Introduction: Pathogenic variants in COL4A1 compromise basement membrane integrity, leading to cerebral small vessel disease (cSVD) characterized by white matter hyperintensities (WMHs), microbleeds, and ischemic or hemorrhagic strokes [1,2,3]. Despite the clinical impact, no imaging biomarkers currently exist to assess disease severity or predict stroke risk in COL4A1-related cSVD. In this study, we evaluated microvascular flow heterogeneity and blood–brain barrier (BBB) permeability using dynamic susceptibility contrast (DSC) MR perfusion imaging [4].
Methods: We retrospectively analyzed five Dynamic Susceptibility Contrast Magnetic Resonance (DSC MR) perfusion imaging studies from four patients with symptomatic COL4A1 mutations (p.G212A, p.G1248R, p.G1242D). Three patients (one with p.G212A and two with p.G1248R) had a single imaging study, while one patient with p.G1242D underwent imaging at two distinct timepoints. The mean age of the COL4A1 cohort was 33.42 years (range: 6.2–47.6 years). For comparison, we included ten age-matched control patients (mean age: 53.6 years; range: 28–74 years) who underwent DSC MR perfusion imaging and showed no evidence of cerebrovascular abnormalities. DSC data were processed using Cercare® software perfusion toolbox v1.0 to extract capillary transit time heterogeneity (CTH), apparent leakage constant (Kapp), oxygen extraction capacity (OEC), and cerebral metabolic rate of oxygen (CMRO2 max). Brain regions were segmented into WMH, normal-appearing white matter (NAWM), and gray matter (GM) using a 3D Slicer 5.4.0. Statistical analyses included unpaired t-tests and one-way ANOVA.
Results: Compared to the controls, COL4A1 patients exhibited significantly increased BBB permeability (Kapp) across all brain regions (p < 0.0001). CTH was elevated in WMH (p = 0.0014) and NAWM (p = 0.0036) but reduced in GM (p = 0.0217). Within COL4A1 patients, WMH regions showed higher CTH, greater OEC, and lower CMRO2 max compared to NAWM, indicating more severe microvascular dysfunction.
Conclusions: These results demonstrate that DSC-MRI perfusion imaging sensitively detects global and regional microvascular abnormalities in COL4A1-related cSVD. Elevated Kapp and altered CTH may serve as promising imaging biomarkers for risk stratification, disease monitoring, and therapeutic evaluation in this population.
Author Contributions
Contributed to the study concept and design, analysis and interpretation of data, and drafting of the manuscript, D.T., J.P.S. and A.L.; responsible for data collection, analysis and interpretation of data, and drafting of the manuscript, D.T. and A.L.; contributed to the analysis and interpretation of data, D.B. and A.L.; provided critical revision of the manuscript for important intellectual content, K.G.H. and K.A.; contributed to the study concept and design, analysis and interpretation of data, drafting of the manuscript, and supervised the study, P.L.M. All authors have read and agreed to the published version of the manuscript.
Funding
This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Massachusetts General Hospital IRB protocol #2018P002134.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The data supporting the findings of this study are not publicly available due to privacy and ethical restrictions. However, de-identified data may be made available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
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