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1.  Intraglandular Injection of Botulinum Toxin A Reduces Tear Production in Rabbits 
Ophthalmic plastic and reconstructive surgery  2013;29(1):10.1097/IOP.0b013e31826e8a86.
To develop an animal model and investigate the dose-dependent effect of an intraglandular injection of botulinum toxin A (BTX-A) on tear production.
In a volume of 0.1-ml, 0.625-, 1.25-, or 2.5-U BTX-A was injected transconjunctivally in the superolateral lobe of the lacrimal gland of adult New Zealand white female rabbits. In the contralateral lacrimal gland, 0.1 ml of 0.9% sodium chloride was injected. Prior to injection and at 1-week postinjection, photographs were taken to evaluate pre- and postoperative eyelid position. Fluorescein and Rose Bengal stain were used to evaluate the corneal surface, and Schirmer test was used to assess tear production.
Glands injected with the intermediate (1.25 U) and the highest (2.5 U) doses of BTX-A displayed a statistically significant decrease in tear production (p = 0.002 and 0.007, respectively) compared with the contralateral saline-injected glands at 1 week. No corneal pathologic factors from excessive dryness were observed following the injection. While postinjection ptosis was observed (p = 0.025), no difference was seen between BTX-A and saline-injected eyes.
In rabbits, intraglandular injection of BTX-A resulted in decreased tear production at 1 week. No additional reduction in tear production was seen with a BTX-A dose greater than 1.25 U, suggesting glandular receptor saturation at this dose. Despite suppression of tear production, no corneal pathologic factors were observed. Further studies are needed to refine this animal model with the ultimate goal of determining optimum delivery route and concentration to reduction in tear production while minimizing side effects in patients.
PMCID: PMC3823535  PMID: 23128538
2.  A Multivariate Twin Study of Hippocampal Volume, Self-Esteem and Well-Being in Middle Aged Men 
Genes, Brain, and Behavior  2012;11(5):539-544.
Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition, and stress responsivity. Whereas most of this evidence is based on studies of older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-age twins. Self-esteem was significantly positively correlated with hippocampal volume (.09, p=.03 for left hippocampus, .10, p=.04 for right). Correlations for well-being were not significant (ps ≫.05). There were strong phenotypic correlations between self-esteem and well-being (.72, p<.001) and between left and right hippocampal volume (.72, p<.001). In multivariate genetic analyses, a 2-factor AE model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fit the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was .12 (p=.03); the correlation between the environmental factors was .09 (p>05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on the one hand and hippocampal volume on the other.
PMCID: PMC3389179  PMID: 22471516
self-esteem; well-being; hippocampus; twins; heritability; aging
3.  Hierarchical Genetic Organization of Human Cortical Surface Area 
Science (New York, N.Y.)  2012;335(6076):1634-1636.
Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non–genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.
PMCID: PMC3690329  PMID: 22461613
4.  Genetic and Environmental Influences of White and Gray Matter Signal Contrast: A New Phenotype for Imaging Genetics? 
Neuroimage  2012;60(3):1686-1695.
The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer’s disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environmental determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from −.11 to −.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from −.16 to −.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics.
PMCID: PMC3328105  PMID: 22500923
5.  The anti-idiotypic antibody 1F7 stimulates monocyte interleukin-10 production and induces endotoxin tolerance 
Pathogens that establish chronic infection elicit immune responses with suppressive cytokines dominating over pro-inflammatory cytokines. Chronic hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection and simian immunodeficiency virus (SIV) infection are associated with high levels of antiviral antibodies expressing a common idiotype specifically recognized by the 1F7 monoclonal antibody (mAb). The 1F7 mAb is a murine IgMκ antibody raised against immunoglobulin pooled from the plasma of multiple HIV-infected individuals. In this study, we investigated direct effects of the 1F7 mAb itself on peripheral blood mononuclear cells (PBMC).
Isolated monocytes or PBMC from healthy controls were incubated with the 1F7 mAb or IgMκ mAb control. Cytokine production was measured in cell culture supernatants by ELISA and cells producing interleukin-10 (IL-10) were identified by subset depletion and intracellular flow cytometry. Endotoxin tolerance was assessed by exposing monocytes to lipopolysaccharide (LPS) following 1F7 mAb or IgMκ mAb control pre-treatment and comparing tumor necrosis factor (TNF)-α levels in cell culture supernatants.
The 1F7 mAb stimulated monocytes and CD36+ lymphocytes to produce IL-10 in a time and dose-dependent manner. Treatment of monocytes with 1F7 mAb also reduced their subsequent responsiveness to LPS stimulation.
Induction of antibodies expressing the 1F7 idiotype by chronic pathogens may facilitate IL-10 production and progression to chronic infection. Direct effects of IL-10 from human monocytes stimulated by 1F7-like antibodies, followed by monocyte transition to an alternatively activated phenotype illustrated by endotoxin tolerance, are two complementary features favouring a tolerogenic or non-responsive immunological environment.
PMCID: PMC3635981  PMID: 23561395
Hepatitis C virus; Monocyte; Interleukin-10; Idiotype; Endotoxin tolerance
6.  Genetic Architecture of the Delis-Kaplan Executive Function System Trail Making Test: Evidence for Distinct Genetic Influences on Executive Function 
Neuropsychology  2011;26(2):238-250.
To examine how genes and environments contribute to relationships among Trail Making test conditions and the extent to which these conditions have unique genetic and environmental influences.
Participants included 1237 middle-aged male twins from the Vietnam-Era Twin Study of Aging (VESTA). The Delis-Kaplan Executive Function System Trail Making test included visual searching, number and letter sequencing, and set-shifting components.
Phenotypic correlations among Trails conditions ranged from 0.29 – 0.60, and genes accounted for the majority (58–84%) of each correlation. Overall heritability ranged from 0.34 to 0.62 across conditions. Phenotypic factor analysis suggested a single factor. In contrast, genetic models revealed a single common genetic factor but also unique genetic influences separate from the common factor. Genetic variance (i.e., heritability) of number and letter sequencing was completely explained by the common genetic factor while unique genetic influences separate from the common factor accounted for 57% and 21% of the heritabilities of visual search and set-shifting, respectively. After accounting for general cognitive ability, unique genetic influences accounted for 64% and 31% of those heritabilities.
A common genetic factor, most likely representing a combination of speed and sequencing accounted for most of the correlation among Trails 1–4. Distinct genetic factors, however, accounted for a portion of variance in visual scanning and set-shifting. Thus, although traditional phenotypic shared variance analysis techniques suggest only one general factor underlying different neuropsychological functions in non-patient populations, examining the genetic underpinnings of cognitive processes with twin analysis can uncover more complex etiological processes.
PMCID: PMC3295889  PMID: 22201299
executive function; genetics; heritability; twins; middle-age; speed; trail making
7.  A Comparison of Heritability Maps of Cortical Surface Area and Thickness and the Influence of Adjustment for Whole Brain Measures: A Magnetic Resonance Imaging Twin Study 
Understanding the genetic and environmental contributions to measures of brain structure such as surface area and cortical thickness is important for a better understanding of the nature of brain-behavior relationships and changes due to development or disease. Continuous spatial maps of genetic influences on these structural features can contribute to our understanding of regional patterns of heritability, since it remains to be seen whether genetic contributions to brain structure respect the boundaries of any traditional parcellation approaches. Using data from magnetic resonance imaging scans collected on a large sample of monozygotic and dizygotic twins in the Vietnam Era Twin Study of Aging, we created maps of the heritability of areal expansion (a vertex-based area measure) and cortical thickness and examined the degree to which these maps were affected by adjustment for total surface area and mean cortical thickness. We also compared the approach of estimating regional heritability based on the average heritability of vertices within the region to the more traditional region-of-interest (ROI)-based approach. The results suggested high heritability across the cortex for areal expansion and, to a slightly lesser degree, for cortical thickness. There was a great deal of genetic overlap between global and regional measures for surface area, so maps of region-specific genetic influences on surface area revealed more modest heritabilities. There was greater inter-regional variability in heritabilities when calculated using the traditional ROI-based approach compared to summarizing vertex-by-vertex heritabilities within regions. Discrepancies between the approaches were greatest in small regions and tended to be larger for surface area than for cortical thickness measures. Implications regarding brain phenotypes for future genetic association studies are discussed.
PMCID: PMC3549553  PMID: 22856366
surface area; cortical thickness; region of interest; heritability maps
8.  Genetic Influences on Hippocampal Volume Differ as a Function of Testosterone Level in Middle-Aged Men 
NeuroImage  2011;59(2):1123-1131.
The hippocampus expresses a large number of androgen receptors; therefore, in men it is potentially vulnerable to the gradual age-related decline of testosterone levels. In the present study we sought to elucidate the nature of the relationship between testosterone and hippocampal volume in a sample of middle-aged male twins (average age 55.8 years). We found no evidence for a correlation between testosterone level and hippocampal volume, as well as no indication of shared genetic influences. However, a significant moderating effect of testosterone on the genetic and environmental determinants of hippocampal volume was observed. Genetic influences on hippocampal volume increased substantially as a function of increasing testosterone level, while environmental influences either decreased or remained stable. These findings provide evidence for an apparent gene-by-hormone interaction on hippocampal volume. To the best of our knowledge, this is the first study to demonstrate that the heritability of a brain structure in adults may be modified by an endogenous biological factor.
PMCID: PMC3230702  PMID: 21983185
Heritability; Hippocampal Volume; Testosterone; Twin Study; Aging
9.  Heritability of brain ventricle volume: Converging evidence from inconsistent results 
Neurobiology of aging  2010;33(1):1-8.
Twin studies generally show great consistency for the heritability of brain structures. Ironically, the lateral ventricles—perhaps the most reliably measured brain regions of interest—are the most inconsistent when it comes to estimating genetic influences on their volume. Heritability estimates in twin studies have ranged from zero to almost 0.80. Here we aggregate heritability estimates from extant twin studies, and we review and re-interpret some of the findings. Based on our revised estimates, we conclude that lateral ventricular volume is indeed heritable. The weighted average heritability of the revised estimates was 0.54. Although accumulated environmental insults might seem most logical as the predominant cause of age-related ventricular expansion, the data strongly suggest that genetic influences on lateral ventricular volume are increasing with age. Genetic influences accounted for 32-35% of the variance in lateral ventricular volume in childhood, but about 75% of the variance in late middle and older age. These conclusions have implications for the basic understanding of the genetic and environmental underpinnings of normative and pathological brain aging.
PMCID: PMC3221930  PMID: 20363053
lateral ventricles; genetics; aging; structural MRI; twins; endophenotype; mild cognitive impairment; Alzheimer’s disease
10.  Untreated Hypertension Decreases Heritability of Cognition in Late Middle Age 
Behavior Genetics  2011;42(1):107-120.
Hypertension is a risk factor for cognitive decline, but the mechanisms underlying the effects of hypertension on cognition, particularly in midlife, are unclear. We examined whether hypertension modifies genetic influences on individual differences in cognition. Nine cognitive domains and general cognitive ability were assessed in a sample of 1237 male twins aged 51–60 who were divided into three blood pressure groups: non-hypertensive; medicated hypertensive; and unmedicated hypertensive. Heritability was significantly lower among unmedicated hypertensives compared to medicated hypertensives and non-hypertensives for visual-spatial ability (p=0.013) and episodic memory (p=0.004). There were no heritability differences between non-hypertensives and medicated hypertensives. In addition, there were no significant differences in mean level cognition across the three blood pressure groups. These results suggest that in middle-aged men, untreated hypertension suppresses normal genetic influences on individual differences in certain domains of cognition prior to the emergence of hypertension-related effects on cognitive performance. These results further suggest that antihypertensive medication may protect against or reverse this effect.
PMCID: PMC3227796  PMID: 21688193
hypertension; cognition; twins; heritability; aging
11.  Genetic Architecture of Context Processing in Late Middle Age: More Than One Underlying Mechanism 
Psychology and aging  2011;26(4):852-863.
Studies comparing young and older adults suggest a deficit in processing context information as a key mechanism underlying cognitive aging. However, the genetic architecture of context processing has not been examined. Consistent with previous results, we found evidence of functionally dissociable components of context processing accuracy in 1127 late middle-aged twins ages 51–60. One component emphasizes use of context cues to prepare responses (proactive cognitive control); the other emphasizes adjustment of responses after probes are presented (reactive control). Approximately one-quarter of the variance in each component was accounted for by genes. Multivariate twin analysis indicated that genetic factors underlying two important components of context processing were independent of one another, thus implicating more than one underlying mechanism. Slower reaction time (RT) on non-context processing trials was positively correlated with errors on the strongly proactive control component on which young adults outperform older adults, but RT was negatively correlated with errors on the strongly reactive control component on which older adults perform better. Although this RT measure was uncorrelated with chronological age in our age-homogeneous sample, slower RT was associated with performance patterns that were more like older adults. However, this did not generalize to other processing speed measures. Genetic correlations, which reflect shared genetic variance, paralleled the phenotypic correlations. There was also a positive genetic correlation between general cognitive ability and accuracy on the proactive control component, but there were still mostly distinct genetic influences underlying these measures. In contrast, the reactive control component was unrelated to general cognitive ability.
PMCID: PMC3222785  PMID: 21875218
twins; heritability; context processing; cognitive aging; processing speed
12.  Genetic Influences on Cortical Regionalization in the Human Brain 
Neuron  2011;72(4):537-544.
Animal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. “Marching seeds” and a data-driven, hypothesis-free, fuzzy clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in non-human mammalian models. Broad similarities in genetic patterning between rodents and humans may suggest a conservation of cortical patterning mechanisms while dissimilarities might reflect the functionalities most essential to each species.
PMCID: PMC3222857  PMID: 22099457
13.  Tamoxifen Downregulates Ets-oncogene Family Members ETV4 and ETV5 in Benign Breast Tissue: Implications for Durable Risk Reduction 
Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials.
Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples.
Tamoxifen downregulated ets-oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis.
A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. Multipotential progenitor cap cells of terminal end buds may be the primary target.
PMCID: PMC3208724  PMID: 21778330
Tamoxifen; Biomarkers; Gene Expression; Proliferation; DNA Methylation
14.  Genetic and Environmental Contributions to Regional Cortical Surface Area in Humans: A Magnetic Resonance Imaging Twin Study 
Cerebral Cortex (New York, NY)  2011;21(10):2313-2321.
Cortical surface area measures appear to be functionally relevant and distinct in etiology, development, and behavioral correlates compared with other size characteristics, such as cortical thickness. Little is known about genetic and environmental influences on individual differences in regional surface area in humans. Using a large sample of adult twins, we determined relative contributions of genes and environment on variations in regional cortical surface area as measured by magnetic resonance imaging before and after adjustment for genetic and environmental influences shared with total cortical surface area. We found high heritability for total surface area and, before adjustment, moderate heritability for regional surface areas. Compared with other lobes, heritability was higher for frontal lobe and lower for medial temporal lobe. After adjustment for total surface area, regionally specific genetic influences were substantially reduced, although still significant in most regions. Unlike other lobes, left frontal heritability remained high after adjustment. Thus, global and regionally specific genetic factors both influence cortical surface areas. These findings are broadly consistent with results from animal studies regarding the evolution and development of cortical patterning and may guide future research into specific environmental and genetic determinants of variation among humans in the surface area of particular regions.
PMCID: PMC3169660  PMID: 21378112
cortex; cortical thickness; heritability
15.  Responses to pandemic ASO3-adjuvanted A/California/07/09 H1N1 influenza vaccine in human immunodeficiency virus-infected individuals 
BMC Immunology  2012;13:49.
Influenza infection may be more serious in human immunodeficiency virus (HIV)-infected individuals, therefore, vaccination against seasonal and pandemic strains is highly advised. Seasonal influenza vaccines have had no significant negative effects in well controlled HIV infection, but the impact of adjuvanted pandemic A/California/07/2009 H1N1 influenza hemaglutinin (HA) vaccine, which was used for the first time in the Canadian population as an authorized vaccine in autumn 2009, has not been extensively studied.
Assess vaccine-related effects on CD4+ T cell counts and humoral responses to the vaccine in individuals attending the Newfoundland and Labrador Provincial HIV clinic.
A single dose of ArepanrixTM split vaccine including 3.75 μg A/California/07/2009 H1N1 HA antigen and ASO3 adjuvant was administered to 81 HIV-infected individuals by intramuscular injection. Plasma samples from shortly before, and 1–5 months after vaccination were collected from 80/81 individuals to assess humoral anti-H1N1 HA responses using a sensitive microbead-based array assay. Data on CD4+ T cell counts, plasma viral load, antiretroviral therapy and patient age were collected from clinical records of 81 individuals.
Overall, 36/80 responded to vaccination either by seroconversion to H1N1 HA or with a clear increase in anti-H1N1 HA antibody levels. Approximately 1/3 (28/80) had pre-existing anti-H1N1 HA antibodies and were more likely to respond to vaccination (22/28). Responders had higher baseline CD4+ T cell counts and responders without pre-existing antibodies against H1N1 HA were younger than either non-responders or responders with pre-existing antibodies. Compared to changes in their CD4+ T cell counts observed over a similar time period one year later, vaccine recipients displayed a minor, transient fall in CD4+ T cell numbers, which was greater amongst responders.
We observed low response rates to the 2009 pandemic influenza vaccine among HIV-infected individuals without pre-existing antibodies against H1N1 HA and a minor transient fall in CD4+ T cell numbers, which was accentuated in responders. A single injection of the ArepanrixTM pandemic A/California/07/2009 H1N1 HA split vaccine may be insufficient to induce protective immunity in HIV-infected individuals without pre-existing anti-H1N1 HA responses.
PMCID: PMC3482569  PMID: 22937824
HIV; influenza; pandemic; A/California/07/2009 H1N1 HA antigen; AS03 oil in water adjuvant; inflammation; CD4+ T cells; age
16.  Genetic and Environmental Influences on the Size of Specific Brain Regions in Midlife: The VETSA MRI Study 
Neuroimage  2009;49(2):1213-1223.
The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs, and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings do provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.
PMCID: PMC3397915  PMID: 19786105
heritability; twins; magnetic resonance imaging (MRI); brain structure; cortical thickness
17.  Genetic Architecture of Learning and Delayed Recall: A Twin Study of Episodic Memory 
Neuropsychology  2011;25(4):488-498.
Although episodic memory is often conceptualized as consisting of multiple component processes, there is a lack of understanding as to whether these processes are influenced by the same or different genetic determinants. The aim of the present study was to utilize multivariate twin analyses in order to elucidate the degree to which learning and delayed recall, two critical measures of episodic memory performance, have common or different genetic and environmental influences.
Participants from the Vietnam Era Twin Study of Aging (314 monozygotic twin pairs, 259 dizygotic twin pairs, and 47 unpaired twins) were assessed using the second edition of the California Verbal Learning Test (CVLT-2). Mean age at the time of the evaluation was 55.4 years (sd = 2.5).
Model fitting revealed the presence of a higher-order latent factor influencing learning, short- and long-delay free recall, with a heritability of .36. The best-fitting model also indicated specific genetic influences on learning, which accounted for 10% of the overall variance. Given that learning involves the acquisition and retrieval of information, whereas delayed recall involves only retrieval, we conclude that these specific effects are likely to reflect genes that are specific to acquisition processes.
These results demonstrate that even in non-clinical populations, it is possible to differentiate component processes in episodic memory. These different genetic influences may have implications for gene association studies, as well as other genetics studies of cognitive aging and disorders of episodic memory such as Alzheimer’s disease or mild cognitive impairment.
PMCID: PMC3125484  PMID: 21463045
Episodic Memory; Twin Study; Genetics; Aging
18.  A 35-Year Longitudinal Assessment of Cognition and Midlife Depression Symptoms: The Vietnam Era Twin Study of Aging 
To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association; to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife.
35-year longitudinal and cross-sectional twin study of cognitive aging.
Large multicenter study in the United States.
1237 male twins ages 51 to 60.
At age 20 and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual-spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale prior to cognitive testing and provided health and lifestyle information during a medical history interview.
Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 (r=−.16, p<.001). In bivariate twin modeling, 77% of the correlation between early cognitive ability and midlife depressive symptoms was due to shared genetic influences. Controlling for current age, age 20 AFQT, and non-independence of observations, depressive symptoms were associated with worse midlife AFQT scores and poorer performance in all cognitive domains except verbal memory
Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Cross-sectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.
PMCID: PMC3101375  PMID: 21606899
19.  Emerging complexities of APOBEC3G action on immunity and viral fitness during HIV infection and treatment 
Retrovirology  2012;9:35.
The enzyme APOBEC3G (A3G) mutates the human immunodeficiency virus (HIV) genome by converting deoxycytidine (dC) to deoxyuridine (dU) on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G’s standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation.
PMCID: PMC3416701  PMID: 22546055
20.  Presence of ApoE ε4 Allele Associated with Thinner Frontal Cortex in Middle Age 
Journal of Alzheimer's Disease  2011;26(Suppl 3):49-60.
The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer’s disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51–59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status.
PMCID: PMC3302177  PMID: 21971450
Magnetic Resonance Imaging; Cerebral Cortex; Brain; Frontal Lobe; Apolipoproteins E; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Genetic Association Studies; Aging
21.  Cortical Thickness is Influenced by Regionally-Specific Genetic Factors 
Biological psychiatry  2009;67(5):493-499.
Although global brain structure is highly heritable, there is still variability in the magnitude of genetic influences on the size of specific regions. Yet, little is known about the patterning of those genetic influences, i.e., whether the same genes influence structure throughout the brain or whether there are regionally-specific sets of genes.
We mapped the heritability of cortical thickness throughout the brain using 3D structural magnetic resonance imaging in 404 middle-aged male twins. To assess the amount of genetic overlap between regions, we then mapped genetic correlations between three selected seed points and all other points comprising the continuous cortical surface.
There was considerable regional variability in the magnitude of genetic influences on cortical thickness. The primary visual (V1) seed point had strong genetic correlations with posterior sensory and motor areas. The anterior temporal seed point had strong genetic correlations with anterior frontal regions, but not with V1. The middle frontal seed point had strong genetic correlations with inferior parietal regions.
These results provide strong evidence of regionally-specific patterns rather than a single, global genetic factor. The patterns are largely consistent with a division between primary and association cortex, as well as broadly-defined patterns of brain gene expression, neuroanatomical connectivity, and brain maturation trajectories, but no single explanation appears to be sufficient. The patterns do not conform to traditionally-defined brain structure boundaries. This approach can serve as a step toward identifying novel phenotypes for genetic association studies of psychiatric disorders, and normal and pathological cognitive aging.
PMCID: PMC3184643  PMID: 19963208
heritability; twins; cortical thickness; endophenotypes; MRI; genetic correlation; imaging genetics
22.  Marriage and Divorce: A genetic perspective 
Marriage is considered one of the most important sources of social support that an individual receives as an adult. Although hypotheses have been formulated as to why individuals may dissolve a marriage, the determinants of marital success or failure are still relatively unknown. Behavioral geneticists have found that both marriage and divorce are, in part, genetically influenced. The goal of this research was to determine the degree of shared genetic and environmental variance between the two marital statuses. Participants were 6,225 twin pairs from the Vietnam Era Twin Registry. Data were obtained on marital history, and if the individual was no longer married, how the marriage ended. Univariate analyses were performed to determine the extent of genetic and environmental influences each of the marital statues (i.e., marriage and divorce), followed by a novel bivariate analysis to test the shared variance between marriage and divorce. Results from this analysis revealed that the two different marital statuses were influenced by entirely distinct genetic and environmental factors.
PMCID: PMC2923822  PMID: 20729979
marriage; divorce; twins; stage modeling
23.  Apolipoprotein E Genotype and Memory in the Sixth Decade of Life 
Neurology  2008;70(19 Pt 2):1771-1777.
Virtually all adult studies of APOE genotypes and cognition have included individuals over 60. In older adults, ε4 carriers may manifest greater cognitive asymmetries than non-ε4 carriers even in the absence of overall mean differences. General cognitive ability may also be affected by aging and APOE genotype, but most studies have inadequately addressed this potential confound. The goals of this study were to examine, in middle age, the relationship of APOE genotype with episodic memory and verbal-visuospatial episodic memory asymmetries, after accounting for prior general cognitive ability.
We compared ε4+ and ε4- individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members.
Compared with ε4- individuals, ε4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, ε4 carriers had higher general cognitive ability than ε4- individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability.
Small, but significant, APOE-ε4-related memory deficits do appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-ε4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.
PMCID: PMC3107734  PMID: 18235080
24.  Evidence of Overlapping Genetic Diathesis of Panic Attacks and Gastrointestinal Disorders in a Sample of Male Twin Pairs 
We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male–male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.
PMCID: PMC3058517  PMID: 21314252
Panic disorder; panic attacks; gastrointestinal disorders; irritable bowel syndrome; peptic ulcer
25.  Adult Romantic Attachment, Negative Emotionality, and Depressive Symptoms in Middle Aged Men: A Multivariate Genetic Analysis 
Behavior Genetics  2011;41(4):488-498.
Adult romantic attachment styles reflect ways of relating in close relationships and are associated with depression and negative emotionality. We estimated the extent to which dimensions of romantic attachment and negative emotionality share genetic or environmental risk factors in 1,237 middle-aged men in the Vietnam Era Twin Study of Aging (VETSA). A common genetic factor largely explained the covariance between attachment-related anxiety, attachment-related avoidance, depressive symptoms, and two measures of negative emotionality: Stress-Reaction (anxiety), and Alienation. Multivariate results supported genetic and environmental differences in attachment. Attachment-related anxiety and attachment-related avoidance were each influenced by additional genetic factors not shared with other measures; the genetic correlation between the attachment measure-specific genetic factors was 0.41, indicating some, but not complete overlap of genetic factors. Genetically informative longitudinal studies on attachment relationship dimensions can help to illuminate the role of relationship-based risk factors in healthy aging.
PMCID: PMC3121938  PMID: 21213033
Adult attachment; Depression; Neuroticism; Negative emotionality; Personality; Twin studies; VETSA; Experiences in Close Relationships Inventory

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