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1.  The NIH Toolbox Cognition Battery: Results from a Large Normative Developmental Sample (PING) 
Neuropsychology  2013;28(1):1-10.
Objective
The NIH Toolbox Cognition Battery (NTCB) was designed to provide a brief, efficient computerized test of key neuropsychological functions appropriate for use in children as young as 3 years of age. This report describes the performance of a large group of typically developing children and adolescents and examines the impact of age and sociocultural variables on test performance.
Method
The NTCB was administered to a sample of 1020 typically developing males and females ranging in age from 3 to 20 years, diverse in terms of socioeconomic status (SES) and race/ethnicity, as part of the new publicly accessible Pediatric Imaging, Neurocognition, and Genetics (PING) data resource, at 9 sites across the United States.
Results
General additive models of nonlinear age-functions were estimated from age-differences in test performance on the 8 NTCB subtests while controlling for family SES and genetic ancestry factors (GAFs). Age accounted for the majority of the variance across all NTCB scores, with additional significant contributions of gender on some measures, and of SES and race/ethnicity (GAFs) on all. After adjusting for age and gender, SES and GAFs explained a substantial proportion of the remaining unexplained variance in Picture Vocabulary scores.
Conclusions
The results highlight the sensitivity to developmental effects and efficiency of this new computerized assessment battery for neurodevelopmental research. Limitations are observed in the form of some ceiling effects in older children, some floor effects, particularly on executive function tests in the youngest participants, and evidence for variable measurement sensitivity to cultural/socioeconomic factors.
doi:10.1037/neu0000001
PMCID: PMC3925365  PMID: 24219608
Computerized Assessment; Cognitive Development; Socioeconomic Status
2.  A web-portal for interactive data exploration, visualization, and hypothesis testing 
Clinical research studies generate data that need to be shared and statistically analyzed by their participating institutions. The distributed nature of research and the different domains involved present major challenges to data sharing, exploration, and visualization. The Data Portal infrastructure was developed to support ongoing research in the areas of neurocognition, imaging, and genetics. Researchers benefit from the integration of data sources across domains, the explicit representation of knowledge from domain experts, and user interfaces providing convenient access to project specific data resources and algorithms. The system provides an interactive approach to statistical analysis, data mining, and hypothesis testing over the lifetime of a study and fulfills a mandate of public sharing by integrating data sharing into a system built for active data exploration. The web-based platform removes barriers for research and supports the ongoing exploration of data.
doi:10.3389/fninf.2014.00025
PMCID: PMC3972454  PMID: 24723882
data exploration; data sharing; genetics; data dictionary; imaging; hypothesis testing
3.  Brain development during the preschool years 
Neuropsychology review  2012;22(4):313-333.
The preschool years represent a time of expansive psychological growth, with the initial expression of many psychological abilities that will continue to be refined into young adulthood. Likewise, brain development during this age is characterized by its “blossoming” nature, showing some of its most dynamic and elaborative anatomical and physiological changes. In this article, we review human brain development during the preschool years, sampling scientific evidence from a variety of sources. First, we cover neurobiological foundations of early postnatal development, explaining some of the primary mechanisms seen at a larger scale within neuroimaging studies. Next, we review evidence from both structural and functional imaging studies, which now accounts for a large portion of our current understanding of typical brain development. Within anatomical imaging, we focus on studies of developing brain morphology and tissue properties, including diffusivity of white matter fiber tracts. We also present new data on changes during the preschool years in cortical area, thickness, and volume. Physiological brain development is then reviewed, touching on influential results from several different functional imaging and recording modalities in the preschool and early school-age years, including positron emission tomography (PET), electroencephalography (EEG) and event-related potentials (ERP), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and near-infrared spectroscopy (NIRS). Here, more space is devoted to explaining some of the key methodological factors that are required for interpretation. We end with a section on multimodal and multidimensional imaging approaches, which we believe will be critical for increasing our understanding of brain development and its relationship to cognitive and behavioral growth in the preschool years and beyond.
doi:10.1007/s11065-012-9214-1
PMCID: PMC3511633  PMID: 23007644
4.  Caudate Volume Predicts Neurocognitive Performance in Youth with Heavy Prenatal Alcohol Exposure 
Background
Fetal alcohol spectrum disorders (FASD) result from heavy prenatal alcohol exposure, and are characterized, in some cases, by CNS anomalies and cognitive impairment. Regional patterns of neuroanatomical abnormalities suggest that alcohol exerts selective damage on the developing fetal brain. This study assessed brain-behavior relationships in a sample of youth with histories of heavy prenatal alcohol exposure. The aim was to characterize how structural brain alterations observed in our previous studies relate to cognitive deficits commonly reported in individuals with histories of heavy prenatal alcohol exposure.
Methods
Twenty-one youth (mean age 13 years) with histories of heavy prenatal alcohol exposure and seven non-exposed healthy comparison subjects underwent structural magnetic resonance imaging (MRI) and neurobehavioral testing. Regional brain volumes within the alcohol-exposed group were correlated with neuropsychological measures of cognitive control and verbal learning/recall, as these aspects of cognition have previously been shown to be vulnerable to alcohol teratogenesis.
Results
Between-group effect sizes revealed moderate to large cognitive performance and brain volume decrements in alcohol-exposed subjects, compared to typically developing peers. Within the alcohol-exposed group, volume of the caudate nuclei was the most consistent predictor of neuropsychological performance, after controlling for potentially confounding variables including total brain volume, IQ, and age.
Conclusions
These data are consistent with previous research associating gestational alcohol exposure with structural and functional changes of the caudate nucleus. Our findings extend this previous work by demonstrating that volume reductions of the caudate have behavioral relevance for this population, in relation to cognitive control and verbal learning and recall abilities.
doi:10.1111/j.1530-0277.2012.01811.x
PMCID: PMC3723132  PMID: 22551091
fetal alcohol spectrum disorders (FASD); fetal alcohol syndrome (FAS); brain-behavior correlations; verbal learning/recall; cognitive control
6.  Clinical factors related to brain structure in HIV: the CHARTER study 
Journal of neurovirology  2011;17(3):248-257.
Despite the widening use of combination anti-retroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n=251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.
doi:10.1007/s13365-011-0032-7
PMCID: PMC3702821  PMID: 21544705
HIV; MRI; Neuroimaging; Immunospupression
7.  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.
doi:10.1111/j.1601-183X.2012.00789.x
PMCID: PMC3389179  PMID: 22471516
self-esteem; well-being; hippocampus; twins; heritability; aging
8.  Postnatal brain development: Structural imaging of dynamic neurodevelopmental processes 
Progress in brain research  2011;189:77-92.
After birth, there is striking biological and functional development of the brain’s fiber tracts as well as remodeling of cortical and subcortical structures. Behavioral development in children involves a complex and dynamic set of genetically guided processes by which neural structures interact constantly with the environment. This is a protracted process, beginning in the third week of gestation and continuing into early adulthood. Reviewed here are studies using structural imaging techniques, with a special focus on diffusion weighted imaging, describing age-related brain maturational changes in children and adolescents, as well as studies that link these changes to behavioral differences. Finally, we discuss evidence for effects on the brain of several factors that may play a role in mediating these brain–behavior associations in children, including genetic variation, behavioral interventions, and hormonal variation associated with puberty. At present longitudinal studies are few, and we do not yet know how variability in individual trajectories of biological development in specific neural systems map onto similar variability in behavioral trajectories.
doi:10.1016/B978-0-444-53884-0.00019-1
PMCID: PMC3690327  PMID: 21489384
MRI; DTI; brain development; cognitive development; individual differences; fiber tracts
9.  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.
doi:10.1126/science.1215330
PMCID: PMC3690329  PMID: 22461613
10.  Functional interactions of HIV-infection and methamphetamine dependence during motor programming 
Psychiatry Research  2012;202(1):46-52.
Methamphetamine (METH) dependence is frequently comorbid with HIV infection and both have been linked to alterations of brain structure and function. In a previous study, we showed that the brain volume loss characteristic of HIV infection contrasts with METH-related volume increases in striatum and parietal cortex, suggesting distinct neurobiological responses to HIV and METH (Jernigan et al., 2005). fMRI has the potential to reveal functional interactions between the effects of HIV and METH. In the present study, 50 participants were studied in four groups: an HIV+ group, a recently METH dependent group, a dually affected group, and a group of unaffected community comparison subjects. An fMRI paradigm consisting of motor sequencing tasks of varying levels of complexity was administered to examine blood oxygenation level dependent (BOLD) changes. Within all groups, activity increased significantly with increasing task complexity in large clusters within sensorimotor and parietal cortex, basal ganglia, cerebellum, and cingulate. The task complexity effect was regressed on HIV status, METH status, and the HIVxMETH interaction term in a simultaneous multiple regression. HIV was associated with less complexity-related activation in striatum, whereas METH was associated with less complexity-related activation in parietal regions. Significant interaction effects were observed in both cortical and subcortical regions; and, contrary to expectations, the complexity-related activation was less aberrant in dually-affected than in single-risk participants, in spite of comparable levels of neurocognitive impairment among the clinical groups. Thus, HIV and METH dependence, perhaps through their effects on dopaminergic systems, may have opposing functional effects on neural circuits involved in motor programming.
doi:10.1016/j.pscychresns.2012.03.006
PMCID: PMC3380171  PMID: 22608157
FMRI; neuroimaging; dopamine; drug abuse
11.  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.
doi:10.1016/j.neuroimage.2012.01.122
PMCID: PMC3328105  PMID: 22500923
12.  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.
doi:10.1017/thg.2012.3
PMCID: PMC3549553  PMID: 22856366
surface area; cortical thickness; region of interest; heritability maps
13.  Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy 
AIDS (London, England)  2002;16(7):1019-1029.
Objectives
To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis.
Design and methods
AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses.
Results
Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein–Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis.
Conclusions
Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.
PMCID: PMC3548569  PMID: 11953468
HIV leukoencephalopathy; antiretroviral therapy
14.  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.
doi:10.1016/j.neurobiolaging.2010.02.007
PMCID: PMC3221930  PMID: 20363053
lateral ventricles; genetics; aging; structural MRI; twins; endophenotype; mild cognitive impairment; Alzheimer’s disease
15.  Genetic Influences on Cortical Regionalization in the Human Brain 
Neuron  2011;72(4):537-544.
Summary
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.
doi:10.1016/j.neuron.2011.08.021
PMCID: PMC3222857  PMID: 22099457
16.  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.
doi:10.1093/cercor/bhr013
PMCID: PMC3169660  PMID: 21378112
cortex; cortical thickness; heritability
17.  Genetic Patterns of Correlation Among Subcortical Volumes in Humans: Results From a Magnetic Resonance Imaging Twin Study 
Human Brain Mapping  2011;32(4):641-653.
Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease.
doi:10.1002/hbm.21054
PMCID: PMC3403693  PMID: 20572207
behavioral genetics; hippocampus; amygdala; striatum; pallidum; caudate; putamen; thalamus; ventricles
18.  Are Time- and Event-based Prospective Memory Comparably Affected in HIV Infection?† 
According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
doi:10.1093/arclin/acr020
PMCID: PMC3081684  PMID: 21459901
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
19.  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.
doi:10.3233/JAD-2011-0002
PMCID: PMC3302177  PMID: 21971450
Magnetic Resonance Imaging; Cerebral Cortex; Brain; Frontal Lobe; Apolipoproteins E; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Genetic Association Studies; Aging
20.  The Neuropathology of Developmental Dysphasia: Behavioral, Morphological, and Physiological Evidence for a Pervasive Temporal Processing Disorder 
Reading and writing  1991;3(3-4):363-377.
Over the past twenty years, Tallal and colleagues have directed their research toward defining the neuropathological mechanisms responsible for developmental dysphasia. We have hypothesized that higher level auditory processing dysfunction, which has previously been associated with developmental dysphasia, may result from more basic temporal processing deficits which interfere with the resolution of rapidly presented, brief duration stimuli. This temporal processing deficit interferes with adequate perception of specific verbal stimuli which require resolution of brief duration formant transitions, resulting in disordered language development. The temporal processing deficit occurs across multiple sensory modalities, and also affects rapid and sequential motor production skills. Despite relatively normal clinical neuroradiological examinations, in vivo morphological analysis, utilizing magnetic resonance imaging techniques for quantitative volumetric measurements of specific brain structures, has identified abnormalities in superior parietal, prefrontal, and temporal cortices, as well as diencephalic and caudate nuclei. Abnormalities in structures which are involved in multimodal processing and sensory motor integration is consistent with the behavioral profile of developmental dysphasia. Two alternative hypotheses regarding the neurophysiological basis of the multimodal temporal processing disorder include: dysfunction in specifc cellular systems which subserve rapid, transient processing; and abnormal gating of sensory relay by intralaminar and reticular thalamic nuclei.
doi:10.1007/BF00354968
PMCID: PMC3167171  PMID: 21904420
developmental dysphasia; dyslexia; temporal processing; MRI; thalamic nuclei; caudate nuclei
21.  Longitudinal Characterization of White Matter Maturation During Adolescence 
Brain research  2010;1327:38-46.
Background:
Late adolescence is comprised of considerable developmental transitions, though brain maturational changes during this period are subtle and difficult to quantitatively evaluate from standard brain imaging acquisitions. To date, primarily cross-sectional studies have characterized typical developmental changes during adolescence, but these processes need further description within a longitudinal framework.
Method:
To assess the developmental trajectory of typical white matter development, we examined 22 healthy adolescents with serial diffusion tensor images (DTI) collected at a mean age of 17.8 years and 16-months later. Diffusion parameters fractional anisotropy, and mean, radial, and axial diffusivity were subjected to whole-brain voxelwise time point comparisons using tract-based spatial statistics.
Results:
At follow-up, adolescents showed significant change (≥ 153 contiguous voxels each at p<.01) in diffusion properties, including in bilateral superior longitudinal fasciculi, superior corona radiata, anterior thalamic radiations, and posterior limb of the internal capsule. Overall, correlations with cognitive performances suggested behavioral improvement corresponding with white matter changes.
Conclusion:
These longitudinal DTI findings support continued microstructural change in white matter during late adolescence, and suggest ongoing refinement of projection and association fibers into early adulthood.
doi:10.1016/j.brainres.2010.02.066
PMCID: PMC2854176  PMID: 20206151
Diffusion tensor imaging; Adolescence; White matter; Development; Maturation
22.  Familial Risk for Mood Disorder and the Personality Risk Factor, Neuroticism, Interact in Their Association with Frontolimbic Serotonin 2A Receptor Binding 
Neuropsychopharmacology  2009;35(5):1129-1137.
Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT2A) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT2A receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [18F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT2A receptor binding (p=0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT2A receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT2A receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.
doi:10.1038/npp.2009.218
PMCID: PMC3055406  PMID: 20043006
5-HT2A; depression; personality; neuroticism; stress; PET; Biological Psychiatry; Serotonin; Depression; Unipolar/Bipolar; Imaging; Clinical or Preclinical; 5-HT; 5-HT2A; affective disorder; personality; PET
23.  White matter tract injury and cognitive impairment in human immunodeficiency virus–infected individuals 
Journal of neurovirology  2009;15(2):187-195.
Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4=529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.
doi:10.1080/13550280902769756
PMCID: PMC3066173  PMID: 19306228
diffusion tensor imaging; HIV dementia; neuropsychological assessment
24.  Effects of traumatic brain injury on cognitive functioning and cerebral metabolites in HIV-infected individuals 
We explored the possible augmenting effect of traumatic brain injury (TBI) history on HIV (human immunodeficiency virus) associated neurocognitive complications. HIV-infected participants with self-reported history of definite TBI were compared to HIV patients without TBI history. Groups were equated for relevant demographic and HIV-associated characteristics. The TBI group evidenced significantly greater deficits in executive functioning and working memory. N-acetylaspartate, a putative marker of neuronal integrity, was significantly lower in the frontal gray matter and basal ganglia brain regions of the TBI group. Together, these results suggest an additional brain impact of TBI over that from HIV alone. One clinical implication is that HIV patients with TBI history may need to be monitored more closely for increased risk of HIV-associated neurocognitive disorder signs or symptoms.
doi:10.1080/13803395.2010.518140
PMCID: PMC3062232  PMID: 21229435
Head injury; HIV associated neurocognitive disorder; Neuropsychological performance; Magnetic resonance spectroscopy; N-acetylaspartate
25.  HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors 
Journal of Neurovirology  2010;17(1):3-16.
Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
doi:10.1007/s13365-010-0006-1
PMCID: PMC3032197  PMID: 21174240
HIV; Combination antiretroviral therapy; HIV dementia

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