Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication

Magnetic Resonance Imaging for the Monitoring of Neuropathology Following Acute Organophosphate Intoxication

Organophosphorus (OP) cholinesterase inhibitors are a diverse category of highly toxic compounds that include pesticides and nerve agents. Unless rapidly treated, acute intoxication with these compounds leads to cholinergic crisis, respiratory distress, status epilepticus, and death. There are an estimated one million life threatening cases of acute OP intoxication each year, primarily due to suicidal and occupational exposures, resulting in 200,000 deaths. Individuals surviving intoxication develop lasting neurologic consequences, including cognitive dysfunction, behavioral changes, and epilepsy. Currently available medical countermeasures for treating acute OP intoxication reduce mortality, but must be administered within minutes of exposure, and do not prevent the development of long-term consequences. There is a pressing need for improved treatment options that address these shortcomings; however, the pathogenesis of long-term sequelae, including the spatiotemporal patterns of neuropathology between the acute exposure and the onset of persistent neurological signs, are not well characterized. Robust animal models and tools are needed to: 1) elucidate the relationship between brain injury immediately following OP intoxication and delayed onset long-term sequalae; and 2) longitudinally monitor the efficacy of novel therapies. This dissertation details the use of in vivo magnetic resonance imaging (MRI) as a tool for noninvasive, longitudinal, monitoring of brain injury, with the goal of providing insights as to pathogenic mechanisms contributing to the development of long-term consequences. In this thesis, a rat model of acute intoxication with the OP pesticide and threat agent, diisopropylfluorophosphate (DFP), was characterized using traditional histologic assessment of neuropathology, as well as high resolution T2-weighted (T2w) and diffusion-weighted (DWI) MRI. Both MR contrast mechanisms were highly effective in detecting the spatiotemporal onset and progression of DFP-induced brain injury. Additionally, quantitative metrics derived from diffusion MRI were highly correlated with the severity of neuropathology defined by histologic assessment of neuronal cell death and neuroinflammatory responses. Initial seizure severity was found to be significantly correlated with the severity of neuropathology, as assessed by MRI and histology. Furthermore, the brain-region-dependent progression of neuropathology documented by MRI and histology in the rat model of acute DFP intoxication were markedly similar to data from other preclinical models of status epilepticus, suggesting that the primary mechanisms underlying persistent injury following acute OP intoxication are due to seizures triggered by OPs. The studies presented in this dissertation support the use of longitudinal MRI for monitoring persistent neuropathology following acute OP intoxication, and in doing so, provide a detailed spatiotemporal map of brain injury following acute DFP intoxication. Collectively, these results demonstrate that MRI is a powerful tool for the longitudinal monitoring of brain injury following acute OP intoxication, and, potentially, evaluation of novel therapies

18FPBR111PET_02of16

This .zip file, one of sixteen parts (see file name), contains dynamic PET scans of DFP or vehicle exposed rats. Data is stored in raw format (4 byte little endian float) with image parameters stored within a header file. Additional information for each animal (eg: treatment, injected radiotracer dose, weight) can be found in the meta data spreadsheet

18FPBR111PET_13of16

This .zip file, one of sixteen parts (see file name), contains dynamic PET scans of DFP or vehicle exposed rats. Data is stored in raw format (4 byte little endian float) with image parameters stored within a header file. Additional information for each animal (eg: treatment, injected radiotracer dose, weight) can be found in the meta data spreadsheet

18FPBR111PET_08of16

This .zip file, one of sixteen parts (see file name), contains dynamic PET scans of DFP or vehicle exposed rats. Data is stored in raw format (4 byte little endian float) with image parameters stored within a header file. Additional information for each animal (eg: treatment, injected radiotracer dose, weight) can be found in the meta data spreadsheet

18FPBR111PET_03of16

This .zip file, one of sixteen parts (see file name), contains dynamic PET scans of DFP or vehicle exposed rats. Data is stored in raw format (4 byte little endian float) with image parameters stored within a header file. Additional information for each animal (eg: treatment, injected radiotracer dose, weight) can be found in the meta data spreadsheet