A Radiation-Induced Hippocampal Vascular Injury Surrogate Marker Predicts Late Neurocognitive Dysfunction

Abstract

Purpose We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiotherapy (RT). Methods and Materials 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. Patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, Ktrans, and the fraction of blood plasma volume, Vp. The temporal changes in the means of hippocampal Ktrans and Vp after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampi was correlated with neurocognitive dysfunction 6 and 18-months post-RT. Results The Ktrans mean increased significantly from pre-RT to 1-month post-RT (p<0.0004), which significantly depended on sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females correlated significantly with changes in memory function at 6 (r = −0.95, p<0.0006) and 18-months (r = −0.88, p<0.02) post-RT. Conclusions The early hippocampal vascular dose-response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future.

Effect of the Maximum Dose on White Matter Fiber Bundles Using Longitudinal Diffusion Tensor Imaging

“…After controlling dose and pathology (glioma vs non-glioma), age showed an interaction effect with dose, as AD/RD changed greater in elderly than in younger patients when received the same dose. Female patients had larger reductions in AD/RD than males given the same dose, consistent with previous observations (25-27) where sex-dependent differences in hippocampal plasticity as well as sex hormone (26) were reported as contributing factors to higher mortality and morbidity in females due to radiation-induced injury (27). Patients with glioma had a larger reduction in AD/RD than those without, possibly due to compromise of normal appearing WM by infiltrating glioma cells.…”

Left hippocampus sparing whole brain radiotherapy (WBRT): A planning study

“…Another recent study of predictors for late neurocognitive dysfunction showed correlations of vascular dose-response in the left hippocampus in females with changes in memory function after radiotherapy 9 . Is it possible that only unilateral hippocampal radio-injury is responsible for subsequent neurocognitive decline?…”

“…Further, some reports suggest different post radiotherapy and/or post surgery changes in the two hippocampi. As a result, unilateral hippocampal sparing has been proposed [7][8][9][10][11] . The most important neurocognitive domain affected by WBRT is memory.…”

“…The most important neurocognitive domain affected by WBRT is memory. Radio-injury of the left, usually dominant, hippocampus may affect the formation of memory to a greater extent, in particular verbal memory 9,11 . Dosimetric consequences of potential unilateral (left) hippocampus sparing during WBRT are not known.…”

Radiation Toxicity in the Central Nervous System: Mechanisms and Strategies for Injury Reduction

“…Imaging-related biomarker identification for normal tissue injury and response in patients receiving radiation is one area of investigation that may show potential promise in identifying patients in whom prevention and interventional strategies are needed. MRI-based vascular hippocampal marker parameters related to blood-brain barrier permeability, K(trans), and the fraction of blood plasma volume, Vp, have recently been evaluated as markers of injury 34 , correlating significantly with changes in memory function at 6 and 18 months after treatment, suggesting that K(trans) could serve as one predictor of late neurocognitive dysfunction for patients.…”