Abstract. Diarrhea is well recognized as a leading cause of childhood mortality and morbidity in developing countries; however, possible long-term cognitive deficits from heavy diarrhea burdens in early childhood remain poorly defined. To assess the potential long-term impact of early childhood diarrhea (in the first 2 years of life) on cognitive function in later childhood, we studied the cognitive function of a cohort of children in an urban Brazilian shantytown with a high incidence of early childhood diarrhea. Forty-six children (age range, 6-10 years) with complete diarrhea surveillance during their first 2 years of life were given a battery of five cognitive tests. Test of Non-Verbal Intelligence-III (TONI) scores were inversely correlated with early childhood diarrhea (P ‫ס‬ .01), even when controlling for maternal education, duration of breast-feeding, and early childhood helminthiasis (Ascaris or Trichuris). Furthermore, Wechsler Intelligence Scale for Children (WISC-III) Coding Tasks and WISC-III Digit Span (reverse and total) scores were also significantly lower in the 17 children with a history of early childhood persistent diarrhea (PD; P < .05), even when controlling for helminths and maternal education. No correlations were seen between diarrhea rates and Wide Range Assessment of Memory and Learning subtests or WISC-III Mazes. This report (with larger numbers of participants and new tests) confirms and substantially extends previous pilot studies, showing that long-term cognitive deficits are associated with early childhood diarrhea. These findings have important implications for the importance of interventions that may reduce early childhood diarrheal illnesses or their consequences.

Polymorphisms in the apolipoprotein E (APOE) have constituted the major rationale to identify potential risk groups for developing late-onset Alzheimer's disease and help to predict recovery of cognitive function after brain injury. However, the APOE impact on cognitive development in children living in poor areas of the developing world, where we have discovered profound significant associations of early childhood diarrhea (at 0-2 y) with lasting impairments of growth, cognition, and school performance, is not known. Therefore, we conducted APOE genotyping in 72 Brazilian shantytown children under active surveillance since birth, using purified DNA extracted from buccal cell samples. We found a high frequency of APOE4 alleles (18% versus 9-11% expected) in children with lower diarrhea burdens. When we examined the children who experienced the heavier diarrhea burdens (greater than or equal to the median of seven illnesses in the first 2 y of life), those with APOE4 did significantly better in the coding subtest (p=0.01) when compared with APOE4-negative children with similar diarrhea burdens. Positive correlations between the APOE4 occurrence and coding scores remained, even after adjusting for family income, maternal education, and breast-feeding. Moreover, the APOE4-positive group, under heavy burdens of diarrhea, had preserved semantic fluency and the mean difference in fluency scores, p=0.025, a standardized coefficient for disproportional verbal fluency impairment. Our findings show that APOE4 is relatively common in favela children and suggest a protective role of the APOE4 allele in children with a history of heavy burdens of diarrhea in their first 2 y of life.

These findings document effects of early childhood diarrhea on later school readiness and performance and hence potential long-term human and economic costs of ECD, which warrant further attention and far greater investment for the control of ECD and its consequences.

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