Early and continuing grandparental care and middle school students' educational and mental health outcomes in China.

Several recent studies have examined the relationship between grandparents and grandchildren, but few have examined the effects of early and continuing grandparental care on children's development in China. Using data from the China Education Panel Survey, this study examines the effects of early and continuing care, in which grandparents serve as primary caregivers on middle school students' educational (measured by academic performance and cognitive scores) and mental health (depression score) outcomes. Using multilevel analyses and robustness tests, the results show that for urban and rural students, students cared for by their grandparents showed no disadvantages in their educational outcomes. For rural students who received grandparental care in early childhood or adolescence academically outperformed those who received only parental care. Urban and rural students who received only grandparental care in early childhood and adolescence show worse mental health outcomes. These results challenge the prevailing belief that grandparent caregiving can harm grandchildren's school preparation and cognitive abilities.

Effects of dabigatran versus warfarin on 2-year cognitive outcomes in old patients with atrial fibrillation: results from the GIRAF randomized clinical trial.

BACKGROUND: Observational studies support a role for oral anticoagulation to reduce the risk of dementia in atrial fibrillation patients, but conclusive data are lacking. Since dabigatran offers a more stable anticoagulation, we hypothesized it would reduce cognitive decline when compared to warfarin in old patients with atrial fibrillation. METHODS: The GIRAF trial was a 24-month, randomized, parallel-group, controlled, open-label, hypothesis generating trial. The trial was done in six centers including a geriatric care unit, secondary and tertiary care cardiology hospitals in São Paulo, Brazil. We included patients aged ≥ 70 years and CHA2DS2-VASc score > 1. The primary endpoint was the absolute difference in cognitive performance at 2 years. Patients were assigned 1:1 to take dabigatran (110 or 150 mg twice daily) or warfarin, controlled by INR and followed for 24 months. Patients were evaluated at baseline and at 2 years with a comprehensive and thorough cognitive evaluation protocol of tests for different cognitive domains including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Exam (MMSE), a composite neuropsychological test battery (NTB), and computer-generated tests (CGNT). RESULTS: Between 2014 and 2019, 5523 participants were screened and 200 were assigned to dabigatran (N = 99) or warfarin (N = 101) treatment. After adjustment for age, log of years of education, and raw baseline score, the difference between the mean change from baseline in the dabigatran group minus warfarin group was - 0.12 for MMSE (95% confidence interval [CI] - 0.88 to 0.63; P = 0.75), 0.05 (95% CI - 0.07 to 0.18; P = 0.40) for NTB, - 0.15 (95% CI - 0.30 to 0.01; P = 0.06) for CGNT, and - 0.96 (95% CI - 1.80 to 0.13; P = 0.02) for MoCA, with higher values suggesting less cognitive decline in the warfarin group. CONCLUSIONS: For elderly patients with atrial fibrillation, and without cognitive compromise at baseline that did not have stroke and were adequately treated with warfarin (TTR of 70%) or dabigatran for 2 years, there was no statistical difference at 5% significance level in any of the cognitive outcomes after adjusting for multiple comparisons. TRIAL REGISTRATION: Cognitive Impairment Related to Atrial Fibrillation Prevention Trial (GIRAF), NCT01994265 .

Cross-sectional and prospective associations between self-reported sleep characteristics and cognitive function in men and women: The Midlife in the United States study.

Sleep behaviour is an important contributing factor in healthy human ageing and cognitive function. Previous studies have linked sleep deficiency with cognitive decline in older adults. However, there is need for more prospective investigations that focus on specific domains of cognitive function. The present study analysed cross-sectional and prospective associations between self-reported sleep and cognitive function in the Midlife in the United States (MIDUS) study. Weekday and weekend sleep duration and habitual sleep quality were obtained via questionnaire data. Brief Test of Adult Cognition by Telephone was conducted to assess overall cognitive function, as well as episodic memory and executive function. We found significant trend for both long weekday and weekend sleep (>8 hr) and lower episodic memory scores in the overall sample. Sex-specific cross-sectional analysis demonstrated men with longer weekend sleep duration have lower overall cognitive function scores, and a negative association between weekend sleep and episodic memory scores. Women demonstrated a positive association between weekend sleep duration and executive function scores. There was no prospective significance for overall or sex-specific analysis. Our present results suggest that sleep duration may contribute to cognitive function, and future studies should include objective sleep measurements and focus on the potential cognitive benefits of improving sleep to further elucidate this association.

Predicting MCI progression with FDG-PET and cognitive scores: a longitudinal study.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. Studies on MCI progression are important for Alzheimer's disease (AD) prevention. 18F fluoro-deoxy-glucose positron emission tomography (FDG-PET) has been proven to be a powerful tool for measuring cerebral glucose metabolism. In this study, we proposed a classification framework for MCI prediction with both baseline and multiple follow-up FDG-PET scans as well as cognitive scores of 33 progressive MCI (pMCI) patients and 46 stable MCI (sMCI) patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHOD: First, PET images were normalized using the Yakushev normalization procedure and registered to the Brainnetome Atlas (BNA). The average metabolic intensities of brain regions were defined as static features. Dynamic features were the intensity variation between baseline and the other three time points and change ratios with the intensity obtained at baseline considered as reference. Mini-mental State Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive section (ADAS-cog) scores of each time point were collected as cognitive features. And F-score was applied for feature selection. Finally, support vector machine (SVM) with radial basis function (RBF) kernel was used for the three above features. RESULTS: Dynamic features showed the best classification performance in accuracy of 88.61% than static features (accuracy of 78.48%). And the combination of cognitive features and dynamic features improved the classification performance in specificity of 95.65% and Area Under Curve (AUC) of 0.9308. CONCLUSION: Our results reported that dynamic features are more representative in longitudinal research for MCI prediction work. And dynamic features and cognitive scores complementarily enhance the classification performance in specificity and AUC. These findings may predict the disease course and clinical changes in individuals with mild cognitive impairment.

Cognitive function after surgery with regional or general anesthesia: A population-based study.

INTRODUCTION: Our aim was to examine whether surgery with regional anesthesia (RA) is associated with accelerated long-term cognitive decline comparable with that previously reported after general anesthesia (GA). METHODS: Longitudinal cognitive function was analyzed in a cohort of 1819 older adults. Models assessed the rate of change in global and domain-specific cognition over time in participants exposed to RA or GA. RESULTS: When compared with those unexposed to anesthesia, the postoperative rate of change of the cognitive global z-score was greater in those exposed to both RA (difference in annual decline of -0.041, P = .011) and GA (-0.061, P < .001); these rates did not differ. In analysis of the domain-specific scores, an accelerated decline in memory was observed after GA (-0.065, P < .001) but not RA (-0.011, P = .565). CONCLUSIONS: Older adults undergoing surgery with RA experience decline of global cognition similar to those receiving GA; however, memory was not affected.

An approach to directly link ICA and seed-based functional connectivity: Application to schizophrenia.

Independent component analysis (ICA) and seed-based analyses are widely used techniques for studying intrinsic neuronal activity in task-based or resting scans. In this work, we show there is a direct link between the two, and show that there are some important differences between the two approaches in terms of what information they capture. We developed an enhanced connectivity-matrix independent component analysis (cmICA) for calculating whole brain voxel maps of functional connectivity, which reduces the computational complexity of voxel-based connectivity analysis on performing many temporal correlations. We also show there is a mathematical equivalency between parcellations on voxel-to-voxel functional connectivity and simplified cmICA. Next, we used this cost-efficient data-driven method to examine the resting state fMRI connectivity in schizophrenia patients (SZ) and healthy controls (HC) on a whole brain scale and further quantified the relationship between brain functional connectivity and cognitive performances measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Current results suggest that SZ exhibit a wide-range abnormality, primarily a decrease, in functional connectivity both between networks and within different network hubs. Specific functional connectivity decreases were associated with MATRICS performance deficits. In addition, we found that resting state functional connectivity decreases was extensively associated with aging regardless of groups. In contrast, there was no relationship between positive and negative symptoms in the patients and functional connectivity. In sum, we have developed a novel mathematical relationship between ICA and seed-based connectivity that reduces computational complexity, which has broad applicability, and showed a specific application of this approach to characterize connectivity changes associated with cognitive scores in SZ.

Role of the thalamus in natural recovery of cognitive impairment in patients with mild traumatic brain injury.

INTRODUCTION: Patients with mild traumatic brain injury (mTBI) may have normal neuroimaging but manifest with a broad-spectrum of cognitive-deficits, which may resolve eventually. The function of the thalamus in the process of natural-recovery remains elusive. The current study investigates the role of the thalamus in natural-recovery of cognitive-deficits in patients with mTBI. METHODS: Twenty-one patients with mTBI were evaluated with an initial MRI scan, within 36 hours of injury and assessed with neuropsychological tests(NPT) at 3-4 weeks after injury. First and second follow-up MRI and NPT were performed at 3-4 months and 6-7 months, respectively. The volume and tensor measures of the thalamus and cognitive-scores were analysed at each assessment using repeated-measures of variance. The association of cognitive-scores with corresponding period imaging measures was analysed using bivariate-correlation. RESULTS: Serial evaluation showed that all the cognitive-domains improved significantly. During this period there was a significant increase in mean thalamic volume (p = 0.049, effect-size = 0.18). After 3-4 months there was emergence of anisotropic thalamo-cortical connections. At 2-3 weeks and 6-7 months after injury, the alterations in diffusivity values were positively associated with improvement in memory-scores. Improvement in attention-scores correlated significantly with changes in tensor values at the 6-7 months after-injury. CONCLUSION: The correlation between improvement in cognitive-scores and changes in thalamic tensor and volume measures reflect the role of the thalamus in natural-recovery after mTBI.

Seeing beyond the symptoms: biomarkers and brain regions linked to cognitive decline in Alzheimer's disease.

Objective: Early Alzheimer's disease (AD) diagnosis remains challenging, necessitating specific biomarkers for timely detection. This study aimed to identify such biomarkers and explore their associations with cognitive decline. Methods: A cohort of 1759 individuals across cognitive aging stages, including healthy controls (HC), mild cognitive impairment (MCI), and AD, was examined. Utilizing nine biomarkers from structural MRI (sMRI), diffusion tensor imaging (DTI), and positron emission tomography (PET), predictions were made for Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale Sum of Boxes (CDRSB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS). Biomarkers included four sMRI (e.g., average thickness [ATH]), four DTI (e.g., mean diffusivity [MD]), and one PET Amyloid-ß (Aß) measure. Ensemble regression tree (ERT) technique with bagging and random forest approaches were applied in four groups (HC/MCI, HC/AD, MCI/AD, and HC/MCI/AD). Results: Aß emerged as a robust predictor of cognitive scores, particularly in late-stage AD. Volumetric measures, notably ATH, consistently correlated with cognitive scores across early and late disease stages. Additionally, ADAS demonstrated links to various neuroimaging biomarkers in all subject groups, highlighting its efficacy in monitoring brain changes throughout disease progression. ERT identified key brain regions associated with cognitive scores, such as the right transverse temporal region for Aß, left and right entorhinal cortex, left inferior temporal gyrus, and left middle temporal gyrus for ATH, and the left uncinate fasciculus for MD. Conclusion: This study underscores the importance of an interdisciplinary approach in understanding AD mechanisms, offering potential contributions to early biomarker development.

Correlation of Blood Metal Concentrations with Cognitive Scores and Neuroimaging Findings in Patients with Total Joint Arthroplasty.

Total joint arthroplasty (TJA) implants are composed of metals, ceramics, and/or polyethylene. Studies suggest that the debris released from metal implants may possess neurotoxic properties with reports of neuropsychiatric symptoms and memory deficits, which could be relevant to Alzheimer's disease and related dementias. This exploratory study examined the cross-sectional correlation of blood metal concentrations with cognitive performance and neuroimaging findings in a convenience sample of 113 TJA patients with history of elevated blood metal concentrations of either titanium, cobalt and/or chromium. Associations with neuroimaging measures were observed but not with cognitive scores. Larger studies with longitudinal follow-up are warranted.

DLPF Targeted Repetitive Transcranial Magnetic Stimulation Improves Brain Glucose Metabolism Along with the Clinical and Electrophysiological Parameters in CBD Patients.

BACKGROUND: Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy. OBJECTIVE: Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients. METHODS: Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p<0.05 was considered significant. RESULTS: We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism. CONCLUSION: Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.

Adolescent cognitive function and incident early-onset type 2 diabetes.

BACKGROUND: Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. METHODS: A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992-2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. FINDINGS: During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10-2.88) for men and 2.33 (95% CI 1.88-2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34-1.48) and 1.46 (95% CI 1.36-1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. INTERPRETATION: This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status.

Functional Connectivity Alterations Based on the Weighted Phase Lag Index: An Exploratory Electroencephalography Study on Alzheimer's Disease.

OBJECTIVE: Numerous electroencephalography (EEG) studies focus on the alteration of electrical activity in patients with Alzheimer's Disease (AD), but there are no consistent results especially regarding functional connectivity. We supposed that the weighted Phase Lag Index (w- PLI), as phase-based measures of functional connectivity, may be used as an auxiliary diagnostic method for AD. METHODS: We enrolled 30 patients with AD, 30 patients with Mild Cognitive Impairment (MCI), and 30 Healthy Controls (HC). EEGs were recorded in all participants at baseline during relaxed wakefulness. Following EEG preprocessing, Power Spectral Density (PSD) and wPLI parameters were determined to further analyze whether they were correlated to cognitive scores. RESULTS: In the patients with AD, the increased PSD in theta band was presented compared with MCI and HC groups, which was associated with disturbances of the directional, computational, and delayed memory capacity. Furthermore, the wPLI revealed a distinctly lower connection strength between frontal and distant areas in the delta band and a higher connection strength of the central and temporo-occipital region in the theta band for AD patients. Moreover,we found a significant negative correlation between theta functional connectivity and cognitive scores. CONCLUSION: Increased theta PSD and decreased delta wPLI may be one of the earliest changes in AD and associated with disease severity. The parameter wPLI is a novel measurement of phase synchronization and has potentials in understanding underlying functional connectivity and aiding in the diagnostics of AD.

Cognitive Outcome Prediction in Infants With Neonatal Hypoxic-Ischemic Encephalopathy Based on Functional Connectivity and Complexity of the Electroencephalography Signal.

Impaired neurodevelopmental outcome, in particular cognitive impairment, after neonatal hypoxic-ischemic encephalopathy is a major concern for parents, clinicians, and society. This study aims to investigate the potential benefits of using advanced quantitative electroencephalography analysis (qEEG) for early prediction of cognitive outcomes, assessed here at 2 years of age. EEG data were recorded within the first week after birth from a cohort of twenty infants with neonatal hypoxic-ischemic encephalopathy (HIE). A proposed regression framework was based on two different sets of features, namely graph-theoretical features derived from the weighted phase-lag index (WPLI) and entropies metrics represented by sample entropy (SampEn), permutation entropy (PEn), and spectral entropy (SpEn). Both sets of features were calculated within the noise-assisted multivariate empirical mode decomposition (NA-MEMD) domain. Correlation analysis showed a significant association in the delta band between the proposed features, graph attributes (radius, transitivity, global efficiency, and characteristic path length) and entropy features (Pen and SpEn) from the neonatal EEG data and the cognitive development at age two years. These features were used to train and test the tree ensemble (boosted and bagged) regression models. The highest prediction performance was reached to 14.27 root mean square error (RMSE), 12.07 mean absolute error (MAE), and 0.45 R-squared using the entropy features with a boosted tree regression model. Thus, the results demonstrate that the proposed qEEG features show the state of brain function at an early stage; hence, they could serve as predictive biomarkers of later cognitive impairment, which could facilitate identifying those who might benefit from early targeted intervention.

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways.

BACKGROUND: Smaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed 'premutation' lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8-16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A 'toxic' role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range. METHODS: Three motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and Clinical Tremor) were related to 11 cognitive tests using Spearman's rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were then incorporated as confounders in correlation analysis. RESULTS: Cognitive tests demonstrating significant correlations with motor scores were those assessing non-verbal reasoning on Matrix Reasoning (p-values from 0.006 to 0.011), and sequencing and alteration on Trails-B (p-values from 0.008 to 0.001). Those showing significant correlations with two motor scores-ICARS and Clinical Tremor- were psychomotor speed on Symbol Digit Modalities (p-values from 0.014 to 0.02) and working memory on Digit Span Backwards (p-values from 0.024 to 0.011). CONCLUSIONS: Subtle motor impairments correlating with cognitive, particularly executive, deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes - motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers.

Differential blood DNA methylation across Lewy body dementias.

INTRODUCTION: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored. METHODS: We performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals. RESULTS: DLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants. DISCUSSION: Our study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.

Cognitive skills in preterm infants with bronchopulmonary dysplasia at 1 year adjusted and 2 years chronological age.

Objective: The objective of this study was to evaluate for decline in cognitive scores from 12 to 24 months of age for preterm infants ≤32 weeks gestational age for those with and without bronchopulmonary dysplasia.Study design: In an observational retrospective study, detailed medical data was collected from the electronic medical records of preterm infants born between January 2009 and December 2015 who had cognitive evaluations using Bayley Scales of Infant Development, 3rd ed (BISD-3) at 12 months corrected gestational age and 24 months chronological age. Infants were divided into three groups, bronchopulmonary dysplasia (BPD), prolonged oxygen requirement that did not meet BPD criteria, or pulmonary insufficiency (PI), and respiratory distress only (RDS). Decline in cognitive functions was based on the BISD-3 standard deviation of 15 points, no decline ≤3.5 point, moderate, > 3.5 to <7.5 points, significant >7.5 points.Results: The sample included 165 preterm infants divided into three groups, BPD, n = 39, PI, n = 79, RDS only, n = 47. The groups did not differ on gender, ethnicity, birthweight or gestational age. The groups did not differ in percent of infants who showed no, moderate or significant decline. In all groups, the percentage of infants showing a cognitive decline of >7.5 points varied from 67% to 76%Conclusion: There was no significant difference in cognitive decline for those with and without BPD. Of note is that a large percentage of infants in each group showed at least one-half standard deviation of cognitive decline across the 12 and 24 months evaluations. Our concern is that correcting for gestational age at 12 months may delay early intervention when significant delays are found at 24 months.

Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences.

Background: Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome. Methods: The plasma metabolomes of children with autism spectrum disorder (ASD; n = 167), idiopathic developmental delay (i-DD; n = 51), Down syndrome (DS; n = 31), and typically developing controls (TD; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child's neurodevelopmental diagnosis, child's sex, child's age, child's race/ethnicity, maternal age at child's birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population. Results: Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child's neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors. Conclusions: Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.

Increased Caspase-6 activity in the human anterior olfactory nuclei of the olfactory bulb is associated with cognitive impairment.

Abnormally elevated hippocampal Caspase-6 (Casp6) activity is intimately associated with age-related cognitive impairment in humans and in mice. In humans, these high levels of Casp6 activity are initially localized in the entorhinal cortex, the area of the brain first affected by the formation of neurofibrillary tangles, according to Braak staging. The reason for the high vulnerability of entorhinal cortex neurons to neurofibrillary tangle pathology and Casp6 activity is unknown. Casp6 activity is involved in axonal degeneration, therefore, one possibility to explain increased vulnerability of the entorhinal cortex neurons would be that the afferent neurons of the olfactory bulb, some of which project their axons to the entorhinal cortex, are equally degenerating. To examine this possibility, we examined the presence of Casp6 activity, neurofibrillary tangle formation and amyloid deposition by immunohistochemistry with neoepitope antisera against the p20 subunit of active Casp6 and Tau cleaved by Casp6 (Tau∆Casp6), phosphorylated Tau paired helical filament (PHF-1) antibodies and anti-ß-amyloid antiserum, respectively, in brains from individuals with no or mild cognitive impairment and Alzheimer disease (AD) dementia. Co-localization of Casp6 activity, PHF-1 and ß-amyloid was detected mostly in the anterior olfactory nucleus (AON) of the olfactory bulb. The levels of active Casp6 in the AON, which were the highest in the AD brains, correlated with PHF-1 levels, but not with ß-amyloid levels. AON Tau∆Casp6 levels correlated with entorhinal cortex Casp6 activity and PHF-1 levels. Multiple regression analyses demonstrated that AON Casp6 activity was associated with lower global cognitive function, mini mental state exam, episodic memory and semantic memory scores. These results suggest that AON Casp6 activity could lead to Casp6-mediated degeneration in the entorhinal cortex, but cannot exclude the possibilities that entorhinal cortex degeneration signals degeneration in the AON or that the pathologies occur in both regions independently. Nevertheless, AON Casp6 activity reflects that of the entorhinal cortex.