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. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

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. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

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. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

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. Surprisingly, the results showed that many of the dendritic changes normally found in the nucleus accumbens, prefrontal cortex, and hippocampus following repeated amphetamine exposure were reversed back to control levels following extensive multi-domain cognitive training. Learning and memory functions associated with different neural networks also appeared normal except in one case. A neural network that includes, but is not limited to, the basolateral amygdala and nucleus accumbens was dysfunctional in rats repeatedly exposed to amphetamine despite the reversal of the majority of dendritic changes in the nucleus accumbens following cognitive training. Importantly, an increase in spine density that normally occurs in these brain regions following repeated amphetamine exposure remained following extensive cognitive training, particularly in the nucleus accumbens.

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. Multiple linear regressions were used to examine associations between spindle characteristics and cognitive outcomes, with age, body mass index (BMI), periodic limb movements index (PLMI) and apnea hypopnea index (AHI) as covariates. NREM Stage 2 total spindle density was significantly associated with executive functioning (central: ß = .363, p = .016; frontal: ß = .408, p = .004). NREM Stage 2 fast spindle density was associated with executive functioning (central: ß = .351, p = .022; frontal: ß = .380, p = .009) and Montreal Cognitive Assessment score (MoCA, central: ß = .285, p = .037; frontal: ß = .279, p = .032). NREM Stage 2 spindle frequency was also associated with MoCA score (central: ß = .337, p = .013). Greater spindle density and fast spindle density were associated with better executive functioning and less cognitive decline in our study population. Our cross-sectional design cannot infer causality. Longitudinal studies will be required to assess the ability of spindle characteristics to predict future cognitive status.

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.

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 = 6.5; obtained from the Brain in Motion Study, Tyndall et al. BMC Geriatr 13:21, 2013. doi: 10.1186/1471-2318-13-21) to evaluate its usefulness as a measurement tool in both aging and clinical research. In terms of test reliability, split-half correlation analyses showed that all network scores were significantly reliable, although the strength of the correlations varied across networks as seen before (r = 0.29, 0.70, and 0.68, for alerting, orienting, and executive networks, respectively, p's < 0.05). In terms of construct validity, ANOVAs confirmed that each network score was significant (18.3, 59.4, and 109.2 ms for the alerting, orienting, and executive networks, respectively, p's < 0.01) and that these scores were generally independent from each other. Importantly, for criterion validity, a series of hierarchical linear regressions showed that the executive network score, in addition to demographic information, was a significant predictor of performance on tests of conflict resolution as well as verbal memory and retrieval (ß = -0.165 and -0.184, p's < 0.05, respectively). These results provide new information regarding the reliability and validity of ANT-I test performance in a healthy older adult population. The results provide insights into the psychometrics of the ANT-I and its potential utility in clinical research settings.

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 (66.5 ± 6.4 years) in the Brain in Motion Study, completed the Lifetime Total Physical Activity Questionnaire and underwent neuropsychological and cerebrovascular blood flow testing. Multiple robust linear regressions were used to model the associations between lifetime PA and global cognition after adjusting for age, sex, North American Adult Reading Test results (i.e., an estimate of premorbid intellectual ability), maximal aerobic capacity, body mass index and interactions between age, sex, and lifetime PA. Mediation analysis assessed the effect of cerebrovascular measures on the association between lifetime PA and global cognition. Post hoc analyses assessed past year PA and current fitness levels relation to global cognition and cerebrovascular measures. Better global cognitive performance was associated with higher lifetime PA (p=.045), recreational PA (p=.021), and vigorous intensity PA (p=.004), PA between the ages of 0 and 20 years (p=.036), and between the ages of 21 and 35 years (p.5), but partially mediated the relation between current fitness and global cognition. This study revealed significant associations between higher levels of PA (i.e., total lifetime, recreational, vigorous PA, and past year) and better cognitive function in later life. Current fitness levels relation to cognitive function may be partially mediated through current cerebrovascular function.

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. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod-shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment.

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. We are currently conducting a study to determine: if a structured 6-month aerobic exercise program is associated with improvements or maintenance of both cerebrovascular function and cognitive abilities in older individuals; and, the extent to which any changes seen persist 6 months after the completion of the structured exercise program. METHODS/DESIGN: Two hundred and fifty men and women aged 55-80 years are being enrolled into an 18-month combined quasi-experimental and prospective cohort study. Participants are eligible for enrollment into the study if they are inactive (i.e., not participating in regular physical activity), non-smokers, have a body mass index <35.0 kg/m(2), are free of significant cognitive impairment (defined as a Montreal Cognitive Assessment score of 24 or more), and do not have clinically significant cardiovascular, cerebrovascular disease, or chronic obstructive pulmonary airway disease. Repeated measurements are done during three sequential six-month phases: 1) pre-intervention; 2) aerobic exercise intervention; and 3) post-intervention. These outcomes include: cardiorespiratory fitness, resting cerebral blood flow, cerebrovascular reserve, and cognitive function. DISCUSSION: This is the first study to our knowledge that will examine contemporaneously the effect of an exercise intervention on both cerebrovascular reserve and cognition in an older population. This study will further our understanding of whether cerebrovascular mechanisms might explain how exercise promotes healthy brain aging. In addition our study will address the potential of increasing physical activity to prevent age-associated cognitive decline.

De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder.

GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD's chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder.

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. Defects in craniofacial tendon growth and adult-onset caudal scoliosis are also seen. We demonstrate a role for Hnrnpul1 in alternative splicing and transcriptional regulation using RNA-sequencing, particularly of genes involved in translation, ubiquitination, and DNA damage. Given its cross-species conservation and role in splicing, it would not be surprising if it had a role in human development. Whole-exome sequencing detected a homozygous frameshift variant in HNRNPUL1 in 2 siblings with congenital limb malformations, which is a candidate gene for their limb malformations. Zebrafish Hnrnpul1 mutants suggest an important developmental role of hnRNPUL1 and provide motivation for exploring the potential conservation of ancient regulatory circuits involving hnRNPUL1 in human development.

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. Results indicate that lesions to ventromedial orbital prefrontal cortex result in generalized fear and impaired extinction. In contrast, infralimbic/prelimbic cortical lesioned animals exhibit appropriate fear response patterns and extinction, but show a specific impairment in spontaneous recovery. To ascertain why I/P PFC lesion rats did not exhibit spontaneous recovery, a second experiment was conducted. All procedures in the second experiment were identical to the first except a decay period was employed in place of extinction training. Results from the second experiment indicate that the difficulty retrieving the extinguished association is related to extinction processes and not decay. Taken together, these findings suggest that OPFC and I/P PFC have distinct roles in associative processes necessary for discriminative fear conditioning, extinction, and spontaneous recovery. These results further implicate OPFC and I/P PFC in the pathology underlying generalized anxiety disorder.

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. Also, aging is a significant risk factor for vascular pathology that may underlie at least some of the cognitive changes. This study investigates the relative contribution of subjective cognitive complaints (SCC), vascular function, and genetic risk for dementia in predicting objective cognitive performance. Multiple regression and relative importance analysis were used to investigate the relative contribution of vascular function, self-reported SCC, and dementia genetic risk, in predicting objective cognition in a sample of 238 healthy community-dwelling older adults. Age, sex, premorbid cognitive abilities, subjective verbal memory complaints, higher cerebrovascular blood flow during submaximal exercise, and certain dementia risk alleles were significant predictors of worse objective verbal memory performance (p < 0.001, R 2 = 35.2-36.4%). Using relative importance analysis, subjective verbal memory complaints, and certain dementia risk alleles contributed more variance than cerebrovascular measures. These results suggest that age-related changes in memory in healthy older adults can be predicted by subjective memory complaints, genetic risk, and to a lesser extent, cerebrovascular function.

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. METHODS: The study is a quasi-experimental single group pre/postintervention study. Neuropsychological tests were used to assess cognition before and after the intervention. Transcranial Doppler ultrasound was used to measure cerebral blood flow velocity. Cerebrovascular regulation was assessed at rest, during euoxic hypercapnia, and in response to submaximal exercise. Multiple linear regression was used to examine the association between changes in cognition and changes in cerebrovascular function. RESULTS: The intervention was associated with improvements in some cognitive domains, cardiorespiratory fitness, and cerebrovascular regulation. Changes in executive functions were negatively associated with changes in cerebrovascular resistance index (CVRi) during submaximal exercise (ß = -0.205, p = 0.013), while fluency improvements were positively associated with changes in CVRi during hypercapnia (ß = 0.106, p = 0.03). CONCLUSION: The 6-month aerobic exercise intervention was associated with improvements in some cognitive domains and cerebrovascular regulation. Secondary analyses showed a novel association between changes in cognition and changes in cerebrovascular regulation during euoxic hypercapnia and in response to submaximal exercise.

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. The GBMTA for males and females revealed two distinct trajectory subgroups, namely, "high-increasing" (HI) and "low-increasing" (LI). Logistic regression was used to assess the association between the identified latent subgroups and (i) demographic characteristics; (ii) physiological characteristics, including cardiovascular and cerebrovascular function; (iii) genetic characteristics; and (iv) adherence with American College of Sports Medicine guidelines on exercise for older adults. Of the 196 participants, 54.1% met the American College of Sports Medicine aerobic exercise targets for intensity and duration during the intervention. Aerobic fitness (maximal oxygen uptake; odds ratio, 1.27; P < 0.01) was significantly different between these trajectory subgroups in males, and cerebrovascular function (cerebrovascular resistance; odds ratio, 0.14; P < 0.01) was significantly different between these trajectory subgroups in females. CONCLUSION: This novel approach to tracking a prespecified exercise program highlights that there are individual and group-specific variations within a prescribed exercise intervention. Characterizing exercise adherence in this way holds promise in developing optimized exercise prescriptions tailored to individual baseline characteristics, and additionally highlighting those participants at greatest risk of not meeting minimum dosage requirements for physiological and/or cognitive health.

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. Participants were generally healthy and screened for inclusion/exclusion criteria for the parent study. Thirty-eight participants were recruited (Mean age = 65.0 [SD = 5.1]; 60% female) and the final longitudinal sample was 32 participants. Participants provided a passive drool sample at: waking, 15, 30, and 45 min post-waking to assess the cortisol awakening response (CAR) and 3, 6, 9, and 12 h post-waking to assess daily area under the curve for cortisol. Salivary cortisol was quantified by liquid chromatography coupled to tandem mass spectrometry. The exercise intervention increased CAR but no differences were observed in daily AUC. In addition, larger increases in CAR were positively associated with greater decreases in subjective stress. Thus, aerobic exercise improved the CAR in otherwise healthy, but sedentary older adults and greater improvements in CAR were associated with greater reductions in perceived stress.

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. DESIGN: A cross-sectional analysis of 194 cognitively healthy adults aged ≥55 years (mean = 65.7, SD = 6.1) was conducted. GL was assessed using a quantitative food frequency questionnaire, and glucoregulation was characterized on the HOMA-IR index. Subjects also completed a cognitive assessment, CRF testing, a validated self-reported PA questionnaire, and a blood draw. Multiple linear regression models adjusted for significant covariates were used to evaluate the relation between GL and cognition, and mediation by CRF and PA was also assessed. RESULTS: GL was inversely associated with global cognition (ß = -0.014; 95% CI -0.024, -0.004) and figural memory (ß = -0.035; 95% CI -0.052, -0.018) in subjects with poor glucoregulation. Neither CRF nor PA mediated these relations. In subjects with good glucoregulation, no association was found between GL and cognitive function (p > 0.05). CONCLUSIONS: A low GL diet is associated with better cognitive function in older adults with poor glucoregulation. This study provides supportive evidence for the role of GL in maintaining better cognitive function during the aging process.

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. Previous research has suggested that in AD, individuals carrying the APOE ε4 allele have decreased sleep quality compared to individuals without the APOE ε4 allele. This observational trial aimed to determine if healthy older adults with the risk allele (APOE ε4+) have more sleep complaints or evidence of objective sleep disruption compared to healthy older adults without the risk allele (APOE ε4-). METHODS: Within the larger Brain in Motion study, a subset of participants completed at-home polysomnography (PSG) and actigraphy sleep assessment. Subjective sleep complaints were determined using the Pittsburgh Sleep Quality Index. RESULTS: This investigation found a significant relationship between presence of APOE ε4 allele and objective sleep disturbances measured by both actigraphy and PSG, but not subjective sleep complaints in a healthy population screened for dementia. CONCLUSIONS: These data suggest that the influence of APOE ε4 allele on objective sleep quality may precede subjective sleep complaints in individuals at increased risk for dementia.

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. A secondary goal was to examine the influence of apolipoprotein E (APOE) ε4 expression on these indices. In a sample of 258 healthy men and women older than 53 years, 29.1% met criteria for MetS. MetS, sex, and age were found to be significant predictors of CVC, and V¯P, MetS, and APOE status were significant predictors of V¯P-reactivity, and CVC-reactivity was best predicted by MetS status. After controlling for these factors, participants with MetS demonstrated lower cerebrovascular measures (CVC, V¯P, CVC-reactivity, and V¯P-reactivity) compared to participants without MetS. APOE ε4 carriers had higher V¯P-reactivity than noncarriers. These results provide evidence that cardiometabolic and vascular risk factors clustered together as the MetS predict measures of cerebrovascular health indices in older adults. Higher V¯P-reactivity in APOE ε4 carriers suggests vascular compensation for deleterious effects of this known risk allele for Alzheimer's disease and stroke.