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

Abstract

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.

Keywords: Diffusion magnetic resonance imaging; Dutch-type hereditary cerebral amyloid angiopathy; cerebral amyloid angiopathy; functional magnetic resonance imaging; vascular reactivity.

Figure 1.

(a) uncorrected PSMD as a function of age in the D-CAA study cohort and PSMD in the 1000BRAINS cohort, and (b) healthy age corrected PSMD as a function of age in the D-CAA study cohort. All graphs include linear regression trends. The standard error for the D-CAA dataset is indicated by the shaded error bar and for the 1000BRAINS cohort it is indicated with standard error bars per age group. PSMD: Peak Width Skeletonized Mean Diffusivity; D-CAA; Dutch-type Cerebral Amyloid Angiopathy.

Figure 2.

BOLD parameters (a) amplitude, (b) time-to-peak, and (c) time-to-baseline as a function of age in the current D-CAA study cohort. BOLD: Blood-Oxygen-Level-Dependent; D-CAA: Dutch-type Cerebral Amyloid Angiopathy.

Figure 3.

Graphs showing the relations between healthy age corrected PSMD and BOLD parameters with corresponding adjusted R² values; (a) quadratic relationship between PSMD and BOLD amplitude, (b) linear relationship between PSMD and BOLD time-to-peak, and (c) linear relationship between PSMD and BOLD time-to-baseline. In b and c, the healthy age corrected PSMD values, of symptomatic D-CAA mutation carriers of whom no timing parameter could be calculated due to minimal BOLD response to the visual stimulus, are jittered on the right side of the plot, presenting the mean and standard deviation. PSMD: Peak Width Skeletonized Mean Diffusivity; BOLD: Blood-Oxygen-Level-Dependent; D-CAA: Dutch-type Cerebral Amyloid Angiopathy.