An Iatrogenic Model of Brain Small-Vessel Disease: Post-Radiation Encephalopathy

Abstract

We studied 114 primitive cerebral neoplasia, that were surgically treated, and underwent radiotherapy (RT), and compared their results to those obtained by 190 patients diagnosed with subcortical vascular dementia (sVAD). Patients with any form of primitive cerebral neoplasia underwent whole-brain radiotherapy. All the tumor patients had regional field partial brain RT, which encompassed each tumor, with an average margin of 2.6 cm from the initial target tumor volume. We observed in our patients who have been exposed to a higher dose of RT (30–65 Gy) a cognitive and behavior decline similar to that observed in sVAD, with the frontal dysexecutive syndrome, apathy, and gait alterations, but with a more rapid onset and with an overwhelming effect. Multiple mechanisms are likely to be involved in radiation-induced cognitive impairment. The active site of RT brain damage is the white matter areas, particularly the internal capsule, basal ganglia, caudate, hippocampus, and subventricular zone. In all cases, radiation damage inside the brain mainly focuses on the cortical–subcortical frontal loops, which integrate and process the flow of information from the cortical areas, where executive functions are “elaborated” and prepared, towards the thalamus, subthalamus, and cerebellum, where they are continuously refined and executed. The active mechanisms that RT drives are similar to those observed in cerebral small vessel disease (SVD), leading to sVAD. The RT’s primary targets, outside the tumor mass, are the blood–brain barrier (BBB), the small vessels, and putative mechanisms that can be taken into account are oxidative stress and neuro-inflammation, strongly associated with the alteration of NMDA receptor subunit composition.

Evaluation of alterations in interstitial fluid dynamics in cases of whole‐brain radiation using the diffusion‐weighted image analysis along the perivascular space method

“…This mechanism is similar to the changes caused by small vessel disease. Small vessel disease is largely associated with loss of arterial elasticity, markedly reduced arterial compliance, and reduced autonomic nervous system function, which leads to diffuse rarefaction of myelin sheaths, followed by axonal disruption and severe astrocyte gliosis 30 . These are suggested to cause disturbances in the interstitial fluid dynamics.…”

Whole brain irradiation–induced endothelial dysfunction in the mouse brain

“…Furthermore, intact endothelial function is crucial for maintaining the integrity of the blood-brain barrier (BBB). Disruption of the BBB, as observed in WBI and γ-irradiationinduced microvascular injury [25][26][27][28][29][30][31][32][33], can lead to neuroinflammation and contribute to the genesis of cognitive impairment [34,35] (Fig. 2).…”

“…Maintaining microvascular health is also crucial for preserving the integrity of the blood-brain barrier (BBB) [23,24]. Strong evidence suggests that WBI and γ-irradiation-induced microvascular injury contribute to BBB disruption [25][26][27][28][29][30][31][32][33], leading to neuroinflammation [34,35].…”

Cognitive outcomes after multimodal treatment in adult glioma patients: A meta-analysis

“…However, other studies have clearly shown that cognitive impairment in fluency, working memory, and verbal memory can already be observed at 1-year follow-up after radiotherapy. 7 Furthermore, test scores were grouped into domains, which does not provide information on test specificity and sensitivity to detect more subtle cognitive changes. Additionally, the existing meta-analyses did not analyze the impact of potential practice effects.…”