text · Article · Nov 2015 · Frontiers in Human Neuroscience
    • "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.
    No preview · Article · Oct 2015 · Human Brain Mapping
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