Summary Brain swelling is the major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR) binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling.

Objective: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/ intracranial volume ratio [HpVR]) across AD stages. Methods:The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE e4 status.Results: Across groups, there were significant sex 3 HpVR interactions for immediate and delayed recall (p , 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR 3 sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p , 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p , 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p 5 0.04) and larger HpVR (delayed, p 5 0.001). The cognitive reserve theory posits that favorable premorbid factors including higher education and IQ delay the onset of clinical deficits despite Alzheimer disease (AD)-related neurodegeneration because compensatory mechanisms are more readily engaged (e.g., alternate brain networks or cognitive strategies). Conclusion:1-3 The theory predicts that the onset of accelerated cognitive decline is closer in time to AD dementia diagnosis in individuals with greater cognitive reserve; however, after onset, their decline is more rapid because neurodegeneration is more advanced at that point. [4][5][6] Throughout life, women outperform men on verbal memory tasks. [7][8][9] We predict that this female advantage may reflect a sex-specific form of cognitive reserve resulting in a delay in the clinical manifestation of memory impairment until more advanced neurodegeneration overwhelms the female advantage and decline begins. Thereafter, we predict that women decline From the Einstein Aging Study and the