Objective: To characterize white matter changes in Huntington’s Disease (HD).

Background: HD is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Diffusion Tensor Imaging (DTI) studies have revealed significant disruptions in white matter integrity in HD gene expansion carriers (HDGECs), particularly in the corpus callosum and corticostriatal pathways – regions crucial for motor control and cognitive function [1–3]. Previous studies highlight the complexity and variability of white matter changes in HD, emphasizing the need for further investigation on this topic.

Method: This study included 46 participants: 15 controls, 15 premanifest, and 16 manifest HDGECs (age=47.6±11.1 years, 31F/15M). Diffusion-weighted MRIs were acquired on a 3T Philips Ingenia scanner. TRACULA (from FreeSurfer 7.2) was used to reconstruct major white matter pathways via probabilistic tractography, incorporating anatomical priors [4, 5]. Tract-averaged Fractional Anisotropy (FA) and Mean Diffusivity (MD) were computed for each tract to characterize microstructural integrity. Clinical evaluation included motor, cognitive, and behavioral assessments. Group differences were analyzed using ANOVA with Tukey’s post hoc test, and correlations between FA, MD, and clinical measures were examined in HDGECs.

Results: Manifest HD patients exhibited significant and widespread white matter degeneration. MD was significantly increased in manifest HD compared to both premanifest HD and control groups across all pathways, except for the middle cerebellar peduncle [Table 1]. A corresponding decrease in FA was observed in many pathways in manifest HD compared to the other groups [Table 1, Figure 1]. No significant differences were found between the premanifest HD and controls. Additionally, greater white matter deterioration was significantly correlated with poorer performance on motor, functional capacity, and cognitive scales [Table 2].

Conclusion: White matter degeneration is linked to the clinical onset of HD, with widespread alterations observed in the manifest phase. HD-related white matter deterioration is significantly associated with clinical severity, as reflected in motor and cognitive symptoms, as well as functional capacity. Our findings underscore the potential of DTI metrics as sensitive biomarkers for tracking disease progression and efficacy of therapeutic interventions.

Funding: HDSA

Table 1

Table 2

Figure 1

References: 1. Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington’s Disease Clinical Trials Corner: March 2024. Journal of Huntington’s Disease. 2024;13:1–14.
2. Blumenstock S, Dudanova I. Cortical and Striatal Circuits in Huntington’s Disease. Front Neurosci. 2020;14.
3. Diana Rosas H, Lee SY, Bender A, Zaleta AK, Vange M, Yu P, et al. Altered White Matter Microstructure in the Corpus Callosum in Huntington’s Disease: implications for cortical “disconnection.” Neuroimage. 2010;49:2995–3004.
4. Maffei C, Lee C, Planich M, Ramprasad M, Ravi N, Trainor D, et al. Using diffusion MRI data acquired with ultra-high gradient strength to improve tractography in routine-quality data. Neuroimage. 2021;245:118706.
5. Yendiki A, Panneck P, Srinivasan P, Stevens A, Zöllei L, Augustinack J, et al. Automated probabilistic reconstruction of white-matter pathways in health and disease using an atlas of the underlying anatomy. Front Neuroinform. 2011;5:23.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/widespread-white-matter-changes-in-manifest-huntingtons-disease/