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Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.

Composite scores of MRI-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed 'AD signatures,' have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared to thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities, and whether diffusion- and thickness/volume-based signatures each capture unique, AD-related phenotypic or genetic information, remains unknown.Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and an MRI-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures, as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1-60.2). Subsequent waves were at approximately 5.7-year intervals.MD and thickness/volume signatures were highly heritable (56-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance.Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Background Stage 1 of the National Institute on Aging–Alzheimer’s Association’s proposed Alzheimer’s disease continuum is defined as amyloid-β (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests that subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ. Methods We examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite, Alzheimer’s Disease Neuroimaging Initiative (ADNI) memory factor composite) with progression to Aβ positivity in 292 nondemented, Aβ-negative ADNI participants. Additional analyses included continuous cerebrospinal fluid biomarker levels to examine the effects of subthreshold pathology. Results Forty participants progressed to Aβ positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline cerebrospinal fluid phosphorylated tau and subthreshold Aβ were associated with increased odds of progression to Aβ positivity. Nevertheless, baseline ADNI memory factor composite performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (Preclinical Alzheimer Cognitive Composite was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline Preclinical Alzheimer Cognitive Composite still significantly predicted progression time to Aβ positivity (ADNI memory factor composite was trend level). Conclusions The possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low-cost, noninvasive cognitive measures can be informative for determining who is likely to progress to Aβ positivity, even after accounting for baseline subthreshold biomarker levels.

BackgroundStudies have investigated white matter microstructure in relation to late-life cognitive impairments, with fractional anisotropy (FA) and mean diffusivity (MD) measures thought to capture demyelination and axonal degradation. However, new post-processing methods allow isolation of free water (FW), which captures extracellular fluid contributions such as atrophy and neuroinflammation, from tissue components. FW also appears to be highly relevant to late-life cognitive impairment. Here, we evaluated whether executive functions are associated with FW, and FA and MD corrected for FW (FAFWcorr and MDFWcorr).MethodWe examined 489 non-demented men in the Vietnam Era Twin Study of Aging (VETSA) at mean age 68. Two latent factors capturing 'common executive function' and 'working-memory specific' processes were estimated based on 6 tasks. Analyses focused on 11 cortical white matter tracts across three metrics: FW, FAFWcorr, and MDFWcorr.ResultsBetter 'common executive function' was associated with lower FW across 9 of the 11 tracts. There were no significant associations with intracellular metrics after false discovery rate correction. Effects also appeared driven by individuals with MCI (13.7% of the sample). Working memory-specific tasks showed some associations with FAFWcorr, including the triangularis portion of the inferior frontal gyrus. There was no evidence that cognitive reserve (i.e., general cognitive ability assessed in early adulthood) moderated these associations between executive function and FW or FA.DiscussionExecutive function abilities in early old age are associated primarily with extracellular fluid (FW) as opposed to white matter (FAFWcorr or MDFWcorr). Moderation analyses suggested cognitive reserve does not play a strong role in these associations, at least in this sample of non-demented men.

Animal studies have suggested essential links between chronic pain and the locus coeruleus (LC), a brainstem region important for attention, but also pain and cognitive modulation. Recently developed MRI sequences now allow us to assess LC integrity in vivo. Our study examined the association between late midlife chronic pain and LC integrity in older adults via neuromelanin-contrast imaging. For this study, 484 community-dwelling men participating in the third wave of the Vietnam Era Twin Study of Aging (mean age=67.55; SD=2.60) underwent MRI-assessed neuromelanin signal detection in the LC. Contrast-to-noise ratios between LC regions and a pontine tegmentum reference region were used to assess LC integrity. The LC was subdivided into rostral and caudal portions. Rostral LC is more cortical-projecting, while caudal LC projects more to the cerebellum and spinal cord. Reporting of pain intensity on the SF-36 Bodily Pain scale from all three study waves was used to classify those with chronic pain, defined as moderate to severe pain across all three waves (n = 80, 16.5%). Bootstrapped multivariable regression models examined associations between late midlife chronic pain and LC integrity, adjusting for age, depressive symptoms, medical comorbidities, opioid usage, and twin clustering. Late midlife chronic pain was associated with .13 standard deviation lower rostral LC integrity (95%CI: -.63 to -.07). Meanwhile, late midlife chronic pain was associated with .12 standard deviation lower caudal LC integrity (95%CI: -.70 to -.21). Chronic pain across late midlife was associated with greater LC integrity in older adults. Pain was not differentially associated with rostral or caudal LC. Future work should seek to understand mechanisms underlying LC-pain associations in older adults, especially regarding the roles of inflammation and accumulating pathology. R01AG050595.

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer’s disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0.38 in the cingulate cortex to 0.66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i.e., the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies.

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E-ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age (t = 1.9, p = 0.05) and hypertension (t = 2.9, p = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled (t = 3.0, p = 0.003) and normotensive (t = 4.0, p = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a2 = 0.81) and shared some genetic influences with systolic blood pressure (rA = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery., Highlights • White matter abnormalities were highly heritable and associated with hypertension. • Only some genetic influences were shared with systolic blood pressure. • There is evidence for unique environmental influences unrelated to hypertension. • Poorly controlled hypertension was associated with more abnormal white matter. • Abnormal white matter may reflect currently active cerebrovascular effects.

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.

We introduce BrainPrint, a compact and discriminative representation of brain morphology. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the eigenvalue problem of the 2D and 3D Laplace–Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. This discriminative characterization enables new ways to study the similarity between brains; the focus can either be on a specific brain structure of interest or on the overall brain similarity. We highlight four applications for BrainPrint in this article: (i) subject identification, (ii) age and sex prediction, (iii) brain asymmetry analysis, and (iv) potential genetic influences on brain morphology. The properties of BrainPrint require the derivation of new algorithms to account for the heterogeneous mix of brain structures with varying discriminative power. We conduct experiments on three datasets, including over 3000 MRI scans from the ADNI database, 436 MRI scans from the OASIS dataset, and 236 MRI scans from the VETSA twin study. All processing steps for obtaining the compact representation are fully automated, making this processing framework particularly attractive for handling large datasets., National Cancer Institute (U.S.) (1K25-CA181632-01), Athinoula A. Martinos Center for Biomedical Imaging (P41-RR014075), Athinoula A. Martinos Center for Biomedical Imaging (P41-EB015896), National Alliance for Medical Image Computing (U.S.) (U54-EB005149), Neuroimaging Analysis Center (U.S.) (P41-EB015902), National Center for Research Resources (U.S.) (U24 RR021382), National Institute of Biomedical Imaging and Bioengineering (U.S.) (5P41EB015896-15), National Institute of Biomedical Imaging and Bioengineering (U.S.) (R01EB006758), National Institute on Aging (AG022381), National Institute on Aging (5R01AG008122-22), National Institute on Aging (AG018344), National Institute on Aging (AG018386), National Center for Complementary and Alternative Medicine (U.S.) (RC1 AT005728-01), National Institute of Neurological Diseases and Stroke (U.S.) (R01 NS052585-01), National Institute of Neurological Diseases and Stroke (U.S.) (1R21NS072652-01), National Institute of Neurological Diseases and Stroke (U.S.) (1R01NS070963), National Institute of Neurological Diseases and Stroke (U.S.) (R01NS083534), National Institutes of Health (U.S.) ((5U01-MH093765)

The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.

Despite an extensive literature, the "g" construct remains a point of debate. Different models explaining the observed relationships among cognitive tests make distinct assumptions about the role of g in relation to those tests and specific cognitive domains. Surprisingly, these different models and their corresponding assumptions are rarely tested against one another. In addition to the comparison of distinct models, a multivariate application of the twin design offers a unique opportunity to test whether there is support for g as a latent construct with its own genetic and environmental influences, or whether the relationships among cognitive tests are instead driven by independent genetic and environmental factors. Here we tested multiple distinct models of the relationships among cognitive tests utilizing data from the Vietnam Era Twin Study of Aging (VETSA), a study of middle-aged male twins. Results indicated that a hierarchical (higher-order) model with a latent g phenotype, as well as specific cognitive domains, was best supported by the data. The latent g factor was highly heritable (86%), and accounted for most, but not all, of the genetic effects in specific cognitive domains and elementary cognitive tests. By directly testing multiple competing models of the relationships among cognitive tests in a genetically-informative design, we are able to provide stronger support than in prior studies for g being a valid latent construct.

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 reinterpret 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. © 2012 Elsevier Inc.

Background: Recent evidence indicates that social contact is related to similarities in weight gain over time. However, no studies have examined this effect in a twin design, in which genetic and other environmental effects can also be estimated. Objective: We determined whether the frequency of social contact is associated with similarity in weight change from young adulthood (mean age: 20 y) to middle age (mean age: 41 y) in twins and quantified the percentage of variance in weight change attributable to social contact, genetic factors, and other environmental influences. Design: Participants were 1966 monozygotic and 1529 dizygotic male twin pairs from the Vietnam-Era Twin Registry. Regression models tested whether frequency of social contact and zygosity predicted twin pair similarity in body mass index (BMI) change and weight change. Twin modeling was used to partition the percentage variance attributable to social contact, genetic, and other environmental effects. Results: Twins gained an average of 3.99 BMI units, or 13.23 kg (29.11 lb), over 21 y. In regression models, both zygosity (P , 0.001) and degree of social contact (P , 0.02) significantly predicted twin pair similarity in BMI change. In twin modeling, social contact between twins contributed 16% of the variance in BMI change (P , 0.001), whereas genetic factors contributed 42%, with no effect of additional shared environmental factors (1%). Similar results were obtained for weight change. Conclusion: Frequency of social contact significantly predicted twin pair similarity in BMI and weight change over 21 y, independent of zygosity and other shared environmental influences. Am J Clin Nutr 2011;94:404‐9.

Prior research suggests that individuals with particular personality traits, like negative emotionality, are at greater risk for adverse health outcomes. Despite bivariate associations between negative emotionality, depressive symptoms and the hypothalamic pituitary adrenal axis (HPA axis), few studies have sought to understand the biological pathways through which negative emotionality, depressive symptomatology and cortisol-one of the primary hormonal products of the HPA axis--are associated. The present study explored whether negative emotionality influenced cortisol dysregulation through current depressive symptomatology and whether negative emotionality served as a moderator of the relationship between depressive symptoms and cortisol. In the community-based Vietnam Era Twin Study of Aging, 783 male twins completed two days of cortisol saliva sampling in their natural environments. Three measures of cortisol were analyzed: waking levels, the cortisol awakening response, and the peak to bed slope. Depressive symptoms significantly mediated the associations between negative emotionality and the peak to bed slope. A 2-way interaction between depressive symptoms and negative emotionality was significant for the peak to bed slope and for waking levels of cortisol. Exploration of the interactions illustrated that depressive symptoms only affected cortisol slopes at average or high levels of negative emotionality and only affected waking levels at low levels of negative emotionality. Negative emotionality and depressive symptoms were not related to the cortisol awakening response. This is the first study to find indirect associations between negative emotionality and peak to bed cortisol slopes through depressive symptoms. These findings illustrate the complex interplay between personality characteristics, depressive symptoms and different indices of the cortisol diurnal rhythm.

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 and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife.A 35-year longitudinal and cross-sectional twin study of cognitive aging.Large multicenter study in the United States.One thousand two hundred thirty-seven male twins aged 51 to 60 years.At the age of 20 years 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 before cognitive testing and provided health and life style information during a medical history interview.Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 years (r = -0.16,p0.001). 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 nonindependence ofobservations, 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. Crosssectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.

Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls.Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes.Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls.Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Background We examined cognitive deficits before and after onset of schizophrenia in a longitudinal study that: 1) covers a long time interval; 2) minimizes test unreliability by including the identical measure at both childhood and post-onset cognitive assessments; and 3) minimizes bias by utilizing a population-based sample in which participants were selected neither for signs of illness in childhood nor for being at risk for schizophrenia. Methods Participants in the present study, Developmental Insult and Brain Anomaly in Schizophrenia (DIBS), were ascertained from an earlier epidemiologic study conducted in Oakland, CA. The original version of the Peabody Picture Vocabulary Test (PPVT), a test of receptive vocabulary, was administered at age 5 or 9 and repeated as part of the DIBS study at an average age of 40. There were 10 DIBS cases with DSM-IV schizophrenia or schizoaffective disorder and 15 demographically similar DIBS controls with both child and adult PPVT scores. Results Cases scored significantly lower than controls in childhood (d = 0.95) and adulthood (d = 1.67). Residualized scores indicating the number of SDs above or below one's predicted adult score revealed a mean case–control difference of − 1.51 SDs, consistent with significant relative decline over time among the cases (p Conclusions In this prospective study, individuals who developed adult schizophrenia manifested impaired receptive vocabulary during childhood and further relative deterioration (or lack of expected improvement) between childhood and midlife. Limitations should also be acknowledged, including the small sample size and the fact that we cannot be certain when the continued deterioration took place.

Background 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. Methods We mapped the heritability of cortical thickness throughout the brain using three-dimensional 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. Results 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. Conclusions 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.

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 of Aging (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 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.

The use of DSM criteria to evaluate liability to substance use disorders (SUDs) and to identify SUD phenotypes may not provide the sensitivity required to identify genes associated with vulnerability to SUDs. The purpose of this study is to evaluate a number of basic aspects of substance use that may be more proximal than full SUDs to risk genes, some of which may thus have greater potential utility as phenotypes in subsequent molecular genetic analyses. In this paper we present results from the first stage of our planned analyses, focusing on how individual symptoms of abuse and dependence may be used to create alternate phenotypes for SUDs. Specifically, we used factor analysis and biometrical modeling on each symptom of illicit substance abuse and dependence within different types of substances, and compared and contrasted factor patterns and heritabilities across the different substances. These analyses were carried out using a population-based sample of 3372 male–male twin pairs from the Vietnam Era Twin Registry who participated in the Harvard Twin Study of Substance Abuse. We obtained extensive data from these participants on substance use and SUDs via telephone interview in 1992, including data on the illicit substances: opiates, cocaine, cannabis, sedatives, stimulants, and psychedelics. The results indicate that: A) although a one-factor model assuming a single underlying liability for abuse and dependence symptoms and behaviors can be rejected for most substances, there is no uniform support for a two-factor model differentiating between abuse versus dependence; B) patterns of symptoms or behaviors reported by substance users vary across substances; C) not all symptoms or behaviors contribute equally to the presentation of an SUD; and D) the heritability of symptoms or behaviors of substance users varies both within and between substances. These results represent important first steps in facilitating the search for SUD-risk genes in subsequent high- throughput molecular genetic analyses by providing alternate phenotypes that may have both optimal validity and increased heritability.

Based on a strategy developed by Seidman et al. (Seidman, L.J., Faraone, S.V., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., 1993. Neuropsychological dysfunctions in the non-psychotic first-degree relatives of schizophrenic patients, Poster presented at the annual meeting of the Society for Research and Psychopathology. Chicago, IL) we examined neuropsychological heterogeneity in schizophrenia using clinical neuropsychological descriptions of individual cases as the starting point. We blindly rated neuropsychological profiles of 74 schizophrenia patients and 91 normal controls based primarily on prototypes from the clinical literature in neuropsychology. Patients were classified as having the following profile types: within normal limits (WNL) (23%, n=17), frontal/abstraction (46%, n=34), widespread/diffuse (14%, n=10), left temporal/verbal memory (8%, n=6) and other (9%, n=7). As expected based on our classification scheme, the groups had different profile shapes (group x function interactions). They were also significantly different from one another in terms of overall severity (main effects); however, severity differences were not inherent in the definition of all groups. Longer duration of illness and greater overall cognitive impairment were observed as one went from the left temporal to the frontal to the widespread groups. Longitudinal studies are needed to determine whether the different neuropsychological profiles reflect true subgroup differences or within-person change over time. Further research-probably including neuroimaging and genetic studies-will also be needed to determine the validity and the utility of this strategy for identifying neuropsychological profile types.

Several studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit structural brain abnormalities that may be manifestations of genes that predispose to schizophrenia. In this work, we examine the utility of such measures for linkage analyses. Subjects were 45 nonpsychotic first-degree adult relatives of schizophrenic patients and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3D magnetic resonance images of the entire brain were acquired on a 1.5-T magnet. We used factor analysis to derive MRI-based phenotypes for analysis. The factor analyses produced three factors that significantly discriminated relatives from controls. We used a linear combination of the three factor scores to derive an MRI phenotype. A receiver operating characteristic (ROC) analysis of this phenotype estimated an area under the curve (AUC) statistic of 0.85. The phenotype also discriminated nonpsychotic relatives having two schizophrenic relatives from those having only one. The nonpsychotic relatives of schizophrenic patients show deviant values on MRI measures of brain structure and the distribution of these deviations among relatives and controls suggests that if these results can be replicated, an MRI-derived phenotype could be useful for genetic linkage and association analyses.

Evidence for neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia, patients with chronic psychotic bipolar disorder and normal controls. Groups were comparable on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also relatively similar on age at onset and number of hospitalizations. Using multivariate analyses of variance with sex and parental SES as covariates (our primary analyses), patients with schizophrenia were significantly more impaired than controls on seven of eight neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on declarative verbal memory, and showed moderate-to-large effect size decrements on abstraction, perceptual-motor speed and vigilance. Results were not attenuated when IQ was controlled, which was significantly lower in patients with schizophrenia. Analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.

Background: The objective of this study was to examine neuropsychological performance at different intelligence quotient (IQ) levels in schizophrenia. Methods: Thirty-six patients with schizophrenia were matched with 36 normal control subjects in two IQ groups: low average (81–94) and average (95–119). Performance level (IQ group main effects) and profile shape (IQ group × function interactions) were compared. Results: Current IQ was lower than estimated premorbid intellectual ability in both patient groups. Patients also displayed poorer neuropsychological function than same-IQ control subjects, suggesting neuropsychological dysfunction beyond their already compromised IQ. Patients had different profile shapes than control subjects, but profile shapes were consistent within patients and control subjects at each IQ level. Patients at both levels had higher verbal and lower performance IQ than control subjects. Abstraction-executive function was one of the lowest neuropsychological scores in both patient groups. Average IQ patients had nonsignificantly better overall neuropsychological performance than low average control subjects, but the effect size (.43) was quite small relative to the IQ difference (effect size = 2.57). Conclusions: Neuropsychological patterns in schizophrenia tend to be consistent at different IQ levels. Even schizophrenia patients with normal current IQs manifest substantial neuropsychological compromise relative to their level of general intellectual ability. The results strengthen the argument that neurocognitive deficits are core deficits of schizophrenic illness.

Background: Kraepelin originally conceptualized schizophrenia as a degenerative brain disorder. It remains unclear whether the illness is characterized by a static encephalopathy or a deterioration of brain function, or periods of each condition. Assessments of cognitive function, as measured by neuropsychologic assessment, can provide additional insight into this question. Few studies of patients with schizophrenia have investigated the effect of aging on executive functions, in an extensive neuropsychologic battery across a wide age range, compared to healthy volunteers. Methods: We examined the interaction of aging and neuropsychologic function in schizophrenia through a cross-sectional study in patients ( n = 87) and healthy control subjects ( n = 94). Subjects were divided into three age groups (20–35, 36–49, and 50–75), and performance on an extensive neuropsychologic battery was evaluated. Results: Compared to control subjects, patients with schizophrenia demonstrated similar age-related declines across most neuropsychologic functions, with the exception of abstraction ability, in which significant evidence of a more accelerated decline was observed. Conclusions: These results are consistent with previous reports indicating similar age effects on most aspects of cognition in patients with schizophrenia and healthy adults, but they support the hypothesis that a degenerative process may result in a more accelerated decline of some executive functions in older age in schizophrenia.

Background: Schizophrenia is characterized by subcortical and cortical brain abnormalities. Evidence indicates that some nonpsychotic relatives of schizophrenic patients manifest biobehavioral abnormalities, including brain abnormalities. The goal of this study was to determine whether amygdala–hippocampal and thalamic abnormalities are present in relatives of schizophrenic patients. Methods: Subjects were 28 nonpsychotic, and nonschizotypal, first-degree adult relatives of schizophrenics and 26 normal control subjects. Sixty contiguous 3 mm coronal, T1-weighted 3D magnetic resonance images of the brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter and cerebrospinal fluid (CSF) were segmented using a semi-automated intensity contour mapping algorithm. Analyses of covariance of the volumes of brain regions, controlling for expected intellectual (i.e., reading) ability and diagnosis, were used to compare groups. Results: The main findings were that relatives had significant volume reductions bilaterally in the amygdala–hippocampal region and thalamus compared to control subjects. Marginal differences were noted in the pallidum, putamen, cerebellum, and third and fourth ventricles. Conclusions: Results support the hypothesis that core components of the vulnerability to schizophrenia include structural abnormalities in the thalamus and amygdala–hippocampus. These findings require further work to determine if the abnormalities are an expression of the genetic liability to schizophrenia.

We used the Schizotypal Personality Questionnaire to evaluate schizotypal traits in 44 normal volunteers and 40 non-psychotic, biological relatives of schizophrenic probands. Relatives endorsed more cognitive-perceptual traits than did controls; a group-by-sex interaction indicated that male relatives accounted for this difference. Although not statistically significant, a similar pattern was observed for interpersonal traits. Thus, elevated rates of some schizotypal traits appear to be more prominent in male than in female relatives of schizophrenic probands, at least when assessed by self-report. Subscale analysis indicated that differences were accounted for primarily by suspiciousness and ideas of reference, suggesting that paranoid-like phenomena from both the cognitive-perceptual and interpersonal factors may constitute an important dimension of schizotypy in relatives. Unlike previous studies, we did not find any differences in constricted affect or disorganization signs. Interviews and other non-self-report techniques are probably best suited for an assessment of these features, although the question remains as to whether the combination of both approaches might provide some incremental discriminatory power.

We investigated the association of neuropsychological risk indicators in a matched sample of first-degree relatives of schizophrenic patients ( n =54) and normal controls ( n =72). We focussed on three functions previously identified in a smaller, initial sample as putative risk indicators of the schizophrenia genotype: abstraction, verbal memory and auditory attention. The expanded sample of relatives displayed significantly lower scores than controls on abstraction, verbal memory and auditory attention. The relatives demonstrated significant intercorrelations among these three functions. The significant correlations among relatives between attention and verbal memory and between attention and abstraction differed significantly from these correlations among controls. We discuss how the use of multiple risk indicators may help us better identify those relatives that carry the schizophrenia genotype.

Some recent studies suggest that men with schizophrenia may have greater neuropsychological deficits than women. It is not known, however, whether similar sex differences may be present in biological relatives of schizophrenic patients. We evaluated neuropsychological functioning of 54 relatives of schizophrenic patients and 72 normal volunteers. It was hypothesized that, if sex differences were present, they would be accounted for largely by deficits in male relatives. We were particularly interested in three neuropsychological functions that we previously identified as putative neuropsychological vulnerability indicators for schizophrenia: 1. (1) abstraction/executive function; 2. (2) verbal memory; 3. (3) auditory attention. There were significant group × sex interactions for verbal memory and motor function, and trends toward significant interactions for auditory attention and mental control/encoding. However, with the exception of motor function, it was the female relatives who accounted for most of the impairment. A speculative explanation for the findings is that women may have a higher threshold than men for developing schizophrenia. If so, female relatives might be able to withstand greater impairments than men before developing psychotic symptoms. Consequently, in a sample that was limited to non-psychotic relatives — as in the present study — there could be over-representation of both less impaired men and more impaired women. Alternative explanations and limitations of the study are also discussed.

In our prior work with a young sample (age < 60), we showed that three neuropsychological functions were impaired among relatives of schizophrenic patients: abstraction, verbal memory, and auditory attention. In the present work we show that these results do not generalize to an older sample aged 60 years and greater. Thus, although we and others have put forth measures of neuropsychological function as indicators of the schizophrenia genotype, the present study suggests that conclusions may be limited to non-elderly samples. Further work is needed to address this issue definitively.

The 'matching fallacy' suggests that matching schizophrenic patients and normal control subjects on education or IQ may cause systematic mismatching of theoretically expected ability. This study supports a modest version of the matching fallacy effect in nonpsychotic biological relatives of schizophrenic patients. At equivalent levels of education, relatives and control subjects had similar Reading and Spelling scores on the Wide Range Achievement Test-Revised--measures that are largely unimpaired by schizophrenia-related processes. However, relatives showed a deficit in IQ (primarily verbal IQ) compared with what would be predicted from their Reading scores. A similar deficit in Arithmetic scores was found in non-college-educated relatives, but college-educated relatives showed an advantage. We discuss possible implications of the findings with regard to genetic and environmental factors.

We extended research originating with the Tsuang-Winokur criteria for paranoid and nonparanoid schizophrenia. To partially resolve problems of subtype instability, 41 consecutive admissions meeting DSM-III-R criteria for schizophrenia were subdivided according to whether they ever experienced prominent systematized delusions. Neuropsychological profiles for paranoid patients and nonparanoids with a history of systematized delusions were extremely similar. When combined, this 'systematized' group had significantly better general verbal ability and verbal memory than patients who never manifested systematized delusions. There was also a significant neuropsychological function-by-group interaction. The neuropsychological data suggested that systematized patients had better premorbid cognitive functioning as well as a greater discrepancy between premorbid verbal ability and current attentional functioning. No between-group differences were found on a measure of prefrontal-executive function, nor were there any neuropsychological differences between traditionally defined (DSM-III-R) paranoid and nonparanoid subgroups. This study suggests a possible shift in the dividing line between paranoid and nonparanoid subtypes and illustrates the potential value of neuropsychological data for refining psychiatric nosologies.

This preliminary study focused on the relationship between prefrontal and temporal lobe MRI measures and neuropsychological performance in chronic schizophrenia. Seventeen schizophrenic inpatients received an MRI and a neuropsychological test battery after clinical stabilization, on average 2 months after admission. The central finding was a significant inverse correlation between neurocognitive measures of prefrontal function and dorsolateral prefrontal cortex (DLPFC) area, strongest in the left hemisphere. Neurocognitive performance did not correlate significantly with orbital frontal area or total temporal lobe volume. The correlations of neuropsychological performance with total frontal volume and whole brain volume were generally not significant, although the pattern was similar to that associated with the DLPFC. Because a number of executive-attention and abstraction measures were significantly associated with the DLPFC, dysfunctions of this region may underlie a syndrome of cognitive dysfunctions. Long-term memory functions were also significantly correlated with the DLPFC, raising the possibility that recall memory defects in schizophrenia are, in part, associated with prefrontal contributions of attention, abstract reasoning, and executive function. This study needs replication with a larger sample of patients and more comprehensive volumetric morphometric analyses.

Schizophrenic patients and normal control subjects took the University of Pennsylvania Smell Identification Test (UPSIT) and Wisconsin Card Sorting Test (WCST) as dual neuropsychological 'probes' of orbitofrontal (OF) and dorsolateral (DL) prefrontal function respectively. Patients were significantly impaired on both tasks compared to controls. UPSIT and WCST performance were uncorrelated in patients but were positively correlated in controls. The lack of correlation found in the patients suggests that the tasks may be tapping independent dysfunctions in schizophrenia reflecting differential impairment in fronto-limbic brain systems. Individual profiles of preserved and impaired performance on the UPSIT and WCST suggested that three schizophrenic patients had OF dysfunction, five had DL dysfunction and seven had a generalized (OF and DL) frontal system dysfunction. The reduced ability of schizophrenic patients to identify odors was largely independent of many deficits or confounds typically associated with schizophrenia and did not appear to be simply a function of generalized deficit. These data are preliminary and require replication with larger samples and validation with other measures of fronto-limbic system dysfunction.

Two groups of schizophrenic patients took the Wisconsin Card Sorting Test (WCST) in separate follow-up studies; a naturalistic clinical follow-up (n = 12, study 1) and a neuroleptic reduction study (n = 10, study 2). 11 of 22 subjects (50%) performed well on the task at one or both time points. In each study no group differences were found between time 1 and time 2 performance on three WCST variables. However, correlational analyses revealed considerable within-subject variation on the WCST in the study 1 sample, which was composed of younger and more acute patients than those in study 2. This variation was present despite within-subject stability on the WAIS-R Vocabulary and Block Design subtests. For the sample combined, a trend was found (p = 0.12) linking better WCST performance at either time period with higher WAIS-R Vocabulary scores. This intra-subject variability may reflect fluctuations in neuropsychological performance in schizophrenics who maintain the residual capacity to do the task. These findings highlight the importance of longitudinal studies of neuropsychological functioning in schizophrenia. Studies of larger samples are needed to confirm these initial results.

Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-ε4 allele may interact with testosterone and moderate the hormone's association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-ε4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-ε4 status. In ε4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ε4 noncarriers. Results support the hypothesis that APOE-ε4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.