Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington’s disease
Peter McColgan ... Sarah J. Tabrizi, the Track-On HD Investigators
Peter McColgan ... Sarah J. Tabrizi, the Track-On HD Investigators
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e92641. doi:10.1172/jci.insight.92641.
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Categories: Research Article Neuroscience

Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington’s disease

Abstract

We lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington’s disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months. This demonstrates a new principle underlying neurodegeneration in HD, whereby brain connections with the greatest topological length are the first to suffer damage that can account for the stereotyped pattern of white matter loss observed in premanifest HD.

Authors

Peter McColgan, Kiran K. Seunarine, Sarah Gregory, Adeel Razi, Marina Papoutsi, Jeffrey D. Long, James A. Mills, Eileanoir Johnson, Alexandra Durr, Raymund A.C. Roos, Blair R. Leavitt, Julie C. Stout, Rachael I. Scahill, Chris A. Clark, Geraint Rees, Sarah J. Tabrizi, the Track-On HD Investigators

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Hierarchy of connection vulnerability. Mixed linear model results for co...

Figure 2

Hierarchy of connection vulnerability.

Mixed linear model results for connectome analysis: preHD vs. controls. Cortico-striatal connections are most affected, followed by interhemispheric connections and then intrahemispheric connections. (A) Cross-sectional cortico-striatal figure illustrates cross-sectional cortico-striatal differences where premanifest Huntington’s disease (preHD) show reduced connection strength between the striatum (caudate and putamen) and cortical modules. Cross-sectional interhemispheric figure illustrates cross-sectional interhemispheric differences, where preHD show reduced connection strength between left and right hemisphere cortical modules. Cross-sectional intrahemispheric figure illustrates cross-sectional intrahemispheric differences, where preHD show reduced connection strength between left cortical modules and right cortical modules separately (F, front-cingulate; T, temporal; M, motor-occipital-parietal; S, striatum). (B) Connection strength at baseline and 24-month followup for cortico-striatal and interhemispheric connections. Cross-sectional group difference was defined as the intercept main effect of group in the full linear mixed effects model. Longitudinal change was defined as a significantly superior fit for the full Linear mixed effects regression (LMER) compared with the reduced LMER omitting group by time interaction (see Methods for further details), which means that the group by time interaction effect was significant and preHD patients show more connectivity loss over time compared with controls. Data presented as dot plots with group means ± 95% CI at each time point for control (magenta), preHD (green). *P < 0.05, **P <0.01. y-axis: connection strength, x-axis: follow-up time in years. y-axis differs between graphs, as connection strengths vary in range between different connections (486 data points displayed for each figure).