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Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can

BackgroundDuring childhood development, particularly the periadolescent epoch, significant changes in cognition and brain structure are known to occur. The development of spatial working memory (SWM), for example, continues throughout the teenage years. The hippocampus is necessary for normal SWM, as seen by the substantial memory deficits seen in patients with Alzheimer's disease (AD) and their associated hippocampal pathology. It is hypothesized that vulnerability to AD could be modulated by early brain development, so understanding the developmental relationship between hippocampal volume (HV) and SWM would provide a key baseline for comparison of different trajectories. Our ongoing study, Polygenetic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK; R01 AG064247), measures brain structure/function, cognitive abilities, and Alzheimer’s polygenetic risk score in periadolescent children (age 8‐13). Here, we report preliminary data from PRANK measuring the association between HV, age, and SWM.MethodUsing preliminary data from the PRANK project, we investigated the association between SWM, age, and HV. Our sample included children (N=80, age 8‐13 years), recruited from the community and tested at University of Nebraska Medical Center; demographics were consistent with the recruitment area. SWM was measured using the Spatial Working Memory task between errors term from the Cambridge Neuropsychological Battery. Structural MRI data were collected using a 3T Siemens Prisma instrument. HV was measured using automated segmentation in Freesurfer.ResultSWM was associated with age, r(80) = ‐.334, p = .002, such that older children showed fewer spatial working memory errors than younger children. HV was not significantly associated with SWM, controlling for age, r(77) = ‐.027, p = .813. However, the direction of the relationship between HV and SWM (larger HV associated with fewer SWM errors) was consistent with previous literature (Faridi et al., 2015).ConclusionThese preliminary results suggest that increasing age is associated with better SWM in typical childhood; findings for HV were non‐significant. We anticipate that our study’s full sample will provide appropriate statistical power to test the association of SWM with HV. In future efforts, we will investigate this association as it relates to polygenic risk for Alzheimer’s disease and whether these results generalize to children with Down syndrome.

BackgroundAlzheimer’s disease (AD) is an insidious neurodegenerative disease that is frequently associated with deficits in both memory and executive functions (EFs). EFs consist of a diverse range of cognitive processes, including inhibition, working memory, and cognitive flexibility. In AD and other disorders, dysfunction in EFs can result in attention deficits, decreased inhibition, and impaired decision‐making abilities. EFs have been historically linked to the prefrontal regions of the brain, but recent studies of brain networks and their functional connectivity have broadened these links to include brain regions such as the hippocampus (Hc). Building upon prior work, the current project investigated the association between decision making and hippocampal resting state functional connectivity (rs‐FC) in periadolescent children.MethodA cohort of healthy periadolescent children aged 8‐13 (N = 80) was sampled from the ongoing NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. PRANK participants completed an array of cognitive and behavioral measures, in addition to an MRI of the brain. Decision making ability was assessed via the NIH Toolbox Dimensional Change Card Sorting (DCCS) task. The rs‐FC between the Hc and regions of the prefrontal cortex (PFC) was measured, and its covariance with DCCS was assessed.Resultrs‐FC of the Hc covaried with performance on the DCCS in the left dorsolateral prefrontal cortex (dlPFC) and dorsal anterior cingulate cortex (dACC). These anatomical regions are in line with larger intrinsic brain networks, such as the frontoparietal network (FPN) and the cingulo‐opercular network (CON).ConclusionThese preliminary results suggest the Hc is associated with anatomical regions and intrinsic brain networks that are important for EFs. A better characterization of the process by which EF occurs within the brain may drive further research that can assess ways to limit the decline of these cognitive abilities associated with healthy aging or brain pathology such as AD.

BackgroundIn typically presenting Alzheimer’s disease (AD), pathological changes to the hippocampus (Hc) and its associated functional brain networks result in impaired declarative/relational memory. While it is known that risk factors for AD (genetic, environmental, etc.) can impact hippocampal resting‐state functional connectivity (RSFC) later in life, the development of the hippocampus and its connections to other brain regions may also be influenced by such risk factors. The goal the current study was to characterize the neurodevelopmental changes in this hippocampal network during the periadolescent epoch and determine whether the observed changes were associated with declarative/relational memory ability. Therefore, we utilized a cross‐sectional approach to test whether individual differences in hippocampal RSFC covary with outcomes on a test of relational memory ability in periadolescent children.MethodData were drawn from an ongoing NIA‐funded project: the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. Our analysis was carried out using data from healthy periadolescent participants (N=90; age 8‐13 years). We assessed declarative/relational memory with Cambridge Cognition’s Paired Associates Learning (PAL) task. To conduct the resting‐state functional MRI analyses, we used a seed‐based approach with the bilateral hippocampus as the seed region of interest. We then analyzed the hippocampal RSFC data to and assessed covariance of individual patterns of hippocampal RSFC with memory performance measured with the PAL task.ResultOur preliminary findings, largely consistent with previous work, demonstrate patterns of hippocampal RSFC sharing territory with the ventral and lateral portions of the default mode network (DMN). In addition, we observed evidence of regional covariance between hippocampal RSFC and PAL task performance.ConclusionThe preliminary findings of the ongoing PRANK study indicate that hippocampal RSFC covaries regionally with hippocampal‐dependent memory ability in periadolescent children. Future work from the PRANK study aims to understand whether genetic and polygenic risk factors for AD influence this hippocampal network development. To do so, we will utilize participants’ AD polygenic risk scores, and determine whether those scores are related to individual differences in hippocampal RSFC.