Early in vivo MR spectroscopy findings in organophosphate‐induced brain damage—potential biomarkers for short‐term survival

Abstract

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and ¹H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P < 0.05). On spectroscopy, N-acetyl aspartate (NAA)/creatine and NAA/choline levels significantly decreased 3 h postintoxication (>20% decrease, P < 0.005), and 3 h lactate peak was evident in all intoxicated animals. On the 8th day, although very little T2 changes were evident, NAA/creatine and choline/creatine were significantly decreased (>15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.

A magnetic resonance imaging study of early brain injury in a rat model of acute DFP intoxication

“…Longitudinal analysis of the earliest lesions revealed that their hyperintensity began to attenuate within 3 d post-exposure, while lesions in the hippocampus continued to increase in extent and intensity throughout the 72 h study. These spatiotemporal patterns of DFP-induced T2w lesions are consistent with T2w MRI assessments of soman intoxication in the rat and guinea pig, which reported that the thalamus and piriform cortex were the most severely damaged regions at 3 and 6 h post-intoxication, respectively (Gullapalli et al, 2010, Shrot et al, 2012). Longitudinal analysis of T2w lesion severity in the soman-intoxicated guinea pig (Gullapalli et al, 2010) also demonstrated a delayed onset of more than 24 h in the appearance of hippocampal hyperintensity relative to other damaged regions.…”

“…However, there are no MRI data published regarding lesion development during the first 3 d following DFP intoxication. While previous MRI studies in rodent models of acute intoxication with OP nerve agents have detected lesions as early as 3 h post-intoxication (Carpentier et al, 2008, Shrot et al, 2012), considerable variation in injury has been reported at these early time points. It is unclear, however, whether these disparate findings reflect differences in the intoxicating OP (soman vs .…”

“…In addition to reducing animal numbers, the collection of longitudinal data increases statistical power and allows animals with varying response patterns to be readily identified. While MRI has been used extensively to study preclinical seizure models, there are a limited number of publications describing the use of MRI to assess seizure-induced brain injury in preclinical models of acute OP intoxication (Bhagat et al, 2001, Bhagat et al, 2005, Carpentier et al, 2008, Gullapalli et al, 2010, Hobson et al, 2017, Rosman et al, 2012, Shrot et al, 2012, Shrot et al, 2015, Testylier et al, 2007). We recently reported a correlative histologic and MRI-based characterization of a rat model of acute intoxication with the OP pesticide, diisopropylfluorophosphate (DFP) (Hobson et al, 2017, Siso et al, 2017).…”

MRS of Brain Metabolite Levels Demonstrates the Ability of Scavenging of Excess Brain Glutamate to Protect against Nerve Agent Induced Seizures

“…Lactate is one of the main cerebral metabolites and the presence of excess lactate level in CSF indicates that glycolysis was activated in an oxygen deficient environment. Several causes for this activation have been described in many pathological conditions, such as ischemia, hypoxia, mitochondrial disorders, epilepsy and organophosphate intoxication [ 15 , 16 , 17 ]. It was shown that the brain lactate/creatine levels as measured 3 h post Paraoxon (PO) intoxication were in positive correlation with 24 h brain edema [ 17 ].…”

“…Brain metabolite concentrations are usually expressed as ratios (relative quantification, mostly normalized to the peak of phosphocreatine) rather than as absolute concentrations [ 18 ]. The level of most common cerebral metabolites can be altered under pathological conditions or after drug administration while the level of phosphocreatine (PCr) remains mostly constant [ 17 ].…”