Progressively reduced cerebral oxygen metabolism and elevated plasma NfL levels in the zQ175DN mouse model of Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG-repeat expansion in exon-1 of the huntingtin gene. Currently, no disease-modifying therapies are available, with a significant challenge in evaluating therapeutic efficacy before clinical symptoms emerge. This highlights the need for early biomarkers and intervention strategies. Therefore, it is essential to develop and characterize accurate mouse models and identify early biomarkers for preclinical therapeutic development. In this study, we characterized the pathological progression of the heterozygous zQ175 neodeleted knock in (zQ175DN) mouse model across four age groups: 3, 6, 10, and 16 months to identify human translatable outcome measures. T2-relaxation-under-spin-tagging (TRUST) MRI was used to assess global CMRO(2), while T2-weighted MRI was used to analyze regional brain volumes. Significant striatal volume loss was detected as early as 6 months of age, worsening progressively with age in the zQ175 DN mice, resembling HD progressive striatal atrophy. A decline in CMRO(2) was observed in 6-month-old zQ175 DN mice, with significant and progressive reductions in 10- and 16- months old HD mice. Additionally, PHP1-positive mutant huntingtin (mHTT) aggregates were detectable in the striatum and cortex of zQ175 DN mice at all four ages, with intranuclear localization prior to 6 months, transitioning to co-exist of intranuclear and increased extracellular aggregates in older zQ175 DN mice, suggesting that the localization of mHTT aggregates may reflect the severity of HD pathogenesis. Interestingly, plasma neurofilament light chain (NfL) protein levels were significantly elevated at 6 months of age and older zQ175DN mice. These findings provide valuable insights for selecting outcome measures in preclinical evaluations of HD therapies using the zQ175 DN mouse model.