Quantitative T2 MRI is predictive of neurodegeneration following organophosphate exposure in a rat model

Abstract

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative t 2 MRI could be used as a biomarker of neurodegeneration. Quantitative T 2 MRi was performed using a 9.4 T MRI on rats prior to and following soman exposure. T 2 images were taken at least 24 h prior, 1 h and 18-24 h after soman exposure. Rats were pre-and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T 2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18-24 h after soman exposure, significant increases in T 2 , a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18-24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18-24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p < 0.001). These findings indicate there is regionally specific neurodegeneration 24 h after exposure to soman. The high correlation between T 2 relaxivity and histopathology supports the use of T 2 as a marker of injury. Globally, there are up to two million cases of acute pesticide poisoning annually 1. Organophosphorus (OPs) compounds are one of the most widely used pesticides and account for 33% of the pesticides used within the United States in 2012 2. Although new regulations have led to a decrease in OP usage in the United States from 2000 2 , pesticide self-poisoning remains a global health problem in low to middle income countries 1. The ingestion of OPs may account for over 100,000 deaths per year 1. More potent forms of OPs include nerve agents that have been developed as chemical warfare agents. Confirmed usage of nerve agents in Syria, in 2013 and 2017, accounted for the death of hundreds of civilians whilst injuring thousands 3. Nerve agents including tabun, sarin, soman, and VX continue to pose a threat to both civilians and military personnel. Exposure can lead to lacrimation, miosis, tremor, paralysis, convulsive seizures, and respiratory failure, often leading to death if untreated 4. A key problem is that following nerve agent exposure, assessing the extent of brain injury is difficult. A noninvasive method that is sensitive to nerve agent related pathology would allow for the monitoring of patients and determining the efficacy of nerve agent treatment protocols. Current treatment protocols are effective in protecting against lethality; however, they may not prevent nerve agent-related neuropathology and associated long-term sequelae. MRI has been used to assess brain pathology post OP exposure 5-12 but few studies have directly correlated the MR changes to histopathology 7,8,10. Diffusion MRI provides contrast that relates to ce...

Tiger nut/coconut dietary intervention as antidotal nutritional remediation strategy against neurobehavioural deficits following organophosphate-induced gut-brain axis dysregulation in mice

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Sex‐based structural and functional MRI outcomes in the rat brain after soman (GD) exposure‐induced status epilepticus

“…2 As the main contributor to neurological damage is from prolonged SRS, which associates to a large extent with SE severity after nerve agent exposure, 16 we hypothesized that soman-exposed animals with severe SE (>20 min) will show MRI-based neurodegeneration in both sexes and with a larger impact on females. As quantitative MRI can predict neurodegeneration in rat models of OPNA exposure, [17][18][19][20] we investigated structural MRI-based brain outcomes in combination with fMRI-based functional changes in adult rats of both sexes with similar SE severity after exposure to soman. To understand the long-term sex-based outcomes of soman exposure on brain glucose metabolism, we performed [18F]-fluorodeoxyglucose (18F-FDG)-based positron emission tomography (PET) imaging.…”