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BACKGROUND: Associations between lead (Pb) and neurodevelopment have been studied widely in the context of global measures of cognitive function, such as IQ. Operant test batteries consist of behavioral tasks that can be used to target discrete cognitive and behavioral mechanisms, which contribute to global cognitive faculties. OBJECTIVES: The goals of this study were to identify Pb-associated deficits in cognitive development and determine the underlying mechanisms involved, utilizing an operant test battery. We evaluated effect modification by child sex. METHODS: This study utilized data from a prospective cohort in Mexico City. We included 549 participants aged 6-to-7 years with complete data on prenatal blood Pb measurements, Operant Test Battery (OTB) tasks, and demographic covariates. General linear models were used to examine the association of Pb levels at each prenatal timepoint and OTB performance. Effect modification by child sex was evaluated using 2-way interaction terms. RESULTS: In three of the operant tasks, we observed that higher late-pregnancy blood Pb concentrations were associated with greater response latencies. In the temporal processing task, we observed that higher late-pregnancy Pb exposure was associated with worse overall task performance. Further, in two operant tasks, the effects of Pb were dependent on the sex of the child, such that the effects of Pb were more pronounced in females in the condition position responding task, but stronger in males in the temporal processing task. CONCLUSIONS: Our results suggest that prenatal Pb concentrations yield broad dysregulation of executive functions, which can be attributed to dysregulation of temporal processing. In addition, we observed sex differences in two operant tasks suggesting that some Pb effects on neurocognitive function may be sexually dimorphic.

Objective: Many interventions that exhibit therapeutic potential in preclinical Alzheimer’s disease (AD) research have not been proven effective clinically. One reason for this lack of translatability between animals and humans might be due to a failure to employ measures in animals that generalize to humans. The National Center for Toxicological Research (NCTR) has developed an operant test battery (OTB) designed to generate translational markers of complex brain function in rats, monkeys, and humans. The NCTR OTB has not, as yet, been used to assess cognitive function in persons with a diagnosis of AD. Thus, the purpose of this study was to assess the utility of the NCTR OTB to detect cognitive impairments in individuals with a diagnosis of AD. Methods: Seven participants with an AD diagnosis and 12 healthy adults (age ≥ 60), completed three operant tasks: Temporal Response Differentiation (TRD); Delayed Matching to Sample (DMTS); and Incremental Repeated Acquisition (IRA). These tasks were used to measure aspects of timing ability, short-term nonverbal memory and attention, and learning, respectively. Results: Persons with a diagnosis of Alzheimer’s disease performed significantly worse on all three tasks, displaying marked deficits in several areas of cognitive function. Conclusion: These results suggest that the NCTR OTB is capable of detecting cognitive impairments in individuals with AD and, therefore, is a useful tool for monitoring disease severity and progression and for screening compounds for cognitive enhancing effects in both preclinical and clinical research.