Social memory in female mice is rapidly modulated by 17ß-estradiol through ERK and Akt modulation of synapse formation.

Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17ß-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and coordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Mice performed a short-term social memory task or were used as task-naïve controls. ERK and PI3K pathway inhibitors were infused intradorsal hippocampally 5 min before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (bassoon puncta positive for GluA1) in task-performing mice but decreased synapse number in task-naïve mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naïve mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. While ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behavior and underscores the importance of estrogen signaling in the brain to social behavior.

Apathy and APOE in mild behavioral impairment, and risk for incident dementia.

Introduction: Mild behavioral impairment (MBI) is a high-risk state for incident dementia and comprises five core domains including affective dysregulation, impulse dyscontrol, social inappropriateness, psychotic symptoms, and apathy. Apathy is among the most common neuropsychiatric symptoms (NPS) in dementia but can also develop in persons with normal cognition (NC) or mild cognitive impairment (MCI). The later-life emergence and persistence of apathy as part of the MBI syndrome may be a driving factor for dementia risk. Therefore, we investigated MBI-apathy-associated progression to dementia, and effect modification by sex, race, cognitive diagnosis, and apolipoprotein E (APOE) genotype. Methods: Dementia-free National Alzheimer's Coordinating Center participants were stratified by persistent apathy status, based on Neuropsychiatric Inventory (NPI)-Questionnaire scores at two consecutive visits. Hazard ratios (HRs) for incident dementia for MBI-apathy and NPI-apathy relative to no NPS, and MBI-apathy relative to no apathy, were determined using Cox proportional hazards regressions, adjusted for baseline age, sex, years of education, race, cognitive diagnosis, and APOE genotype. Interactions with relevant model covariates were explored. Results: Of the 3932 participants (3247 with NC), 354 had MBI-apathy. Of all analytic groups, MBI-apathy had the greatest dementia incidence (HR = 2.69, 95% confidence interval [CI]: 2.15-3.36, P < 0.001). Interaction effects were observed between cognitive diagnosis and APOE genotype with the NPS group. The contribution of apathy to dementia risk was greater in NC (HR = 5.91, 95% CI: 3.91-8.93) than in MCI (HR = 2.16, 95% CI: 1.69-2.77, interaction P < 0.001) and in all APOE genotypes, was greatest in APOE ɛ3 (HR = 4.25, 95% CI: 3.1-5.82, interaction P < 0.001). Discussion: Individuals with MBI-apathy have a markedly elevated risk for future dementia, especially when symptoms emerge in those with NC. Both cognitive status and APOE genotype are important moderators in the relationship between MBI-apathy and incident dementia. MBI-apathy may represent a group in whom apathy is a preclinical or prodromal manifestation of dementia and identify a precision medicine target for preventative interventions.

Screening approaches for identifying fetal alcohol spectrum disorder in children, adolescents, and adults: A systematic review.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a prevalent neurodevelopmental disorder that is caused by prenatal alcohol exposure (PAE) and associated with a range of cognitive, affective, and health concerns. Although the identification of FASD can facilitate the provision of interventions and support, and plays a protective role against adverse outcomes, there are high rates of missed detection. The identification of FASD via screening may improve its recognition across settings. The current systematic review examined the available evidence on FASD screening tools and approaches across age groups and settings. METHODS: A systematic search was carried out for both peer-reviewed studies and gray literature sources published between January 1990 and May 2020 and was preregistered with PROSPERO (#CRD42019122077). Studies included in the review focused on human applications of FASD screening in children, adolescents, and adults. The quality of the studies was assessed using the QUADAS-2 and GRADE frameworks. RESULTS: The search yielded 20 screening tools and approaches across 45 studies, broadly characterized in 2 groups. The first group included approaches currently in use that aim to identify individuals at risk of FASD using a range of markers (n = 19) or associated sentinel dysmorphic facial features (n = 6). Another group of studies, characterized as emerging, focused on identifying promising biomarkers of PAE/FASD (n = 20). Overall, we identified limited research supporting the psychometric properties of most screening approaches. The quality review provided evidence of bias due to the common use of case-control designs and lack of adequate reference standards. CONCLUSIONS: Although several FASD screening tools and approaches are available for use across a range of age groups and settings, the overall evidence base supporting their psychometric properties is weak, with most studies demonstrating significant risk of bias. Service providers should exercise caution in selecting and implementing FASD screening tools given these limitations. It is critically important to accurately identify individuals with FASD across ages and settings to support healthy outcomes. Thus, there is a pressing need for additional research in this area, particularly validation studies in large and representative samples using robust methodological approaches.