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Updated: Mar 8, 2026
Whole-brain Segmentation and Change-point Analysis of Anatomical Brain MRI—Application in Premanifest Huntington's Disease
Published on: June 9, 2018
Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the
Ivan Rattray1,2, Edward J Smith1,2, William R Crum3
1King's College London, Institute of Psychiatry, Department of Neuroscience, London, United Kingdom.
Abstract:
A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the "clinical horizon" of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.
Insights
The HdhQ150 mouse model shows motor deficits by 36 weeks but no cognitive decline by 94 weeks. Brain atrophy, particularly in the striatum, occurs before motor symptoms manifest in this Huntington's disease model.
Area of Science:
- Neuroscience
- Genetics
- Animal Models
Background:
- Huntington's disease (HD) is a neurodegenerative disorder characterized by motor and cognitive dysfunction.
- Mouse models expressing mutant huntingtin (mHTT) are crucial for studying HD pathology.
- The HdhQ150 knock-in mouse model mimics molecular aspects of HD, including mHTT aggregates.
Purpose of the Study:
- To investigate the temporal relationship between molecular pathology, brain structural changes, and behavioral deficits in the HdhQ150 mouse model of Huntington's disease.
- To assess motor and cognitive functions, and brain volumes over time in HdhQ150 mice.
- To correlate neuropathological findings with observed behavioral and volumetric changes.
Main Methods:
- Homozygous HdhQ150 knock-in mice and wild-type littermates were used.
- Behavioral tests included rotarod, locomotor activity, grip strength, T-maze, fear conditioning, odor discrimination, and social interaction.
- T2-weighted MRI and tensor-based morphometry were employed for volumetric analysis.
- Histology was performed to detect mHTT aggregates and inclusions.
Main Results:
- HdhQ150 mice exhibited motor impairments by 36 weeks but no cognitive dysfunction by 94 weeks.
- Significant striatal atrophy (27%) was detected via MRI by 94 weeks, with earlier volumetric changes noted at 15 weeks, preceding motor deficits.
- Widespread mHTT aggregates were observed, but correlations between pathology, brain atrophy, and behavioral outcomes were weak.
- Tensor-based morphometry revealed additional regions of atrophy beyond initial MRI findings.
Conclusions:
- The HdhQ150 mouse model recapitulates key features of Huntington's disease, including an extended pre-manifest period.
- Striatal atrophy precedes the onset of motor impairments, suggesting it as an early biomarker.
- The limited correlation between molecular pathology and behavioral outcomes highlights the complexity of the HD causal cascade.
