Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R² = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10⁻⁶, 95%CI [1.84 × 10⁻⁶, 1.48 × 10⁻⁵], p = 0.02, Adj. R² = 0.25) and TTB (β = 6.57 × 10⁻⁶, 95%CI [1.92 × 10⁻⁶, 1.12 × 10⁻⁵], p = 0.008, Adj. R² = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.