Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL

Abstract

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1-2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Keywords: CADASIL; adaptive optics; functional; remodeling; retinal vessels.

Figure 1.

AO images used for retinal vessel measures. Illustration of AO methods for measuring the structural (first row) and functional (second and third row) parameters from retinal arteries in patients and controls. The measures were obtained in a parapapillary or paramacular artery (first row, left) and using delineation of the vascular wall limits on a segment of 250 μm for measuring the internal and external diameters, lumen and WLR. VR was measured with flicker stimulations in the illumination area (a), after selecting the target retinal artery (b) using 3 measures at baseline and 3 measures at end of the light stimulation on images captured over 2 seconds (corresponding to a stack of 40 images automatically processed by the built-in software) on the successive periods of 22 seconds (c).

Figure 2.

WLR according to age in patients and controls. A significant increase of age-adjusted WLR was observed in CADASIL patients. More specifically, the age effect on WLR differed between patients and healthy individuals (significant group-age interaction in the multivariable model). While a significant increase of WLR was observed in healthy individuals in relation to age, this effect was not found in patients who had increased WLR values since their young age, close to values observed after 65 years of age in controls. The circled points (red) correspond to patient’s values outside the 95% individualized confidence interval derived from healthy individuals (dashed black line)

Figure 3.

VR measures according to age in patients and controls. A significant decrease of vasoreactivity was observed in the group of CADASIL patients at all age. The reactivity to light stimulations was nearly abolished or absent in a large proportion of patients. The measure of VR was however variable and this lack of reactivity was also detected in healthy individuals. Because of this variability, only a small group of 5 patients had their WLR outside the individualized 95% confidence interval estimated from control values (dashed black line).