Huntington’s Disease (HD) is a rare neurodegenerative disease caused by cytosine-adenine guanine (CAG) repeat expansion on the Huntingtin (HTT) gene (Bates et al., 2015). Whilst the striatum remains the principal site of disease-related damage in HD (Domínguez et al., 2016; Georgiou-Karistianis, Scahill, et al., 2013), there is evidence that as the disease advances, alterations to the morphology of the cortical surface occur (Kubera et al., 2019; Nopoulos et al., 2007; H D Rosas et al., 2005; Shishegar et al., 2019; Tabrizi et al., 2011). These changes have been reported to differentially occur in specific regions of the brain at varying stages of disease (H D Rosas et al., 2005; Tan et al., 2022). Specifically, the visual and primary motor cortices have been identified as the two regions that experience the most pronounced cortical morphometry alterations in HD (Kubera et al., 2019; Tabrizi et al., 2009; Tan et al., 2022), with anterior frontal and parietal regions becoming involved as the disease progresses (H D Rosas et al., 2005). One recent study found that pre-symptomatic HD (pre-HD, i.e. individuals who have tested positive for the HD gene but not developed clinical diagnosis) and symptomatic HD (symp-HD, i.e. those who have tested positive for the HD gene and received a clinical diagnosis) demonstrated significant differences in local gyrification index (LGI), a measure of the foldedness of the brain, compared to controls (Tan et al., 2022). Furthermore, there is evidence that whilst pre-HD (and symp-HD individuals experience LGI abnormalities at baseline in the lateral occipital region, only the symp-HD group demonstrated longitudinal change in this area (Tan et al., 2022). Such a finding highlights the possibility that there may be an unidentified process that occurs throughout the symptomatic stage of the disease, that causes these cortical changes. However, the biological mechanisms underpinning changes to cortical morphometry in these regions is not adequately understood.
One proposed hypothesis for changes to cortical morphometry in HD is that a flattened gyrus is a result of reduced white matter tension to these regions (Tan et al., 2022; Van Essen, 1997) resulting in reduced LGI. Another, theory posits that disease related toxic agents (i.e. mutant huntingtin protein) proliferates along axonal pathways, propagating from the striatum to the cortical surface (Babcock & Ganetzky, 2015). This hypothesis is supported by studies that have found white matter tracts degenerate throughout HD (Tabrizi et al., 2013) along specific white matter networks (Govinda R Poudel et al., 2014, 2015). Mapping of white matter networks has shown that white matter degeneration is not uniform (Govinda R Poudel et al., 2015). Tractography analyses in HD have focused on the frontal and parietal (Aylward et al., 2011; Bourbon-Teles et al., 2019; Tabrizi et al., 2013) lobes with particular vulnerability identified in the posterior frontal region (Govinda R Poudel et al., 2015; H Diana Rosas et al., 2006). A longitudinal analysis of white matter connectivity in HD found longitudinal degeneration of white matter connectivity was not uniform, and symp-HD individuals were more vulnerable to white matter microstructure change, compared to pre-HD. It was also reported that clinical and motor symptoms predicted longitudinal white matter microstructure change in symp-HD (Govinda R Poudel et al., 2015).
At present there have been no other studies examining the longitudinal relationship between white matter degeneration and cortical morphometry changes in both pre-HD and symp-HD individuals. Thus, the time course of various regions considered most vulnerable throughout the disease is inadequately understood. Prevailing questions remain, such as: i) which stage of disease do these changes occur in relation to one another; ii) whether white matter degeneration predicts cortical morphometry changes; and iii) whether these processes occur independently of one another. The present study aimed to answer these questions by investigating whether baseline white matter integrity predicted cortical morphometry changes over time in specific gyral based regions of interest in both pre-HD and symp-HD individuals. We also aimed to investigate whether these changes could predict change in clinical outcome measures using the Unified Huntington’s Disease Rating Scale – Total Motor Score (UHDRS-TMS) and disease burden score (DBS). We selected the pre-central, post-central, superior, inferior parietal and lateral occipital regions from the well-validated Desikan-Killiany brain atlas (Desikan et al., 2006) as the five specific regions of interest for our analysis. These regions were specifically chosen based on previous findings that the visual, primary motor and parietal cortices are those that experience the most pronounced cortical morphometry and white matter alterations in HD (Kubera et al., 2019; Govinda R Poudel et al., 2015; H Diana Rosas et al., 2006; Tan et al., 2022).