Multimodal neuroimaging of Col4a1-mutant mice models of Gould Syndrome

Xiao Gao¹Xiaowei Wang²Cassandre Labelle-Dumais²Douglas B Gould^2*Myriam M Chaumeil^1*

• ¹Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, United States
• ²Department of Ophthalmology, University of California, San Francisco, San Francisco, United States

ABSTRACT (217 words) Cerebral small vessel disease (cSVD) is a leading cause of stroke and vascular contributions to cognitive impairment and dementia (VCID). Studying monogenic cSVD can reveal pathways that are dysfunctional in common forms of the disease and may represent therapeutic targets. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause highly penetrant cSVD as part of a multisystem disorder referred to as Gould syndrome, which comprises a constellation of cerebrovascular conditions including porencephaly, early-onset stroke, leukoencephalopathy, and intracerebral hemorrhage (ICH). Col4a1 and Col4a2 mutant mice faithfully capture the pathophysiological hallmarks of Gould syndrome and thus provide an experimentally tractable platform to investigate the correlation between allelic heterogeneity and phenotypic variability using magnetic resonance imaging (MRI) as a radiological assessment of cSVD. In this study, we used five different Col4a1 mutant mouse strains that mimic the clinical spectrum of cerebrovascular manifestations observed in Gould syndrome. These strains were characterized using multimodal MRI at 14.1 Tesla. We show that multimodal MRI successfully identified typical cSVD lesions and reveal heterogeneous expressivity in a Col4a1 murine allelic series in terms of lesion prevalence, size, and number. Importantly, using these standards, we identified brain regions most vulnerable to cSVD lesions in Gould syndrome models, highlighting the capability of our imaging modalities in early detection and diagnosis of cSVD-related pathologies.