Multimodal neuroimaging of Col4a1-mutant mouse models of Gould syndrome

TL;DR

This study uses high-resolution MRI to examine brain changes in mice with mutations in the Col4a1 gene, which is linked to a rare brain disease called Gould syndrome.

Contribution

The study introduces high-field multimodal MRI as a sensitive noninvasive method to detect cerebrovascular abnormalities in Col4a1 mutant mouse models of Gould syndrome.

Findings

Multimodal MRI identified cSVD-associated lesions across all Col4a1 mutant mouse strains.

Allelic variants showed heterogeneous expressivity in lesion prevalence, size, and number.

Certain brain regions were consistently more vulnerable to cSVD-related lesions across strains.

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular contributions to cognitive impairment and dementia (VCID). Studying monogenic forms of cSVD can elucidate molecular pathways that are dysfunctional in the common sporadic forms and may serve as potential therapeutic targets. Mutations in COL4A1 and COL4A2 cause highly penetrant cSVD as part of the multisystem disorder known as Gould syndrome, which includes cerebrovascular manifestations such as porencephaly, early-onset stroke, leukoencephalopathy, and intracerebral hemorrhage (ICH).

To investigate how allelic heterogeneity influences cerebrovascular phenotypes, we examined five Col4a1 mutant mouse strains that collectively model the clinical spectrum of Gould syndrome. Each strain underwent multimodal magnetic resonance imaging (MRI) at 14.1 Tesla to assess radiological features characteristic of cSVD.

Multimodal MRI successfully identified typical cSVD-associated lesions across all Col4a1 mutant strains. The imaging revealed heterogeneous expressivity among the allelic variants in terms of lesion prevalence, size, and number. Furthermore, analysis across strains identified brain regions that were consistently more vulnerable to cSVD-related lesions.

These findings demonstrate that high-field multimodal MRI can sensitively detect and differentiate cerebrovascular abnormalities among Col4a1 mutant mouse models of Gould syndrome. The approach provides a powerful, noninvasive platform for assessing genotype–phenotype relationships and for identifying brain regions at heightened risk in cSVD, supporting its potential use in early diagnosis and mechanistic studies of vascular pathology.

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