Degree of memory impairment is often used to infer early versus late amnestic mild cognitive impairment (aMCI). Previously, 318 Alzheimer's Disease Neuroimaging Initiative participants with aMCI-determined by a single memory test-were divided based on Rey Auditory Verbal Learning Task (AVLT) delayed recall: AVLT-impaired (n = 225) and AVLT-normal (n = 93). Equally consistent with differential progression or differential diagnosis, the AVLT-impaired group had more abnormal Alzheimer's disease (AD) biomarkers, more neurodegeneration over time, and was more likely to develop AD. In the present study, higher AD polygenic risk scores were associated with increased odds of being AVLT-impaired (odds ratio 1.8, p < 0.001). Thus, impairment severity does not necessarily reflect early versus late aMCI because disease progression cannot alter polygenic risk. Presumed early MCI is likely a heterogeneous category that includes excess false-positives. The additional cognitive test improved diagnostic precision by reducing false positives. Impairment severity may reflect differences in underlying disease risk but cannot be used to infer early versus late MCI based on cross-sectional data alone.

Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.

Objectives

Attachment theory has become a key framework for understanding responses to and consequences of trauma across the life course. We predicted that more severe post-traumatic stress (PTS) symptoms at age 37 years would be associated with insecure attachment at age 55 and with worse PTS symptoms 24 years later at age 61, and that age 55 attachment would mediate the influence of earlier PTS symptoms on later symptoms.

Design

Data on PTS self-reported symptoms were available for 975 community-dwelling participants from the longitudinal Vietnam Era Twin Study of Aging at ages 37 and 61 years. At age 55, participants completed the Experiences in Close Relationships Inventory, a measure of adult attachment.

Results

PTS symptoms at ages 37 and 61 correlated (r = 0.43; p <0.0001). Multiple mediation models found significant direct effects of age 37 PTS symptoms on age 61 PTS symptoms (β = 0.26; 95% confidence interval: 0.19-0.33). Anxious and avoidant attachment at age 55 predicted PTS symptoms at age 61 (r = 0.34 and 0.25; ps <0.0001, respectively) and also significantly mediated PTS symptoms over time, showing that insecure attachment increased PTS severity. Participants with higher age 37 PTS symptoms were more likely to have a history of divorce; marital status did not mediate PTS.

Conclusions

Analyses demonstrate the persistence of PTS symptoms from early midlife into early old age. Mediation analyses revealed that one path through which PTS symptoms persisted was indirect: through their influence on attachment insecurity. This study provides insight into ongoing interconnections between psychological and interpersonal responses to stress.

Background

Identifying mild cognitive impairment (MCI) in midlife could improve early identification of Alzheimer's disease (AD). Also, AD is highly heritable, but the heritability of MCI has not been established. We estimated prevalence rates, association with premorbid general cognitive ability (GCA) and heritability for different definitions of neuropsychologically defined MCI in adults in their 50s.

Method

We examined 1126 twins aged 51-59 years when recruited into the Vietnam Era Twin Study of Aging (VETSA). Six neurocognitive domains were assessed using tests designed to avoid ceiling effects. To differentiate MCI from low overall ability, criteria included adjustment for GCA measured at approximately age 20 years.

Results

As in older adults, prevalence rates varied widely. Among the lower prevalence rates were some definitions of multiple-domain MCI and single-domain amnestic MCI, which may be less likely than other MCI categories to revert to normal on follow-up. Low prevalence rates in middle-aged adults are also more likely to be valid. MCI was also associated with lower premorbid GCA. Heritability estimates for any MCI and amnestic MCI averaged .40-.48.

Conclusions

By testing multiple cognitive domains and avoiding ceiling effects, MCI can be identified before age 60 years. Premorbid GCA is a risk/protective factor, but deficits after adjusting for early adult GCA suggest additional processes leading to declining trajectories. Heritabilities were comparable to AD, suggesting MCI as an appropriate phenotype for genetic association studies. Full validation will require follow-up assessments (currently under way). Community-based studies are important for this early identification because adults of this age are unlikely to present in clinics.

Right-left regional cerebral differences are a feature of the human brain linked to functional abilities, aging, and neurodevelopmental and mental disorders. The role of genetic factors in structural asymmetry has been incompletely studied. We analyzed data from 515 individuals (130 monozygotic twin pairs, 97 dizygotic pairs, and 61 unpaired twins) from the Vietnam Era Twin Study of Aging to answer three questions about genetic determinants of brain structural asymmetry: First, does the magnitude of heritability differ for homologous regions in each hemisphere? Despite adequate power to detect regional differences, heritability estimates were not significantly larger in one hemisphere versus the other, except left > right inferior lateral ventricle heritability. Second, do different genetic factors influence left and right hemisphere size in homologous regions? Interhemispheric genetic correlations were high and significant; in only two subcortical regions (pallidum and accumbens) did the estimate statistically differ from 1.0. Thus, there was little evidence for different genetic influences on left and right hemisphere regions. Third, to what extent do genetic factors influence variability in left-right size differences? There was no evidence that variation in asymmetry (i.e., the size difference) of left and right homologous regions was genetically determined, except in pallidum and accumbens. Our findings suggest that genetic factors do not play a significant role in determining individual variation in the degree of regional cortical size asymmetries measured with MRI, although they may do so for volume of some subcortical structures. Despite varying interpretations of existing data, we view the present results as consistent with previous findings.

Animal data show that cortical development is initially patterned by genetic gradients largely along three orthogonal axes. We previously reported differences in genetic influences on cortical surface area along an anterior-posterior axis using neuroimaging data of adult human twins. Here, we demonstrate differences in genetic influences on cortical thickness along a dorsal-ventral axis in the same cohort. The phenomenon of orthogonal gradations in cortical organization evident in different structural and functional properties may originate from genetic gradients. Another emerging theme of cortical patterning is that patterns of genetic influences recapitulate the spatial topography of the cortex within hemispheres. The genetic patterning of both cortical thickness and surface area corresponds to cortical functional specializations. Intriguingly, in contrast to broad similarities in genetic patterning, two sets of analyses distinguish cortical thickness and surface area genetically. First, genetic contributions to cortical thickness and surface area are largely distinct; there is very little genetic correlation (i.e., shared genetic influences) between them. Second, organizing principles among genetically defined regions differ between thickness and surface area. Examining the structure of the genetic similarity matrix among clusters revealed that, whereas surface area clusters showed great genetic proximity with clusters from the same lobe, thickness clusters appear to have close genetic relatedness with clusters that have similar maturational timing. The discrepancies are in line with evidence that the two traits follow different mechanisms in neurodevelopment. Our findings highlight the complexity of genetic influences on cortical morphology and provide a glimpse into emerging principles of genetic organization of the cortex.

Objective

In an effort to address earliest detection of mild cognitive impairment (MCI), we examined hippocampal volumes and atrophy in middle-aged men to explore neuroanatomical support for different neuropsychological definitions of MCI.

Methods

460 men aged 51-60 years underwent neuropsychological testing and MRI. MCI was defined according to five criteria sets. MRI-derived hippocampal volume and hippocampal occupancy (HOC) were obtained via FreeSurfer. Statistical analyses were performed using linear mixed models.

Results

Differences in HOC between normal cognitive functioning, amnestic, and non-amnestic MCI were observed using MCI criteria that required one impaired (>1.5 SD) cognitive measure in a given cognitive domain or a cognitive composite score method with a cut-point 2 SD below the mean. Differences in standard hippocampal volume were only found between normal and amnestic presentations and only when using the composite score method.

Conclusion

Results provide empirical support for detection of pre-MCI in younger cohorts. Convergence of neuropsychological and neuroanatomical data, particularly HOC (as opposed to standard cross-sectional volume), supports early identification of MCI as defined by some neuropsychological criteria.