Age-dependent Association Research Articles

Multimodal examination of emotion processing systems associated with negative affectivity across early childhood

High Temperamental Negative Affectivity in early childhood has been found to predict later emotion dysregulation. While much work has been conducted to separately probe bio-behavioral systems associated with Negative Affectivity, very little work has examined the relations among multiple systems across age. In this study, we use multi-modal methods to index neurobiological systems associated with Negative Affectivity in 53 4-7-year-old children. Prefrontal activation during emotion regulation was measured using functional near-infrared spectroscopy over the lateral prefrontal cortex (PFC) while children played a game designed to elicit frustration in Social (Happy and Angry faces) and Nonsocial contexts. Gaze behaviors while free-viewing Happy and Angry faces were also measured. Finally, Negative Affectivity was indexed using a score composite based on factor analysis of parent-reported temperament. Using mixed-effects linear models, we found an age-dependent association between Negative Affectivity and both PFC activation during frustration and fixation duration on the mouth area of Happy faces, such that older children high in Negative Affectivity spent less time looking at the mouths of Happy faces and had lower PFC activation in response to frustration (ps<0.034). These results provide further insight to how Negative Affectivity may be associated with changes in affective neurobiological systems across early childhood.

Large-scale association analyses identify host factors influencing human gut microbiome composition.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Hyper-Coordinated DNA Methylation is Altered in Schizophrenia and Associated with Brain Function

Abstract DNA methylation is an epigenetic biological process that is emerging as an important mediator of environmental risk effects on the susceptibility of severe illness, such as schizophrenia. DNA methylation shows coordination across biologically-related genes, but it is not known whether the resulting network structure has a mediating effect on illness risk. Here we identified a large gene network with hyper-coordinated DNA methylation in several biological processes that are changed in the brain of patients with schizophrenia, and that are associated with schizophrenia-relevant brain function as well as genetic illness susceptibility. We found that DNA methylation was physiologically coordinated in a reproducible network that comprised 6399 genes and showed a similar architecture in blood and brain. The network was hyper-coordinated in biological processes of core importance for schizophrenia, including synaptic processes that are associated with the strongest common genetic risk variants for schizophrenia. Coordinated methylation in these processes was decreased in brain samples from donors with schizophrenia, and showed an age-dependent association with schizophrenia-relevant brain function. These results support the coordination of DNA methylation as a regulatory principle relevant to schizophrenia that may be sensitive to environmental risk exposure during specific developmental periods and compound genetic illness predisposition.

Age and sex dependent association of uric acid and incident hypertension

Background and aimsA previous meta-analysis suggested that the relationship between hyperuricemia and hypertension may be stronger in younger individuals and women. We aimed to investigate the age and sex dependent association of uric acid (UA) and incident hypertension. Methods and resultsWe analyzed data from the Health Examinees Study, a community-based prospective cohort study conducted in Korea from 2004 to 2013. It included 29,088 non-hypertensive subjects aged 40–79 (age, 52.5 ± 7.8 years; men, 31.4%) who had serum UA measurement and participated in the follow-up survey. The risk factors of hypertension were assessed using Cox regression. Over a mean 3.8 years of follow-up, 1388 men (15.2%) and 1942 women (9.7%) were newly diagnosed with hypertension. Upon age- and sex-based stratification, the risk of hypertension was highest in hyperuricemic subjects aged 40–49 years (HR: women, 2.16; men, 1.30). Across the entire cohort, the risk of incident hypertension was higher in groups with higher serum UA levels, and highest in women aged 40–49 years (HR, 1.44; P < 0.001). On multivariable linear regression analysis, the higher the baseline serum UA level, the greater the increase in blood pressure during follow-up, and this effect was strongest in women aged 40–49 years (β = 0.87 and P < 0.01 for systolic blood pressure). ConclusionsThe relationship between uric acid and incident hypertension tended to be dependent on age and sex. Younger women are at highest risk of UA-related incident hypertension.

Novel ALDH5A1 variants and genotype: Phenotype correlation in SSADH deficiency.

To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency. ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study. Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype. Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.

MicroRNA-99b-5p downregulates protein synthesis in human primary myotubes.

microRNAs (miRNAs) are important regulators of cellular homeostasis and exert their effect by directly controlling protein expression. We have previously reported an age-dependent negative association between microRNA-99b (miR-99b-5p) expression and muscle protein synthesis in human muscle in vivo. Here we investigated the role of miR-99b-5p as a potential negative regulator of protein synthesis via inhibition of mammalian target for rapamycin (MTOR) signaling in human primary myocytes. Overexpressing miR-99b-5p in human primary myotubes from young and old subjects significantly decreased protein synthesis with no effect of donor age. A binding interaction between miR-99b-5p and its putative binding site within the MTOR 3'-untranslated region (UTR) was confirmed in C2C12 myoblasts. The observed decline in protein synthesis was, however, not associated with a suppression of the MTOR protein but of its regulatory associated protein of mTOR complex 1 (RPTOR). These results demonstrate that modulating the expression levels of a miRNA can regulate protein synthesis in human muscle cells and provide a potential mechanism for muscle wasting in vivo.

Obesity at a young age is associated with development of diabetes mellitus: A prospective cohort study in rural China

ABSTRACT Objectives We aimed to assess the age-dependent association of obesity with the risk of developing diabetes mellitus (DM) among a low-income population in China. Methods In this prospective cohort study, we estimated the hazard ratios (HR) for the association of body mass index (BMI) with DM risk from 1991 to 2014, after adjusting for other possible risk factors, using Cox-regression analysis. Results A total of 971 participants were followed up for 23 years in this study. The incidence of DM in this population was as high as 467.0/100,000 person-years. Compared with normal weight, the HR (and 95% confidence interval [CI]) for overweight affecting DM risk was 2.23 (1.45–3.41) overall, including 2.43 (1.05–5.63) for men and 2.17 (1.31–3.59) for women. The HR associated with the impact of obesity was 3.59 (2.06–6.27) overall, including 6.04 (1.84–19.81) for men and 3.23 (1.69–6.16) for women. Being overweight had a significant association with DM for people aged 40–49 years (HR, 1.99; 95% CI, 1.03–3.84); the HR for an association between DM and obesity was the highest among individuals aged 30–39 years (HR, 4.43; 95% CI, 1.84–10.67). There was no statistical significance between BMI and DM among individuals aged ≥50 years. Conclusions These findings suggest that obesity is associated with developing DM in rural China, especially among adults aged <50 years. Weight management is the highest priority for reducing the heavy burden of DM.

Age-dependent association of CYP2C19 polymorphisms with clinical outcome of clopidogrel therapy in minor stroke patients with large-artery atherosclerosis.

Previous studies on the association between CYP2C19 polymorphisms and therapeutic outcome of clopidogrel in stroke patients are inconclusive. We aimed to investigate the impact of CYP2C19 polymorphisms on therapeutic efficacy of clopidogrel in both young and old minor stroke patients associated with large-artery atherosclerosis (LAA). A total of 510 eligible patients were enrolled between April 2015 and April 2018. During 1year of follow-up, the modified Rankin Scale (mRS) was recorded. Statistical comparisons were performed using Pearson's chi squared test, Mann Whitney U test, and the Breslow-Day test to determine the effects of CYP2C19 polymorphisms on clinical outcome in different age strata. Multivariate binary logistic analysis was used to examine the potential prognostic predictors for clinical outcome. Model fitness was detected with Hosmer-Lemeshow test. Sixty years old was identified as the optimal cutoff age for CYP2C19 polymorphisms to affect the clinical outcome of clopidogrel therapy in LAA-associated minor stroke patients (OR = 1.67; 95% CI 1.08-2.58). Comparisons of baseline characteristics between patients with favorable and poor outcome indicated the correlation between CYP2C19 loss-of-function (LOF) allele and poorer clinical outcome in ≤ 60-year-old patients (OR = 4.29; 95% CI 1.68-10.93). The heterogeneity test showed a presence of interaction between age and CYP2C19 LOF (OR = 3.75; 95% CI 1.30-10.81). The logistic analyses further suggested that CYP2C19 LOF predicted poor clinical outcome in ≤ 60-year-old but not in > 60-year-old LAA-associated minor stroke patients receiving clopidogrel for the second prevention. Carriage of the CYP2C19 LOF allele may prevent expected clinical outcome during clopidogrel therapy in young LAA-associated minor stroke patients, whereas not in older patients.

Abstract C049: A common microRNA-flanking variant (rs13136737) in hsa-miR-302/367 affects risk of prostate cancer progression in young men

Abstract A clinical challenge in prostate cancer (PCa) is identifying the characteristics of primary lesions that give rise to metastatic disease so that patients receive immediate treatment. Genetic variation in microRNA (miRNA) genes can affect mature miRNA biogenesis and/or mRNA targeting, which can consequently influence cancer susceptibility and progression. We identified an under-studied genetic variant (rs13136737, G/T) that is near the 3’ end of the polycistronic primary miRNA, hsa-miR-302/367, which we show to be biofunctional. In this study we investigated the biological effects and clinical consequences of this sequence variant in PCa. We found that production of mature miRNAs from the hsa-miR-302/367 cluster is dependent on rs13136737 genotype, and that the T-allele primary transcript is inefficiently processed with respect to production of mature miR-302d and miR-367. To evaluate the consequences of rs13136737 germ line variation we genotyped the locus in a mixed-race cohort of prostate cancer patients and tested for an association with cancer stage at diagnosis as an indicator of aggressiveness. We observed an age-dependent association between rs13136737 genotype and increased risk of advanced stage PCa which was present only in younger men [&amp;lt;65 years, OR = 3.13, 95% confidence interval 1.46 – 7.52; p=0.003] and replicated this association in an independent data set of African-American men [OR: 1.58; 95% confidence interval 1.10 – 2.26; p=0.013]. When the cancer risk of the polymorphism was stratified with age in an African American population, the 45-54 years of age group shows significance (p=0.0374) whereas there was no significant association in older men. This suggests SNP rs13136737 T allele is associated with risk in early-onset PCa patients. The consistency of this result in discovery and validation datasets, which varied substantially in their racial composition, suggests that rs13136737 genotype may be a robust biomarker for risk of advanced stage PCa among younger men. The rs13136737 risk allele (T) occurs at high frequencies in European, South Asian, Hispanic, and Native American populations (0.51, 0.52, 0.57, and 0.71, respectively) and at relatively low frequency in African/African-American populations (0.12). This indicates that the clinical utility of rs13136737 will be sensitive to patient ancestry due to variation in the frequency of the risk allele. Citation Format: Ronald L Heimark, Kelsey Guest, Virginia Ware, Kari Hernandez, Brenna Rheinheimer, Jessica M Patnode, Raquel Dias, Mitchell Sokoloff, Jason A Wilder. A common microRNA-flanking variant (rs13136737) in hsa-miR-302/367 affects risk of prostate cancer progression in young men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C049.

Age-dependent association of polymorphisms in the promoter and 5′-untranslated region of the norepinephrine transporter gene with generalized anxiety disorder

BackgroundNorepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders. MethodsThree common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5′-untranslated region (5′-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20–65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates. ResultsAn interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups. LimitationsOnly 3 common SNPs in the promoter and 5′-UTR of the NET gene were analyzed. ConclusionsOur findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5′-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.

Relationship of depressive symptoms with arterial stiffness and carotid atherosclerotic burden in the Corinthia study.

It has been long hypothesized that emotional factors and depression may play role in the development of cardiovascular diseases. The aim of this study was to examine the association between depression, arterial stiffness and atheromatic burden in carotid arteries. Corinthia study is a cross-sectional epidemiological study conducted in subjects aged 40-99 years, inhabitants of the homonym region of Greece. Intima media thickness (IMT) was measured in the left and right common carotid artery, carotid bulb and internal carotid artery. The average of the measurements (mean IMT) and the maximum IMT were determined as the representative value of carotid atherosclerosis burden. Pulse wave velocity was used to evaluate arterial stiffness. The Zung Self-Rating Depression Scale was used to evaluate depressive symptoms in subjects <65 years and the Geriatric Depression Scale in those >65 years. In this analysis, we included data from 1510 participants. In older subjects (i.e. >65 years), maximum IMT was significantly increased in subjects with depression compared to those without (1.57 ± 0.97 mm vs. 1.74 ± 1.05 mm, P = 0.04). Similarly, the prevalence of atheromatic plaques was higher in subjects with depression (46% vs. 34%, P = 0.005). In the younger subgroup (<65years), there was no difference in mean and maximum IMT. Pulse wave velocity was found higher in the presence of depression (8.35 ± 2.36m/s vs. 7.88 ± 1.77m/s, P = 0.007). No differences emerged for the rest of the variables assessed in the individual subgroups. There is an age-dependent association between depression, arterial stiffness and carotid atheromatic burden highlighting the interplay between cardiovascular diseases and emotional status.

Age-Dependent Association of Occult Hypoperfusion and Outcomes in Trauma

Occult hypoperfusion (OH), or global hypoperfusion with normal vital signs, is a risk factor for poor outcomes in elderly trauma patients. We hypothesized that OH is associated with worse outcomes than shock in both young and elderly trauma patients. We conducted a single-center cohort study of adult (16 years or older) trauma patients from 2016 to 2018 with base excess measured on arrival. Perfusion states were defined as shock if heart rate was >120 beats/min or systolic blood pressure was <90 mmHg; OH if base excess was < -2 mmol/L, heart rate was <120 beats/min, and systolic blood pressure was >90mmHg; and normal for all others. Patients were stratified as young (younger than 55years) or elderly (55 years or older). Bayesian regression was used to assess the relationship between arrival perfusion state and mortality or serious complication. Of 3,126 included patients, 808 were elderly. Rates of shock (33% and 31%) and OH (25% and 23%) were similar in young and elderly patients, respectively. OH on arrival was associated with higher odds of mortality or serious complication than normal perfusion, regardless of age group. Compared with shock, OH was associated with an odds ratio of 1.21 (95% CI, 0.97 to 1.52, posterior probability 96%) for poor outcomes in elderly patients and an odds ratio of 0.52 (95% CI, 0.42 to 0.65, posterior probability <1%) for poor outcomes in younger patients. Findings were similar on sensitivity analysis, excluding shock patients with base excess ≥ -2 mmol/L. In elderly but not younger patients, OH is associated with worse outcomes than shock. Although shock parameters might need to be redefined in elderly patients, more attention is necessary for the diagnosis and treatment of all hypoperfused states in this age group.

Age dependent association of inbreeding with risk for schizophrenia in Egypt

BackgroundSelf-reported consanguinity is associated with risk for schizophrenia (SZ) in several inbred populations, but estimates using DNA-based coefficients of inbreeding are unavailable. Further, it is not known whether recessively inherited risk mutations can be identified through homozygosity by descent (HBD) mapping. MethodsWe studied self-reported and DNA-based estimates of inbreeding among Egyptian patients with SZ (n = 421, DSM IV criteria) and adult controls without psychosis (n = 301), who were evaluated using semi-structured diagnostic interview schedules and genotyped using the Illumina Infinium PsychArray. Following quality control checks, coefficients of inbreeding (F) and regions of homozygosity (ROH) were estimated using PLINK software for HBD analysis. Exome sequencing was conducted in selected cases. ResultsInbreeding was associated with schizophrenia based on self-reported consanguinity (χ2 = 4.506, 1 df, p = 0.034) and DNA-based estimates for inbreeding (F); the latter with a significant F × age interaction (β = 32.34, p = 0.0047). The association was most notable among patients older than age 40 years. Eleven ROH were over-represented in cases on chromosomes 1, 3, 6, 11, and 14; all but one region is novel for schizophrenia risk. Exome sequencing identified six recessively-acting genes in ROH with loss-of-function variants; one of which causes primary hereditary microcephaly. ConclusionsWe propose consanguinity as an age-dependent risk factor for SZ in Egypt. HBD mapping is feasible for SZ in adequately powered samples.

Physical Activity, APOE Genotype, and Cognitive Decline: Exploring Gene-Environment Interactions in the UK Biobank.

Apolipoprotein E (APOE) genotype affects the risk of Alzheimer's disease (AD) with inconclusive evidence on the opportunity to mitigate related adverse effects by lifestyle changes. To examine the individual and interactive associations of APOE and objectively-measured physical activity (PA) and sedentary activity with cognitive decline. We used data from middle-aged and older UK Biobank participants with repeat tests on visuospatial memory (n = 52,767) and fluid intelligence (n = 19,713), and who also took part in the accelerometer sub-study. PA and sedentary activity were assessed by a wrist-worn accelerometer over a seven-day period. Cognitive decline was defined as >1 standard deviation (SD) reduction in memory or fluid intelligence score, and the mean follow up from baseline was 5.8 years. There was an age dependent association between APOEɛ4 genotype and memory decline (page-interaction = 0.01), with the association only seen in participants who were >65 years (OR 1.33, 95% CI 1.11 to 1.24; for <65 years OR 1.06, 95% CI 0.99 to 1.14). The OR for the APOEɛ4 association with fluid intelligence decline was 1.11 (95% CI 0.99 to 1.24), and there was no evidence for age interaction (page-interaction = 0.99). High PA and low sedentary activity were associated with reduced mean memory decline (p < 0.02 for both). There was no interaction between PA or sedentary activity with APOEɛ4 regarding either of the cognitive decline measures (p > 0.63 for all). This large-scale study using objectively measured PA did not find differential effects of PA on cognitive decline based on APOE genotype.

Age-dependent association of white matter abnormality with cognition after TIA or minor stroke

ObjectiveTo investigate if the association between MRI-detectable white matter hyperintensity (WMH) and cognitive status reported in previous studies persists at older ages (>80 years), when some white matter abnormality is almost universally reported in clinical practice.MethodsConsecutive eligible patients from a population-based cohort of all TIA/nondisabling stroke (Oxford Vascular Study) underwent multimodal MRI, including fluid-attenuated inversion recovery and diffusion-weighted imaging, allowing automated measurement of WMH volume, mean diffusivity (MD), and fractional anisotropy (FA) in normal-appearing white matter using FSL tools. These measures were related to cognitive status (Montreal Cognitive Assessment) at age ≤80 vs >80 years.ResultsOf 566 patients (mean [range] age 66.7 [20–102] years), 107 were aged >80 years. WMH volumes and MD/FA were strongly associated with cognitive status in patients aged ≤80 years (all p < 0.001 for WMH, MD, and FA) but not in patients aged >80 years (not significant for WMH, MD, and FA), with age interactions for WMH volume (pinteraction = 0.016) and MD (pinteraction = 0.037). Voxel-wise analyses also showed that lower Montreal Cognitive Assessment scores were associated with frontal WMH in patients ≤80 years, but not >80 years.ConclusionMRI markers of white matter damage are strongly related to cognition in patients with TIA/minor stroke at younger ages, but not at age >80 years. Clinicians and patients should not overinterpret the significance of these abnormalities at older ages.

Age-dependent association of pulse wave velocity with coronary artery disease and myocardial aging in high-risk patients.

Progressive arterial stiffening, as a marker of arterial aging, may reach a plateau in elderly patients and may thus lose its clinical utility. This phenomenon may be more prominent in high-risk patients. We aimed to investigate if carotid-to-femoral pulse wave velocity (cf-PWV) is related to coronary artery disease (CAD) and diastolic dysfunction in elderly high-risk patients as compared to a control group of younger individuals. One-hundred and ninety-two high-risk stable patients who underwent coronary artery angiography and assessment of cf-PWV were consecutively recruited. Indices of diastolic dysfunction were also measured by echocardiography, including the volume of the left atrium and the ratio of early transmitral peak velocity (E) to the mitral annular early diastolic velocity (E'). Increased cf-PWV was associated with the presence of CAD [odds ratio (OR) 1.34, P = 0.02], number of diseased coronary vessels (OR 1.17, P = 0.029) and CAD severity (P = 0.023) as assessed by Gensini score, in patients less than 65 years old after adjustment for traditional risk factors. Moreover, cf-PWV correlated with E/E' (P = 0.019) and increased the odds by 16% (OR 1.16, P = 0.048) for more severe diastolic dysfunction in patients aged below 65 years old. None of these outcomes correlated with cf-PWV in the elderly. In high cardiovascular risk patients, an age-dependent association of cf-PWV with CAD and diastolic dysfunction was evinced. In contrast to younger patients, these results suggest that measuring arterial stiffness in elderly high-risk patients may lack clinical value.

A Genome-Wide Association Study for Susceptibility to Visual Experience-Induced Myopia.

PurposeThe rapid rise in prevalence over recent decades and high heritability of myopia suggest a role for gene–environment (G × E) interactions in myopia susceptibility. Few such G × E interactions have been discovered to date. We aimed to test the hypothesis that genetic analysis of susceptibility to visual experience-induced myopia in an animal model would identify novel G × E interaction loci.MethodsChicks aged 7 days (n = 987) were monocularly deprived of form vision for 4 days. A genome-wide association study (GWAS) was carried out in the 20% of chicks most susceptible and least susceptible to form deprivation (n = 380). There were 304,963 genetic markers tested for association with the degree of induced axial elongation in treated versus control eyes (A-scan ultrasonography). A GWAS candidate region was examined in the following three human cohorts: CREAM consortium (n = 44,192), UK Biobank (n = 95,505), and Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4989).ResultsA locus encompassing the genes PIK3CG and PRKAR2B was genome-wide significantly associated with myopia susceptibility in chicks (lead variant rs317386235, P = 9.54e−08). In CREAM and UK Biobank GWAS datasets, PIK3CG and PRKAR2B were enriched for strongly-associated markers (meta-analysis lead variant rs117909394, P = 1.7e−07). In ALSPAC participants, rs117909394 had an age-dependent association with refractive error (−0.22 diopters [D] change over 8 years, P = 5.2e−04) and nearby variant rs17153745 showed evidence of a G × E interaction with time spent reading (effect size −0.23 D, P = 0.022).ConclusionsThis work identified the PIK3CG-PRKAR2B locus as a mediator of susceptibility to visually induced myopia in chicks and suggests a role for this locus in conferring susceptibility to myopia in human cohorts.

Herpes Simplex Virus, APOEɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study.

Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer's disease (AD) development. The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOEɛ4) in a large population-based cohort with a long follow-up time. The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOEɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared. Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOEɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOEɛ4 for episodic memory decline (p < 0.001). In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOEɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.

The age-dependent relationship between resting heart rate variability and functional brain connectivity

Resting heart rate variability (HRV), an index of parasympathetic cardioregulation and an individual trait marker related to mental and physical health, decreases with age. Previous studies have associated resting HRV with structural and functional properties of the brain – mainly in cortical midline and limbic structures. We hypothesized that aging affects the relationship between resting HRV and brain structure and function. In 388 healthy subjects of three age groups (140 younger: 26.0 ± 4.2 years, 119 middle-aged: 46.3 ± 6.2 years, 129 older: 66.9 ± 4.7 years), gray matter volume (GMV, voxel-based morphometry) and resting state functional connectivity (eigenvector centrality mapping and exploratory seed-based functional connectivity) were related to resting HRV, measured as the root mean square of successive differences (RMSSD). Confirming previous findings, resting HRV decreased with age. For HRV-related GMV, there were no statistically significant differences between the age groups, nor similarities across all age groups. In whole-brain functional connectivity analyses, we found an age-dependent association between resting HRV and eigenvector centrality in the bilateral ventromedial prefrontal cortex (vmPFC), driven by the younger adults. Across all age groups, HRV was positively correlated with network centrality in the bilateral posterior cingulate cortex. Seed-based functional connectivity analysis using the vmPFC cluster revealed an HRV-related cortico-cerebellar network in younger but not in middle-aged or older adults. Our results indicate that the decrease of HRV with age is accompanied by changes in functional connectivity along the cortical midline. This extends our knowledge of brain-body interactions and their changes over the lifespan.