Basal ganglia‐cortical structural connectivity in Huntington's disease

Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine‐adenine‐guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia‐cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia‐cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3‐Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel‐based analyses of probabilistic tractography were used to quantify basal ganglia‐cortical structural connections. Canonical variate analysis was used to demonstrate disease‐associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia‐cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity. Hum Brain Mapp 36:1728–1740, 2015. © 2015 Wiley Periodicals, Inc.

[1]  Sarah A. J. Reading,et al.  Regional white matter change in pre-symptomatic Huntington's disease: A diffusion tensor imaging study , 2005, Psychiatry Research: Neuroimaging.

[2]  Daniel C. Alexander,et al.  Probabilistic Monte Carlo Based Mapping of Cerebral Connections Utilising Whole-Brain Crossing Fibre Information , 2003, IPMI.

[3]  A W Toga,et al.  Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington's disease. , 2012, Cerebral cortex.

[4]  Jane S. Paulsen,et al.  Unified Huntington's disease rating scale: Reliability and consistency , 1996, Movement disorders : official journal of the Movement Disorder Society.

[5]  Karl J. Friston,et al.  Functional Connectivity: Eigenimages and multivariate analyses , 2003 .

[6]  C. Schönfeldt-Lecuona,et al.  Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease , 2008, Experimental Neurology.

[7]  David S Tuch,et al.  Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures , 2006, Movement disorders : official journal of the Movement Disorder Society.

[8]  Nick C Fox,et al.  Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data , 2009, The Lancet Neurology.

[9]  C. Schönfeldt-Lecuona,et al.  Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load , 2008, European journal of neurology.

[10]  John L Bradshaw,et al.  A longitudinal diffusion tensor imaging study in symptomatic Huntington's disease , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[11]  W. Heindel,et al.  fMRI reveals altered auditory processing in manifest and premanifest Huntington's disease , 2008, Neuropsychologia.

[12]  Jane S. Paulsen,et al.  Diffusion Tensor Imaging in Preclinical Huntington’s Disease , 2009, Brain Imaging and Behavior.

[13]  W. Hauser,et al.  A comparison of self-report and caregiver assessment of depression, apathy, and irritability in Huntington's disease. , 2005, The Journal of neuropsychiatry and clinical neurosciences.

[14]  D. Sah,et al.  Oligonucleotide therapeutic approaches for Huntington disease. , 2011, The Journal of clinical investigation.

[15]  G. Gioia,et al.  Behavior Rating Inventory for Executive Function , 2000 .

[16]  Andrea Bergmann,et al.  Statistical Parametric Mapping The Analysis Of Functional Brain Images , 2016 .

[17]  Stefan Klöppel,et al.  White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington's disease. , 2008, Brain : a journal of neurology.

[18]  G. Egan,et al.  Connectivity-based segmentation of the striatum in Huntington's disease: Vulnerability of motor pathways , 2011, Neurobiology of Disease.

[19]  R. Turner,et al.  Characterizing Dynamic Brain Responses with fMRI: A Multivariate Approach , 1995, NeuroImage.

[20]  G. Huston.  The Hospital Anxiety and Depression Scale. , 1987, The Journal of rheumatology.

[21]  Timothy Edward John Behrens,et al.  In vivo evidence for the selective subcortical degeneration in Huntington's disease , 2009, NeuroImage.

[22]  M. MacDonald,et al.  CAG repeat number governs the development rate of pathology in Huntington's disease , 1997, Annals of neurology.

[23]  S. Lehéricy,et al.  The structural correlates of functional deficits in early huntington's disease , 2013, Human brain mapping.

[24]  Jeroen van der Grond,et al.  Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington's disease , 2012, Human brain mapping.

[25]  Jane S. Paulsen,et al.  fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's Disease. , 2004, AJNR. American journal of neuroradiology.

[26]  D. Aquino,et al.  Decreased Diffusivity in the Caudate Nucleus of Presymptomatic Huntington Disease Gene Carriers: Which Explanation? , 2010, American Journal of Neuroradiology.

[27]  P. Basser,et al.  Estimation of the effective self-diffusion tensor from the NMR spin echo. , 1994, Journal of magnetic resonance. Series B.

[28]  M. A. Gray,et al.  Automated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: The IMAGE-HD study , 2013, Neurobiology of Disease.

[29]  Chris Frost,et al.  Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data , 2012, The Lancet Neurology.

[30]  R. Ferrante,et al.  Neuropathological Classification of Huntington's Disease , 1985, Journal of neuropathology and experimental neurology.

[31]  Wilhelm Gaus,et al.  Evidence for more widespread cerebral pathology in early HD: An MRI-based morphometric analysis , 2004, Neurology.

[32]  A. Aron,et al.  Contrasting gray and white matter changes in preclinical Huntington disease , 2010, Neurology.

[33]  Jane S. Paulsen,et al.  fMRI detection of early neural dysfunction in preclinical Huntington's disease , 2007, Journal of the International Neuropsychological Society.

[34]  Mario Mascalchi,et al.  Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain. , 2004, Radiology.

[35]  J. Brandt,et al.  Reduced basal ganglia volume associated with the gene for Huntington's disease in asymptomatic at‐risk persons , 1994, Neurology.

[36]  Kurt E. Weaver,et al.  Longitudinal diffusion tensor imaging in Huntington's Disease , 2009, Experimental Neurology.

[37]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[38]  Richard S. J. Frackowiak,et al.  Evidence for Segregated and Integrative Connectivity Patterns in the Human Basal Ganglia , 2008, The Journal of Neuroscience.

[39]  M. Catani,et al.  The rises and falls of disconnection syndromes. , 2005, Brain : a journal of neurology.

[40]  G. Gioia,et al.  TEST REVIEW Behavior Rating Inventory of Executive Function , 2000 .

[41]  Christine Delmaire,et al.  Mapping Cortico-Striatal Connectivity onto the Cortical Surface: A New Tractography-Based Approach to Study Huntington Disease , 2013, PloS one.

[42]  Frederik Maes,et al.  Diffusion-weighted versus volumetric imaging of the striatum in early symptomatic Huntington disease , 2009, Journal of Neurology.

[43]  Kalvis M. Jansons,et al.  Persistent angular structure: new insights from diffusion magnetic resonance imaging data , 2003 .

[44]  Jean-Francois Mangin,et al.  Analysis of the Striato-Thalamo-Cortical Connectivity on the Cortical Surface to Infer Biomarkers of Huntington's Disease , 2010, MICCAI.

[45]  Karl J. Friston,et al.  A multivariate analysis of PET activation studies , 1996, Human brain mapping.

[46]  Daniel C. Alexander,et al.  Camino: Open-Source Diffusion-MRI Reconstruction and Processing , 2006 .

[47]  Anusha Sritharan,et al.  Diffusion Tensor Imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits , 2011, Brain Imaging and Behavior.

[48]  A Weindl,et al.  Neural correlates associated with impaired disgust processing in pre-symptomatic Huntington's disease. , 2004, Brain : a journal of neurology.

[49]  Klaus Seppi,et al.  Diffusion‐weighted imaging in Huntington's disease , 2006, Movement disorders : official journal of the Movement Disorder Society.

[50]  A. Young,et al.  Impaired recognition of disgust in Huntington's disease gene carriers. , 1997, Brain : a journal of neurology.

[51]  Richard S. Frackowiak,et al.  Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease , 2012, Brain : a journal of neurology.

[52]  Anders M. Dale,et al.  An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest , 2006, NeuroImage.

[53]  Alan Connelly,et al.  Robust determination of the fibre orientation distribution in diffusion MRI: Non-negativity constrained super-resolved spherical deconvolution , 2007, NeuroImage.

[54]  M. A. Gray,et al.  Prefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: The IMAGE-HD study , 2013, Experimental Neurology.

[55]  Peng Yu,et al.  Altered white matter microstructure in the corpus callosum in Huntington's disease: Implications for cortical “disconnection” , 2010, NeuroImage.

[56]  David I. Perrett,et al.  Facial expressions of emotion: Stimuli and tests (FEEST) , 2002 .

[57]  Richard S. J. Frackowiak,et al.  Irritability in pre-clinical Huntington's disease , 2010, Neuropsychologia.

[58]  P. S. Achilles.  THE PSYCHOLOGICAL CORPORATION. , 1923, Science.

[59]  Chris Frost,et al.  Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis , 2011, The Lancet Neurology.

[60]  John Ashburner,et al.  A fast diffeomorphic image registration algorithm , 2007, NeuroImage.

[61]  M Filippi,et al.  Regional Distribution and Clinical Correlates of White Matter Structural Damage in Huntington Disease: A Tract-Based Spatial Statistics Study , 2010, American Journal of Neuroradiology.

[62]  G. Egan,et al.  White matter connectivity reflects clinical and cognitive status in Huntington's disease , 2014, Neurobiology of Disease.