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.

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

“…It is significant that cognitive decline due to microvascular causes is potentially reversible (Warrington et al 2011(Warrington et al , 2012. Our findings, taken together with the results of earlier studies (reviewed in Warrington et al (2013)), point to potential benefits of interventions that rescue glio-vascular coupling mechanisms and promote microvascular health for prevention of cognitive decline both in WBI-treated patients and the elderly. There is increasing realization that DNA damage-induced cellular senescence programs play a critical role in brain aging process (reviewed in Chinta et al (2014)), thus we propose that the present clinically relevant model of fractionated WBI should be considered to study fundamental mechanisms of brain and cognitive aging as well.…”

“…Among them, impaired neurovascular coupling responses (Fabiani et al 2013;Park et al 2007;Stefanova et al 2013;Topcuoglu et al 2009;Toth et al 2014a;Zaletel et al 2005) are thought to importantly contribute to the cognitive decline (Sorond et al 2013) in the elderly. From the results of this study and from recent findings by other laboratories (Warrington et al 2013), the picture emerges that WBI-induced DNA damage responses induce an accelerated aging-like phenotype in the neurovascular The somatosensory evoked potential responses in the somatosensory cortex evoked by contralateral whisker pad stimulation are comparable in control and WBI-treated mice. The amplitude of the negative wave of the field potentials was not significantly different.…”

“…2 0 1 5 b ) . B e c a u s e t h e p h e n o t y p e o f cerebromicrovascular endothelial cells can also be altered by irradiation-induced DNA damage Warrington et al 2013); future studies should also determine the role of endothelial dysfunction in WBI-induced impairment of functional hyperemia.…”

“…Previously, we demonstrated that C57BL/6J mice exhibit significant impairment of hippocampal-encoded functions of learning and memory at 5 months post-WBI treatment (Warrington et al 2013). To gain insight into the time-course of the development of irradiationinduced cognitive decline, in the present study, we assessed learning and memory function in mice 3 months post-WBI and in age-matched controls in the radial arm water maze (Fig.…”

“…Although the mechanisms underlying cognitive deficits after WBI are likely multifaceted, there is increasing pre-clinical and clinical evidence that WBI compromises the structural integrity of the cerebral microcirculation, which significantly contributes to cognitive impairment (Ashpole et al 2014;Warrington et al 2011Warrington et al , 2012Warrington et al , 2013). Previous studies demonstrate that clinical series of fractionated WBI induce a 40% decrease in capillary density in the brain regions associated with learning and memory (Warrington et al 2012), mimicking aging phenotype.…”