Development of novel therapies for Huntington's disease (HD) necessitates discovery of early and sensitive biomarkers. In this study, using diffusion MRI and 3D anatomical MRI, we investigated which structural alterations in the brain could be rescued in the LacQ140 HD mice, upon partial lowering of mHtt (~50%) in a time-controlled manner.
Eleven-month-old heterozygous (HET) LacQ140 mice, WT littermates and HET LacQ140(2M) mice exhibiting mHtt lowering from 2 months of age onward (n = ± 20/group) at the age of 11 months, were scanned on a 9.4T Biospec MRI scanner. A 3D MRI scan was acquired to assess global and local volume changes by using manual delineation of the whole brain and tensor-based morphometry (TBM), respectively. Multi-shell (b = 800, 1200, 2800 s/mm2) diffusion MRI data was acquired to assess macro- and microstructural changes using diffusion tensor/kurtosis imaging and fixel based analysis (FBA).
Significantly decreased whole brain volume was detected in the LacQ140 (-4%) and LacQ140(2M) (-3%) mice compared to the WT control group. No significant differences were measured between the two HET groups. TBM showed smaller local brain volume in the striatum of LacQ140 (-37%) and LacQ140(2M) (-26%) mice compared to the WT group. FBA revealed a reduced fiber density cross-section in the corpus callosum (CC) and striatum, in both the LacQ140 (CC: -14%; striatum: -6%) and LacQ140(2M) (CC: -11%; striatum: -4%) compared to WT mice. Interestingly, while mean kurtosis (a measure of tissue complexity) was found to be significantly increased (+3%) in the striatum of the LacQ140 group compared to control mice, this measure was preserved in LacQ140(2M) animals.
We can conclude that early ~50% lowering of mHtt in LacQ140 mice diminishes the structural alterations in brain regions relevant for Huntington's disease.
