The Use of PET Imaging to Assess Neurochemical Changes After Prophylactic Whole Cranial Radiation

Abstract

The Use of PET Imaging to Assess Neurochemical Changes After Prophylactic Whole Cranial Radiation

Radiation therapy to the brain can cause a non-focal syndrome characterized by global cognitive decline. Occasionally it persists and even progresses to dementia, often with extrapyramidal movement abnormalities. The pathophysiology of this toxicity is unknown. Therefore, strategies to minimize this devastating side effect are limited and based predominantly on changing radiation dosage and fractionation. We will test the hypotheses that toxic effects of global cranial irradiation are mediated by mild neuronal injury. Importantly, we propose that particular subsets of neurons and synapses may be particularly vulnerable to therapeutic irradiation and may serve as sub-clinical imaging surrogates for this toxicity.

We propose a prospective pilot study that will involve 14 patients who require prophylactic whole brain irradiation (WBR). They will be studies with specific non-invasive quantification of two neuronal synaptic measure: 1) the density of vesicular monoamine transporter type-2 (VMAT2), determined with [11C]dihydrotetrabenazine (DTBZ) PET; and 2) the density of benzodiazepine binding sites on CNS GABAA receptors determined with [11C]flumazenil (FMZ) PET.

Each subject will be studied at baseline and at 6 months and 18 months after WBR. We hypothesize that VMAT2 sites on nigrostriatal terminals may be particularly vulnerable to radiation free radical damage, owing to the reported sensitivity of these dopamine neurons to oxidative metabolic stress. FMZ PET is a biomarker of inhibitory CNS synapses and will track changes in cortical and subcortical neuropil for comparison with striatal DTBZ binding. We will also perform structural proton MRI and MR spectroscopy (MRS) to permit correction of the PET measure for potential structural changes and to assess the relationship of PET synaptic marker changes with previously-reported transient reductions of N-acetyl-aspartate. Structured neuropsychometric assessments of motor performance examinations will be obtained, and correlated with the imaging measures.

This study will provide unique insight into the potential biochemical basis for neuro-behavior deficits following cranial irradiation. The ability to both observe and predict for these changes may allow us to minimize the toxicity of cranial irradiation in the future by adjusting the dosage or by administration of protective agents. The neurochemical findings of our study may enhance these goals by providing an objective, sub-clinical surrogate marker of radiation toxicity.