White matter connectivity reflects clinical and cognitive status in Huntington's disease☆,☆☆,★
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
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Cited by (0)
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Statistical analysis was performed by Dr Govinda R. Poudel School of Psychological Sciences; Monash Biomedical Imaging (MBI), Monash University, VIC, Australia.
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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.
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Author Disclosures: All authors have no relevant biomedical, financial or potential conflicts of interest to declare.