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

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (\u3c37 \u3erepeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington\u27s Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P \u3c .001), cognitive (P \u3c .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P \u3c .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P \u3c .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion