Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications

Abstract

Mild cognitive impairment is a well-documented consequence of whole brain radiation therapy (WBRT) that affects 40-50% of long-term brain tumor survivors. The exact mechanisms for the decline in cognitive function after WBRT remain elusive and no treatment or preventative measures are available for use in the clinic. Here, we review recent findings indicating how changes in the neurovascular unit may contribute to the impairments in learning and memory. In addition to affecting neuronal development, WBRT induces profound capillary rarefaction within the hippocampus - a region of the brain important for learning and memory. Therapeutic strategies such as hypoxia, which restore the capillary density, result in the rescue of cognitive function. In addition to decreasing vascular density, WBRT impairs vasculogenesis and/or angiogenesis, which may also contribute to radiation-induced cognitive decline. Further studies aimed at uncovering the specific mechanisms underlying these WBRT-induced changes in the cerebrovasculature are essential for developing therapies to mitigate the deleterious effects of WBRT on cognitive function.

Figure 1. Mice subjected to fractionated WBRT have progressive impairment in learning ability when assessed on the Barnes maze

Compared to non-radiated controls, radiated mice make more errors (A) and exhibit increased latency (B) to locate the hidden escape box. This impairment is worse at 5 months post-WBRT. [“a” represents significance compared to control 2 months, “b” – compared to control 5 months, and “c” – compared to radiated 2 months; p<0.05]. Adapted from [21].

Figure 2. WBRT reduces hippocampal capillary density while systemic hypoxia reverses capillary rarefaction

(A) CD31 (red) and smooth muscle actin (green) capillaries are reduced following WBRT and restored with systemic hypoxia. Quantification of capillary density measured by (B) endothelial cell and (C) smooth muscle cell staining in CA1, CA3 and dentate gyrus (DG) of the hippocampus. **p<0.01, ***p<0.001 compared to Normoxia; #p<0.05, ##p<0.01 compared to Control Normoxia. Adapted from [41].