Cognitive impairment appears progressive in the mdx mouse.

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.