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Updated: Dec 22, 2025
Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Cognitive impairment appears progressive in the mdx mouse
Emine Bagdatlioglu1, Paola Porcari2, Elizabeth Greally1
1John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Times Square, Newcastle upon Tyne NE1 3BZ, United Kingdom.
Abstract:
Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Approximately one-third of DMD patient's exhibit cognitive problems yet it is unknown if cognitive impairments worsen with age. The mdx mouse model is deficient in dystrophin demonstrates cognitive abnormalities, but no studies have investigated this longitudinally. We assessed the consequences of dystrophin deficiency on brain morphology and cognition in male mdx mice. We utilised non-invasive methods to monitor CNS pathology with an aim to identify changes longitudinally (between 4 and 18 months old) which could be used as outcome measures. MRI identified a total brain volume (TBV) increase in control mice with ageing (p < 0.05); but the mdx mice TBV increased significantly more (p < 0.01). Voxel-based morphometry (VBM) identified decreases in grey matter volume, particularly in the hippocampus of the mdx brain, most noticeable from 12 months onwards, as were enlarged lateral ventricles in mdx mice. The caudate putamen of older mdx mice showed increases in T2- relaxometry which may be considered as evidence of increased water content. Hippocampal spatial learning and memory was decreased in mdx mice, particularly long-term memory, which progressively worsened with age. The novel object recognition (NOR) task highlighted elevated anxiety-related behaviour in older mdx mice. Our studies suggest that dystrophin deficiency causes a progressive cognitive impairment in mice (compared to ageing control mice), becoming evident at late disease stages, and may explain why progressive CNS symptoms are not obvious in DMD patients.
Insights
Duchenne muscular dystrophy (DMD) causes progressive brain changes and cognitive decline in mdx mice. These impairments, including memory deficits and anxiety, worsen with age, offering insights into DMD
Area of Science:
- Neuroscience
- Genetics
- Biomedical Engineering
Background:
- Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, leading to dystrophin deficiency.
- Cognitive impairments affect about one-third of DMD patients, but their progression with age remains unclear.
- The mdx mouse model, lacking dystrophin, exhibits cognitive abnormalities, yet longitudinal studies are lacking.
Purpose of the Study:
- To investigate the longitudinal effects of dystrophin deficiency on brain morphology and cognitive function in male mdx mice.
- To identify non-invasive imaging biomarkers for monitoring central nervous system (CNS) pathology in DMD.
- To assess age-related changes in cognition and behavior in the mdx mouse model.
Main Methods:
- Longitudinal MRI and voxel-based morphometry (VBM) to analyze brain volume and structure.
- T2-relaxometry to detect changes in brain tissue composition.
- Behavioral tests including spatial learning/memory (hippocampus-dependent) and novel object recognition (NOR) for anxiety assessment.
Main Results:
- Mdx mice showed a significantly greater increase in total brain volume (TBV) compared to controls with aging.
- VBM revealed grey matter reduction in the hippocampus and enlarged ventricles in mdx mice from 12 months.
- Spatial long-term memory progressively worsened with age in mdx mice, and older mdx mice exhibited increased anxiety-related behaviors.
Conclusions:
- Dystrophin deficiency leads to progressive brain structural changes and cognitive impairment in mdx mice.
- Cognitive deficits, particularly in long-term memory and anxiety, become more pronounced with age in mdx mice.
- These findings suggest that age-related cognitive decline in DMD may be linked to progressive CNS pathology.
