Genetic relatedness of axial and radial diffusivity indices of cerebral white matter microstructure in late middle age.

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.

Heritability of white matter microstructure in late middle age: A twin study of tract-based fractional anisotropy and absolute diffusivity indices.

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.

Is bigger always better? The importance of cortical configuration with respect to cognitive ability.

General cognitive ability (GCA) has substantial explanatory power for behavioral and health outcomes, but its cortical substrate is still not fully established. GCA is highly polygenic and research to date strongly suggests that its cortical substrate is highly polyregional. We show in map-based and region-of-interest-based analyses of adult twins that a complex cortical configuration underlies GCA. Having relatively greater surface area in evolutionary and developmentally high-expanded prefrontal, lateral temporal, and inferior parietal regions is positively correlated with GCA, whereas relatively greater surface area in low-expanded occipital, medial temporal, and motor cortices is negatively correlated with GCA. Essentially the opposite pattern holds for relative cortical thickness. The phenotypic positive-to-negative gradients in our cortical-GCA association maps were largely driven by a similar pattern of genetic associations. The patterns are consistent with regional cortical stretching whereby relatively greater surface area is related to relatively thinner cortex in high-expanded regions. Thus, the typical "bigger is better" view does not adequately capture cortical-GCA associations. Rather, cognitive ability is influenced by complex configurations of cortical development patterns that are strongly influenced by genetic factors. Optimal cognitive ability appears to be driven both by the absolute size and the polyregional configuration of the entire cortex rather than by small, circumscribed regions.

The Genetic Association Between Neocortical Volume and General Cognitive Ability Is Driven by Global Surface Area Rather Than Thickness.

Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations.

Does degree of gyrification underlie the phenotypic and genetic associations between cortical surface area and cognitive ability?

The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer's disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA.

Exploring Retinal Blood Vessel Diameters as Biomarkers in Multiple Sclerosis.

We aimed to determine whether retinal vessel diameters and retinal oxygen saturation in newly diagnosed patients with multiple sclerosis (pwMS) are different from those of a healthy population. Retinal blood vessel diameters were measured using imaging with a spectrophotometric non-invasive retinal oximeter. Twenty-three newly diagnosed untreated relapsing-remitting MS (RRMS) patients (mean age: 32.2 ± 7.5 years, age range = 18-50 years, 56.5% female) were measured and compared to 23 age- and sex-matched healthy controls (HCs) (mean age: 34.8 ± 8.1 years). Patients with Optic Neuritis were excluded. Retinal venular diameter (143.8 µm versus 157.8 µm: mean; p = 0.0013) and retinal arteriolar diameter (112.6 µm versus 120.6 µm: mean; p = 0.0089) were smaller in pwMS when compared with HCs, respectively. There was no significant difference in the oxygen saturation in retinal venules and arterioles in pwMS (mean: 60.0% and 93.7%; p = 0.5980) compared to HCs (mean: 59.3% and 91.5%; p = 0.8934), respectively. There was a significant difference in the median low contrast visual acuity (2.5% contrast) between the pwMS and the HC groups (p = 0.0143) Retinal arteriolar and venular diameter may have potential as objective biomarkers for MS.

Hypertension-related alterations in white matter microstructure detectable in middle age.

Most studies examining associations between hypertension and brain white matter microstructure have focused on older adults or on cohorts with a large age range. Because hypertension effects on the brain may vary with age, it is important to focus on middle age, when hypertension becomes more prevalent. We used linear mixed-effect models to examine differences in white matter diffusion metrics as a function of hypertension in a well-characterized cohort of middle-aged men (n=316; mean, 61.8 years; range, 56.7-65.6). Diffusion metrics were examined in 9 tracts reported to be sensitive to hypertension in older adults. Relative to normotensive individuals, individuals with long-standing hypertension (>5.6 years) showed reduced fractional anisotropy or increased diffusivity in most tracts. Effects were stronger among carriers than among noncarriers of the apolipoprotein E ε4 allele for 2 tracts connecting frontal regions with other brain areas. Significant differences were observed even after adjustment for potentially related lifestyle and cardiovascular risk factors. Shorter duration of hypertension or better blood pressure control among hypertensive individuals did not lessen the adverse effects. These findings suggest that microstructural white matter alterations appear early in the course of hypertension and may persist despite adequate treatment. Although longitudinal studies are needed to confirm these findings, the results suggest that prevention-rather than management-of hypertension may be vital to preserving brain health in aging.

Brain volume reductions in adolescent heavy drinkers.

BACKGROUND: Brain abnormalities in adolescent heavy drinkers may result from alcohol exposure, or stem from pre-existing neural features. METHODS: This longitudinal morphometric study investigated 40 healthy adolescents, ages 12-17 at study entry, half of whom (n=20) initiated heavy drinking over the 3-year follow-up. Both assessments included high-resolution magnetic resonance imaging. FreeSurfer was used to segment brain volumes, which were measured longitudinally using the newly developed quantitative anatomic regional change analysis (QUARC) tool. RESULTS: At baseline, participants who later transitioned into heavy drinking showed smaller left cingulate, pars triangularis, and rostral anterior cingulate volume, and less right cerebellar white matter volumes (p<.05), compared to continuous non-using teens. Over time, participants who initiated heavy drinking showed significantly greater volume reduction in the left ventral diencephalon, left inferior and middle temporal gyrus, and left caudate and brain stem, compared to substance-naïve youth (p<.05). CONCLUSION: Findings suggest pre-existing volume differences in frontal brain regions in future drinkers and greater brain volume reduction in subcortical and temporal regions after alcohol use was initiated. This is consistent with literature showing pre-existing cognitive deficits on tasks recruited by frontal regions, as well as post-drinking consequences on brain regions involved in language and spatial tasks.