Microstructural brain abnormalities in Huntington's disease: A two‐year follow‐up

Odish, Omar F. F.; Leemans, Alexander; Reijntjes, R.; Bogaard, Simon J.A. van den; Dumas, Eve M.; Wolterbeek, Ron; Tax, Chantal M. W.; Kuijf, Hugo J.; Vincken, Koen L.; Roos, Raymund A.C.

doi:10.1002/hbm.22756

Cited by 29 publications

(31 citation statements)

References 74 publications

(95 reference statements)

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“…We revealed that longitudinal increases in MD of the SFOF were prominent as individuals approached a motor diagnosis and correlated with disease burden. Past studies of prHD have not uncovered significant 18‐ to 24‐month longitudinal changes in WM using histogram analyses of the entire brain or skeleton‐based analyses of central WM fibers . Reasons for the discrepancies are unknown, but may relate to different analytic approaches and/or small prHD samples (ie, 22 to 28).…”

Section: Discussionmentioning

confidence: 99%

“…Although WM pathology correlates with disease burden in some studies, longitudinal studies are needed to chart the course of disease progression. However, most longitudinal dMRI studies of prHD have not found abnormal 12‐ to 30‐month changes in diffusivity profiles of whole‐brain WM, centers of WM tracts, or the striatum, although the latter result may relate to limitations of the tensor model in GM. Longitudinal dMRI findings contrast with 12‐ to 24‐month striatal, GM, and WM volume loss in prHD, suggesting that volumetric measures may be more sensitive to longitudinal changes.…”

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confidence: 98%

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Cross‐sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease

et al. 2016

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Objectives Diffusivity in white-matter tracts is abnormal throughout the brain in cross-sectional studies of prodromal Huntington’s disease. To date, longitudinal changes have not been observed. The present study investigated cross-sectional and longitudinal changes in white-matter diffusivity in relationship to the phase of prodromal Huntington’s progression, and compared them with changes in brain volumes and clinical variables that track disease progression. Methods Diffusion MRI profiles were studied over two years in 37 gene-negative controls and 64 prodromal Huntington’s disease participants in varied phases of disease progression. To estimate the relative importance of diffusivity metrics in the prodromal phase, group effects were rank ordered relative to those obtained from analyses of brain volumes, motor, cognitive and sensory variables. Results First, at baseline diffusivity was abnormal throughout all tracts, especially as individuals approached a manifest Huntington’s disease diagnosis. Baseline diffusivity metrics in six tracts and basal ganglia volumes best distinguished amongst the groups. Second, group differences in longitudinal change in diffusivity were localized to the superior fronto-occipital fasciculus, most prominently in individuals closer to a diagnosis. Group differences were also observed in longitudinal changes of most brain volumes, but not clinical variables. Lastly, increases in motor symptoms across time were associated with greater changes in the superior fronto-occipital fasciculus diffusivity and corpus callosum, cerebrospinal fluid, and lateral ventricle volumes. Conclusions These novel findings provide new insights into changes within two years in different facets of brain structure and their clinical relevance to changes in symptomatology that is decisive for a manifest Huntington’s diagnosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

Cross‐sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease

et al. 2016

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“…Diffusivity is an indirect marker of white matter tract organization. Increases of diffusivity across both the whole brain and in select white matter pathways, such as within the sensorimotor network, are suggestive of white matter degeneration in premanifest (preHD) and early manifest HD (Della Nave et al, 2010; Douaud et al, 2009; Dumas et al, 2012; Klöppel et al, 2008; Matsui et al, 2014; Novak et al, 2014; Odish et al, 2015; Poudel et al, 2014, 2015). In a recent study of the sensorimotor network, we observed a broad structural HD phenotype that encompassed gray and white matter volume, cortical thickness, and altered diffusivity in left white matter tracts in the sensorimotor network, which was associated with CAG repeat length (Orth et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Gregory

Crawford

Seunarine

et al. 2018

Human Brain Mapping

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Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG‐repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome‐wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene‐carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD‐related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene‐carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally‐occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function.

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“…Recently, several longitudinal clinical studies have been performed. They showed a decrease in creatine and other metabolites (myo-inositol, N-acetylaspartate and choline) in striatum, white matter axial diffusivity and connectome changes in HD gene carriers during disease onset [44][45][46]. Various changes in brain metabolite concentration have also been found in different HD animal models (mice, non-human primates).…”

Section: Magnetic Resonance Imaging (Mri) and Spectroscopy (Mrs)mentioning

confidence: 90%

Porcine Model of Huntington's Disease

Rausova¹,

Vochozková²,

Vidinská³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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At present, we are probably the only research facility to be breeding transgenic Huntington's disease minipigs (TgHD). These minipigs express N-terminal part of human mutated huntingtin including 124Q under the control of human huntingtin promoter. The founder animal, born in 2009, gave birth to four subsequent generations with an equal contribution of wild-type (WT) and transgenic (TgHD) piglets in all litters. We take different approaches, some of which are unique for large animal models, to study the phenotype development comparing WT and TgHD siblings. In this chapter, we review these approaches and the phenotype progression in the minipigs. Additionally, we outline perspectives in generation of new models using novel methodology and the potential of pig models in preclinical HD studies.

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Microstructural brain abnormalities in Huntington's disease: A two‐year follow‐up

Cited by 29 publications

References 74 publications

Cross‐sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease

Cross‐sectional and longitudinal multimodal structural imaging in prodromal Huntington's disease

Natural biological variation of white matter microstructure is accentuated in Huntington's disease

Porcine Model of Huntington's Disease

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