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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.

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.

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 and dementia progression. In addition, 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, 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 subjective cognitive complaints, 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 < .001, R2 = 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.

ObjectiveTo 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.MethodsThe 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.ResultsThe 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 (β = −0.205,p= 0.013), while fluency improvements were positively associated with changes in CVRi during hypercapnia (β = 0.106,p =0.03).ConclusionThe 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.

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.

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: β = .363, p = .016; frontal: β = .408, p = .004). NREM Stage 2 fast spindle density was associated with executive functioning (central: β = .351, p = .022; frontal: β = .380, p = .009) and Montreal Cognitive Assessment score (MoCA, central: β = .285, p = .037; frontal: β = .279, p = .032). NREM Stage 2 spindle frequency was also associated with MoCA score (central: β = .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.

Background Sleep disturbances have been shown to be associated with the presence of the apolipoprotein (APOE) ɛ4 allele, the well-known genetic risk factor for late-onset sporadic Alzheimer's disease (AD). Objective This study quantifies the effects of a six-month aerobic exercise intervention on objective and subjective sleep quality in middle-aged to older individuals including those at increased genetic risk for late-onset sporadic Alzheimer's disease (AD), who carry the apolipoprotein (APOE) ɛ4 risk allele. Methods 199 sedentary men and women without significant cognitive impairments were enrolled in the Brain in Motion study, a quasi-experimental single group pre-test/post-test study with no control group. Participants completed a six-month aerobic exercise intervention and consented to genetic testing. Genotyping of APOE confirmed that 54 individuals were carriers of the ɛ4 allele. Participants' subjective quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) pre- and post-intervention. A convenience sample of participants (n = 29, APOE ɛ4+ = 7) consented to undergo two nights of in-home polysomnography (PSG) pre- and post intervention. Sleep architecture and respiratory variables were assessed. Results The six-month aerobic exercise intervention significantly improved participants' total PSQI score, sleep efficiency, and sleep latency in the full sample (n = 199). PSG results showed that total sleep time and sleep onset latency significantly improved over the course of the exercise intervention only in individuals who carried the APOE ɛ4 allele. These results are, however, exploratory and need to be carefully interpreted due to the rather small number of APOE ɛ4+ in the PSG subgroup. Conclusions The six-month aerobic exercise intervention significantly improved participants' sleep quality with beneficial effects on PSG shown in individuals at increased genetic risk for late-onset sporadic AD.

Summary 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 (β = −0.014; 95% CI −0.024, −0.004) and figural memory (β = −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.

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 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.

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.

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 (![Formula][1] ), 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 ) e 4 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 ![Formula][2] , MetS, and APOE status were significant predictors of ![Formula][3] ‐reactivity, and CVC‐reactivity was best predicted by MetS status. After controlling for these factors, participants with MetS demonstrated lower cerebrovascular measures (CVC, ![Formula][4] , CVC‐reactivity, and ![Formula][5] ‐reactivity) compared to participants without MetS. APOE e 4 carriers had higher ![Formula][6] ‐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 ![Formula][7] ‐reactivity in APOE e 4 carriers suggests vascular compensation for deleterious effects of this known risk allele for Alzheimer's disease and stroke. [1]: /embed/mml-math-1.gif [2]: /embed/mml-math-2.gif [3]: /embed/mml-math-3.gif [4]: /embed/mml-math-4.gif [5]: /embed/mml-math-5.gif [6]: /embed/mml-math-6.gif [7]: /embed/mml-math-7.gif

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 theBrain in MotionStudy, completed theLifetime Total Physical Activity Questionnaireand 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 hocanalyses 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 (pp>.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. (JINS, 2015,21, 816–830)

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 (β = −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.

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. METHODOLOGY/PRINCIPAL FINDINGS: This study used the water-based snowcone maze in order to assess male and female preference for landmark or geometric cues, with specific emphasis placed on the effects of estrus cycle phase for female rat. Performance and preference for the geometric cue was examined in relation to total hippocampal and hippocampal subregions (CA1&2, CA3 and dentate gyrus) volumes and entorhinal cortex thickness in order to determine the relation between strategy and spatial performance and brain area size. The study revealed that males outperformed females overall during training trials, relied on the geometric cue when the platform was moved and showed significant correlations between entorhinal cortex thickness and spatial memory performance. No gross differences in behavioural performance was observed within females when accounting for cyclicity, and only total hippocampal volume was correlated with performance during the learning trials. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the sex-specific use of cues and brain areas in a spatial learning task.