Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy

Abstract

Objective: In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction.

Methods: Functional MRI was performed on 25 nondemented subjects with probable CAA (mean ± standard deviation age, 70.2 ± 7.8 years) and 12 healthy elderly controls (age, 75.3 ± 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling).

Results: CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 ± 0.28 vs 0.89 ± 0.14; p < 0.01), prolonged time to peak (11.1 ± 5.1 vs 6.4 ± 1.8 seconds; p < 0.001), and prolonged time to baseline (16.5 ± 6.7 vs 11.6 ± 3.1 seconds; p < 0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 ± 12.6 vs 45.0 ± 10.0 ml/100 g/min, p = 0.8).

Interpretation: Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury.

Figure 1

Visually activated region of interest. Figure 1a shows the functional ROI on the left hemisphere inflated mid-gray cortical surface (darker grayscale values represent sulci). Figure 1b shows functional activation on the inflated mid-gray surface of the left hemispheres of a representative control (left) and CAA (right) subject. The color scale denotes the Z-statistic for activation using the canonical hemodynamic response function (see Methods); Z>3.1 corresponds to the level of significance (p<0.001) used to create the functional ROI. There is apparent decreased strength of activation of the CAA subject compared to the control.

Figure 1

Visually activated region of interest. Figure 1a shows the functional ROI on the left hemisphere inflated mid-gray cortical surface (darker grayscale values represent sulci). Figure 1b shows functional activation on the inflated mid-gray surface of the left hemispheres of a representative control (left) and CAA (right) subject. The color scale denotes the Z-statistic for activation using the canonical hemodynamic response function (see Methods); Z>3.1 corresponds to the level of significance (p<0.001) used to create the functional ROI. There is apparent decreased strength of activation of the CAA subject compared to the control.

Figure 2

BOLD response within the functional region of interest. Figure 2a shows average group block responses relative to baseline (set at 0%) for the CAA (blue) and control (red) subjects in the functional ROI. The shaded area denotes the duration of the visual stimulus “on” period for the first 20 seconds of each block. Figure 2b illustrates the trapezoid fits of the representative control (left) and CAA (right) subjects also shown in Figure 1b. Using these fits to measure amplitude, time-to-peak (TTP) response, and time-to-baseline (TTB) response, we found that the CAA subjects had reduced amplitude, prolonged time to peak, and prolonged time to baseline (Table 2).

Figure 2

BOLD response within the functional region of interest. Figure 2a shows average group block responses relative to baseline (set at 0%) for the CAA (blue) and control (red) subjects in the functional ROI. The shaded area denotes the duration of the visual stimulus “on” period for the first 20 seconds of each block. Figure 2b illustrates the trapezoid fits of the representative control (left) and CAA (right) subjects also shown in Figure 1b. Using these fits to measure amplitude, time-to-peak (TTP) response, and time-to-baseline (TTB) response, we found that the CAA subjects had reduced amplitude, prolonged time to peak, and prolonged time to baseline (Table 2).

Figure 3

Association between time to peak response and normalized white matter hyperintensity volume. Values for each CAA subject are plotted on logarithmic scales (Pearson R=0.53, p=0.007).