Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy

Purpose and Objectives

Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy.

Methods and Materials

We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex for each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests.

Results

Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002).

Conclusions

Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.

Introduction

Brain radiation therapy (RT) is often associated with cognitive impairment, likely mediated in part by incidental irradiation of normal brain tissue 1, 2, 3. Recent decades have seen advances in RT that provide unprecedented control and accuracy in dose delivery to therapeutic targets while minimizing exposure to normal tissues. However, although neurosurgical experience describes regions of eloquent brain to be carefully avoided (4), little is known about the regional vulnerability of the brain when it comes to RT. Current and long-standing clinical practice for fractionated RT is to consider the optic pathway, brainstem, and cranial nerves as organs at risk, whereas the brain parenchyma is treated as essentially homogeneous in terms of RT exposure risk, with only broad dose constraints to avoid overt radiation necrosis (5). There is current interest in identifying brain subregions with particular vulnerability to radiation damage as candidates for avoidance in RT planning 6, 7.

Although historically radiation damage has been thought to affect the brain's white matter rather than the cortex itself 1, 8, a recent study used quantitative magnetic resonance imaging (MRI) of glioma patients to demonstrate radiation dose-dependent cortical atrophy (9). Quantitative MRI is a well-validated technique that makes it possible to noninvasively measure the thickness of human cerebral cortex with accuracy comparable to that of postmortem histologic analysis 10, 11, 12. This technique has been successfully implemented to study the effects of age and degenerative disease, where cortical thickness has been shown to correlate with disease progression, cause, and cognitive dysfunction 13, 14, 15, 16, 17. There are presently no published data on variable response in humans of sublobar cortical regions to radiation dose.

Neurologic deficits observed after brain RT typically involve decline in higher cognitive functions such as attention and memory rather than more basic somatosensory defects, cortical blindness, or paralysis 1, 2, 3. This clinical observation may provide a clue to underlying radiation biology. Whereas the more basic functions are performed by the primary cortex (eg, primary visual cortex, primary motor, and primary somatosensory), it is the higher-order association cortex that is most critical for the functions of human cognition most frequently affected after RT (18). Inferior lateral parietal cortex is an area involved in a range of cognitive tasks including spatial attention and memory retrieval 19, 20, 21, 22. The entorhinal cortex, which is the primary input source for the hippocampal formation, in turn integrates input from nearly all association cortices for its pivotal role in memory and can be considered a special case of limbic association cortex 23, 24, 25. In the present quantitative MRI study, we sought to find out whether these cortical areas subserving higher-order functions (inferior parietal and entorhinal) are selectively vulnerable to radiation-induced atrophy.