Elsevier

Neurobiology of Disease

Volume 65, May 2014, Pages 180-187
Neurobiology of Disease

White matter connectivity reflects clinical and cognitive status in Huntington's disease,☆☆,

https://doi.org/10.1016/j.nbd.2014.01.013Get rights and content

Highlights

  • We examined white matter connectivity in HD using DTI tractography.

  • Neuroanatomical networks aberrant in premanifest and symptomatic HD were isolated.

  • Integrity of putamen-prefrontal network was associated with cognitive dysfunction in presymptomatic HD.

  • Integrity of fronto-parietal tract was associated with clinical symptoms.

Abstract

Objective

To investigate structural connectivity and the relationship between axonal microstructure and clinical, cognitive, and motor functions in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease.

Method

Diffusion tensor imaging (DTI) data were acquired from 35 pre-HD, 36 symp-HD, and 35 controls. Structural connectivity was mapped between 40 brain regions of interest using tractography. Between-group differences in structural connectivity were identified using network based statistics. Radial diffusivity (RD) and fractional anisotropy (FA) were compared in the white matter tracts from aberrant networks. RD values in aberrant tracts were correlated with clinical severity, and cognitive and motor performance.

Results

A network connecting putamen with prefrontal and motor cortex demonstrated significantly reduced tractography streamlines in pre-HD. Symp-HD individuals showed reduced streamlines in a network connecting prefrontal, motor, and parietal cortices with both caudate and putamen. The symp-HD group, compared to controls and pre-HD, showed both increased RD and decreased FA in the fronto-parietal and caudate-paracentral tracts and increased RD in the putamen-prefrontal and putamen-motor tracts. The pre-HDclose, compared to controls, showed increased RD in the putamen-prefrontal and fronto-parietal tracts. In the pre-HD group, significant negative correlations were observed between SDMT and Stroop performance and RD in the bilateral putamen-prefrontal tract. In the symp-HD group, RD in the fronto-parietal tract was significantly positively correlated with UHDRS motor scores and significantly negatively correlated with performance on SDMT and Stroop tasks.

Conclusions

We have provided evidence of aberrant connectivity and microstructural integrity in white matter networks in HD. Microstructural changes in the cortico-striatal fibers were associated with cognitive and motor performance in pre-HD, suggesting that changes in axonal integrity provide an early marker for clinically relevant impairment in HD.

Introduction

Neuropathological processes in Huntington's disease (HD) primarily target medium spiny neurons of the striatum (Graveland et al., 1985). Neurodegeneration is also seen in pyramidal projection neurons in the motor and prefrontal cortices, and cingulate and angular gyri (Macdonald and Halliday, 2002, Thu et al., 2010). Together, these neurodegenerative changes are considered to be the cause of onset of clinical symptoms in HD (Thu et al., 2010). In contrast, the mechanisms underlying cognitive changes, which often appear several years before clinical diagnosis, remain largely unknown.

Disruption of structural connectivity in specific neural circuits has been proposed to be one of the possible mechanisms leading to early cognitive and motor changes in premanifest Huntington's disease (pre-HD) (Li and Conforti, 2013). Structural connectivity can deteriorate in HD due to axonal dysfunction and degeneration associated with huntingtin aggregates which can appear early in HD (reviewed by Li and Conforti, 2013). Hence, white matter atrophy is evident in T1-weighted neuroimaging studies of HD (Tabrizi et al., 2009, Thieben et al., 2002), with posterior-frontal white-matter degeneration apparent even in individuals far from onset (Tabrizi et al., 2009). Diffusion tensor imaging (DTI) studies of HD have also suggested selective microstructural changes in white matter encompassing cortico-striatal motor circuit, corpus callosum, periventricular region, corona radiata, and prefrontal cortex (Bohanna et al., 2011, Dumas et al., 2012, Rosas et al., 2006, Rosas et al., 2010, Weaver et al., 2009).

DTI also enables investigation of axonal fibers between gray matter structures using tractography methods (Bohanna et al., 2011, Jones, 2008). DTI tractography has been used in HD to isolate structural connections in specific neuroanatomical circuits including the motor loop and fronto-striatal circuit (Bohanna et al., 2011, Dumas et al., 2012, Kloppel et al., 2008), providing evidence for circuit specific alterations in white matter microstructure in HD. For example, microstructural damage in the striatal nodes of the motor loop has been shown to be associated with motor dysfunction in HD (Bohanna et al., 2011). Structural connectivity changes of the fronto-caudal tracts have been shown not only to reflect years to onset, but also to be associated with oculomotor function in pre-HD (Kloppel et al., 2008). Moreover, reduced fiber connectivity between the prefrontal cortex and the caudate has been shown to reflect symptomatology in pre-HD (Kloppel et al., 2008). DTI-tractography has also been used to determine pair-wise connections between gray matter structures in the brain enabling calculation of a structural connectivity matrix for individual subjects (Zalesky et al., 2010). Network-based statistical methods can be used to isolate network connections that are altered in disease from the connectivity matrix (Zalesky et al., 2010, Zalesky et al., 2011). The identification of structural networks in pre-HD and symp-HD may provide insight into early markers of disease progression in HD.

The aims of the current study were to identify cortico-striatal networks affected in pre-HD and symp-HD, determine the microstructural alterations in the axonal fibers connecting these pathways, and investigate the relationship between axonal microstructural changes and clinical, cognitive and motor functions in pre-HD and symp-HD. We hypothesized that structural connectivity in neural circuits connecting motor and prefrontal cortices with the caudate and putamen would be affected in both pre-HD and symp-HD. Microstructural white matter degeneration in symp-HD has been reported in the body of the corpus callosum, which structurally connects frontal and parietal areas (Rosas et al., 2010). We hypothesized that symp-HD individuals would show further white matter structural disconnectivity in the fronto-parietal network. Fronto-striatal neural circuits are crucial for cognitive control (Liston et al., 2006). We hypothesized that the microstructural integrity of the fronto-striatal tracts would be associated with cognitive dysfunction in both pre-HD and symp-HD. To test these hypotheses, tractography was used to identify the extent of axonal connectivity between 40 neocortico and striatal brain regions. A network-based statistical method (Zalesky et al., 2010) was used to isolate neuroanatomical networks that showed connectivity differences between the groups. DTI-based measures of radial diffusivity (RD) are thought to be sensitive to demyelinative processes (Song et al., 2005). We measured RD values from the tracts identified as aberrant in pre-HD and symp-HD, and investigated the relationship of RD changes with clinical severity, and cognitive and motor performance.

Section snippets

Participants

Thirty-five pre-HD, 36 symp-HD, and 35 healthy control volunteers were included in this investigation, all recruited as part of the Australian-based IMAGE-HD study (Georgiou-Karistianis et al., 2013, Georgiou-Karistianis et al., in press, Gray et al., 2013). Recruitment procedures and inclusion criteria have been published previously (Georgiou-Karistianis et al., 2013). Controls were matched to pre-HD participants for age, gender and IQ [National Adult Reading Test 2nd edition, NART-2 (Nelson

Results

A total of (17 ± 1) × 104 streamlines were generated on average for each participant. There were no significant differences in total number of streamlines generated between groups (pre-HD: (17 ± 1) × 104; symp-HD: (17 ± 2) × 104; controls: (17 ± 2) × 104; pre-HD versus controls: t = 1.6, p = 0.12; symp-HD versus controls: t = 1.4, p = 0.17).

Discussion

This study investigated white matter connectivity between frontal, parietal, and striatal brain regions in Huntington's disease using DTI fiber deterministic tractography and network based statistical analysis. A neuroanatomical network connecting putamen with prefrontal and motor cortices showed reduced white matter connectivity and microstructural changes in pre-HD compared with healthy controls. Symp-HD showed impairment in a network connecting frontal and parietal cortices, and striatum. RD

Acknowledgments

We would like to acknowledge the contribution of all the participants who took part in this study. We are also grateful to the CHDI Foundation Inc. (grant number A-3433), New York (USA), and to the National Health and Medical Research Council (NHMRC) (grant number 606650) for their support in funding this research. This research was supported by the VLSCI's Life Sciences Computation Centre, in collaboration with Melbourne, Monash and La Trobe Universities and this research is also an initiative

References (42)

  • S.J. Tabrizi et al.

    Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data

    Lancet Neurol.

    (2009)
  • J.D. Tournier et al.

    Resolving crossing fibres using constrained spherical deconvolution: validation using diffusion-weighted imaging phantom data

    NeuroImage

    (2008)
  • N. Tzourio-Mazoyer et al.

    Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain

    NeuroImage

    (2002)
  • C.M. Waters et al.

    Immunocytochemical studies on the basal ganglia and substantia nigra in Parkinson's disease and Huntington's chorea

    Neuroscience

    (1988)
  • K.E. Weaver et al.

    Longitudinal diffusion tensor imaging in Huntington's Disease

    Exp. Neurol.

    (2009)
  • A. Zalesky et al.

    Network-based statistic: identifying differences in brain networks

    NeuroImage

    (2010)
  • A. Zalesky et al.

    Disrupted axonal fiber connectivity in schizophrenia

    Biol. Psychiatry

    (2011)
  • R.L. Albin et al.

    Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia

    Ann. Neurol.

    (1990)
  • F. Bai et al.

    Topologically convergent and divergent structural connectivity patterns between patients with remitted geriatric depression and amnestic mild cognitive impairment

    J. Neurosci.

    (2012)
  • T.E. Conturo et al.

    Tracking neuronal fiber pathways in the living human brain

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • C. Delmaire et al.

    The structural correlates of functional deficits in early Huntington's disease

    Hum. Brain Mapp.

    (2013)
  • Cited by (0)

    Statistical analysis was performed by Dr Govinda R. Poudel School of Psychological Sciences; Monash Biomedical Imaging (MBI), Monash University, VIC, Australia.

    ☆☆

    Author contributions: Govinda Poudel was involved in drafting/revising the manuscript for content; study concept or design; analysis or interpretation of data and statistical analysis. Julie C. Stout was involved in drafting/revising the manuscript for content; study concept or design; analysis or interpretation of data and obtainment of funding. Juan F. Domínguez D was involved in drafting/revising the manuscript for content; analysis or interpretation of data and acquisition of data. Louisa Salmon was involved in drafting/revising the manuscript for content; analysis or interpretation of data and acquisition of data. Andrew Churchyard was involved in the study concept or design; obtainment of funding and acquisition of data. Phyllis Chua was involved in the study concept or design; obtainment of funding and acquisition of data. Nellie Georgiou-Karistianis was involved in drafting/revising the manuscript for content; study concept or design; analysis or interpretation of data; obtainment of funding and study supervision or coordination. Gary F. Egan was involved in drafting/revising the manuscript for content; study concept or design; analysis or interpretation of data; obtainment of funding and study supervision or coordination.

    Author Disclosures: All authors have no relevant biomedical, financial or potential conflicts of interest to declare.

    View full text