Abstract Body: Introduction: Pathogenic variants in COL4A1 lead to a broad spectrum of cerebrovascular diseases, with symptomatic onset ranging from fetal stages to adulthood. Loss of vessel wall integrity due to abnormal collagen causes diffuse cerebral small vessel disease (cSVD) characterized by extensive bilateral periventricular white matter hyperintensities (WMH) and lacunar ischemic and hemorrhagic infarctions with a predilection for the anterior circulation. To date, there are no disease biomarkers that can determine risk of stroke or rate of disease progression. To address this gap, we probed microvascular flow and blood-brain barrier (BBB) permeability functions in patients with pathogenic COL4A1 missense variants using dynamic susceptibility contrast (DSC) MR perfusion.

Methods: We conducted a retrospective review of MRI Dynamic Susceptibility Contrast (DSC) perfusion imaging across three scans from two unique symptomatic COL4A1 patients with pathogenic variants c.3742 G>A, p.G1248R and c.3725 G>A, p.G1242D along with 10 control patients without cerebral pathologies. Microvascular flow patterns including capillary transit time heterogeneity (CTH) and blood-brain barrier (BBB) apparent leakage parameter (Kapp) were obtained with Cercare® perfusion software. Co-registration and brain matter segmentation were performed using 3D Slicer. Data were compared using unpaired t-test and one-way ANOVA analyses.

Results: Our analysis revealed COL4A1 patients had significantly elevated CTH in both WMH (p=0.0014) and normal-appearing white matter (p=0.0036) and decreased CTH in gray matter (p=0.0217) compared to controls. Additionally, Kapp was significantly increased in COL4A1 patient data across all regions relative to controls (p=<0.0001).

Conclusion: MR DSC perfusion imaging effectively detects COL4A1-related microvascular dysfunction throughout the brain, and these are most pronounced in WMH. Microvascular flow heterogeneity and BBB permeability appear to be sensitive markers of cSVD. DSC-MRI perfusion may therefore serve as a valuable biomarker for risk stratification and could aid monitoring therapeutic interventions. Further studies correlating structural MRI lesion and neurological symptoms burden in a larger and longitudinal cohort are needed.