Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate.

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

Dysarthria Profiles in Adults With Hereditary Ataxia.

Purpose This preliminary study examined whether speech profiles exist for adults with hereditary ataxia based on 2 competing frameworks: a pattern of instability/inflexibility or a pattern of differential subsystem involvement. Method Four dysarthria experts rated the speech samples of 8 adults with dysarthria from hereditary ataxia using visual analog scales and presence/severity rating scales of speech characteristics. Speaking tasks included diadochokinetics, sustained phonation, and a monologue. Results Speech profiles aligned with the instability/inflexibility framework, with the pattern of instability being the most common. Speech profiles did not emerge for the majority of speakers using the differential subsystem framework. Conclusions The findings extend previous research on pure ataxic dysarthria and suggest a possible framework for understanding the speech heterogeneity associated with the ataxias. The predominance of the instability profile is consistent with the notion of impaired feedforward control in speakers with cerebellar disruption.