We aimed to investigate whether angiogenesis exists in and has an impact on white matter hyperintensities (WMH) penumbrae and to evaluate factors affecting the presence of angiogenesis.

The normal-appearing white matter(NAWM) surrounding WMH with reduced cerebral blood flow (CBF) and white matter injury are considered WMH penumbrae, and associate with WMH progression.It is unclear whether there is collateral revascularization in WMH penumbrae.

In this cross-sectional study, we recruited patients with confluent WMH of Fazekas grade 2 or higher on MRI, between November 30, 2016 and February 24, 2018. Participants underwent ⁶⁸Ga-NOTA-PRGD2 PET/MRI and were divided into two groups based on ⁶⁸Ga-NOTA-PRGD2 uptake. Seven NAWM layers were dilated away from the WMH by 2 mm each time. The structure WMH penumbrae were analyzed using diffusion tensor imaging-derived metrics,  fractional anisotropy (FA) and mean diffusivity (MD). The CBF WMH penumbrae were analyzed using CBF detected by arterial spin labeling. 

The ⁶⁸Ga-NOTA-PRGD2 uptake was significantly increased at the WMH and NAWM junction area. For patients with increased ⁶⁸Ga-NOTA-PRGD2 uptake (group 1), the mean CBF of WMH and NAWM L1–L3 and FA of WMH and NAWM L1–L3 were significantly lower than NAWM L7 (p=0.002 and p=0.007, respectively). For patients without increased ⁶⁸Ga-NOTA-PRGD2 uptake (group 2), the mean CBF of WMH and NAWM L1–L2 was lower than NAWM L7 (p=0.012). In group 1, the WMH volume was higher (OR:1.017; 95% CI:1.000-1.154). There were negative correlations between SUVr and CBF (β = -0.091, p=0.001), SUVr and FA (β = -16.557, p=0.001). There was a positive correlation between SUVr and MD (β =4.644 p=0.004).

Our study provides evidence that angiogenesis exists in WMH penumbrae. We found that angiogenesis is correlated with reduced CBF and microstructure integrity. Further studies are warranted to verify angiogenesis as a predictive marker and a potential intervention target for the progression of WMH.