Klotho gene polymorphism, brain structure and cognition in early-life development.
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ABSTRACT:
SUBMITTER: de Vries CF
PROVIDER: S-EPMC6588504 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
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Project description:Education in people's early lives are positively related to their cognitive function, but its modulating effects on detailed cognition domains, its interaction with leisure activities and the associated brain changes have yet to be investigated. This report used data from 659 cognitively normal community dwelling elderly who completed neuropsychological tests, leisure activities measurement, and 78 of them underwent structural and diffusion MRI scans. We found that: (i) the highly educated elderly had a better cognitive functioning in multi-domains, higher frequencies of participation in knowledge-related leisure activities, and slower age-related reductions of executive function; (ii) the intellectual and social types of leisure activities mediated the association between education and multiple cognitive domains, including memory, language, attention and executive function; (iii) there was a significant age by education interaction on the gray matter volume of the anterior brain regions and white matter integrity; and (iv) the interaction between age and education affected cognition indirectly through white matter integrity analyzed using structural equation model. Overall, our results revealed that high education in early life served as a protective factor in aging that may help to postpone cognitive and brain reserve decline in cognitively normal aging.
| S-EPMC6682517 | biostudies-literature
Project description:Anesthetics induce widespread cell death, permanent neuronal deletion, and neurocognitive impairment in immature animals, raising substantial concerns about similar effects occurring in young children. Epidemiologic studies have been unable to sufficiently address this concern, in part due to reliance on group-administered achievement tests, inability to assess brain structure, and limited control for confounders.We compared healthy participants of a language development study at age 5 to 18 years who had undergone surgery with anesthesia before 4 years of age (n = 53) with unexposed peers (n = 53) who were matched for age, gender, handedness, and socioeconomic status. Neurocognitive assessments included the Oral and Written Language Scales and the Wechsler Intelligence Scales (WAIS) or WISC, as appropriate for age. Brain structural comparisons were conducted by using T1-weighted MRI scans.Average test scores were within population norms, regardless of surgical history. However, compared with control subjects, previously exposed children scored significantly lower in listening comprehension and performance IQ. Exposure did not lead to gross elimination of gray matter in regions previously identified as vulnerable in animals. Decreased performance IQ and language comprehension, however, were associated with lower gray matter density in the occipital cortex and cerebellum.The present findings suggest that general anesthesia for a surgical procedure in early childhood may be associated with long-term diminution of language abilities and cognition, as well as regional volumetric alterations in brain structure. Although causation remains unresolved, these findings nonetheless warrant additional research into the phenomenon's mechanism and mitigating strategies.
| S-EPMC4485006 | biostudies-other
Project description:AbstractThe overarching objective is to review how early exposure to adversity interacts with inflammation to alter brain maturation. Both adversity and inflammation are significant risk factors for psychopathology. Literature relevant to the effects of adversity in children and adolescents on brain development is reviewed. These studies are supported by research in animals exposed to species-relevant stressors during development. While it is known that exposure to adversity at any age increases inflammation, the effects of inflammation are exacerbated at developmental stages when the immature brain is uniquely sensitive to experiences. Microglia play a vital role in this process, as they scavenge cellular debris and prune synapses to optimize performance. In essence, microglia modify the synapse to match environmental demands, which is necessary for someone with a history of adversity. Overall, by piecing together clinical and preclinical research areas, what emerges is a picture of how adversity uniquely sculpts the brain. Microglia interactions with the inhibitory neurotransmitter GABA (specifically, the subtype expressing parvalbumin) are discussed within contexts of development and adversity. A review of inflammation markers in individuals with a history of abuse is combined with preclinical studies to describe their effects on maturation. Inconsistencies within the literature are discussed, with a call for standardizing methodologies relating to the age of assessing adversity effects, measures to quantify stress and inflammation, and more brain-based measures of biochemistry. Preclinical studies pave the way for interventions using anti-inflammation-based agents (COX-2 inhibitors, CB2 agonists, meditation/yoga) by identifying where, when, and how the developmental trajectory goes awry.
| S-EPMC8820591 | biostudies-literature
Project description:BackgroundWe aimed to investigate the expression of Klotho gene in peripheral blood of patients with cerebral infarction (CI) and the association of its polymorphisms with the occurrence of CI.MethodsA total of 60 CI patients (CI group) and 20 healthy people receiving physical examination (control group) were enrolled as the research subjects. The expression of Klotho gene in CI group and control group was determined using enzyme-linked immunosorbent assay kit. Single nucleotide polymorphisms (rs192031, rs200131 and rs102312) in the promoter region of the Klotho gene were typed via conformational difference gel electrophoresis. Besides, whether the distribution frequencies of Klotho genotypes conformed to Hardy-Weinberg equilibrium was evaluated by chi-square test. Meanwhile, the associations of Klotho alleles and gene polymorphisms with CI occurrence were analyzed.ResultsThe protein expression level of Klotho in the peripheral blood was remarkably lower in patients in CI group than that in control group (P<0.05).HardyWeinberg equilibrium analysis revealed that Klotho gene polymorphisms (rs192031, rs200131 and rs102312) conformed to the genetic equilibrium distribution (P>0.05). Gene-based association analysis manifested that only rs192031 polymorphism and alleles were correlated with CI occurrence (P<0.05). Systolic blood pressure and highdensity lipoprotein cholesterol were notably higher in CI patients with TT genotype of Klotho gene polymorphism rs192031 than those in control group (P<0.05). Furthermore, there were no associations of rs200131 and rs102312 polymorphisms and alleles with the occurrence of CI (P>0.05).ConclusionsThe expression level of Klotho is evidently reduced in the peripheral blood of CI patients. Rs192031 in the promoter region of the Klotho gene is associated with the occurrence of CI, while rs200131 and rs102312 have no relations with CI.
| S-EPMC9010054 | biostudies-literature
Project description:Early-life adversity has profound consequences for youth neurodevelopment and adjustment; however, experiences of adversity are heterogeneous and interrelated in complex ways that can be difficult to operationalize and organize in developmental research. We sought to characterize the underlying dimensional structure of co-occurring adverse experiences among a subset of youth (ages 9-10) from the Adolescent Brain Cognitive Development (ABCD) Study (N = 7115), a community sample of youth in the United States. We identified 60 environmental and experiential variables that reflect adverse experiences. Exploratory factor analysis identified 10 robust dimensions of early-life adversity co-occurrence, corresponding to conceptual domains such as caregiver substance use and biological caregiver separation, caregiver psychopathology, caregiver lack of support, and socioeconomic disadvantage / neighborhood lack of safety. These dimensions demonstrated distinct associations with internalizing problems, externalizing problems, cognitive flexibility, and inhibitory control. Non-metric multidimensional scaling characterized qualitative similarity among the 10 identified dimensions. Results supported a nonlinear three-dimensional structure representing early-life adversity, including continuous gradients of "perspective", "environmental uncertainty", and "acts of omission/commission". Our findings suggest that there are distinct dimensions of early-life adversity co-occurrence in the ABCD sample at baseline, and the resulting dimensions may have unique implications for neurodevelopment and youth behavior.
| S-EPMC10209808 | biostudies-literature
Project description:BackgroundGenetics play a significant role in the etiology of late-life neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. Part of the individual differences in risk for these diseases can be traced back decades before the onset of disease symptoms. Previous studies have shown evidence for plausible links of apolipoprotein E (APOE), the most important genetic marker for Alzheimer's disease, with early-life cognition and neuroimaging markers. We aimed to assess whether genome-wide genetic burden for the aforementioned neurodegenerative diseases plays a role in early-life processes.MethodsWe studied children from the Generation R Study, a prospective birth cohort. APOE genotypes and polygenic genetic burdens for Alzheimer's disease, Parkinson's disease, and frontotemporal dementia were obtained through genome-wide genotyping. Non-verbal intelligence was assessed through cognitive tests at the research center around the age of 6 years, and educational attainment through a national school performance test around the age of 11 years. The Child Behavior Checklist was administered around the age of 10 years, and data from the anxious/depressed, withdrawn/depressed, and the internalizing behavior problems scales were used. Children participated in a neuroimaging study when they were 10 years old, in which structural brain metrics were obtained. Lipid serum profiles, which may be influenced by APOE genotype, were assessed from venal blood obtained around the age of 6 years. The sample size per analysis varied between 1,641 and 3,650 children due to completeness of data.ResultsWe did not find evidence that APOE genotype or the polygenic scores impact on childhood nonverbal intelligence, educational attainment, internalizing behavior, and global brain structural measures including total brain volume and whole brain fractional anisotropy (all p > 0.05). Carriership of the APOE ε2 allele was associated with lower and APOE ε4 with higher low-density lipoprotein cholesterol concentrations when compared to APOE ε3/ε3 carriers.ConclusionWe found no evidence that genetic burden for late-life neurodegenerative diseases associates with early-life cognition, internalizing behavior, or global brain structure.
| S-EPMC7018686 | biostudies-literature
Project description:A genome-wide association study of cognitive deficits in patients with schizophrenia in Japan found association with a missense genetic variant (rs7157599, Asn8Ser) in the delta(4)-desaturase, sphingolipid 2 (DEGS2) gene. A replication analysis using Caucasian samples showed a directionally consistent trend for cognitive association of a proxy single-nucleotide polymorphism (SNP), rs3783332. Although the DEGS2 gene is expressed in human brain, it is unknown how DEGS2 expression varies during human life and whether it is affected by psychiatric disorders and genetic variants. To address these questions, we examined DEGS2 messenger RNA using next-generation sequencing in postmortem dorsolateral prefrontal cortical tissue from a total of 418 Caucasian samples including patients with schizophrenia, bipolar disorder and major depressive disorder. DEGS2 is expressed at very low levels prenatally and increases gradually from birth to adolescence and consistently expressed across adulthood. Rs3783332 genotype was significantly associated with the expression across all subjects (F3,348=10.79, P=1.12 × 10(-)(3)), particularly in control subjects (F1,87=13.14, P=4.86 × 10(-4)). Similar results were found with rs715799 genotype. The carriers of the risk-associated minor allele at both loci showed significantly lower expression compared with subjects homozygous for the non-risk major allele and this was a consistent finding across all diagnostic groups. DEGS2 expression showed no association with diagnostic status after correcting for multiple testing (P>0.05). Our findings demonstrate that a SNP showing genome-wide association study significant association with cognition in schizophrenia is also associated with regulation of DEGS2 expression, implicating a molecular mechanism for the clinical association.
| S-EPMC4462608 | biostudies-literature
Project description:Despite a growing understanding that early adversity in childhood broadly affects risk for psychopathology, the contribution of stressful life events to the development of symptoms of attention-deficit/hyperactivity disorder (ADHD) is not clear. In the present study, we examined the association between number of stressful life events experienced and ADHD symptoms, assessed using the Attention Problems subscale of the Child Behavior Checklist, in a sample of 214 children (43% male) ages 9.11-13.98 years (M = 11.38, SD = 1.05). In addition, we examined whether the timing of the events (i.e., onset through age 5 years or after age 6 years) was associated with ADHD symptoms. Finally, we examined variation in brain structure to determine whether stressful life events were associated with volume in brain regions that were found to vary as a function of symptoms of ADHD. We found a small to moderate association between number of stressful life events and ADHD symptoms. Although the strength of the associations between number of events and ADHD symptoms did not differ as a function of the age of occurrence of stressful experiences, different brain regions were implicated in the association between stressors and ADHD symptoms in the two age periods during which stressful life events occurred. These findings support the hypothesis that early adversity is associated with ADHD symptoms, and provide insight into possible brain-based mediators of this association.
| S-EPMC6249129 | biostudies-literature
Project description:BackgroundCognitive impairment is a core feature of schizophrenia that is more serious in patients with early-onset schizophrenia (EOS). However, the neuroimaging basis of cognitive functions, including neurocognition and social cognition, remains unclear in patients with EOS.MethodsForty-three patients with EOS underwent structural and resting state functional magnetic resonance imaging scans. Brain structure and function were evaluated through the analysis of brain gray matter volume (GMV) and amplitude of low-frequency fluctuations (ALFF). They underwent comprehensive assessments for neurocognition (verbal memory, verbal expression, attention, and executive function) and social cognition (theory of mind and attributional bias). Correlation analyses were conducted to detect the potential link between cognitive function indices and brain imaging parameters.ResultsFirst, neurocognition was linked to brain structure characterized by higher immediate recall scores associated with increased GMV in the left temporal pole, higher verbal fluency scores associated with increased GMV in the left temporal pole: middle temporal gyrus, and higher Stroop-word scores associated with increased GMV in the right middle frontal gyrus. Second, social cognition was related to brain function characterized by lower sense of reality scores associated with increased ALFF in the left precentral gyrus, higher scores of accidental hostility bias associated with increased ALFF in the right middle temporal gyrus, and higher scores of accidental aggression bias associated with increased ALFF in the left precentral gyrus.ConclusionThese findings may add to the existing knowledge about the cognitive function-brain relationship. They may have clinical significance for studying the mechanism of neurocognitive and social cognitive impairment in patients with EOS and providing potential neural targets for their treatment and intervention.
| S-EPMC8866448 | biostudies-literature