Modeling space radiation-induced cognitive dysfunction using targeted and non-targeted effects

Authors: SHURYAK, IGOR - Columbia University Medical Center; BRENNER, DAVID - Columbia University Medical Center; BLATTNIG, STEVEN - National Aeronautics And Space Administration (NASA); Shukitt-Hale, Barbara; RABIN, BERNARD - University Of Maryland

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2021
Publication Date: 4/23/2021
Citation: Shuryak, I., Brenner, D.J., Blattnig, S.R., Shukitt Hale, B., Rabin, B.M. 2021. Modeling space radiation-induced cognitive dysfunction using targeted and non-targeted effects. Scientific Reports. 11:8845. https://doi.org/10.1038/s41598-021-88486-z.
DOI: https://doi.org/10.1038/s41598-021-88486-z

Interpretive Summary: Changes in memory caused by radiation-induced damage are similar to those seen in aging. Radiation-induced brain damage is recognized as a risk for human exploration of distant planets. One possible mechanism is where the damage is caused by direct impact of the radioactive particles on the cells; another mechanism occurs when other cells respond to the signals released by radiation-impacted cells. To determine which mechanism has the most detrimental effect on brain cells and the resulting cognitive damage, a large set of published cognitive data in rats exposed to various doses of different radioactive particles having wide ranges of energy was examined. Our results suggest that indirect radiation effects on brain function are previously unrecognized but potentially important for space mission risk assessments and point to the importance of studying countermeasures such as nutrition.

Technical Abstract: Radiation-induced cognitive dysfunction is increasingly recognized as an important risk for human exploration of distant planets. These adverse cognitive deficits are similar to those seen in aging and are thought to be caused by a similar mechanism, i.e., production of oxidative stress and inflammation. Mechanistically-motivated mathematical modeling helps to interpret and quantify this phenomenon. Here we considered two general mechanisms of ionizing radiation-induced damage: targeted effects (TE), caused by traversal of cells by ionizing tracks, and non-targeted effects (NTE), caused by responses of other cells to signals released by traversed cells. We compared the performances of 18 dose-response model variants based on these concepts, fitted by robust nonlinear regression to a large published data set on novel object recognition testing in rats exposed to multiple space-relevant radiation types (H, C, O, Si, Ti and Fe ions), covering wide ranges of LET (0.22-181 keV/um) and dose (0.001-2 Gy). The strongest support (by Akaike information criterion) was found for an NTE+TE model where NTE saturate at low doses (~0.01 Gy) and occur at all tested LETs, whereas TE depend on dose linearly with a slope that increases with LET. Importance of NTE was also found by additional analyses of the data using quantile regression and random forests. These results suggest that NTE-based radiation effects on brain function are potentially important for astronaut health and for space mission risk assessments, and point to the importance of studying countermeasures such as nutrition to prevent these declines. Previous studies have shown that polyphenolic-rich berry diets, which also show promising results in aging animals, can improve cognitive function when fed to animals prior to radiation exposure.