SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

Purpose: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.

Methods: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.

Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo.

Mutations in RNA-binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb, and neurological symptoms. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription, and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. We show a developmental role for Hnrnpul1 in zebrafish, resulting in reduced body and fin growth and missing bones.

An assessment of the functional effects of amphetamine-induced dendritic changes in the nucleus accumbens, medial prefrontal cortex, and hippocampus on different types of learning and memory function.

The present experiments investigated the effects of repeated amphetamine exposure on neural networks mediating different forms of learning and memory. Different components of these networks were assessed using various functional assays. The hypothesis was that abnormal dendritic changes in nucleus accumbens, medial prefrontal cortex, and hippocampus mediated by repeated amphetamine exposure would produce impairments on forms of learning and memory dependent on neural circuits relying on these brain systems, and have little or no effect on other forms of learning not dependent on these networks.

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8.

Genetic Risk, Vascular Function, and Subjective Cognitive Complaints Predict Objective Cognitive Function in Healthy Older Adults: Results From the Brain in Motion Study.

Aging is associated with subjective memory complaints. Approximately half of those with subjective memory complaints have objective cognitive impairment. Previous studies have provided evidence of an association between genetic risk for Alzheimer's disease (AD) and dementia progression.

Aerobic exercise improves cognition and cerebrovascular regulation in older adults.

Objective: To test the hypothesis that aerobic exercise is associated with improvements in cognition and cerebrovascular regulation, we enrolled 206 healthy low-active middle-aged and older adults (mean ± SD age 65.9 ± 6.4 years) in a supervised 6-month aerobic exercise intervention and assessed them before and after the intervention.

Association of sleep spindle characteristics with executive functioning in healthy sedentary middle-aged and older adults.

To determine the relationship between sleep spindle characteristics (density, power and frequency), executive functioning and cognitive decline in older adults, we studied a convenience subsample of healthy middle-aged and older participants of the Brain in Motion study. Participants underwent a single night of unattended in-home polysomnography with neurocognitive testing carried out shortly afterwards. Spectral analysis of the EEG was performed to derive spindle characteristics in both central and frontal derivations during non-rapid eye movement (NREM) Stage 2 and 3.

Aerobic exercise increases cortisol awakening response in older adults.

Evidence from both preclinical and clinical studies suggests aerobic exercise may dampen age-related decline in cognitive performance. Alterations in hypothalamic-pituitary-adrenal (HPA) axis function and reactivity may be a mechanism by which aerobic exercise benefits cognitive performance, and reduces perceived stress. This investigation was completed as an ancillary investigation of the Brain in Motion (BIM) study, a 6-month supervised aerobic exercise intervention.

Novel Approach to Characterize Heterogeneity in an Aerobic Exercise Intervention.

Purpose: Exercise intervention studies for brain health can be difficult to interpret due to heterogeneity in exercise intensity, exercise duration, and in adherence to the exercise intervention. This study aimed to characterize heterogeneity in these components in a cohort of healthy middle-age and older adults who participated in a prescribed 6-month supervised aerobic exercise intervention as part of the Brain in Motion study.

Methods And Results: Group-based multitrajectory analysis (GBMTA) was used to characterize variation in the trajectory of exercise intensity and duration for male and female participants in the first 3 months of the exercise program.

Protective Effects of Exercise on Cognition and Brain Health in Older Adults.

Accelerated trajectories of cognitive decline in older adults may increase the risk of developing Alzheimer disease and related dementias (ADRD). Physical activity has potential modifying effects on these changes that could prevent or delay ADRD. This review explores the hypothesis that multiple, mutually complimentary, and interacting factors explain the positive association between exercise and the optimization of cognition in older adults.

Association between glycemic load and cognitive function in community-dwelling older adults: Results from the Brain in Motion study.

Background: Impaired glucose tolerance is a risk factor for non-age-related cognitive decline and is also associated with measures of physical activity (PA) and cardiorespiratory fitness (CRF). A low glycemic load (GL) diet can aid in the management of blood glucose levels, but little is known about its effect on cognition with poor glucoregulation.

Objective: We assessed the relation between GL and cognitive function by glucoregulation and possible mediatory effects by CRF and PA in older adults from the Brain in Motion Study.

Evidence of association between sleep quality and APOE ε4 in healthy older adults: A pilot study.

Background: It has been estimated that the prevalence of Alzheimer disease (AD) and related dementias will triple by 2035, unless effective interventions or treatments are found for the neurodegenerative disease. Understanding sleep changes as a marker for both AD risk and progression is a burgeoning area of investigation. Specifically, there is emerging evidence that both sleep disturbances and the APOE ε4 allele are associated with increased dementia risk.

Cardiometabolic risk factors predict cerebrovascular health in older adults: results from the Brain in Motion study.

Aging and physical inactivity are associated with an increased risk of developing metabolic syndrome (MetS). With the rising prevalence of MetS, it is important to determine the extent to which it affects cerebrovascular health. The primary purpose of this report is to examine the impact of MetS on cerebrovascular health (resting cerebral blood flow (CBF) peak velocity (V¯P), cerebrovascular conductance (CVC), and CBF responses to hypercapnia) in healthy older adults with normal cognition.

The Attention Network Test-Interaction (ANT-I): reliability and validity in healthy older adults.

The Attention Network Test (ANT) is a frequently used computer-based tool for measuring the three attention networks (alerting, orienting, and executive control). We examined the psychometric properties of performance on a variant of the ANT, the Attention Network Test-Interaction (ANT-I) in healthy older adults (N = 173; mean age = 65.4, SD = 6.

Cerebrovascular Responsiveness to Hypercapnia Is Stable over Six Months in Older Adults.

The primary purpose of this Brain in Motion (BIM) sub-study was to determine the 6-month stability of resting blood flow velocity and cerebrovascular responsiveness to a euoxic hypercapnic challenge in a group of physically inactive community dwelling men and men aged ≥55 yrs (range 55-92 yrs). At baseline and 6 months later 88 women (65±6 yr) and 78 men (67±7 yr) completed a hypercapnic challenge (step changes from resting end-tidal PCO2 ((PETCO2) to +1, +5 and +8 mmHg above rest) while cerebral blood flow velocity was assessed using transcranial Doppler ultrasound. Peak velocity of the middle cerebral artery (MCAv) was increased (p<0.

Association between Lifetime Physical Activity and Cognitive Functioning in Middle-Aged and Older Community Dwelling Adults: Results from the Brain in Motion Study.

To determine if total lifetime physical activity (PA) is associated with better cognitive functioning with aging and if cerebrovascular function mediates this association. A sample of 226 (52.2% female) community dwelling middle-aged and older adults (66.

Sex difference in cue strategy in a modified version of the Morris water task: correlations between brain and behaviour.

Background: Sex differences in spatial memory function have been reported with mixed results in the literature, with some studies showing male advantages and others showing no differences. When considering estrus cycle in females, results are mixed at to whether high or low circulating estradiol results in an advantage in spatial navigation tasks. Research involving humans and rodents has demonstrated males preferentially employ Euclidean strategies and utilize geometric cues in order to spatially navigate, whereas females employ landmark strategies and cues in order to spatially navigate.

The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults.

Background: Aging and physical inactivity are associated with declines in some cognitive domains and cerebrovascular function, as well as an elevated risk of cerebrovascular disease and other morbidities. With the increase in the number of sedentary older Canadians, promoting healthy brain aging is becoming an increasingly important population health issue. Emerging research suggests that higher levels of physical fitness at any age are associated with better cognitive functioning and this may be mediated, at least in part, by improvements in cerebrovascular reserve.

Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats.

Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined.

Prefrontal cortical contributions during discriminative fear conditioning, extinction, and spontaneous recovery in rats.

This research examined the roles played by the ventromedial orbital prefrontal cortex (OPFC) and the infralimbic/prelimbic prefrontal cortex (I/P PFC) during discriminative fear conditioning. The first experiment included nine rats with bilateral lesions to the I/P PFC, an additional nine with OPFC lesions, and eight sham lesion controls. Behavioural analysis was conducted using a discriminative fear conditioning to context task 10 days after surgery.