Diffusion MRI marks progressive alterations in fiber integrity in the zQ175DN mouse model of Huntington's disease

• Published in: Neurobiology of disease Vol. 193; p. 106438
• Main Authors: Vidas-Guscic, Nicholas, van Rijswijk, Joëlle, Van Audekerke, Johan, Jeurissen, Ben, Nnah, Israel, Tang, Haiying, Muñoz-Sanjuan, Ignacio, Pustina, Dorian, Cachope, Roger, Van der Linden, Annemie, Bertoglio, Daniele, Verhoye, Marleen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2024; Elsevier
• Subjects: Animals; Biomarkers; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Disease Models, Animal; Fixel-based analysis; Humans; Huntington Disease - diagnostic imaging; Huntington Disease - genetics; Huntington's disease; Longitudinal; Mice; Neurodegeneration; Neurodegenerative Diseases; Neurofilament; Preclinical; White Matter - diagnostic imaging; Neurofilament; Longitudinal; Preclinical; Huntington's disease; Neurodegeneration; Fixel-based analysis
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106438

Huntington's disease (HD) is a progressive neurodegenerative disease affecting motor and cognitive abilities. Multiple studies have found white matter anomalies in HD-affected humans and animal models of HD. The identification of sensitive white-matter-based biomarkers in HD animal models will be important in understanding disease mechanisms and testing the efficacy of therapeutic interventions. Here we investigated the progression of white matter deficits in the knock-in zQ175DN heterozygous (HET) mouse model of HD at 3, 6 and 11 months of age (M), reflecting different states of phenotypic progression. We compared findings from traditional diffusion tensor imaging (DTI) and advanced fixel-based analysis (FBA) diffusion metrics for their sensitivity in detecting white matter anomalies in the striatum, motor cortex, and segments of the corpus callosum. FBA metrics revealed progressive and widespread reductions of fiber cross-section and fiber density in myelinated bundles of HET mice. The corpus callosum genu was the most affected structure in HET mice at 6 and 11 M based on the DTI and FBA metrics, while the striatum showed the earliest progressive differences starting at 3 M based on the FBA metrics. Overall, FBA metrics detected earlier and more prominent alterations in myelinated fiber bundles compared to the DTI metrics. Luxol fast blue staining showed no loss in myelin density, indicating that diffusion anomalies could not be explained by myelin reduction but diffusion anomalies in HET mice were accompanied by increased levels of neurofilament light chain protein at 11 M. Altogether, our findings reveal progressive alterations in myelinated fiber bundles that can be measured using diffusion MRI, representing a candidate noninvasive imaging biomarker to study phenotype progression and the efficacy of therapeutic interventions in zQ175DN mice. Moreover, our study exposed higher sensitivity of FBA than DTI metrics, suggesting a potential benefit of adopting these advanced metrics in other contexts, including biomarker development in humans. [Display omitted] •Diffusion MRI reveals white matter microstructure anomalies in zQ175DN mice.•White matter anomalies precede plasma neurofilament light increase in zQ175DN mice.•Fixel-Based Analysis has increased sensitivity over DTI to detect early white matter anomalies.