Meta-analysis of Cognitive Performance by Novel Object Recognition after Proton and Heavy Ion Exposures

Abstract

Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our study reveals that linear or linear-quadratic dose-response models of relative risk (RR) do not provide accurate descriptions. However, good descriptions for doses up to 1 Gy are provided by exponentially increasing fluence or dose-response models observed with an LET dependence similar to a classical radiation quality response, which peaks near 100-120 keV/µm and declines at higher LET values. Exponential models provide accurate predictions of experimental results for NOR in mice after mixed-beam exposures of protons and ⁵⁶Fe, and protons, ¹⁶O and ²⁸Si. RBE estimates are limited by available X-ray or gamma-ray experiments to serve as a reference radiation. RBE estimates based on use of data from combined gamma-ray and high-energy protons of low-LET experiments suggest modest RBEs, with values <8 for most heavy ions, while higher values <20 are based on limited gamma-ray data. In addition, we consider a log-normal model for the variation of subject responses at defined dose levels. The log-normal model predicts a heavy ion dose threshold of approximately 0.01 Gy for NOR-related cognitive detriments.

FIG. 1.

Dose-response plot of relative risk for novel object recognition (RR_NOR) computed from experimental data. Total number of data points is 236 and all error bars are standard error of the mean (SEM).

FIG. 2.

Comparison of experimental data with modeling results of separate linear fitting to fluence model. Absolute goodness of fit of data to model is measured by root mean squared error (RMSE).

FIG. 3.

Fluence model coefficient A₁ as a function of radiation LET and Z²/β². Goodness of fit is measured by the sum of the squared errors (SSE), correlation coefficients (R² and adjusted R²) and root mean square error (RMSE).

FIG. 4.

Relative biological effectiveness (RBE) computed using fluence model with reference to gamma rays (left) and with reference to the average of square error (RMSE).gamma rays and protons (right). Goodness of fit is measured by sum of the squared errors (SSE), correlation coefficients (R² and adjusted R²) and root mean

FIG. 5.

Comparison of relative risks (RR_NOR) from prediction of models to experiment by Raber et al. (30) for male B6D2F1 mice (4 to 6 months old) irradiated with mixed field, delivered in several minutes, of 20%, 20% and 60% of ²⁸Si (263 MeV/u), ¹⁶O (250 MeV/u) and protons (1,000 MeV), respectively, to several total doses. The novel object recognition (NOR) test was administered 2 months postirradiation.

FIG. 6.

Parameters (D₀ and σ) for log-normal distribution as a function of dose. Goodness of fit is measured by the sum of the squared errors (SSE), correlation coefficients (R² and adjusted R²) and root mean square error (RMSE).