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WUSTL Neuroscience Publications Archive - August 2015

August 2015

Scopus weekly report:

August 25, 2015

Brier, M.R.a , Mitra, A.b , McCarthy, J.E.c , Ances, B.M.a b d , Snyder, A.Z.a b 
Partial covariance based functional connectivity computation using Ledoit-Wolf covariance regularization
(2015) NeuroImage, 121, pp. 29-38. 

DOI: 10.1016/j.neuroimage.2015.07.039


a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Functional connectivity refers to shared signals among brain regions and is typically assessed in a task free state. Functional connectivity commonly is quantified between signal pairs using Pearson correlation. However, resting-state fMRI is a multivariate process exhibiting a complicated covariance structure. Partial covariance assesses the unique variance shared between two brain regions excluding any widely shared variance, hence is appropriate for the analysis of multivariate fMRI datasets. However, calculation of partial covariance requires inversion of the covariance matrix, which, in most functional connectivity studies, is not invertible owing to rank deficiency. Here we apply Ledoit-Wolf shrinkage (L<inf>2</inf> regularization) to invert the high dimensional BOLD covariance matrix. We investigate the network organization and brain-state dependence of partial covariance-based functional connectivity. Although RSNs are conventionally defined in terms of shared variance, removal of widely shared variance, surprisingly, improved the separation of RSNs in a spring embedded graphical model. This result suggests that pair-wise unique shared variance plays a heretofore unrecognized role in RSN covariance organization. In addition, application of partial correlation to fMRI data acquired in the eyes open vs. eyes closed states revealed focal changes in uniquely shared variance between the thalamus and visual cortices. This result suggests that partial correlation of resting state BOLD time series reflect functional processes in addition to structural connectivity. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus



Liu, H.a , Jin, H.a , Yue, X.a , Zhang, X.a , Yang, H.a , Li, J.a , Flores, H.b , Su, Y.b , Perlmutter, J.S.a b c , Tu, Z.a 
Preclinical evaluation of a promising C-11 labeled PET tracer for imaging phosphodiesterase 10A in the brain of living subject
(2015) NeuroImage, 121, pp. 253-262. 

DOI: 10.1016/j.neuroimage.2015.07.049


a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathology. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [11C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [3H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiographic studies in rat brain slices. The carbon-11 labeled [11C]TZ1964B was utilized in the ex vivo autoradiography studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [11C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05-2.00mg/kg). Both in vitro binding assays and in vitro autoradiographic studies revealed a nanomolar binding affinity of [3H]TZ1964B to the rat striatum. The striatal binding of [3H]TZ1964B and [11C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiography and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate reference region. The binding potentials (BP<inf>ND</inf>) of [11C]TZ1964B in the NHP striatum that were calculated using either the Logan reference model (LoganREF, 3.96±0.17) or the simplified reference tissue model (SRTM, 4.64±0.47), with the cerebellum as the reference region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31±0.09mg/kg (LoganREF)/0.45±0.17mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabeled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [11C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject. © 2015 Elsevier Inc.


Author Keywords
Autoradiography;  Binding assay;  Brain imaging;  C-11;  H-3;  MicroPET;  PDE10A;  Radioligand


Document Type: Article
Source: Scopus



McDonough, I.M.a , Bui, D.C.b , Friedman, M.C.c , Castel, A.D.d 
Retrieval monitoring is influenced by information value: The interplay between importance and confidence on false memory
(2015) Acta Psychologica, 161, pp. 7-17. 

DOI: 10.1016/j.actpsy.2015.07.017


a Department of Psychology, University of Alabama, 505 Hackberry Lane, Tuscaloosa, AL, United States
b Department of Psychology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States
c Harvard Initiative for Learning and Teaching, Harvard University, 125 Mt. Auburn Street, Cambridge, MA, United States
d Department of Psychology, University of California, 1285 Franz Hall, Box 951563, Los Angeles, CA, United States


Abstract
The perceived value of information can influence one's motivation to successfully remember that information. This study investigated how information value can affect memory search and evaluation processes (i.e., retrieval monitoring). In Experiment 1, participants studied unrelated words associated with low, medium, or high values. Subsequent memory tests required participants to selectively monitor retrieval for different values. False memory effects were smaller when searching memory for high-value than low-value words, suggesting that people more effectively monitored more important information. In Experiment 2, participants studied semantically-related words, and the need for retrieval monitoring was reduced at test by using inclusion instructions (i.e., endorsement of any word related to the studied words) compared with standard instructions. Inclusion instructions led to increases in false recognition for low-value, but not for high-value words, suggesting that under standard-instruction conditions retrieval monitoring was less likely to occur for important information. Experiment 3 showed that words retrieved with lower confidence were associated with more effective retrieval monitoring, suggesting that the quality of the retrieved memory influenced the degree and effectiveness of monitoring processes. Ironically, unless encouraged to do so, people were less likely to carefully monitor important information, even though people want to remember important memories most accurately. © 2015 Elsevier B.V.


Author Keywords
False memory;  Heuristics;  Memory;  Metamemory;  Value;  Word recognition


Document Type: Article
Source: Scopus



Sun, T.a , Plutynski, A.b c , Ward, S.a , Rubin, J.B.a 
An integrative view on sex differences in brain tumors
(2015) Cellular and Molecular Life Sciences, 72 (17), pp. 3323-3342. 

DOI: 10.1007/s00018-015-1930-2


a Department of Pediatrics, Washington University, School of Medicine, Department of Philosophy, Washington University in St Louis, St Louis, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO, United States
c 660 South Euclid Ave, St Louis, MO, United States


Abstract
Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations. © 2015 The Author(s).


Author Keywords
Cancer;  Evolution;  Immunity;  Metabolism;  Sex determination;  Sexual dimorphism


Document Type: Review
Source: Scopus



Wong, A.W.K.a , Lai, J.-S.b , Correia, H.c , Cella, D.c 
Evaluating Psychometric Properties of the Spanish-version of the Pediatric Functional Assessment of Chronic Illness Therapy-Perceived Cognitive Function (pedsFACIT-PCF)
(2015) Quality of Life Research, 24 (9), pp. 2289-2295. 

DOI: 10.1007/s11136-015-0949-z


a Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Medical Social Sciences and Pediatrics, Northwestern University Feinberg School of Medicine, 633 N St. Clair, #19-039, Chicago, IL, United States
c Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States


Abstract
Purpose: The pediatric Functional Assessment of Chronic Illness Therapy-Perceived Cognitive Function (pedsFACIT-PCF) is a 13-item short-form derived from the pediatric Perceived Cognitive Function item bank (pedsPCF), which was developed to measure children’s daily cognitive behaviors and was validated on the US general population and children with cancer. This study evaluated the psychometric properties of Spanish language pedsFACIT-PCF and the measurement equivalence between Spanish and English versions. Methods: pedsFACIT-PCF items were translated into Spanish using a standard iterative methodology. A total of 1358 English- and 604 Spanish-speaking children aged 8–17 years who completed English and Spanish versions of pedsFACIT-PCF, respectively, were administered through an Internet survey company. Unidimensionality was evaluated using confirmatory factor analysis. Item responses were modeled using item response theory. The presence and impact of differential item functioning (DIF) were evaluated using ordinal logistic regression. Results: Unidimensionality of the pedsFACIT-PCF was supported. One of the 13 items demonstrated statistically significant DIF by language; however, impacts of language DIF on both individual scores and at the test level were negligible. No Spanish items showed DIF with respect to age and gender. Conclusions: The 13-item pedsFACIT-PCF demonstrated stable measurement properties on language, gender and age and can be used for future trials. © 2015, Springer International Publishing Switzerland.


Author Keywords
Age;  Children;  Differential item functioning;  Gender;  Language;  Perceived Cognitive Function


Document Type: Article
Source: Scopus



Kim, A.a , Fagan, A.M.b c d , Goate, A.M.b c d e f , Benzinger, T.L.S.c g , Morris, J.C.b c , Head, D.a c g h 
Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory
(2015) Cognitive, Affective and Behavioral Neuroscience, 15 (3), pp. 625-643. 

DOI: 10.3758/s13415-015-0343-x


a Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis, MO, United States
c Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
e Department of Psychiatry, Washington University, St. Louis, MO, United States
f Department of Genetics, Washington University, St. Louis, MO, United States
g Department of Radiology, Washington University, St. Louis, MO, United States
h Department of Psychology, Washington University in St. Louis, One Brookings Drive, Box 1125, St. Louis, MO, United States


Abstract
Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in nonhuman animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume, and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status, nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. © 2015, Psychonomic Society, Inc.


Author Keywords
Episodic memory;  Hippocampus


Document Type: Article
Source: Scopus



O’Callaghan, C.
Objects for multisensory perception
(2015) Philosophical Studies, 21 p. Article in Press. 

DOI: 10.1007/s11098-015-0545-7


Department of Philosophy, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO, United States


Abstract
Object perception deploys a suite of perceptual capacities that constrains attention, guides reidentification, subserves recognition, and anchors demonstrative thought. Objects for perception—perceptual objects—are the targets of such capacities. Characterizing perceptual objects for multisensory perception faces two puzzles. First is the diversity of objects across sensory modalities. Second is the unity of multisensory perceptual objects. This paper resolves the puzzles. Objects for perception are structured mereologically complex individuals. Perceptual objects are items that bear perceptible features and have perceptible parts arranged to form a unified whole. This circumscribes the targets of object perception where neutral talk concerning intentional objects and objects of perception cannot. Nonetheless, it is more permissive than identifying perceptual objects with material bodies, which excludes too much and leans too heavily on vision. The account thus is tailored to capture the role of objects in perception beyond vision: tactual, auditory, and olfactory objects are individuals with differing structures. Its flexibility also enables the account to accommodate shared objects for multisensory perception: multisensory perceptual objects are mereologically complex individuals with hybrid structure. For instance, one can bimodally perceive a common whole with parts accessible to one but not both modalities. Each sense provides a partial perspective on a complex whole that is perceptible through the coordinated use of multiple senses. Understanding perceptual objects as structured mereologically complex individuals thus provides a theoretically useful notion of an object for multisensory perception that resolves the puzzles of diversity and of unity. © 2015 Springer Science+Business Media Dordrecht


Author Keywords
Intentional objects;  Multisensory perception;  Object perception;  Objects;  Perception;  Perceptual objects


Document Type: Article in Press
Source: Scopus



Grant, J.D.a , Lynskey, M.T.b , Madden, P.A.F.a , Nelson, E.C.a , Few, L.R.a , Bucholz, K.K.a , Statham, D.J.c , Martin, N.G.d , Heath, A.C.a , Agrawal, A.a 
The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders
(2015) Psychological Medicine, 11 p. Article in Press. 

DOI: 10.1017/S0033291715001518


a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
b Institute of Psychiatry, Psychology & Neuroscience, Addictions Department, King's College London, London, UK
c University of the Sunshine Coast, Queensland, Australia
d QIMR Berghofer Medical Research Institute, Queensland, Australia


Abstract
Background: Genetic influences contribute significantly to co-morbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses. Method: Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose co-twin was not interviewed (aged 24–37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder. Results: Additive genetic (a2 = 0.48–0.65) and non-shared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a2 = 0.39) and shared environmental (c2 = 0.15) factors. All substance use disorders were influenced by shared genetic factors (r <inf>g</inf> = 0.38–0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40–73% of the genetic variance per substance. Conclusions: Among substance users in this sample, the well-documented clinical co-morbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols. Copyright © Cambridge University Press 2015


Author Keywords
Alcohol;  cannabis;  conduct disorder;  genetic overlap;  nicotine;  substance use disorders;  twins


Document Type: Article in Press
Source: Scopus



Guha, A.a , Wang, L.a , Tanenbaum, A.a , Esmaeili-Firidouni, P.b , Wendelken, L.A.b , Busovaca, E.b , Clifford, K.b , Desai, A.b , Ances, B.M.a c d , Valcour, V.b 
Intrinsic network connectivity abnormalities in HIV-infected individuals over age 60
(2015) Journal of NeuroVirology, 8 p. Article in Press. 

DOI: 10.1007/s13365-015-0370-y


a Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Memory and Aging Center, Sandler Neurosciences Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, United States
c Department of Biomedical Engineering, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States


Abstract
Individuals infected with HIV are living longer due to effective treatment with combination antiretroviral therapy (cART). Despite these advances, HIV-associated neurocognitive disorders (HAND) remain prevalent. In this study, we analyzed resting state functional connectivity (rs-fc) data from HIV-infected and matched HIV-uninfected adults aged 60 years and older to determine associations between HIV status, neuropsychological performance, and clinical variables. HIV-infected participants with detectable plasma HIV RNA exhibited decreased rs-fc within the salience (SAL) network compared to HIV-infected participants with suppressed plasma HIV RNA. We did not identify differences in rs-fc within HIV-infected individuals by HAND status. Our analysis identifies focal deficits in the SAL network that may be mitigated with suppression of plasma virus. However, these findings suggest that rs-fc may not be sensitive as a marker of HAND among individuals with suppressed plasma viral loads. © 2015 Journal of NeuroVirology, Inc.


Author Keywords
Cognition;  Functional MRI;  HIV;  Network connectivity


Document Type: Article in Press
Source: Scopus



Nakamura, R.a , Sene, A.a , Santeford, A.a , Gdoura, A.a , Kubota, S.a , Zapata, N.a , Apte, R.S.a b 
IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis
(2015) Nature Communications, 6, art. no. 7847, . 

DOI: 10.1038/ncomms8847


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163 + eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy. © 2015 Macmillan Publishers Limited. All rights reserved.


Document Type: Article
Source: Scopus



Rubinov, M.a b , Ypma, R.J.F.a c , Watson, C.d e , Bullmore, E.T.a f g , Raichle, M.E.h 
Wiring cost and topological participation of the mouse brain connectome
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (32), pp. 10032-10037. 

DOI: 10.1073/pnas.1420315112


a Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
b Churchill College, University of Cambridge, Cambridge, United Kingdom
c Hughes Hall, University of Cambridge, Cambridge, United Kingdom
d Neuroscience Research Australia, University of New South Wales, Sydney, NSW, Australia
e Faculty of Health Sciences, Curtin University, Kent Street, Bentley, WA, Australia
f Cambridgeshire and Peterborough NHS Foundation Trust, Huntingdon, United Kingdom
g Alternative Discovery and Development, GlaxoSmithKline, Stevenage, United Kingdom
h Washington University in St. Louis, St. Louis, MO, United States


Abstract
Brain connectomes are topologically complex systems, anatomically embedded in 3D space. Anatomical conservation of "wiring cost" explains many but not all aspects of these networks. Here, we examined the relationship between topology and wiring cost in the mouse connectome by using data from 461 systematically acquired anterograde- tracer injections into the right cortical and subcortical regions of the mouse brain. We estimated brain-wide weights, distances, and wiring costs of axonal projections and performed a multiscale topological and spatial analysis of the resulting weighted and directed mouse brain connectome. Our analysis showed that the mouse connectome has small-world properties, a hierarchical modular structure, and greater-than-minimalwiring costs. High-participation hubs of this connectome mediated communication between functionally specialized and anatomically localized modules, had especially high wiring costs, and closely corresponded to regions of the default mode network. Analyses of independently acquired histological and geneexpression data showed that nodal participation colocalized with low neuronal density and high expression of genes enriched for cognition, learning and memory, and behavior. The mouse connectome contains high-participation hubs, which are not explained by wiring-cost minimization but instead reflect competitive selection pressures for integrated network topology as a basis for higher cognitive and behavioral functions.


Author Keywords
Conservation law;  Cytoarchitectonics;  Graph theory;  Transcriptomics;  Viral tracing


Document Type: Article
Source: Scopus



Guan, F.a e , Li, L.b , Qiao, C.b , Chen, G.b , Yan, T.b c , Li, T.b c , Zhang, T.d , Liu, X.a b c 
Evaluation of genetic susceptibility of common variants in CACNA1D with schizophrenia in Han Chinese
(2015) Scientific Reports, 5, art. no. 12935, . 

DOI: 10.1038/srep12935


a Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xian, China
b Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine AndForensics, Xian Jiaotong University, Xian, China
c Department of Forensic Psychiatry, School of Medicine AndForensics, Xian Jiaotong University, Xian, China
d Department of Psychiatry, Washington University in Saint LouisMO, United States
e Institute of Human Genomics AndForensic Sciences, Xian, China


Abstract
The heritability of schizophrenia (SCZ) has been estimated to be as high as 80%, suggesting that genetic factors may play an important role in the etiology of SCZ. Cav1.2 encoded by CACNA1C and Cav1.3 encoded by CACNA1D are dominant calcium channel-forming subunits of L-type Voltage-dependent Ca 2+ channels, expressed in many types of neurons. The CACNA1C has been consistently found to be a risk gene for SCZ, but it is unknown for CACNA1D. To investigate the association of CACNA1D with SCZ, we designed a two-stage case-control study, including a testing set with 1117 cases and 1815 controls and a validation set with 1430 cases and 4295 controls in Han Chinese. A total of selected 97 tag single nucleotide polymorphisms (SNPs) in CACNA1D were genotyped, and single-SNP association, imputation analysis and gender-specific association analyses were performed in the two independent datasets. None was found to associate with SCZ. Further genotype and haplotype association analyses indicated a similar pattern in the two-stage study. Our findings suggested CACNA1D might not be a risk gene for SCZ in Han Chinese population, which add to the current state of knowledge regarding the susceptibility of CACNA1D to SCZ.


Document Type: Article
Source: Scopus



Salminen, L.E.a , Schofield, P.R.b c , Pierce, K.D.b , Luo, X.d , Zhao, Y.d , Laidlaw, D.H.e , Cabeen, R.P.e , Conturo, T.E.f , Lane, E.M.g , Heaps, J.M.h , Bolzenius, J.D.a , Baker, L.M.a , Cooley, S.A.a , Scott, S.h , Cagle, L.M.a , Paul, R.H.a h 
Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism
(2015) Journal of Neural Transmission, 12 p. Article in Press. 

DOI: 10.1007/s00702-015-1434-0


a Department of Psychological Sciences, University of Missouri-St. Louis, 1 University Blvd., Stadler Hall 442A, St. Louis, MO, United States
b Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, Australia
c School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
d Department of Biostatistics and Center for Statistical Sciences, Brown University, Providence, RI, United States
e Computer Science Department, Brown University, Providence, RI, United States
f Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway, St. Louis, MO, United States
g Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, United States
h Missouri Institute of Mental Health, 4633 World Parkway Circle, Berkeley, MO, United States


Abstract
Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele. © 2015 Springer-Verlag Wien


Author Keywords
APOE;  CETP;  DTI;  Gray matter


Document Type: Article in Press
Source: Scopus



Zimmerman, C.a , Atherton, P.J.b , Pachman, D.b , Seisler, D.b , Wagner-Johnston, N.c , Dakhil, S.d , Lafky, J.M.a , Qin, R.a b , Grothey, A.a , Loprinzi, C.L.a 
MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy
(2015) Supportive Care in Cancer, 8 p. Article in Press. 

DOI: 10.1007/s00520-015-2876-5


a Mayo Clinic, 200 1st St SW, Rochester, MN, United States
b Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, United States
c Washington University School of Medicine, St. Louis, MO, United States
d Cancer Center of Kansas, Wichita, KS, United States


Abstract
Purpose: Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity. Methods: Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II–III (67 %) or stage IV (33 %) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument. Results: Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34). Conclusions: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting. © 2015 Springer-Verlag Berlin Heidelberg


Author Keywords
Chemotherapy-induced neuropathy prevention;  Venlafaxine


Document Type: Article in Press
Source: Scopus



Cohen-Shikora, E.R., Balota, D.A.
An examination of age-related changes in the control of lexical and sublexical pathways in mapping spelling to sound
(2015) Aging, Neuropsychology, and Cognition, 16 p. Article in Press. 

DOI: 10.1080/13825585.2015.1075467


Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA


Abstract
The current study investigated the extent to which young and older adults are able to direct attention to distinct processes in mapping spelling onto sound. Young and older adults completed either a speeded pronunciation task (reading aloud words) or regularization task (pronouncing words based on spelling-to-sound correspondences, e.g., pronouncing PINT such that it rhymes with HINT) in order to bias processing of lexical, whole-word information, or sublexical, spelling-to-sound mapping, respectively. Both younger and older adults produced reduced word-frequency effects and lexicality effects in the regularization task compared to the normal pronunciation task. Importantly, compared to younger adults, older adults produced exaggerated effects of task (i.e., pronunciation vs. regularization) on the observed frequency and lexicality effects. These results highlight both the flexibility of the lexical processing system and changes in the influence of the underlying lexical route due to additional 50 years of reading experience and/or changes in attentional control. © 2015 Taylor & Francis


Author Keywords
aging;  attention;  lexicality;  Word frequency;  word recognition;  word regularity


Document Type: Article in Press
Source: Scopus



Kumar, G.a , Uhrig, D.a , Fowler, S.b , DeLaney, M.C.c , Alexandrov, A.V.d 
Intravenous Recombinant Tissue Plasminogen Activator Does Not Impact Mortality in Acute Ischemic Stroke at Any Time Point up to 6 Months: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials
(2015) CNS Drugs, 9 p. Article in Press. 

DOI: 10.1007/s40263-015-0265-8


a Department of Neurology, Comprehensive Stroke Center, University of Alabama at Birmingham, 1813 6th Ave South, RWUH M226, Birmingham, AL, United States
b Becker Medical Library, Washington University in St. Louis, St. Louis, MO, United States
c Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
d Department of Neurology, University of Tennessee-Memphis, Memphis, TN, United States


Abstract
Background and Objective: Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic stroke with the only drug proven to positively impact outcomes and reduce disability. Recent literature indicates an increase in mortality with alteplase within 7 days, an effect that does not persist from 3 months onwards. The objective of this meta-analysis was to pool mortality estimates from randomized controlled clinical trials (RCTs) at 7 days, 30 days, 90 days, and 6 months after stroke onset. Methods: PubMed, Embase, Scopus, CENTRAL, and clinicaltrials.gov were searched through to April 2014, using “hedges” for tissue plasminogen activator, acute ischemic stroke, and placebo. Two independent authors abstracted data and assessed study quality. Data were pooled using Dersimonian and Laird’s random effects model. Results: Eleven RCTs (n = 6905) were included in the final analysis. Two authors independently performed study selection and data abstraction. There was no publication bias and total variance attributable to heterogeneity was not significant (I2 < 50 %) at any time point. There was no difference in mortality between alteplase and placebo groups at any time point. Trials that randomized patients beyond 3 h (excluded patients within the 3-h window) did not drive the mortality difference seen at any time point. Exclusion sensitivity analysis revealed that exclusion of the NINDS trial rendered the 7-day difference significant towards increased mortality with alteplase. Quality adjustment did not alter the results. Conclusion: Intravenous alteplase did not impact mortality in patients with acute ischemic stroke at any of the measured time points up to 6 months (i.e., there was no increase in the risk of death with alteplase). Therefore, intravenous alteplase should be given to all eligible patients with acute ischemic stroke to improve long-term neurologic outcomes. The effects of alteplase on early survival are more complex than previously understood. © 2015 Springer International Publishing Switzerland


Document Type: Article in Press
Source: Scopus



Sasse, S.K.a , Zuo, Z.b , Kadiyala, V.a , Zhang, L.c , Pufall, M.A.c , Jain, M.K.d , Phang, T.L.e , Stormo, G.D.b , Gerber, A.N.a e 
Response element composition governs correlations between binding site affinity and transcription in glucocorticoid receptor feed-forward loops
(2015) Journal of Biological Chemistry, 290 (32), pp. 19756-19769. 

DOI: 10.1074/jbc.M115.668558


a Dept. of Medicine, National Jewish Health, Rm. K621, 1400 Jackson St., Denver, CO, United States
b Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biochemistry, University of Iowa, Iowa City, IA, United States
d Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, United States
e Department of Medicine, University of Colorado, Denver, CO, United States


Abstract
Combinatorial gene regulation through feed-forward loops (FFLs) can bestow specificity and temporal control to client gene expression; however, characteristics of binding sites that mediate these effects are not established. We previously showed that the glucocorticoid receptor (GR) and KLF15 form coherent FFLs that cooperatively induce targets such as the amino acid-metabolizing enzymes AASS and PRODH and incoherent FFLs exemplified by repression of MT2A by KLF15. Here, we demonstrate that GR and KLF15 physically interact and identify low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15. We used deep sequencing and electrophoretic mobility shift assays to derive in vitro GR binding affinities across sequence space. We applied these data to show that AASS GRE activity correlated (r2 = 0.73) with predicted GR binding affinities across a 50-fold affinity range in transfection assays; however, the slope of the linear relationship more than doubled when KLF15 was expressed. Whereas activity of the MT2A GRE was even more strongly (r2 = 0.89) correlated with GR binding site affinity, the slope of the linear relationship was sharply reduced by KLF15, consistent with incoherent FFL logic. Thus, GRE architecture and co-regulator expression together determine the functional parameters that relate GR binding site affinity to hormone-induced transcriptional responses. Utilization of specific affinity response functions and GR binding sites by FFLs may contribute to the diversity of gene expression patterns within GR-regulated transcriptomes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Document Type: Article
Source: Scopus



Hugdahl, K.a b c d , Raichle, M.E.e , Mitra, A.e , Specht, K.a f 
On the existence of a generalized non-specific task-dependent network
(2015) Frontiers in Human Neuroscience, 9 (AUGUST), art. no. 430, pp. 1-15. 

DOI: 10.3389/fnhum.2015.00430


a Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
b Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
c Department of Radiology, Haukeland University Hospital, Bergen, Norway
d NORMENT Center of Excellence, University of Bergen, Bergen, Norway
e Department of Radiology, Washington University School of Medicine, St. Louis, MI, United States
f Department of Clinical Engineering, Haukeland University Hospital, Bergen, Norway


Abstract
In this paper we suggest the existence of a generalized task-related cortical network that is up-regulated whenever the task to be performed requires the allocation of generalized non-specific cognitive resources, independent of the specifics of the task to be performed. We have labeled this general purpose network, the extrinsic mode network (EMN) as complementary to the default mode network (DMN), such that the EMN is down-regulated during periods of task-absence, when the DMN is up-regulated, and vice versa. We conceptualize the EMN as a cortical network for extrinsic neuronal activity, similar to the DMN as being a cortical network for intrinsic neuronal activity. The EMN has essentially a fronto-temporo-parietal spatial distribution, including the inferior and middle frontal gyri, inferior parietal lobule, supplementary motor area, inferior temporal gyrus. We hypothesize that this network is always active regardless of the cognitive task being performed. We further suggest that failure of network up- and down-regulation dynamics may provide neuronal underpinnings for cognitive impairments seen in many mental disorders, such as, e.g., schizophrenia. We start by describing a common observation in functional imaging, the close overlap in fronto-parietal activations in healthy individuals to tasks that denote very different cognitive processes. We now suggest that this is because the brain utilizes the EMN network as a generalized response to tasks that exceeds a cognitive demand threshold and/or requires the processing of novel information. We further discuss how the EMN is related to the DMN, and how a network for extrinsic activity is related to a network for intrinsic activity. Finally, we discuss whether the EMN and DMN networks interact in a common single brain system, rather than being two separate and independent brain systems. © 2015 Hugdahl, Raichle, Mitra and Specht.


Author Keywords
Cognition;  Connectivity;  Cortical networks;  Default mode network (DMN);  Extrinsic mode network (EMN);  fMRI;  Problem solving


Document Type: Article
Source: Scopus



Dearborn, J.T.a , Harmon, S.K.b , Fowler, S.C.e , O'Malley, K.L.b , Taylor, G.T.f , Sands, M.S.a , Wozniak, D.F.c d 
Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers
(2015) Scientific Reports, 5, art. no. 12752, . 

DOI: 10.1038/srep12752


a Department of Internal Medicine, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
e Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States
f Department of Psychology, University of Missouri-St. Louis, St. Louis, MO, United States


Abstract
Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is a neurodegenerative lysosomal storage disease caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). The PPT1-deficient mouse (Cln1-/-) is a useful phenocopy of human INCL. Cln1-/- mice display retinal dysfunction, seizures, motor deficits, and die at 
8 months of age. However, little is known about the cognitive and behavioral functions of Cln1-/- mice during disease progression. In the present study, younger (1-2 months of age) Cln1-/- mice showed minor deficits in motor/sensorimotor functions while older (5-6 months of age) Cln1-/- mice exhibited more severe impairments, including decreased locomotor activity, inferior cued water maze performance, decreased running wheel ability, and altered auditory cue conditioning. Unexpectedly, certain cognitive functions such as some learning and memory capabilities seemed intact in older Cln1-/- mice. Younger and older Cln1-/- mice presented with walking initiation defects, gait abnormalities, and slowed movements, which are analogous to some symptoms reported in INCL and parkinsonism. However, there was no evidence of alterations in dopaminergic markers in Cln1-/- mice. Results from this study demonstrate quantifiable changes in behavioral functions during progression of murine INCL and suggest that Parkinson-like motor/sensorimotor deficits in Cln1-/- mice are not mediated by dopamine deficiency.


Document Type: Article
Source: Scopus



Nelson, E.C., Agrawal, A., Heath, A.C., Bogdan, R., Sherva, R., Zhang, B., Al-Hasani, R., Bruchas, M.R., Chou, Y.-L., Demers, C.H., Carey, C.E., Conley, E.D., Fakira, A.K., Farrer, L.A., Goate, A., Gordon, S., Henders, A.K., Hesselbrock, V., Kapoor, M., Lynskey, M.T., Madden, P.A.F., Moron, J.A., Rice, J.P., Saccone, N.L., Schwab, S.G., Shand, F.L., Todorov, A.A., Wallace, L., Wang, T., Wray, N.R., Zhou, X., Degenhardt, L., Martin, N.G., Hariri, A.R., Kranzler, H.R., Gelernter, J., Bierut, L.J., Clark, D.J., Montgomery, G.W.
Evidence of CNIH3 involvement in opioid dependence
(2015) Molecular Psychiatry, . Article in Press. 

DOI: 10.1038/mp.2015.102


Department of Psychiatry, Washington University, St Louis, MO, USA


Abstract
Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55–0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.Molecular Psychiatry advance online publication, 4 August 2015; doi:10.1038/mp.2015.102. © 2015 Macmillan Publishers Limited


Document Type: Article in Press
Source: Scopus



Shinn, M.a , Samuels, J.b , Fischer, S.N.c , Thompkins, A.c , Fowler, P.J.d 
Longitudinal Impact of a Family Critical Time Intervention on Children in High-Risk Families Experiencing Homelessness: A Randomized Trial
(2015) American Journal of Community Psychology, 12 p. Article in Press. 

DOI: 10.1007/s10464-015-9742-y


a Peabody College, Vanderbilt University, #90, 230 Appleton Place, Nashville, TN, United States
b Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States
c New York University, New York, NY, United States
d Washington University in St. Louis, St. Louis, MO, United States


Abstract
A randomized trial compared effects of a Family Critical Time Intervention (FCTI) to usual care for children in 200 newly homeless families in which mothers had diagnosable mental illness or substance problems. Adapted from an evidence-based practice to prevent chronic homelessness for adults with mental illnesses, FCTI combines housing and structured, time-limited case management to connect families leaving shelter with community services. Families were followed at five time points over 24 months. Data on 311 children—99 ages 1.5–5 years, 113 ages 6–10 years, and 99 ages 11–16 years—included mother-, teacher-, and child-reports of mental health, school experiences, and psychosocial well-being. Analyses used hierarchical linear modeling to investigate intervention effects and changes in child functioning over time. Referral to FCTI reduced internalizing and externalizing problems in preschool-aged children and externalizing for adolescents 11–16. The intervention led to declines in self-reported school troubles for children 6–10 and 11–16. Both experimental and control children in all age groups showed reductions in symptoms over time. Although experimental results were scattered, they suggest that FCTI has the potential to improve mental health and school outcomes for children experiencing homelessness. © 2015 Society for Community Research and Action


Author Keywords
Child development;  Family homelessness;  Housing;  Intervention;  Longitudinal randomized trial


Document Type: Article in Press
Source: Scopus



Olfson, E., Saccone, N.L., Johnson, E.O., Chen, L.-S., Culverhouse, R., Doheny, K., Foltz, S.M., Fox, L., Gogarten, S.M., Hartz, S., Hetrick, K., Laurie, C.C., Marosy, B., Amin, N., Arnett, D., Barr, R.G., Bartz, T.M., Bertelsen, S., Borecki, I.B., Brown, M.R., Chasman, D.I., van Duijn, C.M., Feitosa, M.F., Fox, E.R., Franceschini, N., Franco, O.H., Grove, M.L., Guo, X., Hofman, A., Kardia, S.L.R., Morrison, A.C., Musani, S.K., Psaty, B.M., Rao, D.C., Reiner, A.P., Rice, K., Ridker, P.M., Rose, L.M., Schick, U.M., Schwander, K., Uitterlinden, A.G., Vojinovic, D., Wang, J.-C., Ware, E.B., Wilson, G., Yao, J., Zhao, W., Breslau, N., Hatsukami, D., Stitzel, J.A., Rice, J., Goate, A., Bierut, L.J.
Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans
(2015) Molecular Psychiatry, . Article in Press. 

DOI: 10.1038/mp.2015.105


Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA


Abstract
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score
?4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)?0.05), aggregate low frequency variants (0.05>MAF?0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10-11; African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.Molecular Psychiatry advance online publication, 4 August 2015; doi:10.1038/mp.2015.105. © 2015 Macmillan Publishers Limited


Document Type: Article in Press
Source: Scopus



Johnson, C.H.a , Patti, G.J.b , Courade, J.-P.c , Shriver, L.P.d , Hoang, L.T.a , Manchester, M.e , Siuzdak, G.a f 
Alterations in Spinal Cord Metabolism during Treatment of Neuropathic Pain
(2015) Journal of Neuroimmune Pharmacology, 6 p. Article in Press. 

DOI: 10.1007/s11481-015-9624-y


a Scripps Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, United States
b Departments of Chemistry, Genetics and Medicine, Washington University, St. Louis, MO, United States
c Departments of Chemistry and Biology, University of Akron, Akron, OH, United States
d Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, United States
e Departments of Chemistry, Molecular, and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, United States
f UCB Biopharma, UCB New Medicines, Chemin du Foriest, Braine-l’Alleud, Belgium


Abstract
Therapeutic options for neuropathic pain have improved over the last 20 years yet still only provide partial relief with numerous side effects. Recently, metabolomics revealed that the concentration of the endogenous metabolite N,N-dimethylsphingosine (DMS) is increased in the spinal cord in a model of neuropathic pain. Additionally, it was shown that introduction of DMS to the central nervous system (CNS) resulted in mechanical allodynia. Here, we have examined two compounds; pregabalin (Lyrica®), a drug used to treat neuropathic pain, and N-oleoylethanolamine (NOE), an endogenous endocannabinoid-like compound that is known to affect multiple lipid pathways. We found that the concentration of DMS in the spinal cord was not significantly altered upon pregabalin treatment of rats suffering from neuropathic pain. We further explored whether modulating lipid metabolism may impact neuropathic pain by testing NOE as a potential novel therapeutic. © 2015 Springer Science+Business Media New York


Author Keywords
Antimetabolite;  Metabolomics;  N,N-dimethylsphingosine;  N-oleoylethanolamine;  Neuropathic pain;  Pregabalin


Document Type: Article in Press
Source: Scopus



Jeong, J.-W.a b , McCall, J.G.c d e , Shin, G.b , Zhang, Y.f g , Al-Hasani, R.c d , Kim, M.b , Li, S.b , Sim, J.Y.h , Jang, K.-I.b , Shi, Y.f i , Hong, D.Y.c , Liu, Y.b , Schmitz, G.P.c , Xia, L.c j , He, Z.f k , Gamble, P.l , Ray, W.Z.l , Huang, Y.f , Bruchas, M.R.c d e j , Rogers, J.A.b m n o 
Wireless Optofluidic Systems for Programmable In Vivo Pharmacology and Optogenetics
(2015) Cell, 162 (3), pp. 662-674. 

DOI: 10.1016/j.cell.2015.06.058


a Department of Electrical, Computer, and Energy Engineering, University of Colorado, Boulder, CO, United States
b Department of Materials Science and Engineering, Beckman Institute for Advanced Science and Technology and Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, United States
c Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO, United States
d Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Departments of Civil and Environmental Engineering and Mechanical Engineering, Center for Engineering and Health, Northwestern University, Evanston, IL, United States
g Center for Mechanics and Materials, Tsinghua University, Beijing, China
h Bio-Medical IT Convergence Research Department, Electronics and Telecommunications Research Institute, Daejeon, South Korea
i State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing, China
j Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
k School of Materials Science and Engineering, Harbin Institute of Technology, Harbin, China
l Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
m Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
n Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
o Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States


Abstract
In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (μ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine. ©2015 Elsevier Inc.


Document Type: Article
Source: Scopus



Rodebaugh, T.L.a , Lim, M.H.a b , Shumaker, E.A.a c , Levinson, C.A.a d , Thompson, T.e 
Social Anxiety and Friendship Quality over Time
(2015) Cognitive Behaviour Therapy, 10 p. Article in Press. 

DOI: 10.1080/16506073.2015.1062043


a Department of Psychology, Washington University, St. Louis, MO, USA
b Brain and Psychological Sciences Center, Swinburne University of Technology, Hawthorn, Australia
c Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
e Brown School of Social Work, Washington University, St. Louis, MO, USA


Abstract
High social anxiety in adults is associated with self-report of impaired friendship quality, but not necessarily with impairment reported by friends. Further, prospective prediction of social anxiety and friendship quality over time has not been tested among adults. We therefore examined friendship quality and social anxiety prospectively in 126 young adults (67 primary participants and 59 friends, aged 17–22 years); the primary participants were screened to be extreme groups to increase power and relevance to clinical samples (i.e., they were recruited based on having very high or very low social interaction anxiety). The prospective relationships between friendship quality and social anxiety were then tested using an Actor–Partner Interdependence Model. Friendship quality prospectively predicted social anxiety over time within each individual in the friendship, such that higher friendship quality at Time 1 predicted lower social anxiety approximately 6 months later at Time 2. Social anxiety did not predict friendship quality. Although the results support the view that social anxiety and friendship quality have an important causal relationship, the results run counter to the assumption that high social anxiety causes poor friendship quality. Interventions to increase friendship quality merit further consideration. © 2015 Swedish Association for Behaviour Therapy


Author Keywords
friendship;  relationship quality;  social anxiety;  social anxiety disorder;  social support


Document Type: Article in Press
Source: Scopus



Akbari, S.H.A.a , Limbrick, D.D., Jr.a b , McKinstry, R.C.c , Altaye, M.f , Ragan, D.K.b , Yuan, W.d , Mangano, F.T.e , Holland, S.K.d , Shimony, J.S.c 
Periventricular hyperintensity in children with hydrocephalus
(2015) Pediatric Radiology, 45 (8), pp. 1189-1197. 

DOI: 10.1007/s00247-015-3298-8


a Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, St. Louis Children’s Hospital, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO, United States
d Department of Pediatric Radiology, Cincinnati Children’s Hospital, Cincinnati, OH, United States
e Department of Pediatric Neurological Surgery, Cincinnati Children’s Hospital, Cincinnati, OH, United States
f Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital, Cincinnati, OH, United States


Abstract
Background: Magnetic resonance images of children with hydrocephalus often include a rim of hyperintensity in the periventricular white matter (halo). Objective: The purpose of this study was to decide between the hypothesis that the halo is caused by cerebrospinal fluid (CSF) flow during the cardiac cycle, and the alternate hypothesis that the halo is caused by anatomical changes (stretching and compression of white matter). Materials and methods: Participants were selected from a multicenter imaging study of pediatric hydrocephalus. We compared 19 children with hydrocephalus to a group of 52 controls. We quantified ventricle enlargement using the frontal-occipital horn ratio. We conducted qualitative and quantitative analysis of diffusion tensor imaging in the corpus callosum and posterior limb of the internal capsule. Parameters included the fractional anisotropy (FA), mean diffusivity, axial diffusivity and radial diffusivity. Results: The halo was seen in 16 of the 19 children with hydrocephalus but not in the controls. The corpus callosum of the hydrocephalus group demonstrated FA values that were significantly decreased from those in the control group (P = 4 · 10−6), and highly significant increases were seen in the mean diffusivity and radial diffusivity in the hydrocephalus group. In the posterior limb of the internal capsule the FA values of the hydrocephalus group were higher than those for the control group (P = 0.002), and higher values in the hydrocephalus group were also noted in the axial diffusivity. We noted correlations between the diffusion parameters and the frontal-occipital horn ratio. Conclusion: Our results strongly support the hypothesis that the halo finding in hydrocephalus is caused by structural changes rather than pulsatile CSF flow. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
Children;  Diffusion tensor imaging;  Fractional anisotropy;  Hydrocephalus;  Magnetic resonance imaging;  Periventricular hyperintensity


Document Type: Article
Source: Scopus



Chu, W.a , Zhou, D.a , Gaba, V.b , Liu, J.b , Li, S.a , Peng, X.a , Xu, J.a , Dhavale, D.b , Bagchi, D.P.b , D'Avignon, A.c , Shakerdge, N.B.d , Bacskai, B.J.d , Tu, Z.a , Kotzbauer, P.T.b , Mach, R.H.a d e 
Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for α-Synuclein Fibrils
(2015) Journal of Medicinal Chemistry, 58 (15), pp. 6002-6017. 

DOI: 10.1021/acs.jmedchem.5b00571


a Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Chemistry, Washington University, St. Louis, MO, United States
d MassGeneral Institute of Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, United States
e University of Pennsylvania, Chemistry Building, 231 South 34th Street, Philadelphia, PA, United States


Abstract
A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (α-syn), beta amyloid (Aβ), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for α-syn and no selectivity for α-syn versus Aβ or tau fibrils. Homologation to the corresponding diene analogues yielded a mixture of Z,E and E,E isomers; substitution of the indoline nitrogen with an N-benzyl group resulted in increased binding to α-syn and reasonable selectivity for α-syn versus Aβ and tau. Introduction of a para-nitro group into the benzene ring of the diene enabled separation of the Z,E and E,E isomers and led to the identification of the Z,E configuration as the more active regioisomer. The data described here provide key structural information in the design of probes which bind preferentially to α-syn versus Aβ or tau fibrils. © 2015 American Chemical Society.


Document Type: Article
Source: Scopus



Kimball, C.a , Luo, J.b , Yin, S.c , Hu, H.d , Dhaka, A.e 
The Pore Loop Domain of TRPV1 Is Required for Its Activation by the Volatile Anesthetics Chloroform and Isoflurane
(2015) Molecular pharmacology, 88 (1), pp. 131-138. 

DOI: 10.1124/mol.115.098277


a Department of Biological Structure, University of Washington, Seattle, Washington (C.K., A.D.); and The Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.L., S.Y., H.H.)
b Department of Biological Structure, University of Washington, Seattle, Washington (C.K., A.D.); and The Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.L., S.Y., H.H.)
c Department of Biological Structure, University of Washington, Seattle, Washington (C.K., A.D.); and The Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.L., S.Y., H.H.)
d Department of Biological Structure, University of Washington, Seattle, Washington (C.K., A.D.); and The Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.L., S.Y., H.H.)
e Department of Biological Structure, University of Washington, Seattle, Washington (C.K., A.D.); and The Center for the Study of Itch, Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.L., S.Y., H.H.) dhaka@uw.edu


Abstract
The environmental irritant chloroform, a naturally occurring small volatile organohalogen, briefly became the world's most popular volatile general anesthetic (VGA) before being abandoned because of its low therapeutic index. When chloroform comes in contact with skin or is ingested, it causes a painful burning sensation. The molecular basis for the pain associated with chloroform remains unknown. In this study, we assessed the role of transient receptor potential (TRP) channel family members in mediating chloroform activation and the molecular determinants of VGA activation of TRPV1. We identified the subpopulation of dorsal root ganglion (DRG) neurons that are activated by chloroform. Additionally, we transiently expressed wild-type or specifically mutated TRP channels in human embryonic kidney cells and used calcium imaging or whole-cell patch-clamp electrophysiology to assess the effects of chloroform or the VGA isoflurane on TRP channel activation. The results revealed that chloroform activates DRG neurons via TRPV1 activation. Furthermore, chloroform activates TRPV1, and it also activates TRPM8 and functions as a potent inhibitor of the noxious chemical receptor TRPA1. The results also indicate that residues in the outer pore region of TRPV1 previously thought to be required for either proton or heat activation of the channel are also required for activation by chloroform and isoflurane. In addition to identifying the molecular basis of DRG neuron activation by chloroform and the opposing effects chloroform has on different TRP channel family members, the findings of this study provide novel insights into the structural basis for the activation of TRPV1 by VGAs. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Document Type: Article
Source: Scopus



Ragan, D.K.a , Cerqua, J.b , Nash, T.c , McKinstry, R.C.d , Shimony, J.S.e , Jones, B.V.f , Mangano, F.T.g , Holland, S.K.h , Yuan, W.i , Limbrick, D.D., Jrj 
The accuracy of linear indices of ventricular volume in pediatric hydrocephalus: technical note
(2015) Journal of neurosurgery. Pediatrics, 15 (6), pp. 547-551. 

DOI: 10.3171/2014.10.PEDS14209


a Departments of 1 Neurosurgery and
b Departments of 2 Radiology and
c Departments of 2 Radiology and
d 3Radiology, Washington University School of Medicine, St. Louis, Missouri; and
e 3Radiology, Washington University School of Medicine, St. Louis, Missouri; and
f Departments of 2 Radiology and
g 4Neurosurgery, University of Cincinnati, Ohio
h Departments of 2 Radiology and
i Departments of 2 Radiology and
j Departments of 1 Neurosurgery and


Abstract
Assessment of ventricular size is essential in clinical management of hydrocephalus and other neurological disorders. At present, ventricular size is assessed using indices derived from the dimensions of the ventricles rather than the actual volumes. In a population of 22 children with congenital hydrocephalus and 22 controls, the authors evaluated the relationship between ventricular volume and linear indices in common use, such as the frontooccipital horn ratio, Evans' index, and the bicaudate index. Ventricular volume was measured on high-resolution anatomical MR images. The frontooccipital horn ratio was found to have a stronger correlation with both absolute and relative ventricular volume than other indices. Further analysis of the brain volumes found that congenital hydrocephalus produced a negligible decrease in the volume of the brain parenchyma.


Author Keywords
ABV = approximation of the brain volume;  FOHR = frontooccipital horn ratio;  hydrocephalus;  ICV = intracranial volume;  linear indices;  MRI;  volumes


Document Type: Review
Source: Scopus



Luo, J.a , Feng, J.a , Liu, S.a , Walters, E.T.b , Hu, H.a 
Molecular and cellular mechanisms that initiate pain and itch
(2015) Cellular and Molecular Life Sciences, 72 (17), pp. 3201-3223. 

DOI: 10.1007/s00018-015-1904-4


a Department of Anesthesiology, Center for the Study of Itch, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Integrative Biology and Pharmacology, University of Texas, Health Science Center at Houston, 6431 Fannin Street, Houston, TX, United States


Abstract
Somatosensory neurons mediate our sense of touch. They are critically involved in transducing pain and itch sensations under physiological and pathological conditions, along with other skin-resident cells. Tissue damage and inflammation can produce a localized or systemic sensitization of our senses of pain and itch, which can facilitate our detection of threats in the environment. Although acute pain and itch protect us from further damage, persistent pain and itch are debilitating. Recent exciting discoveries have significantly advanced our knowledge of the roles of membrane-bound G protein-coupled receptors and ion channels in the encoding of information leading to pain and itch sensations. This review focuses on molecular and cellular events that are important in early stages of the biological processing that culminates in our senses of pain and itch. © 2015 Springer Basel.


Author Keywords
Dorsal root ganglion;  Innate immune cells;  Keratinocytes;  Mas-related G-protein-coupled receptors;  Neuropeptides;  Transient receptor potential channels


Document Type: Article
Source: Scopus



Sylvester, P.T.a , Evans, J.A.a , Zipfel, G.J.a , Chole, R.A.b , Uppaluri, R.b , Haughey, B.H.b , Getz, A.E.b , Silverstein, J.a c , Rich, K.M.a , Kim, A.H.a , Dacey, R.G.a , Chicoine, M.R.a 
Combined high-field intraoperative magnetic resonance imaging and endoscopy increase extent of resection and progression-free survival for pituitary adenomas
(2015) Pituitary, 18 (1), pp. 72-85. 

DOI: 10.1007/s11102-014-0560-2


a Department of Neurosurgery, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8057, St. Louis, MO, United States
b Department of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Internal Medicine/Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Purpose: The clinical benefit of combined intraoperative magnetic resonance imaging (iMRI) and endoscopy for transsphenoidal pituitary adenoma resection has not been completely characterized. This study assessed the impact of microscopy, endoscopy, and/or iMRI on progression-free survival, extent of resection status (gross-, near-, and sub-total resection), and operative complications. Methods: Retrospective analyses were performed on 446 transsphenoidal pituitary adenoma surgeries at a single institution between 1998 and 2012. Multivariate analyses were used to control for baseline characteristics, differences during extent of resection status, and progression-free survival analysis. Results: Additional surgery was performed after iMRI in 56/156 cases (35.9 %), which led to increased extent of resection status in 15/156 cases (9.6 %). Multivariate ordinal logistic regression revealed no increase in extent of resection status following iMRI or endoscopy alone; however, combining these modalities increased extent of resection status (odds ratio 2.05, 95 % CI 1.21–3.46) compared to conventional transsphenoidal microsurgery. Multivariate Cox regression revealed that reduced extent of resection status shortened progression-free survival for near- versus gross-total resection [hazard ratio (HR) 2.87, 95 % CI 1.24–6.65] and sub- versus near-total resection (HR 2.10; 95 % CI 1.00–4.40). Complication comparisons between microscopy, endoscopy, and iMRI revealed increased perioperative deaths for endoscopy versus microscopy (4/209 and 0/237, respectively), but this difference was non-significant considering multiple post hoc comparisons (Fisher exact, p = 0.24). Conclusions: Combined use of endoscopy and iMRI increased pituitary adenoma extent of resection status compared to conventional transsphenoidal microsurgery, and increased extent of resection status was associated with longer progression-free survival. Treatment modality combination did not significantly impact complication rate. © 2014, Springer Science+Business Media New York.


Author Keywords
Endoscopy;  Extent of resection;  Intraoperative MRI;  Pituitary adenoma;  Progression-free survival


Document Type: Article
Source: Scopus



Tso, I.F.a b , Calwas, A.M.c , Chun, J.d e , Mueller, S.A.b , Taylor, S.F.a , Deldin, P.J.a b 
Altered attentional and perceptual processes as indexed by N170 during gaze perception in schizophrenia: Relationship with perceived threat and paranoid delusions
(2015) Journal of Abnormal Psychology, 124 (3), pp. 519-531. Cited 1 time.

DOI: 10.1037/abn0000056


a Department of Psychiatry, University of Michigan, United States
b Department of Psychology, University of Michigan, United States
c Washington University School of Medicine, St. Louis, United States
d Department of Psychiatry, Beth Israel Deaconess Medical Center, United States
e Harvard Medical School, United States


Abstract
Using gaze information to orient attention and guide behavior is critical to social adaptation. Previous studies have suggested that abnormal gaze perception in schizophrenia (SCZ) may originate in abnormal early attentional and perceptual processes and may be related to paranoid symptoms. Using event-related brain potentials (ERPs), this study investigated altered early attentional and perceptual processes during gaze perception and their relationship to paranoid delusions in SCZ. Twenty-eight individuals with SCZ or schizoaffective disorder and 32 demographically matched healthy controls (HCs) completed a gaze-discrimination task with face stimuli varying in gaze direction (direct, averted), head orientation (forward, deviated), and emotion (neutral, fearful). ERPs were recorded during the task. Participants rated experienced threat from each face after the task. Participants with SCZ were as accurate as, though slower than, HCs on the task. Participants with SCZ displayed enlarged N170 responses over the left hemisphere to averted gaze presented in fearful relative to neutral faces, indicating a heightened encoding sensitivity to faces signaling external threat. This abnormality was correlated with increased perceived threat and paranoid delusions. Participants with SCZ also showed a reduction of N170 modulation by head orientation (normally increased amplitude to deviated faces relative to forward faces), suggesting less integration of contextual cues of head orientation in gaze perception. The psychophysiological deviations observed during gaze discrimination in SCZ underscore the role of early attentional and perceptual abnormalities in social information processing and paranoid symptoms of SCZ. © 2015 American Psychological Association.


Author Keywords
Event-related potentials (ERPs);  N170;  Psychosis;  Social cognition


Document Type: Article
Source: Scopus



Elran-Barak, R.a , Fitzsimmons-Craft, E.E.b , Benyamini, Y.a , Crow, S.J.c , Peterson, C.B.c , Hill, L.L.d , Crosby, R.D.e , Mitchell, J.E.e , Le Grange, D.f 
Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder in Midlife and beyond
(2015) Journal of Nervous and Mental Disease, 203 (8), pp. 583-590. 

DOI: 10.1097/NMD.0000000000000333


a Bob Shapell School of Social Work, Tel Aviv University, Tel Aviv, Israel
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, University of Minnesota, School of Medicine, Minneapolis, MN, United States
d Center for Balanced Living, Worthington, OH, United States
e Department of Clinical Neuroscience, University of North Dakota, School of Medicine and Health Sciences, Fargo, ND, United States
f Department of Psychiatry, University of California, San Francisco, CA, United States


Abstract
We examined eating disorders in midlife and beyond by comparing frequency of anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other specified feeding or eating disorder (OSFED) among midlife eating disorder treatment-seeking individuals and younger controls. We also compared demographic and eating disorder-related characteristics across diagnoses and age groups. Participants included 2,118 treatment-seeking adults who self-reported their eating-related symptoms on the Eating Disorder Questionnaire. Results showed that percent of patients with BN was significantly lower whereas percent of patients with BED and OSFED was significantly higher among midlife relative to younger patients. Percent of patients with AN did not differ between midlife and younger patients. Additionally, midlife and younger patients with BED and OSFED differed on several demographic (e.g., marital status) and eating disorder-related characteristics (e.g., BMI, compulsive exercising). This study suggests that BN is less common whereas BED and OSFED are more common among midlife eating disorder treatment-seeking individuals relative to younger controls. In addition, AN and BN present fairly similarly whereas BED and OSFED present fairly differently among midlife patients relative to younger controls. Attention to these differences and similarities is necessary to understand eating disorders in midlife. © 2015 Wolters Kluwer Health, Inc.


Author Keywords
anorexia nervosa;  binge eating disorder;  bulimia nervosa;  Eating disorders;  midlife


Document Type: Article
Source: Scopus



Bailey, H.R.a , Sargent, J.Q.a , Flores, S.a , Nowotny, P.b , Goate, A.b , Zacks, J.M.a 
APOE ε4 genotype predicts memory for everyday activities
(2015) Aging, Neuropsychology, and Cognition, 22 (6), pp. 639-666. 

DOI: 10.1080/13825585.2015.1020916


a Department of Psychology, Washington University, St. Louis, MO, United States
b Department of Psychiatry, Washington University, St. Louis, MO, United States


Abstract
The apolipoprotein E (ApOE) ε4 allele is associated with neuropathological buildup of amyloid in the brain, and with lower performance on some laboratory measures of memory in some populations. In two studies, we tested whether ApOE genotype affects memory for everyday activities. In Study 1, participants aged 20-79 years old (n = 188) watched movies of actors engaged in daily activities and completed memory tests for the activities in the movies. In Study 2, cognitively healthy and demented older adults (n = 97) watched and remembered similar movies, and also underwent structural MRI scanning. All participants provided saliva samples for genetic analysis. In both samples we found that, in older adults, ApOE ε4 carriers demonstrated worse everyday memory performance than did ε4 noncarriers. In Study 2, ApOE ε4 carriers had smaller medial temporal lobes (MTL) volumes, and MTL volume mediated the relationship between ApOE genotype and everyday memory performance. These everyday memory tasks measure genetically determined cognitive decline that can occur prior to a clinical diagnosis of dementia. Further, these tasks are easily administered and may be a useful clinical tool in identifying ε4 carriers who may be at risk for MTL atrophy and further cognitive decline that is a common characteristic of the earliest stages of Alzheimers disease. © 2015 Taylor and Francis.


Author Keywords
aging;  Alzheimer's disease;  APOE;  episodic memory;  Everyday memory


Document Type: Article
Source: Scopus



Quiroz, Y.T.a b c d e , Schultz, A.P.c d , Chen, K.f g h , Protas, H.D.f g , Brickhouse, M.c d i , Fleisher, A.S.f j k , Langbaum, J.B.f g , Thiyyagura, P.f g , Fagan, A.M.l , Shah, A.R.l , Muniz, M.m , Arboleda-Velasquez, J.F.n o , Munoz, C.e , Garcia, G.e , Acosta-Baena, N.e , Giraldo, M.e , Tirado, V.e , Ramírez, D.L.e , Tariot, P.N.f g p , Dickerson, B.C.c d i , Sperling, R.A.a c d q , Lopera, F.e , Reiman, E.M.fg p r 
Brain imaging and blood biomarker abnormalities in children with autosomal dominant Alzheimer disease a cross-sectional study
(2015) JAMA Neurology, 72 (8), pp. 912-919. 


a Department of Neurology, Massachusetts General Hospital, Boston, United States
b Department of Psychiatry, Massachusetts General Hospital, 1 Bowdoin Square, Ste 701, Boston, MA, United States
c Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, United States
d Harvard Medical School, Boston, MA, United States
e Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia
f Banner Alzheimer's Institute, Phoenix, AZ, United States
g Arizona Alzheimer's Consortium, Phoenix, United States
h Department of Mathematics and Statistics, Arizona State University, Tempe, United States
i Frontotemporal Dementia Unit, Department of Neurology, Massachusetts General Hospital, Boston, United States
j Eli Lilly and Company, Indianapolis, IN, United States
k Department of Neurosciences, University of California, San Diego, United States
l Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
m Psychology Department, Boston University, Boston, MA, United States
n Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, United States
o Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
p Department of Psychiatry, University of Arizona, Phoenix, United States
q Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, United States
r Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, AZ, United States


Abstract
Importance Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. Design, Setting, and Participants Cross-sectional Measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. Main Outcomes and Measures All Participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome Measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. Results Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P <.001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P <.001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were.0.590 [0.50] for noncarriers and.0.087 [0.38] for carriers; P <.005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P <. 049, corrected for multiple comparisons). Conclusions and Relevance Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental reMains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD. © 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus



Munn-Chernoff, M.A.a b , Grant, J.D.a b , Bucholz, K.K.a b , Agrawal, A.a b , Lynskey, M.T.c , Madden, P.A.F.a b , Heath, A.C.a b , Duncan, A.E.a b d 
Bulimic Behaviors and Early Substance Use: Findings from a Cotwin-Control Study
(2015) Alcoholism: Clinical and Experimental Research, . Article in Press. 

DOI: 10.1111/acer.12829


a Department of Psychiatry Washington University School of Medicine St. Louis, Missouri
b Midwest Alcoholism Research Center Washington University School of Medicine St. Louis, Missouri
c Institute of Psychiatry, Psychology and Neuroscience Kings College London London United Kingdom
d George Warren Brown School of Social Work Washington University St. Louis, Missouri


Abstract
Background: Bulimic behaviors (i.e., binge eating and compensatory behaviors) and substance use frequently co-occur. However, the etiology underlying this association is poorly understood. This study evaluated the association between bulimic behaviors and early substance use, controlling for genetic and shared environmental factors. Methods: Participants were 3,540 young adult women from the Missouri Adolescent Female Twin Study. A telephone adaptation of the Semi-Structured Assessment for the Genetics of Alcoholism interview assessed DSM-IV bulimic behaviors, substance use, and other psychological characteristics. Lifetime bulimic behaviors were examined in twin pairs concordant and discordant for early substance use. Logistic regressions were adjusted for the nonindependence of twin data, zygosity, age, body mass index, early menarche (onset before age 12), and early sex (first consensual sexual intercourse before age 15). Results: In the entire study population, women who reported early use of alcohol or nicotine were more likely to engage in bulimic behaviors after adjusting for covariates. In 53 pairs of monozygotic twins discordant for alcohol experimentation before age 15, the twin who reported early alcohol experimentation had 3.21 (95% confidence interval = 1.54 to 6.67) times higher odds of reporting bulimic behaviors than the cotwin who did not report early alcohol experimentation, even after adjustment for covariates. Conclusions: Findings suggest that early alcohol experimentation may contribute to the development of bulimic behaviors via mechanisms extending beyond shared vulnerability, including individual-specific environmental experiences or causal pathways. © 2015 by the Research Society on Alcoholism.


Author Keywords
Bulimia;  Cotwin-Control Design;  Early Substance Use;  Eating Disorders;  Sexual Intercourse


Document Type: Article in Press
Source: Scopus



Yarbrough, C.K.a , Greenberg, J.K.a , Park, T.S.a b 
Clinical Outcome Measures in Chiari I Malformation
(2015) Neurosurgery Clinics of North America, . Article in Press. 

DOI: 10.1016/j.nec.2015.06.008


a Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8057, St. Louis, MO 63110, USA
b Department of Neurological Surgery, St Louis Children's Hospital, Suite 4S20, St Louis, MO 63110, USA


Abstract
Chiari malformation type 1 (CM-I) is a common and often debilitating neurologic disease. Reliable evaluation of treatments has been hampered by inconsistent use of clinical outcome measures. A variety of outcome measurement tools are available, although few have been validated in CM-I. The recent development of the Chicago Chiari Outcome Scale and the Chiari Symptom Profile provides CM-I-specific instruments to measure outcomes in adults and children, although validation and refinement may be necessary. © 2015 Elsevier Inc.


Author Keywords
Chiari malformation type 1;  Clinical research;  Outcome instruments;  Outcome methods;  Quality of life;  Treatment outcome


Document Type: Article in Press
Source: Scopus



McCall, J.G.a b c d , Al-Hasani, R.a b c , Siuda, E.R.a b c d , Hong, D.Y.a , Norris, A.J.a , Ford, C.P.e , Bruchas, M.R.a b c d 
CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety
(2015) Neuron, 87 (3), pp. 606-621. 

DOI: 10.1016/j.neuron.2015.07.002


a Division of Basic Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
e Department of Physiology and Biophysics, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States


Abstract
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of invivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity ofthe LC-NE system is necessary and sufficient forstress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone+ (CRH+) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus



Sartor, C.E.a b , Agrawal, A.b , Grant, J.D.b , Duncan, A.E.c , Madden, P.A.F.b , Lynskey, M.T.d , Heath, A.C.b , Bucholz, K.K.b 
Differences between African-American and European-American women in the association of childhood sexual abuse with initiation of marijuana use andprogression to problem use
(2015) Journal of Studies on Alcohol and Drugs, 76 (4), pp. 569-577. 

DOI: 10.15288/jsad.2015.76.569


a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
d National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom


Abstract
Objective: Childhood sexual abuse (CSA) is associated with elevated risk of early marijuana use and cannabis use disorder (CUD). Both the prevalence of CSA and the course of marijuana use differ between African Americans and European Americans. The current study aimed to determine whether these differences manifest in racial/ ethnic distinctions in the association of CSA with early and problem use of marijuana. Method: Data were derived from female participants in a female twin study and a high-risk family study of substance use (n = 4,193, 21% African-American). Cox proportional hazard regression analyses using CSA to predict initiation of marijuana use and progression to CUD symptom(s) were conducted separately by race/ethnicity. Sibling status on the marijuana outcome was used to adjust for familial influences. Results: CSA was associated with both stages of marijuana use in African-American and European-American women. The association was consistent over the risk period (hazard ratio [HR] = 1.57, 95% confidence interval [CI] [1.37, 1.79] for initiation; HR = 1.51, 95% CI [1.21, 1.88] for CUD symptom onset) in European-American women. In African-American women, the HRs for initiation were 2.52 (95% CI [1.52, 4.18]) before age 15, 1.82 (95% CI [1.36, 2.44]) at ages 15–17, and nonsignificant after age 17. In the CUD symptom model, CSA predicted onset only at age 21 and older (HR = 2.17, 95% CI [1.31, 3.59]). Conclusions: The association of CSA with initiation of marijuana use and progression to problem use is stable over time in European-American women, but in African-American women, it varies by developmental period. Findings suggest the importance of considering race/ethnicity in prevention efforts with this high-risk population. © 2015, Alcohol Research Documentation Inc. All rights reserved.


Document Type: Article
Source: Scopus



Galor, A.a b , Felix, E.R.c d , Feuer, W.b , Shalabi, N.a b , Martin, E.R.e f , Margolis, T.P.g , Sarantopoulos, C.D.a h , Levitt, R.C.a f g h 
Dry eye symptoms align more closely to non-ocular conditions than to tear film parameters
(2015) British Journal of Ophthalmology, 99 (8), pp. 1126-1129. 

DOI: 10.1136/bjophthalmol-2014-306481


a Department of Ophthalmology, Miami Veterans Administration Medical Center, 900 NW 17th Street, Miami, FL, United States
b Bascom Palmer Eye Institute, University of Miami, Miami, FL, United States
c Research Service, Miami Veterans Administration Medical Center, Miami, FL, United States
d Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, FL, United States
e John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
f John T MacDonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
g Ophthalmology Department, Washington University School of Medicine, St. Louis, MO, United States
h Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States


Abstract
Objective To evaluate the relationship between dry eye symptoms, non-ocular conditions and tear film parameters. Methods Design: Cross-sectional study. Participants/ setting: The study population consisted of patients who were seen in the Miami Veterans Affairs eye clinic. Patients filled out standardised questionnaires assessing dry eye symptoms (dry eye questionnaire 5 (DEQ5) and ocular surface disease index (OSDI)), non-ocular pain, depression and post-traumatic stress disorder (PTSD), and also underwent measurement of tear film parameters. Main outcome measures: Correlations between dry eye symptoms and non-ocular conditions as compared with tear film parameters. Results 136 patients with a mean age of 65 (SD 11) years participated in the study. All correlations between the dry eye questionnaire scores (DEQ5 and OSDI) and (A) self-reported non-ocular pain measures (numerical rating scale and pain history), (B) depression and (C) PTSD were significant and moderate in strength (Pearson's coefficient 0.24 to 0.60, p<0.01 for all). All correlations between the dry eye questionnaires and tear film measures were weak (Pearson's coefficient -0.10 to 0.18) and most were not significant. Multivariable linear regression analyses revealed that PTSD and non-ocular pain more closely associated with dry eye symptoms than did tear film parameters. Specifically, non-ocular pain and PTSD accounted for approximately 36% of the variability in DEQ5 scores (R=0.60) and approximately 40% of variability in OSDI scores (R=0.64). Of note, none of the tear parameters remained significantly associated with dry eye symptoms in either model. Conclusions Dry eye symptoms more closely align to non-ocular pain, depression and PTSD than to tear film parameters.


Document Type: Article
Source: Scopus



Voth Schrag, R.J.
Economic Abuse and Later Material Hardship: Is Depression a Mediator?
(2015) Affilia - Journal of Women and Social Work, 30 (3), pp. 341-351. 

DOI: 10.1177/0886109914541118


George Warren Brown School of Social Work, Washington University in St. LouisMO, United States


Abstract
This study aimed to assess the mediating impact of depression on the association between three forms of intimate partner violence (economic abuse, physical/sexual abuse, and emotional abuse) and later experiences of material hardship. Partial mediation effects were found for economic and physical/sexual abuse, while no impact of emotional abuse on experiences of material hardship was observed. Experiencing economic (odds ratio [OR] = 1.39) or physical/sexual abuse (OR = 1.55) both had strong direct effects on later experiences of material hardship. Implications for social work practice include the need to address both economic abuse and long-term economic stability with survivors. © 2014, © The Author(s) 2014.


Author Keywords
domestic violence;  economic justice;  intimate partner violence;  mental health


Document Type: Article
Source: Scopus



Hendricks-Ferguson, V.L.a , Kane, J.R.b , Pradhan, K.R.c , Shih, C.-S.c , Gauvain, K.M.d , Baker, J.N.e , Haase, J.E.f 
Evaluation of Physician and Nurse Dyad Training Procedures to Deliver a Palliative and End-of-Life Communication Intervention to Parents of Children with a Brain Tumor
(2015) Journal of Pediatric Oncology Nursing, 32 (5), pp. 337-347. 

DOI: 10.1177/1043454214563410


a Saint Louis University School of Nursing, St. Louis, MO, United States
b Texas A&M College of Medicine, Temple, TX, United States
c Indiana University School of Medicine, Indianapolis, IN, United States
d Washington University School of Medicine, St Louis, MO, United States
e St Jude Children’s Research Hospital, Memphis, TN, United States
f Indiana University School of Nursing, Indianapolis, IN, United States


Abstract
When a child’s prognosis is poor, physicians and nurses (MDs/RNs) often struggle with initiating discussions about palliative and end-of-life care (PC/EOL) early in the course of illness trajectory. We describe evaluation of training procedures used to prepare MD/RN dyads to deliver an intervention entitled: Communication Plan: Early Through End of Life (COMPLETE) intervention. Our training was delivered to 5 pediatric neuro-oncologists and 8 pediatric nurses by a team of expert consultants (i.e., in medical ethics, communication, and PC/EOL) and parent advisors. Although half of the group received training in a 1-day program and half in a 2-day program, content for all participants included 4 modules: family assessment, goal-directed treatment planning, anticipatory guidance, and staff communication and follow-up. Evaluations included dichotomous ratings and qualitative comments on content, reflection, and skills practice for each module. Positive aspects of our training included parent advisers’ insights, emphasis on hope and non-abandonment messages, written materials to facilitate PC/EOL communication, and an MD/RN dyad approach. Lessons learned and challenges related to our training procedures will be described. Overall, the MDs and RNs reported that our PC/EOL communication-training procedures were helpful and useful. Future investigators should carefully plan training procedures for PC/EOL communication interventions. © 2015, © 2015 by Association of Pediatric Hematology/Oncology Nurses.


Author Keywords
end-of-life care;  palliative and end-of-life communication training;  palliative care;  parents of children with a brain tumor


Document Type: Article
Source: Scopus



Laumann, T.O.a , Gordon, E.M.a , Adeyemo, B.a , Snyder, A.Z.a b , Joo, S.J.c , Chen, M.-Y.c , Gilmore, A.W.d , McDermott, K.B.b d , Nelson, S.M.e f , Dosenbach, N.U.F.a , Schlaggar, B.L.a b g h i , Mumford, J.A.j , Poldrack, R.A.c k l m , Petersen, S.E.a b d i 
Functional System and Areal Organization of a Highly Sampled Individual Human Brain
(2015) Neuron, 87 (3), pp. 658-671. 

DOI: 10.1016/j.neuron.2015.06.037


a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychology, University of Texas at Austin, Austin, TX, United States
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
e VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
f Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
i Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
j Center for Investigating Healthy Minds at the Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
k Department of Neuroscience, University of Texas at Austin, Austin, TX, United States
l Imaging Research Center, University of Texas at Austin, Austin, TX, United States
m Department of Psychology, Stanford University, Stanford, CA, United States


Abstract
Resting state functional MRI (fMRI) has enabled description of group-level functional brain organization at multiple spatial scales. However, cross-subject averaging may obscure patterns of brain organization specific to each individual. Here, we characterized the brain organization of a single individual repeatedly measured over more than a year. We report a reproducible and internally valid subject-specific areal-level parcellation that corresponds with subject-specific task activations. Highly convergent correlation network estimates can be derived from this parcellation if sufficient data are collected-considerably more than typically acquired. Notably, within-subject correlation variability across sessions exhibited a heterogeneous distribution across the cortex concentrated in visual and somato-motor regions, distinct from the pattern of intersubject variability. Further, although the individual's systems-level organization is broadly similar to the group, it demonstrates distinct topological features. These results provide a foundation for studies of individual differences in cortical organization and function, especially for special or rare individuals. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus



Chen, L.-S.a b , Baker, T.B.c , Jorenby, D.c , Piper, M.c , Saccone, N.d , Johnson, E.e , Breslau, N.f , Hatsukami, D.g , Carney, R.M.a , Bierut, L.J.a b 
Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation
(2015) Drug and Alcohol Dependence, 154, pp. 278-282. 

DOI: 10.1016/j.drugalcdep.2015.06.022


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
c Center for Tobacco Research and Intervention, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e Division of Health, Social and Economic Research, Research Triangle Institute International, Research Triangle Park, NC, United States
f Department of Epidemiology, Michigan State University, East Lansing, MI, United States
g Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States


Abstract
Objective: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. Method: In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. Results: For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X2=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Conclusions: Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking. © 2015 Elsevier Ireland Ltd.


Author Keywords
CHRNA5;  Nicotine replacement therapy;  Pharmacogenetic;  Smoking cessation;  Varenicline


Document Type: Article
Source: Scopus



Cavazos-Rehg, P.A., Krauss, M.J., Sowles, S.J., Bierut, L.J.
“Hey everyone, I’m drunk.” An evaluation of drinking-related twitter chatter
(2015) Journal of Studies on Alcohol and Drugs, 76 (4), pp. 635-643. 

DOI: 10.15288/jsad.2015.76.635


Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Objective: The promotion of drinking behaviors correlates with increased drinking behaviors and intent to drink, especially when peers are the promotion source. Similarly, online displays of peer drinking behaviors have been described as a potential type of peer pressure that might lead to alcohol misuse when the peers to whom individuals feel attached value such behaviors. Social media messages about drinking behaviors on Twitter (a popular social media platform among young people) are common but understudied. In response, and given that drinking alcohol is a widespread activity among young people, we examined Twitter chatter about drinking. Method: Tweets containing alcohol- or drinking-related keywords were collected from March 13 to April 11, 2014. We assessed a random sample (n = 5,000) of the most infl uential Tweets for sentiment, theme, and source. Results: Most alcohol-related Tweets refl ected a positive sentiment toward alcohol use, with pro-alcohol Tweets outnumbering anti-alcohol Tweets by a factor of more than 10. The most common themes of pro-drinking Tweets included references to frequent or heavy drinking behaviors and wanting/needing/ planning to drink alcohol. The most common sources of pro-alcohol Tweets were organic (i.e., noncommercial). Conclusions: Our fi ndings highlight the need for online prevention messages about drinking to counter the strong pro-alcohol presence on Twitter. However, to enhance the impact of anti-drinking messages on Twitter, it may be prudent for such Tweets to be sent by individuals who are widely followed on Twitter and during times when heavy drinking is more likely to occur (i.e., weekends, holidays). © 2015, Alcohol Research Documentation Inc. All rights reserved.


Document Type: Article
Source: Scopus



Kahle, K.T.a , Kulkarni, A.V.b , Limbrick, D.D.c , Warf, B.C.a 
Hydrocephalus in children
(2015) The Lancet, . Article in Press. 

DOI: 10.1016/S0140-6736(15)60694-8


a Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
b Division of Neurosurgery, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
c Division of Neurosurgery, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, USA


Abstract
Hydrocephalus is a common disorder of cerebral spinal fluid (CSF) physiology resulting in abnormal expansion of the cerebral ventricles. Infants commonly present with progressive macrocephaly whereas children older than 2 years generally present with signs and symptoms of intracranial hypertension. The classic understanding of hydrocephalus as the result of obstruction to bulk flow of CSF is evolving to models that incorporate dysfunctional cerebral pulsations, brain compliance, and newly characterised water-transport mechanisms. Hydrocephalus has many causes. Congenital hydrocephalus, most commonly involving aqueduct stenosis, has been linked to genes that regulate brain growth and development. Hydrocephalus can also be acquired, mostly from pathological processes that affect ventricular outflow, subarachnoid space function, or cerebral venous compliance. Treatment options include shunt and endoscopic approaches, which should be individualised to the child. The long-term outcome for children that have received treatment for hydrocephalus varies. Advances in brain imaging, technology, and understanding of the pathophysiology should ultimately lead to improved treatment of the disorder. © 2015 Elsevier Ltd.


Document Type: Article in Press
Source: Scopus



Slutske, W.S.a b , Deutsch, A.R.a b , Statham, D.J.c , Martin, N.G.d 
Local area disadvantage and gambling involvement and disorder: Evidence for gene-environment correlation and interaction
(2015) Journal of Abnormal Psychology, 124 (3), pp. 606-622. 

DOI: 10.1037/abn0000071


a Department of Psychological Sciences, University of Missouri, United States
b Alcoholism Research Center, Washington University School of Medicine, United States
c University of the Sunshine Coast, Australia
d QIMR Berghofer Medical Research Institute, Brisbane, Australia


Abstract
Previous research has demonstrated that local area characteristics (such as disadvantage and gambling outlet density) and genetic risk factors are associated with gambling involvement and disordered gambling. These 2 lines of research were brought together in the present study by examining the extent to which genetic contributions to individual differences in gambling involvement and disorder contributed to being exposed to, and were also accentuated by, local area disadvantage. Participants were members of the national communitybased Australian Twin Registry who completed a telephone interview in which the past-year frequency of gambling and symptoms of disordered gambling were assessed. Indicators of local area disadvantage were based on census data matched to the participants' postal codes. Univariate biometric model-fitting revealed that exposure to area disadvantage was partially explained by genetic factors. Bivariate biometric model-fitting was conducted to examine the evidence for gene-environment interaction while accounting for geneenvironment correlation. These analyses demonstrated that: (a) a small portion of the genetic propensity to gamble was explained by moving to or remaining in a disadvantaged area, and (b) the remaining genetic and unique environmental variation in the frequency of participating in electronic machine gambling (among men and women) and symptoms of disordered gambling (among women) was greater in more disadvantaged localities. As the gambling industry continues to grow, it will be important to take into account the multiple contexts in which problematic gambling behavior can emerge-from genes to geography-as well as the ways in which such contexts may interact with each other. © 2015 American Psychological Association.


Author Keywords
Disordered gambling;  Gambling;  Gene-environment correlation;  Gene-environment interaction;  Natural experiment;  Neighborhood disadvantage


Document Type: Article
Source: Scopus



Sobieski, C.a b , Jiang, X.a , Crawford, D.C.a b e , Mennerick, S.a c d 
Loss of local astrocyte support disrupts action potential propagation and glutamate release synchrony from unmyelinated hippocampal axon terminals in vitro
(2015) Journal of Neuroscience, 35 (31), pp. 11105-11117. 

DOI: 10.1523/JNEUROSCI.1289-15.2015


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, United States


Abstract
Neuron–astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (-astrocyte) within the same culture dish. -Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. © 2015 the authors.


Author Keywords
Action potential;  Astrocyte;  Glutamate;  Synchrony


Document Type: Article
Source: Scopus



Ji, W.a , Gamanut, R.b c , Bista, P.a , D'Souza, R.D.a , Wang, Q.a d , Burkhalter, A.a 
Modularity in the Organization of Mouse Primary Visual Cortex
(2015) Neuron, 87 (3), pp. 633-644. 

DOI: 10.1016/j.neuron.2015.07.004


a Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
b Stem Cell and Brain Research Institute, INSERM U846, Bron, France
c Université Claude Bernard Lyon, Lyon, France
d Allen Institute for Brain Science, Seattle, WA, United States


Abstract
Layer 1 (L1) of primary visual cortex (V1) is the target of projections from many brain regions outside of V1.We found that inputs to the non-columnar mouse V1 from the dorsal lateral geniculate nucleus and feedback projections from multiple higher cortical areas to L1 are patchy. The patches are matched to a pattern of M2 muscarinic acetylcholine receptor expression at fixed locations of mouse, rat, and monkey V1. Neurons in L2/3 aligned with M2-rich patches have high spatial acuity, whereas cells in M2-poor zones exhibited high temporal acuity. Together M2+ and M2- zones form constant-size domains that are repeated across V1. Domains map subregions of the receptive field, such that multiple copies are contained within the point image. The results suggest that the modular network in mouse V1 selects spatiotemporally distinct clusters of neurons within the point image for top-down control and differential routing of inputs to cortical streams. © 2015 Elsevier Inc.


Document Type: Article
Source: Scopus



Zaidman, C.M.a b , Malkus, E.C.a , Connolly, A.M.a b 
Muscle ultrasound quantifies disease progression over time in infants and young boys with duchenne muscular dystrophy
(2015) Muscle and Nerve, 52 (3), pp. 334-338. Cited 1 time.

DOI: 10.1002/mus.24609


a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Introduction: Quantitative muscle ultrasound (QUS) in boys with Duchenne muscular dystrophy (DMD) shows increased echointensity as muscle is replaced with fat and fibrosis. Studies of quantitative ultrasound in infants/young boys with DMD over time have not been reported. Methods: We used calibrated muscle backscatter (cMB), a reproducible measure of ultrasound echointensity, to quantify muscle pathology in 5 young boys with DMD (ages 0.5-2.8 years) over 17-29 months. We compared the results with repeated assessments of function (n=4) and with muscle ultrasound images from a cross-section of 6 male controls (0.6-3.1 years). Results: cMB in boys with DMD increased (worsened) over time (P<0.001), whereas function improved. After age 2 years, cMB in most (4 of 5) boys with DMD was higher than in any control. Conclusions: QUS measures disease progression in young boys with DMD despite functional improvements. QUS could be employed as an outcome measure for serial assessment of young boys with DMD. © 2015 Wiley Periodicals, Inc.


Author Keywords
Backscatter;  Children;  Duchenne muscular dystrophy;  Muscle;  Myopathy;  Ultrasound


Document Type: Article
Source: Scopus



Sengupta, R.a , Barone, A.a , Marasa, J.b , Taylor, S.c , Jackson, E.d , Warrington, N.M.a , Rao, S.a , Kim, A.H.c e , Leonard, J.R.e , Piwnica-Worms, D.d f g , Rubin, J.B.a f 
Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions
(2015) Oncotarget, 6 (21), pp. 18282-18292. 


a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b High Throughput Screening Core, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
d Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, United States


Abstract
Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.


Author Keywords
Co-culture;  GBM;  High throughput screen;  Iridin;  Perivascular niche


Document Type: Article
Source: Scopus



Safarpour, D.a c , Thibault, D.P.a , Desanto, C.L.e , Boyd, C.M.f g , Dorsey, E.R.h , Racette, B.A.e i , Willis, A.W.a b c d 
Nursing home and end-of-life care in Parkinson disease
(2015) Neurology, 85 (5), pp. 413-419. Cited 1 time.

DOI: 10.1212/WNL.0000000000001715


a Departments of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
b Departments of Biostatistics and Epidemiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
c Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
d Leonard Davis Institute of Health Economics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
e Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
f Departments of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
g Departments of Health Policy and Management, Johns Hopkins School of Medicine, Baltimore, MD, United States
h Department of Neurology, Center of Human Experimental Therapeutics, University of Rochester, Medical CenterNY, United States
i School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa


Abstract
Objective: To examine long-term care facility (LTCF or nursing home) use and end-of-life care for individuals with Parkinson disease (PD). Methods: In this nationwide retrospective cohort study, we compared LTCF and hospice utilization among Medicare beneficiaries diagnosed with PD by demographic, clinical, and physician characteristics. We also examined the impact of outpatient neurologist care for institutionalized patients with PD on end-of-life care. Results: We identified 469,055 individuals with PD who received Medicare benefits in 2002. Nearly 25% (more than 100,000 in total) resided in an LTCF. Women with PD had greater odds of nursing facility residence (adjusted odds ratio [AOR] 1.34, 95% confidence interval [CI] 1.30-1.38) compared with men. Black individuals with PD were 34% more likely than white individuals to reside in an LTCF (AOR 1.34, 95% CI 1.30-1.38), contrary to the race patterns typically observed for LTCF use. Hip fracture (AOR 2.10, 95% CI 2.04-2.15) and dementia (AOR 4.06, 95% CI 4.00-4.12) were the strongest clinical predictors of LTCF placement. Only 33% (n 38,334) of nursing home residents with PD had outpatient neurologist care. Eighty-four percent (n 80,877) of LTCF residents with PD died by December 31, 2005. Hospice utilization varied little by race and sex. LTCF residents who had outpatient neurologist care were twice as likely to utilize hospice services before death (AOR 2.35, 95% CI 2.24-2.47). Conclusions and relevance: A large proportion of the Medicare PD population resides in an LTCF. There is substantial unmet need for palliative care in the PD population. Increased efforts to provide specialist care to dependent individuals with PD may improve end-of-life care. © © 2015 American Academy of Neurology.


Document Type: Article
Source: Scopus

 

Morris, M.a , Willis, A.W.b , Searles Nielsen, S.c , McCann, F.d , Birke, A.a , Racette, B.A.a e

Physician response to a medication alert system in inpatients with levodopa-treated diseases
(2015) Neurology, 85 (5), pp. 420-424. 

DOI: 10.1212/WNL.0000000000001745


a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Departments of Neurology and Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
c Department of Neurology, University of Washington, Seattle, WA, United States
d Barnes-Jewish Hospital, St. Louis, MO, United States
e School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa


Abstract
Objective: To evaluate the appropriateness of dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases after implementation of an automated prescription alert system. Methods: We examined dopamine receptor antagonist prescriptions in hospitalized patients with dopamine-requiring diseases and physician response to an automated drug contraindication alert system at Barnes-Jewish Hospital from 2009 to 2013. A detailed review of patient medical records was performed for all alert events generated when a physician prescribed a dopamine receptor antagonist concurrently with a dopamine receptor agonist in hospitalized patients. Two movement disorders neurologists determined the appropriateness of each prescription, based on patient medical history, through consensus. Physician response to alert was compared by indication for the prescription and physician specialty. Results: Of 237 orders, 197 (83.1%) prescriptions for dopamine receptor antagonists were considered inappropriate. The prevalence of inappropriate dopamine receptor antagonist prescriptions per levodopa prescriptions was 16.10% (95% confidence interval 9.47, 22.73) in psychiatry, 7.51% (6.16, 8.86) in general medicine, 6.14% (4.49, 7.79) in the surgical specialties, and 0.85% (0.46, 1.25) in the neurologic/neurosurgical specialties. Of the inappropriate prescriptions, 146 (74.1%) were continued despite the alert. The strongest predictor of discontinuation of dopamine receptor antagonist medications was use of the medication to treat nausea or emesis (p < 0.001). Conclusions: Despite successfully identifying instances when dopamine antagonists were prescribed to patients with dopamine-requiring diseases, the alert system modestly affected physician prescribing behavior, highlighting the need for improved education of health care providers. © © 2015 American Academy of Neurology.


Document Type: Article
Source: Scopus



Paganoni, S.a b c , Hyman, T.d , Shui, A.e , Allred, P.d , Harms, M.d , Liu, J.d , Maragakis, N.f , Schoenfeld, D.e , Yu, H.a , Atassi, N.a , Cudkowicz, M.a , Miller, T.M.d 
Pre-morbid type 2 diabetes mellitus is not a prognostic factor in amyotrophic lateral sclerosis
(2015) Muscle and Nerve, 52 (3), pp. 339-343. 

DOI: 10.1002/mus.24688


a Neurological Clinical Research Institute, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
b Department of Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA, United States
c VA Healthcare System, Boston, MA, United States
d Department of Neurology, Washington University School of Medicine, 115 Biotech Building, Box 8111, 660 South Euclid, Street, St. Louis, United States
e Massachusetts General Hospital Biostatistics Center, Boston, MA, United States
f Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States


Abstract
Introduction: The aim of this study was to determine whether a history of pre-morbid type 2 diabetes mellitus (DM2) is a prognostic factor in amyotrophic lateral sclerosis (ALS). Methods: The relationship between DM2 and survival was analyzed in a study population consisting of 1,322 participants from 6 clinical trials. Results: Survival did not differ by diabetes status (log-rank test, P=0.98), but did differ by body mass index (BMI) (log-rank test, P=0.008). In multivariate analysis, there was no significant association between diabetes and survival (P=0.18), but the risk of reaching a survival endpoint decreased by 4% for each unit increase in baseline BMI (HR 0.96, 95% CI 0.94-0.99, P=0.001). DM2 was less prevalent among ALS clinical trial participants than predicted. Conclusions: A history of pre-morbid DM2 is not an independent prognostic factor in ALS clinical trial databases. The low DM2 prevalence rate should be examined in a large, prospective study to determine whether DM2 affects ALS risk. © 2015 Wiley Periodicals, Inc.


Author Keywords
ALS;  BMI;  Diabetes;  Prognosis;  Survival


Document Type: Article
Source: Scopus



Richmond-Rakerd, L.S.a b , Slutske, W.S.a b , Deutsch, A.R.a b , Lynskey, M.T.c d , Agrawal, A.b d , Madden, P.A.F.b d , Bucholz, K.K.b d , Heath, A.C.b d , Martin, N.G.e 
Progression in substance use initiation: A multilevel discordant monozygotic twin design
(2015) Journal of Abnormal Psychology, 124 (3), pp. 596-605. 

DOI: 10.1037/abn0000068


a Department of Psychological Sciences, University of Missouri-Columbia, United States
b Alcoholism Research Center, Washington University School of Medicine, United States
c Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom
d Department of Psychiatry, Washington University School of Medicine, United States
e QIMR Berghofer Medical Research Institute, Brisbane, Australia


Abstract
Considerable attention has been paid to the "gateway" pattern of drug use initiation in which individuals progress from tobacco and alcohol use to cannabis and other illicit drugs. The extent to which this sequence reflects a causal impact of licit substance use on illicit substance involvement remains unclear. Clarifying the mechanisms underlying substance use initiation may help inform our understanding of risk for psychopathology, as increasing research is demonstrating associations between initiation patterns and heavier involvement. This study examined patterns of substance use initiation using a discordant twin design. Participants were 3,476 monozygotic twins (37% male) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation. Multilevel proportional hazard regression models were used to (a) estimate within-twin-pair and between-twin-pair contributions to associations between the ages of onset of different drugs; and (b) examine whether the magnitude of effects differed as a function of the order of substance use initiation. Finding significant effects within twin pairs would support the hypothesis that the age of initiation of a substance causally influences the age of initiation of a subsequent substance. Finding significant effects between twin pairs would support the operation of familial influences that explain variation in the ages of initiation of multiple drugs. Within-twin-pair effects for typical patterns were modest. When initiation was atypical, however, larger within-twin-pair effects were observed and causal influences were more strongly implicated. Results support the utility of examining the timing and ordering of substance use initiation within sophisticated, genetically informative designs. © 2015 American Psychological Association.


Author Keywords
Discordant twins;  Multilevel modeling;  Substance use initiation


Document Type: Article
Source: Scopus



Hawasli, A.H., Leuthardt, E.C.
Response
(2015) Neurosurgical Focus, 39 (2), p. E20. 


Washington University, St. Louis, MO, United States


Document Type: Letter
Source: Scopus



Li, Z.a , Yuan, J.b , Wei, L.b , Zhou, L.a , Mei, K.c , Yue, J.d , Gao, H.e , Zhang, M.a , Jia, L.a , Kang, Q.a , Huang, X.a , Cao, D.a f 
SATB2 is a sensitive marker for lower gastrointestinal well-differentiated neuroendocrine tumors
(2015) International Journal of Clinical and Experimental Pathology, 8 (6), pp. 7072-7082. 


a Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital (Beijing Cancer Hospital), Beijing, China
b Department of Pathology, The Chinese PLA General Hospital, Beijing, China
c Department of Pathology, The Second Affiliated Hospital, Guangzhou Medical University, Guangdong, China
d Department of Pathology, Hubei Cancer Hospital, Wuhan, China
e Department of Pathology, The Second Affiliated Hospital, Jilin University, Changchun, China
f Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Special AT-rich sequence binding protein-2 (SATB2) is selectively expressed in the lower gastrointestinal tract mucosa and has been identified as a sensitive marker for colorectal adenocarcinomas. The goal of this study was to investigate the expression of SATB2 in well-differentiated neuroendocrine tumors to explore its potential as a diagnostic marker for hindgut well-differentiated neuroendocrine tumors. Immunohistochemical staining with a monoclonal antibody to SATB2 was performed on full tissue blocks in 167 well-differentiated neuroendocrine tumors of various origins. The staining was semi-quantitatively scored as 0 (no tumor cell staining), 1+ (1-25%), 2+ (26-50%), 3+ (51-75%) and 4+ (76-100%). Positive SATB2 staining was seen in 17% foregut (14/84, 12/66 primary and 2/18 metastatic), 12% midgut (3/22, 3/18 primary and 0/7 metastatic), and 90% hindgut (52/58, 44/49 primary and 8/9 metastatic) well differentiated neuroendocrine tumors. Most hindgut well-differentiated neuroendocrine tumors (41/58) showed 4+ staining. The specificity of SATB2 for foregut, midgut and hindgut well-differentiated neuroendocrine tumors was 34%, 54% and 84%, respectively. Our results indicate that SATB2 is a sensitive marker for hindgut well-differentiated neuroendocrine tumors though it is not entirely specific. SATB2 should be included in the immunohistochemical panel in working out metastatic well-differentiated neuroendocrine tumor of an unknown origin.


Author Keywords
Foregut;  Hindgut;  Midgut;  SATB2;  Well-differentiated neuroendocrine tumor


Document Type: Article
Source: Scopus



Kelly, M.P.a , Guillaume, T.J.b , Lenke, L.G.a 
Spinal Deformity Associated with Chiari Malformation
(2015) Neurosurgery Clinics of North America, . Article in Press. 

DOI: 10.1016/j.nec.2015.06.005


a Department of Orthopedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box8233, Saint Louis, MO 63110, USA
b Department of Orthopedic Surgery, Gillette Children's Hospital, 200 University Ave E, StPaul, MN 55101, USA


Abstract
Despite the frequency of Chiari-associated spinal deformities, this disease process remains poorly understood. Syringomyelia is often present; however, this is not necessary and scoliosis has been described in the absence of a syrinx. Decompression of the hindbrain is often recommended. In young patients (<10years old) and/or those with small coronal Cobb measurements (<40°), decompression of the hindbrain may lead to resolution of the spinal deformity. Spinal fusion is reserved for those curves that progress to deformities greater than 50°. Further research is needed to understand the underlying pathophysiology to improve prognostication and treatment of this patient population. © 2015 Elsevier Inc.


Author Keywords
Chiari malformation;  Early onset;  Scoliosis;  Syringomyelia;  Syrinx


Document Type: Article in Press
Source: Scopus



Corral-Frías, N.S.a , Nikolova, Y.S.b , Michalski, L.J.c , Baranger, D.A.A.c d , Hariri, A.R.b , Bogdan, R.a c d 
Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology
(2015) Psychological Medicine, 45 (12), pp. 2605-2617. 

DOI: 10.1017/S0033291715000525


a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
b Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, United States
c BRAIN Laboratory, Department of Psychology, Washington University in St Louis, St Louis, MO, United States
d Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, United States


Abstract
Background Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. Method Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. Results Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. Conclusions These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping. © Cambridge University Press 2015.


Author Keywords
Alcohol;  anhedonia;  depression;  early life stress;  fMRI;  reward;  ventral striatum


Document Type: Article
Source: Scopus



Greenberg, J.K.a , Yarbrough, C.K.a , Radmanesh, A.c , Godzik, J.a , Yu, M.a , Jeffe, D.B.d , Smyth, M.D.a , Park, T.S.a , Piccirillo, J.F.b , Limbrick, D.D.a 
The Chiari Severity index: A preoperative grading system for Chiari malformation type 1
(2015) Neurosurgery, 76 (3), pp. 279-285. Cited 1 time.

DOI: 10.1227/NEU.0000000000000608


a Department of Neurological Surgery, Washington University, School of Medicine in St. Louis, St. Louis Children's Hospital, One Children's Way, 4S20, St. Louis, MO, United States
b Department of Otolaryngology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Medicine, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
d Mallincrodt Institute of Radiology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
BACKGROUND: To develop evidence-based treatment guidelines for Chiari malformation type 1 (CM-1), preoperative prognostic indices capable of stratifying patients for comparative trials are needed. OBJECTIVE: To develop a preoperative Chiari Severity Index (CSI) integrating the clinical and neuroimaging features most predictive of long-term patient-defined improvement in quality of life (QOL) after CM-1 surgery. METHODS: We recorded preoperative clinical (eg, headaches, myelopathic symptoms) and neuroimaging (eg, syrinx size, tonsillar descent) characteristics. Brief follow-up surveys were administered to assess overall patient-defined improvement in QOL. We used sequential sequestration to develop clinical and neuroimaging grading systems and conjunctive consolidation to integrate these indices to form the CSI. We evaluated statistical significance using the Cochran-Armitage test and discrimination using the C statistic. RESULTS: Our sample included 158 patients. Sequential sequestration identified headache characteristics and myelopathic symptoms as the most impactful clinical parameters, producing a clinical grading system with improvement rates ranging from 81% (grade 1) to 58% (grade 3) (P =.01). Based on sequential sequestration, the neuroimaging grading system included only the presence (55% improvement) or absence (74% improvement) of a syrinx ≥6 mm (P =.049). Integrating the clinical and neuroimaging indices, improvement rates for the CSI ranged from 83% (grade 1) to 45% (grade 3) (P =.002). The combined CSI had moderately better discrimination (c = 0.66) than the clinical (c = 0.62) or neuroimaging (c = 0.58) systems alone. CONCLUSION: Integrating clinical and neuroimaging characteristics, the CSI is a novel tool that predicts patient-defined improvement after CM-1 surgery. The CSI may aid preoperative counseling and stratify patients in comparative effectiveness trials. Copyright © 2015 by the Congress of Neurological Surgeons.


Author Keywords
Chiari malformation type 1;  Comparative effectiveness research;  Outcome assessment (health care);  Pediatric neurosurgery;  Quality of life;  Severity of illness index


Document Type: Article
Source: Scopus



Carlson, E.N.a , Oltmanns, T.F.b 
The role of metaperception in personality disorders: Do people with personality problems know how others experience their personality?
(2015) Journal of Personality Disorders, 29 (4), pp. 449-467. Cited 1 time.

DOI: 10.1521/pedi.2015.29.4.449


a Department of Psychology, University of Toronto, Canada
b Department of Psychology, Washington University in St. Louis, United States


Abstract
Do people with personality problems have insight into how others experience them? In a large community sample of adults (N = 641), the authors examined whether people with personality disorder (PD) symptoms were aware of how a close acquaintance (i.e., a romantic partner, family member, or friend) perceived them by measuring participants' metaperceptions and self-perceptions as well as their acquaintance's impression of them on Five-Factor Model traits. Compared to people with fewer PD symptoms, people with more PD symptoms tended to be less accurate and tended to overestimate the negativity of the impressions they made on their acquaintance, especially for the traits of extraversion, agreeableness, and conscientiousness. Interestingly, these individuals did not necessarily assume that their acquaintance perceived them as they perceived themselves; instead, poor insight was likely due to their inability to detect or utilize information other than their selfperceptions. Implications for the conceptualization, measurement, and treatment of PDs are discussed. © 2015 The Guilford Press.


Document Type: Article
Source: Scopus



Cavanaugh, J.T.a , Ellis, T.D.b , Earhart, G.M.c , Ford, M.P.d , Bo Foreman, K.e , Dibble, L.E.f 
Toward understanding ambulatory activity decline in parkinson disease
(2015) Physical Therapy, 95 (8), pp. 1142-1150. 

DOI: 10.2522/ptj.20140498


a Department of Physical Therapy, University of New England, Portland, ME, United States
b Department of Physical Therapy and Athletic Training, Boston University, Boston, MA, United States
c Program in Physical Therapy, School of Medicine, Washington University, St Louis, MO, United States
d Department of Physical Therapy, Samford University, Birmingham, AL, United States
e Department of Physical Therapy, University of Utah, Salt Lake City, UT, United States
f Department of Physical Therapy, University of Utah, United States


Abstract
Background. Declining ambulatory activity represents an important facet of disablement in Parkinson disease (PD). Objective. The primary study aim was to compare the 2-year trajectory of ambulatory activity decline with concurrently evolving facets of disability in a small cohort of people with PD. The secondary aim was to identify baseline variables associated with ambulatory activity at 1- and 2-year follow-up assessments. Design. This was a prospective, longitudinal cohort study. Methods. Seventeen people with PD (Hoehn and Yahr stages 1–3) were recruited from 2 outpatient settings. Ambulatory activity data were collected at baseline and at 1- and 2-year annual assessments. Motor, mood, balance, gait, upper extremity function, quality of life, self-efficacy, and levodopa equivalent daily dose data and data on activities of daily living also were collected. Results. Participants displayed significant 1- and 2-year declines in the amount and intensity of ambulatory activity concurrently with increasing levodopa equivalent daily dose. Worsening motor symptoms and slowing of gait were apparent only after 2 years. Concurrent changes in the remaining clinical variables were not observed. Baseline ambulatory activity and physical performance variables had the strongest relationships with 1- and 2-year mean daily steps. Limitations. The sample was small and homogeneous. Conclusions. Future research that combines ambulatory activity monitoring with a broader and more balanced array of measures would further illuminate the dynamic interactions among evolving facets of disablement and help determine the extent to which sustained patterns of recommended daily physical activity might slow the rate of disablement in PD. © 2015 American Physical Therapy Association.


Document Type: Article
Source: Scopus



Liu, Q.a , Zoellner, N.a , Gutmann, D.H.b , Johnson, K.J.a c 
Parental age and Neurofibromatosis Type 1: a report from the NF1 Patient Registry Initiative
(2015) Familial Cancer, 14 (2), pp. 317-324. 

DOI: 10.1007/s10689-014-9774-8


a Brown School, Washington University in St. Louis, 237 Goldfarb Hall, One Brookings Drive, Campus Box 1196, St. Louis, MO, United States
b Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States


Abstract
One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95 % CI 3.23–5.46, p ≤ 0.0001) and 3.39 years (95 % CI 1.57–5.20, p ≤ 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1. © 2014, Springer Science+Business Media Dordrecht.


Author Keywords
Brain tumor;  Cancer predisposition syndrome;  Neurofibromatosis Type 1 (NF1);  Rare disease;  Registry

 


Document Type: Article
Source: Scopus

 

August 18, 2015

Zipfel, G.J.
Editorial: Arteriovenous malformations and embolization
(2015) Journal of neurosurgery, 122 (6), pp. 1490-1491. 

DOI: 10.3171/2014.9.JNS141419


Departments of Neurological Surgery and Neurology, Washington University School of Medicine, St. Louis, Missouri


Document Type: Editorial
Source: Scopus




Hood, A.a c , Pulvers, K.a , Spady, T.J.b , Kliebenstein, A.a , Bachand, J.a
Anxiety mediates the effect of acute stress on working memory performance when cortisol levels are high: a moderated mediation analysis
(2015) Anxiety, Stress and Coping, 28 (5), pp. 545-562. 

DOI: 10.1080/10615806.2014.1000880


a Department of Psychology, California State University San Marcos, San Marcos, CA, United States
b Department of Biological Sciences, California State University San Marcos, San Marcos, CA, United States
c Department of Psychology, Washington University in St Louis, St Louis, MO, United States


Abstract
Background: Anxiety is an aversive emotional state characterized by perceived uncontrollability and hypervigilance to threat that can frequently cause disruptions in higher-order cognitive processes like working memory. The attentional control theory (ACT) predicts that anxiety negatively affects the working memory system. Design: This study tested the association between anxiety and working memory after the addition of stress and measured the glucocorticoid, cortisol. To better understand this relationship, we utilized a moderated mediation model. Methods: Undergraduate students from a public university (N = 103) self-reported their anxiety levels. Participants first completed a short-term memory test. During and after a forehead cold pressor task (stress vs. control procedure) participants completed a working memory test. Salivary cortisol was taken at baseline and after the last working memory test. Results: Overall, acute stress had no effect on working memory. However, we found that anxiety levels mediated the influence of condition (stressed vs. control) on working memory, but only among those individuals who had high cortisol levels after exposure to acute stress, supporting a moderated mediation model. Conclusions: These results imply that activation of the hypothalamic–pituitary–adrenal axis was necessary for working memory impairment in anxious individuals. These results provide support for the ACT. © 2015 Taylor & Francis.


Author Keywords
ACT;  BAI;  bootstrapping;  glucocorticoids;  mediation;  stress


Document Type: Article
Source: Scopus




Alawieh, A.a , Elvington, A.b , Tomlinson, S.c d
Complement in the homeostatic and ischemic brain
(2015) Frontiers in Immunology, 6 (JUL), art. no. 417, . 

DOI: 10.3389/fimmu.2015.00417


a Neuroscience Institute, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
d Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC, United States


Abstract
The complement system is a component of the immune system involved in both recognition and response to pathogens, and it is implicated in an increasing number of homeostatic and disease processes. It is well documented that reperfusion of ischemic tissue results in complement activation and an inflammatory response that causes post-reperfusion injury. This occurs following cerebral ischemia and reperfusion and triggers secondary damage that extends beyond the initial infarcted area, an outcome that has rationalized the use of complement inhibitors as candidate therapeutics after stroke. In the central nervous system, however, recent studies have revealed that complement also has essential roles in synaptic pruning, neurogenesis and neuronal migration. In the context of recovery after stroke, these apparent divergent functions of complement may account for findings that the protective effect of complement inhibition in the acute phase after stroke is not always maintained in the sub-acute and chronic phases. The development of effective stroke therapies based on modulation of the complement system will require a detailed understanding of complement-dependent processes in both early neurodegenerative events, as well as delayed neuro-reparatory processes. Here, we review the role of complement in normal brain physiology, the events initiating complement activation after cerebral ischemia-reperfusion injury and the contribution of complement to both injury and recovery. We also discuss how the design of future experiments may better characterize the dual role of complement in recovery after ischemic stroke. © 2015 Alawieh, Elvington and Tomlinson.


Author Keywords
Brain ischemia;  Complement;  Innate immunity;  Neuroprotection;  Reperfusion injury;  Stroke


Document Type: Review
Source: Scopus




Kubanek, J.a b , Hill, N.J.c , Snyder, L.H.a b , Schalk, G.c
Cortical alpha activity predicts the confidence in an impending action
(2015) Frontiers in Neuroscience, 9 (JUL), art. no. 00243, . 

DOI: 10.3389/fnins.2015.00243


a Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c National Center for Adaptive Neurotechnologies, Wadsworth Center, New York State Department of Health, Albany, NY, United States


Abstract
When we make a decision, we experience a degree of confidence that our choice may lead to a desirable outcome. Recent studies in animals have probed the subjective aspects of the choice confidence using confidence-reporting tasks. These studies showed that estimates of the choice confidence substantially modulate neural activity in multiple regions of the brain. Building on these findings, we investigated the neural representation of the confidence in a choice in humans who explicitly reported the confidence in their choice. Subjects performed a perceptual decision task in which they decided between choosing a button press or a saccade while we recorded EEG activity. Following each choice, subjects indicated whether they were sure or unsure about the choice. We found that alpha activity strongly encodes a subject's confidence level in a forthcoming button press choice. The neural effect of the subjects' confidence was independent of the reaction time and independent of the sensory input modeled as a decision variable. Furthermore, the effect is not due to a general cognitive state, such as reward expectation, because the effect was specifically observed during button press choices and not during saccade choices. The neural effect of the confidence in the ensuing button press choice was strong enough that we could predict, from independent single trial neural signals, whether a subject was going to be sure or unsure of an ensuing button press choice. In sum, alpha activity in human cortex provides a window into the commitment to make a hand movement. © 2015 Kubanek, Hill, Snyder and Schalk.


Author Keywords
Certainty;  EEG;  Human;  Neural correlates;  Perceptual decision-making


Document Type: Article
Source: Scopus




Spurney, C.F.a , McCaffrey, F.M.b , Cnaan, A.a , Morgenroth, L.P.a , Ghelani, S.J.a , Gordish-Dressman, H.a , Arrieta, A.a , Connolly, A.M.c , Lotze, T.E.d , McDonald, C.M.e , Leshner, R.T.a f , Clemens, P.R.g h
Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies
(2015) Journal of the American Society of Echocardiography, 28 (8), pp. 999-1008. 

DOI: 10.1016/j.echo.2015.03.003


a Children's National Health System, Washington, DC, United States
b Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
c Washington University, St. Louis, MO, United States
d Texas Children's Hospital, Houston, TX, United States
e University of California, Davis, Sacramento, CA, United States
f University of California, San Diego, San Diego, CA, United States
g University of Pittsburgh, Pittsburgh, PA, United States
h Department of Veterans, Affairs Medical Center, Pittsburgh, PA, United States


Abstract
Background Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. Methods Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function. Results Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient [ICC] = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E′ velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects. Conclusions In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD. © 2015 American Society of Echocardiography.


Author Keywords
Cardiac strain;  Cardiomyopathy;  Echocardiography;  Muscular dystrophy


Document Type: Article
Source: Scopus




Bergonzi, K.M.a , Bauer, A.Q.b , Wright, P.W.a , Culver, J.P.a b c
Mapping functional connectivity using cerebral blood flow in the mouse brain
(2015) Journal of Cerebral Blood Flow and Metabolism, 35 (3), pp. 367-370. 

DOI: 10.1038/jcbfm.2014.211


a Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
b Department of Radiology, Washington University in St Louis, Washington University School of Medicine, Campus Box 8225, 660 South Euclid Avenue, St Louis, MO, United States
c Department of Physics, Washington University in St Louis, St Louis, MO, United States


Abstract
Brain function can be assessed from resting-state functional connectivity (rs-fc) maps, most commonly created by analyzing the dynamics of cerebral hemoglobin concentration. Here, we develop the use of Laser Speckle Contrast Imaging (LSCI) for mapping rs-fc using cerebral blood flow (CBF) dynamics. Because LSCI is intrinsically noisy, we used spatial and temporal averaging to sufficiently raise the signal-to-noise ratio for observing robust functional networks. Although CBF-based rs-fc maps in healthy mice are qualitatively similar to simultaneously-acquired HbO 2 ]-based maps, some quantitative regional differences were observed. These combined flow/concentration maps might help clarify mechanisms involved in network disruption during disease. © 2015 ISCBFM All rights reserved.


Author Keywords
brain imaging;  cortical mapping;  intrinsic optical imaging;  neurovascular coupling


Document Type: Article
Source: Scopus




Smyth, M.D.a , Han, R.H.a , Yarbrough, C.K.a , Patterson, E.E.b , Yang, X.-F.c h i , Miller, J.W.d e , Rothman, S.M.f , D'Ambrosio, R.d e g
Temperatures Achieved in Human and Canine Neocortex During Intraoperative Passive or Active Focal Cooling
(2015) Therapeutic Hypothermia and Temperature Management, 5 (2), pp. 95-103. 

DOI: 10.1089/ther.2014.0025


a Department of Neurosurgery, Washington University School of Medicine, One Children's Place, Suite 4s20, St. Louis, MO, United States
b Department of Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States
c Department of Pediatrics (Clinical Neuroscience), University of Minnesota, Minneapolis, MN, United States
d Department of Neurological Surgery, University of Washington, Seattle, WA, United States
e Department of Neurology, Regional Epilepsy Center, University of Washington, Seattle, WA, United States
f Mercy Clinic Child Neurology, St. Louis, MO, United States
g Center for Human Development and Disability, University of Washington, Seattle, WA, United States
h Electrophysiology Laboratory, Xuanwu Hospital Capital Medical University, Beijing, China
i Center of Epilepsy, Institute for Brain Disorders, Beijing, China


Abstract
Focal cortical cooling inhibits seizures and prevents acquired epileptogenesis in rodents. To investigate the potential clinical utility of this treatment modality, we examined the thermal characteristics of canine and human brain undergoing active and passive surface cooling in intraoperative settings. Four patients with intractable epilepsy were treated in a standard manner. Before the resection of a neocortical epileptogenic focus, multiple intraoperative studies of active (custom-made cooled irrigation-perfused grid) and passive (stainless steel probe) cooling were performed. We also actively cooled the neocortices of two dogs with perfused grids implanted for 2 hours. Focal surface cooling of the human brain causes predictable depth-dependent cooling of the underlying brain tissue. Cooling of 0.6-2°C was achieved both actively and passively to a depth of 10-15 mm from the cortical surface. The perfused grid permitted comparable and persistent cooling of canine neocortex when the craniotomy was closed. Thus, the human cortex can easily be cooled with the use of simple devices such as a cooling grid or a small passive probe. These techniques provide pilot data for the design of a permanently implantable device to control intractable epilepsy. © Copyright 2015, Mary Ann Liebert, Inc.

 


Document Type: Article
Source: Scopus

 

 

August 11, 2015

 

Arnedo, J.a , Mamah, D.b , Baranger, D.A.b , Harms, M.P.b , Barch, D.M.b c , Svrakic, D.M.b , de Erausquin, G.A.d , Cloninger, C.R.b e , Zwir, I.a b
Decomposition of brain diffusion imaging data uncovers latent schizophrenias with distinct patterns of white matter anisotropy
(2015) NeuroImage, 120, pp. 43-54. 

DOI: 10.1016/j.neuroimage.2015.06.083


a Department of Computer Science and Artificial Intelligence, University of Granada, Spain
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychology, Department of Anatomy, Neurobiology Washington University, St. Louis, MO, United States
d Roskamp Laboratory of Brain Development, Modulation and Repair, Department of Psychiatry and Behavioral Neurosciences (GAE), University of South Florida, Tampa, FL, United States
e Department of Genetics (CRC), Washington University School of Medicine, St. Louis, MO, United States


Abstract
Fractional anisotropy (FA) analysis of diffusion tensor-images (DTI) has yielded inconsistent abnormalities in schizophrenia (SZ). Inconsistencies may arise from averaging heterogeneous groups of patients. Here we investigate whether SZ is a heterogeneous group of disorders distinguished by distinct patterns of FA reductions. We developed a Generalized Factorization Method (GFM) to identify biclusters (i.e., subsets of subjects associated with a subset of particular characteristics, such as low FA in specific regions). GFM appropriately assembles a collection of unsupervised techniques with Non-negative Matrix Factorization to generate biclusters, rather than averaging across all subjects and all their characteristics. DTI tract-based spatial statistics images, which output is the locally maximal FA projected onto the group white matter skeleton, were analyzed in 47 SZ and 36 healthy subjects, identifying 8 biclusters. The mean FA of the voxels of each bicluster was significantly different from those of other SZ subjects or 36 healthy controls. The eight biclusters were organized into four more general patterns of low FA in specific regions: 1) genu of corpus callosum (GCC), 2) fornix (FX) + external capsule (EC), 3) splenium of CC (SCC). +. retrolenticular limb (RLIC) + posterior limb (PLIC) of the internal capsule, and 4) anterior limb of the internal capsule. These patterns were significantly associated with particular clinical features: Pattern 1 (GCC) with bizarre behavior, pattern 2 (FX + EC) with prominent delusions, and pattern 3 (SCC + RLIC + PLIC) with negative symptoms including disorganized speech. The uncovered patterns suggest that SZ is a heterogeneous group of disorders that can be distinguished by different patterns of FA reductions associated with distinct clinical features. © 2015 Elsevier Inc.


Author Keywords
Biclusters;  Conceptual clustering;  Consensus clustering;  Fractional anisotropy;  Fuzzy clustering;  Generalized factorization;  Model-based clustering;  Non-negative Matrix Factorization;  Positive and negative symptoms;  Possibilistic clustering;  Relational clustering;  Schizophrenias;  White matter


Document Type: Article
Source: Scopus

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Wilkinson, L.a , Steel, A.a , Mooshagian, E.a b c , Zimmermann, T.a b , Keisler, A.a , Lewis, J.D.a , Wassermann, E.M.a
Online feedback enhances early consolidation of motor sequence learning and reverses recall deficit from transcranial stimulation of motor cortex
(2015) Cortex, 71, pp. 134-147. 

DOI: 10.1016/j.cortex.2015.06.012


a Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
b Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences and the Henry M. Jackson Foundation, United States
c Washington University School of Medicine, Department of Anatomy and Neurobiology, Saint Louis, MO, United States


Abstract
Feedback and monetary reward can enhance motor skill learning, suggesting reward system involvement. Continuous theta burst (cTBS) transcranial magnetic stimulation (TMS) of the primary motor area (M1) disrupts processing, reduces excitability and impairs motor learning. To see whether feedback and reward can overcome the learning impairment associated with M1 cTBS, we delivered real or sham stimulation to two groups of participants before they performed a motor sequence learning task with and without feedback. Participants were trained on two intermixed sequences, one occurring 85% of the time (the "probable" sequence) and the other 15% of the time (the "improbable" sequence). We measured sequence learning as the difference in reaction time (RT) and error rate between probable and improbable trials (RT and error difference scores). Participants were also tested for sequence recall with the same indices of learning 60 min after cTBS. Real stimulation impaired initial sequence learning and sequence knowledge recall as measured by error difference scores and impaired sequence knowledge recall as measured by RT difference score. Relative to non-feedback learning, the introduction of feedback during sequence learning improved subsequent sequence knowledge recall indexed by RT difference score, in both real and sham stimulation groups and feedback reversed the RT difference score based sequence knowledge recall impairment from real cTBS that we observed in the non-feedback learning condition. Only the real cTBS group in the non-feedback condition showed no evidence of explicit sequence knowledge when tested at the end of the study. Feedback improves recall of implicit and explicit motor sequence knowledge and can protect sequence knowledge against the effect of M1 inhibition. Adding feedback and monetary reward/punishment to motor skill learning may help overcome retention impairments or accelerate training in clinical and other settings. © 2015.


Author Keywords
Consolidation;  Motor cortex;  Motor skill;  Sequence learning;  Serial reaction time task;  Theta burst stimulation


Document Type: Article
Source: Scopus

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Nobuta, H.a e , Cilio, M.R.a b , Danhaive, O.a , Tsai, H.-H.a e , Tupal, S.f , Chang, S.M.a e , Murnen, A.a , Kreitzer, F.g , Bravo, V.g , Czeisler, C.i , Gokozan, H.N.i , Gygli, P.i , Bush, S.i , Weese-Mayer, D.E.j , Conklin, B.c g , Yee, S.-P.h , Huang, E.J.d , Gray, P.A.f , Rowitch, D.a c e , Otero, J.J.a d e i
Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome
(2015) Acta Neuropathologica, 130 (2), pp. 171-183. 

DOI: 10.1007/s00401-015-1441-0


a Department of Pediatrics, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
b Department of Neurology, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
c Department of Medicine, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
d Department of Pathology, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
e Department of Howard Hughes Medical Institute, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, United States
f Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States
g Gladstone Institutes, 1650 Owens Street, San Francisco, CA, United States
h Department of Genetics and Developmental Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, United States
i Department of Pathology, The Ohio State University College of Medicine, 4169 Graves Hall, 333 W 10th Ave, Columbus, OH, United States
j Center for Autonomic Medicine in Pediatrics (CAMP), Ann and Robert H. Lurie Children’s Hospital of Chicago and Stanley Manne Children’s Research Institute, Northwestern University Feinberg School of Medicine, 225 East Chicago Avenue, Box 165, Chicago, IL, United States


Abstract
Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B?8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B?8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B?8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS. © 2015, The Author(s).


Author Keywords
Congenital central hypoventilation syndrome;  Locus coeruleus;  Noradrenergic system;  PHOX2B


Document Type: Article
Source: Scopus

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Kudesia, R.S.a , Nyima, V.T.b
Mindfulness Contextualized: An Integration of Buddhist and Neuropsychological Approaches to Cognition
(2015) Mindfulness, 6 (4), pp. 910-925. 

DOI: 10.1007/s12671-014-0337-8


a Olin Business School, Washington University in St. Louis, Campus Box 1156, St. Louis, MO, United States
b New Jonang Buddhist Community, Dallas, TX, United States


Abstract
A significant limiting factor in the current mindfulness literature is that while core concepts have been incorporated into Western psychology, they appear in a decontextualized manner. This causes construct validity issues as evidenced by vastly diverging definitions of key terms. In this paper, a behavioral scientist and Buddhist monk collaborate to help address this limitation. We begin with an in-depth and accessible review of Buddhist psychology from a particular Tibetan tradition. This review covers descriptive models of core cognitive processes as well as the prescriptive mind training approach designed to refine these processes. Instead of attempting to transfer these Buddhist constructs to Western psychology piecemeal, however, we then highlight important higher-order parallels between the two disciplines. These parallels clarify the cognitive underpinnings of enlightenment and how enlightenment differs from conventional modes of stimulus processing. We close by offering a contextualized definition of mindfulness that integrates both Buddhist and Western accounts of the phenomenon. © 2014, Springer Science+Business Media New York.


Author Keywords
Buddhism;  Construct;  Cross-cultural;  Mindfulness;  Psychology


Document Type: Article
Source: Scopus

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Lucey, B.P.a b , Gonzales, C.c , Das, U.d , Li, J.d , Siemers, E.R.c , Slemmon, J.R.e , Bateman, R.J.a b , Huang, Y.f , Fox, G.B.d , Claassen, J.A.H.R.g , Slats, D.g , Verbeek, M.M.h , Tong, G.i , Soares, H.j , Savage, M.J.k , Kennedy, M.l , Forman, M.m , Sjögren, M.n , Margolin, R.o , Chen, X.p , Farlow, M.R.q , Dean, R.A.c , Waring, J.F.d
An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter
(2015) Alzheimer's Research and Therapy, 7 (1), art. no. 53, . 

DOI: 10.1186/s13195-015-0136-z


a Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO, United States
b Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St Louis, MO, United States
c Eli Lilly and Company, Lilly Corporate Center, 893 South Delaware Avenue, Indianapolis, IN, United States
d AbbVie Inc., 1 N. Waukegan Road, North Chicago, IL, United States
e Johnson and Johnson, One Johnson and Johnson Plaza, New Brunswick, NJ, United States
f Department of Medicine, St. Luke's Hospital, 232 South Woodsmill Road, Chesterfield, MO, United States
g Department of Geriatric Medicine, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Route 925, PO Box 9101, Nijmegen, Netherlands
h Department of Neurology, Neurochemistry Lab, Radboud University Nijmegen Medical Center, PO Box 9101, Nijmegen, Netherlands
i Lundbeck LLC, Four Parkway North, Deerfield, IL, United States
j Bristol-Myers Squibb, 311 Pennington-Rocky Hill Road, Pennington, NJ, United States
k Merck and Company, RY50-1D-131 126 East Lincoln Avenue, PO Box 2000, Rahway, NJ, United States
l Merck and Company, 33 Avenue Louis Pasteur, Boston, MA, United States
m Merck and Company, 2000 Galloping Hill Road, Kenilworth, NJ, United States
n Mental Health Centre Ballerup, Capital Region of Denmark, Maglevanget 2, Ballerup, Denmark
o CereSpir, Inc., 41 Madison Avenue, 31st Floor, New York, NY, United States
p Boeringher Ingelheim, 900 Ridgebury Road, Ridgefield, CT, United States
q Department of Neurology, Indiana University School of Medicine, Goodman Hall Suite 4700, 355 West 16th Street, Indianapolis, IN, United States


Abstract
Introduction: Amyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time. Methods: Grouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time. Results: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors' studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection. Conclusions: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs. © 2015 Lucey et al.


Document Type: Article
Source: Scopus

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Patel, G.H.a b , Yang, D.c , Jamerson, E.C.d , Snyder, L.H.e , Corbetta, M.e f g , Ferrera, V.P.a h
Functional evolution of new and expanded attention networks in humans
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (30), pp. 9454-9459. 

DOI: 10.1073/pnas.1420395112


a Department of Psychiatry, Columbia University, College of Phys. and Surg., New York, NY, United States
b New York State Psychiatric Institute, New York, NY, United States
c State University of New York, College of Optometry, New York, NY, United States
d Columbia University, New York, NY, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, Saint Louis, MO, United States
f Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
g Department of Radiology, Washington University, School of Medicine, Saint Louis, MO, United States
h Department of Neuroscience, Columbia University, New York, NY, United States


Abstract
Macaques are often used as a model system for invasive investigations of the neural substrates of cognition. However, 25 million years of evolution separate humans and macaques from their last common ancestor, and this has likely substantially impacted the function of the cortical networks underlying cognitive processes, such as attention. We examined the homology of frontoparietal networks underlying attention by comparing functional MRI data from macaques and humans performing the same visual search task. Although there are broad similarities, we found fundamental differences between the species. First, humans have more dorsal attention network areas than macaques, indicating that in the course of evolution the human attention system has expanded compared with macaques. Second, potentially homologous areas in the dorsal attention network have markedly different biases toward representing the contralateral hemifield, indicating that the underlying neural architecture of these areas may differ in the most basic of properties, such as receptive field distribution. Third, despite clear evidence of the temporoparietal junction node of the ventral attention network in humans as elicited by this visual search task, we did not find functional evidence of a temporoparietal junction in macaques. None of these differences were the result of differences in training, experimental power, or anatomical variability between the two species. The results of this study indicate that macaque data should be applied to human models of cognition cautiously, and demonstrate how evolution may shape cortical networks.


Author Keywords
Attention;  Cortex;  FMRI;  Human;  Monkey


Document Type: Article
Source: Scopus

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Bugg, J.M., Braver, T.S.
Proactive control of irrelevant task rules during cued task switching
(2015) Psychological Research, 17 p. Article in Press. 

DOI: 10.1007/s00426-015-0686-5


Department of Psychology, Campus Box 1125, Washington University in St. Louis, St. Louis, MO, United States


Abstract
In task-switching paradigms, participants are often slower on incongruent than congruent trials, a pattern known as the task-rule congruency effect. This effect suggests that irrelevant task rules or associated responses may be retrieved automatically in spite of task cues. The purposeof the present study was to examine whether the task-rule congruency effect may be modulated via manipulations intended to induce variation in proactive control. Manipulating the proportion of congruent to incongruent trials strongly influenced the magnitude of the task-rule congruency effect. The effect was significantly reduced in a mostly incongruent list relative to a mostly congruent list, a pattern that was observed for not only biased but also 50 % congruent items. This finding implicates a role for global attentional control processes in the task-rule congruency effect. In contrast, enhancing the preparation of relevant (cued) task rules by the provision of a monetary incentive substantially reduced mixing costs but did not affect the task-rule congruency effect. These patterns support the view that there may be multiple routes by which proactive control can influence task-switching performance; however, only select routes appear to influence the automatic retrieval of irrelevant task rules. © 2015 Springer-Verlag Berlin Heidelberg


Document Type: Article in Press
Source: Scopus

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Parsa, P.V.a b , D'Souza, R.D.a b c , Vijayaraghavan, S.a b
Signaling between periglomerular cells reveals a bimodal role for GABA in modulating glomerular microcircuitry in the olfactory bulb
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (30), pp. 9478-9483. 

DOI: 10.1073/pnas.1424406112


a Department of Physiology and Biophysics, University of Colorado, School of Medicine, Aurora, CO, United States
b Neuroscience Program, University of Colorado, School of Medicine, Aurora, CO, United States
c Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
In the mouse olfactory bulb glomerulus, the GABAergic periglomerular (PG) cells provide a major inhibitory drive within the microcircuit. Here we examine GABAergic synapses between these interneurons. At these synapses, GABA is depolarizing and exerts a bimodal control on excitability. In quiescent cells, activation of GABAA receptors can induce the cells to fire, thereby providing a means for amplification of GABA release in the glomerular microcircuit via GABA-induced GABA release. In contrast, GABA is inhibitory in neurons that are induced to fire tonically. PG-PG interactions are modulated by nicotinic acetylcholine receptors (nAChRs), and our data suggest that changes in intracellular calcium concentrations triggered by nAChR activation can be amplified by GABA release. Our results suggest that bidirectional control of inhibition in PG neurons can allow for modulatory inputs, like the cholinergic inputs from the basal forebrain, to determine threshold set points for filtering out weak olfactory inputs in the glomerular layer of the olfactory bulb via the activation of nAChRs.


Author Keywords
Cholinergic;  Excitatory GABA;  Interneurons;  Nicotinic;  Normalization


Document Type: Article
Source: Scopus

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Joshi, P.K.a ib , Esko, T.b c d e , Mattsson, H.f g , Eklund, N.f , Gandin, I.h , Nutile, T.i , Jackson, A.U.j , Schurmann, C.k l , Smith, A.V.m n , Zhang, W.o p , Okada, Y.q r , Stancáková, A.s , Faul, J.D.t , Zhao, W.u , Bartz, T.M.v , Concas, M.P.w , Franceschini, N.x , Enroth, S.y , Vitart, V.z , Trompet, S.aa , Guo, X.ab ac , Chasman, D.I.ad , O'Connel, J.R.ae , Corre, T.af ag , Nongmaithem, S.S.ah , Chen, Y.ai , Mangino, M.aj ak , Ruggiero, D.i , Traglia, M.al , Farmaki, A.-E.am , Kacprowski, T.an , Bjonnes, A.ao , Van Der Spek, A.ap , Wu, Y.aq , Giri, A.K.ar , Yanek, L.R.as , Wang, L.at , Hofer, E.au av , Rietveld, C.A.aw , McLeod, O.ax , Cornelis, M.C.ay az , Pattaro, C.ba ci , Verweij, N.bb , Baumbach, C.bc bd be , Abdellaoui, A.bf , Warren, H.R.bg bh , Vuckovic, D.h , Mei, H.bi , Bouchard, C.bj , Perry, J.R.B.bk , Cappellani, S.bl , Mirza, S.S.ap , Benton, M.C.bm , Broeckel, U.bn , Medland, S.E.bo , Lind, P.A.bo , Malerba, G.bp , Drong, A.bq , Yengo, L.br , Bielak, L.F.u , 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I.aj , Gottesman, O.k , Graff, M.x , Grodstein, F.az , Gu, C.dn , Haley, C.z do , Hammond, C.J.aj , Harris, S.E.da dh , Harris, T.B.dp , Hastie, N.D.z , Heard-Costa, N.L.df dq , Heikkilä, K.dr , Hocking, L.J.ds , Homuth, G.an , Hottenga, J.-J.bf , Huang, J.dt , Huffman, J.E.z , Hysi, P.G.aj , Ikram, M.A.ap du , Ingelsson, E.bq dv , Joensuu, A.f g , Johansson, A.y dw , Jousilahti, P.dx , Jukema, J.W.dy , Kähönen, M.dz , Kamatani, Y.r , Kanoni, S.cd , Kerr, S.M.z , Khan, N.M.ar , Koellinger, P.aw , Koistinen, H.A.ea eb ec , Kooner, M.K.p , Kubo, M.ed , Kuusisto, J.ee , Lahti, J.ef eg , Launer, L.J.dp , Lea, R.A.bm , Lehne, B.o , Lehtimäki, T.eh , Liewald, D.C.M.dh , Lind, L.ei , Loh, M.o hx , Lokki, M.-L.ej , London, S.J.ek , Loomis, S.J.el , Loukola, A.dr , Lu, Y.k l , Lumley, T.em , Lundqvist, A.en , Männistö, S.dx , Marques-Vidal, P.eo , Masciullo, C.al , Matchan, A.ep , Mathias, R.A.as eq , Matsuda, K.er , Meigs, J.B.es , Meisinger, C.bd , Meitinger, T.et eu , Menni, C.aj , Mentch, F.D.cf , Mihailov, E.b , Milani, L.b , Montasser, M.E.ae , Montgomery, G.W.ev , Morrison, A.cz , Myers, R.H.ew , Nadukuru, R.k , Navarro, P.z , Nalis, M.b , Nieminen, M.S.ex , Nolte, I.M.bt , O'Connor, G.T.df ey , Ogunniyi, A.ez , Padmanabhan, S.fa , Palmas, W.R.cv , Pankow, J.S.fb , Patarcic, I.fc , Pavani, F.ba ci , Peyser, P.A.u , Pietilainen, K.g eb fd , Poulter, N.fe , Prokopenko, I.ff , Ralhan, S.fg , Redmond, P.dg , Rich, S.S.fh , Rissanen, H.en , Robino, A.bl , Rose, L.M.ad , Rose, R.fi , Sala, C.al , Salako, B.ez , Salomaa, V.dx , Sarin, A.-P.f g , Saxena, R.ao , Schmidt, H.fj , Scott, L.J.j , Scott, W.R.o p , Sennblad, B.ax fk , Seshadri, S.df dq , Sever, P.fe , Shrestha, S.ah , Smith, B.H.fl , Smith, J.A.u , Soranzo, N.ep , Sotoodehnia, N.fm , Southam, L.bq ep , Stanton, A.V.fn , Stathopoulou, M.G.fo , Strauch, K.be fp , Strawbridge, R.J.ax , Suderman, M.J.bv , Tandon, N.fq , Tang, S.-T.fr , Taylor, K.D.ab ac , Tayo, B.O.fs , Töglhofer, A.M.fj , Tomaszewski, M.ck ft , Tšernikova, N.b fu , Tuomilehto, J.ea fv fw , Uitterlinden, A.G.ap fx , Vaidya, D.as fy , Van Hylckama Vlieg, A.co , Van Setten, J.ce , Vasankari, T.fz , Vedantam, S.c d e , Vlachopoulou, E.ej , Vozzi, D.bl , Vuoksimaa, E.dr , Waldenberger, M.bc bd , Ware, E.B.u , Wentworth-Shields, W.cp , Whitfield, J.B.ga , Wild, S.hy , Willemsen, G.bf , Yajnik, C.S.gb , Yao, J.ab , Zaza, G.gc , Zhu, X.gd , Salem, R.M.c d e , Melbye, M.cn ge , Bisgaard, H.ch , Samani, N.J.ck ft , Cusi, D.cl , Mackey, D.A.cm , Cooper, R.S.fs , Froguel, P.br ff , Pasterkamp, G.ce , Grant, S.F.A.cf gf , Hakonarson, H.cf gf , Ferrucci, L.gg , Scott, R.A.bk , Morris, A.D.gh , Palmer, C.N.A.gi , Dedoussis, G.am , Deloukas, P.cd gj , Bertram, L.bz gk hz , Lindenberger, U.by , Berndt, S.I.bw , Lindgren, C.M.d bq , Timpson, N.J.bv , Tönjes, A.gl , Munroe, P.B.bg bh , Sørensen, T.I.A.bv cj gm , Rotimi, C.N.bu , Arnett, D.K.gn , Oldehinkel, A.J.go , Kardia, S.L.R.u , Balkau, B.gp , Gambaro, G.gq , Morris, A.P.b bq gr , Eriksson, J.G.dx eg gs gt gu , Wright, M.J.gv , Martin, N.G.ga , Hunt, S.C.gw , Starr, J.M.dh gx , Deary, I.J.dg dh , Griffiths, L.R.bm , Tiemeier, H.ap gy , Pirastu, N.h bl , Kaprio, J.g dr gz , Wareham, N.J.bk , Pérusse, L.ha , Wilson, J.G.hb , Girotto, G.h , Caulfield, M.J.bg bh , Raitakari, O.hc hd , Boomsma, D.I.bf , Gieger, C.bc bd be , Van Der Harst, P.bb cs he , Hicks, A.A.ba ci , Kraft, P.dc , Sinisalo, J.ex , Knekt, P.en , Johannesson, M.hf , Magnusson, P.K.E.hg , Hamsten, A.ax , Schmidt, R.au , Borecki, I.B.hh , Vartiainen, E.dx , Becker, D.M.as hi , Bharadwaj, D.ar ia , Mohlke, K.L.aq , Boehnke, M.j , Van Duijn, C.M.ap , Sanghera, D.K.hj hk , Teumer, A.cw , Zeggini, E.ep , Metspalu, A.b fu , Gasparini, P.bl hl , Ulivi, S.bl , Ober, C.cp , Toniolo, D.al , Rudan, I.a , Porteous, D.J.da dh , Ciullo, M.i , Spector, T.D.aj , Hayward, C.z , Dupuis, J.ai df , Loos, R.J.F.k l hm , Wright, A.F.z , Chandak, G.R.ah hn , Vollenweider, P.eo , Shuldiner, A.R.ae ho hp , Ridker, P.M.ad , Rotter, J.I.ab ac , Sattar, N.hq , Gyllensten, U.y , North, K.E.x hr , Pirastu, M.w , Psaty, B.M.hs ht , Weir, D.R.t , Laakso, M.ee , Gudnason, V.m n , Takahashi, A.r , Chambers, J.C.o p hu , Kooner, J.S.p fr hu , Strachan, D.P.hv , Campbell, H.a , Hirschhorn, J.N.c d e , Perola, M.b f , Polašek, O.a fc , Wilson, J.F.a z
Directional dominance on stature and cognition in diverse human populations
(2015) Nature, 523 (7561), pp. 459-462. 

DOI: 10.1038/nature14618


a Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom
b Estonian Genome Center, University of Tartu, Riia 23b, Tartu, Estonia
c Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, MA, United States
d Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, MA, United States
e Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, MA, United States
f Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, Finland
g Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, Finland
h Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, Trieste, Italy
i Institute of Genetics and Biophysics 'A.Buzzati-Traverso', CNR, via Pietro Castellino, 111, Naples, Italy
j Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MA, United States
k Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
l Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
m Icelandic Heart Association, Holtasmari 1, Kopavogur, Iceland
n Faculty of Medicine, University of Iceland, Reykjavik, Iceland
o Department of Epidemiologyand Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom
p Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, United Kingdom
q Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
r Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan
s Department of Medicine, University of Eastern Finland, Kuopio, Finland
t Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, MI, United States
u Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, United States
v Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Seattle, WA, United States
w Institute of Population Genetics, National Research Council, Trav. La Crucca n. 3 - Reg. Baldinca, Sassari, Italy
x Epidemiology, University of North Carolina, 137 E. Franklin St., Chapel Hill, NC, United States
y Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden
z MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh, United Kingdom
aa Department of Gerontology and Geriatrics, Leiden University, Medical Center, PO Box 9600, Leiden, Netherlands
ab Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, CA, United States
ac Department of Pediatrics, Harbor-UCLA, Medical Center, Torrance, CA, United States
ad Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, 900 Commonwealth Avenue, East, Boston, MA, United States
ae Division of Endocrinology, Diabetes, and Nutrition, Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland, School of Medicine, 685 Baltimore St. MSTF, Baltimore, MD, United States
af Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, Lausanne, Switzerland
ag Swiss Institute of Bioinformatics, Quartier Sorge - batiment génopode, Lausanne, Switzerland
ah Genomic Research on Complex Diseases (GRC) Group, CSIR, Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, India
ai Department of Biostatistics, Boston University, School of Public Health, 801 Massachusetts Avenue, Boston, MA, United States
aj Department of Twin Research and Genetic Epidemiology, King's College London, South Wing, Block D Westminster Bridge Road, London, United Kingdom
ak NIHR, Biomedical Research Centre, Guy's and St. Thomas' Foundation Trust, Westminster Bridge Road, London, United Kingdom
al Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy
am Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens, Greece
an Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, Greifswald, Germany
ao Center for Human Genetic Research, Massachusetts General Hospital, 55 Fruit StreetMA, United States
ap Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, Netherlands
aq Department of Genetics, University of North Carolina, Chapel Hill, NC, United States
ar Genomics and Molecular Medicine, CSIR, Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, India
as Gene STAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
at Department of Genetics, Washington University, School of Medicine, 4444 Forest Park Boulevard, Saint Louis, MO, United States
au Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, Austria
av Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz2, Graz, Austria
aw Erasmus School of Economics, Erasmus University Rotterdam, Burgemeester Oudlaan 50, Rotterdam, Netherlands
ax Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, CMM L8:03, Solna, Stockholm, Sweden
ay Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood, Boston, MA, United States
az Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, MA, United States
ba Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy
bb University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, Netherlands
bc Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, Germany
bd Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, Germany
be Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, Germany
bf Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Amsterdam, Netherlands
bg Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom
bh NIHR, Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, Charterhouse Square, London, United Kingdom
bi Department of Medicine, University of Mississippi, Medical Center, 2500 N. State St., Jackson, MS, United States
bj Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, LA, United States
bk MRC Epidemiology Unit, University of Cambridge, School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom
bl Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', via dell'Istria 65, Trieste, Italy
bm Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, GPO Box 2434, Brisbane, QLD, Australia
bn Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI, United States
bo Quantitative Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, Australia
bp Dipartimento di Scienze della Vita e della Riproduzione, University of Verona, Strada Le Grazie 15, Verona, Italy
bq Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, United Kingdom
br CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, Lille, France
bs Department of Biostatistics, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL, United States
bt Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, P.O. box 30.001, Groningen, Netherlands
bu Center for Research on Genomics and Global Health, National Human Genome Research Institute, 12 South Dr., Bethesda, MD, United States
bv MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, United Kingdom
bw Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, United States
bx Cancer Genomics Research Laboratory, National Cancer Institute, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States
by Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin, Germany
bz Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, Germany
ca Charité Research Group on Geriatrics, Charité - Universitätsmedizin, Reinickendorferstr. 61, Berlin, Germany
cb Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany
cc Division of Population Health Sciences, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee, United Kingdom
cd William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, United Kingdom
ce Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Netherlands
cf Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA, United States
cg Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, United Kingdom
ch COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Allé 34, Copenhagen, Denmark
ci Institute of the University of Lübeck, Lübeck, Germany
cj Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, Denmark
ck Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester, United Kingdom
cl Department of Health Sciences, University of Milan, via A. di Rudinì 8, Milan, Italy
cm Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, 2 Verdun Street, Perth, WA, Australia
cn Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, Denmark
co Clinical Epidemiology, Leiden University, Medical Center, PO Box 9600, Leiden, Netherlands
cp Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, IL, United States
cq Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, CA, United States
cr Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, Netherlands
cs Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, Netherlands
ct Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, Gower Street, London, United Kingdom
cu University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, Groningen, Netherlands
cv Department of Medicine, Columbia University, 622 W. 168th Street, New York, NY, United States
cw Institute for Community Medicine, University Medicine Greifswald, W.-Rathenau-Str. 48, Greifswald, Germany
cx Department of Economics, Cornell University, 480 Uris Hall, Ithaca, NY, United States
cy Department of Economics, Center for Economic and Social Research, University of Southern California, 314C Dauterive Hall, 635 Downey Way, Los Angeles, CA, United States
cz Human Genetics Center, School of Public Health, University of Texas, Health Science Center at Houston, 1200 Pressler Street, Houston, TX, United States
da Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
db McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
dc Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, MA, United States
dd Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, United States
de College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, College Office, Level 10, Dundee, United Kingdom
df National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, MA, United States
dg Psychology, University of Edinburgh, 7 George Square, Edinburgh, United Kingdom
dh Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh, United Kingdom
di Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald, Germany
dj Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Genève 14, Switzerland
dk Robertson Centre, University of Glasgow, Boyd Orr Building, Glasgow, United Kingdom
dl Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, United States
dm Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald, Germany
dn Division of Biostatistics, Washington University, 660 S Euclid, St. Louis, MO, United States
do Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom
dp National Institutes on Aging, National Institutes of Health, Bethesda, MD, United States
dq Department of Neurology, Boston University, School of Medicine, 72 E Concord St, Boston, MA, United States
dr Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, Finland
ds Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
dt State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, 197 Rui Jin Er Road, Shanghai, China
du Department of Radiology, Erasmus Medical Center, PO Box 2040, Rotterdam, Netherlands
dv Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
dw Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
dx Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, Finland
dy Department of Cardiology, Leiden University, Medical Center, C5-P, PO Box 9600, Leiden, Netherlands
dz Department of Clinical Physiology, University of Tampere, Tampere University Hospital, P.O. Box 2000, Tampere, Finland
ea Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, Helsinki, Finland
eb Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, Finland
ec Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki, Finland
ed Laboratory for Genotyping Development, RCfIMS, 1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa, Japan
ee Department of Medicine, University of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
ef Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, Helsinki, Finland
eg Folkhälsan Reasearch Centre, University of Helsinki, PB 63, Helsinki, Finland
eh Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland
ei Department of Medical Sciences, University Hospital, Uppsala, Sweden
ej Transplantation laboratory, Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki, Finland
ek National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, United States
el Ophthalmology, Massachusetts Eye and Ear, 243 Charles Street, Boston, MA, United States
em Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, New Zealand
en Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, Finland
eo Department of Internal Medicine, University Hospital, Rue du Bugnon 44, Lausanne, Switzerland
ep Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
eq Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
er Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan
es Division of General Internal Medicine, Massachusetts General Hospital, 50 Staniford St, Boston, MA, United States
et Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, Germany
eu Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, München, Germany
ev Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, Australia
ew Genome Science Institute, Boston University, School of Medicine, 72 East Concord Street, E-304, Boston, MA, United States
ex HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, Finland
ey Pulmonary Center, Department of Medicine, Boston University, School of Medicine, 72 E Concord St, Boston, MA, United States
ez Department of Medicine, University of Ibadan, Ibadan, Nigeria
fa ICAMS, University of Glasgow, 126 University Way, Glasgow, United Kingdom
fb Division of Epidemiology and Community Health, University of Minnesota, 1300 S 2nd Street, Minneapolis, MN, United States
fc Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, Split, Croatia
fd Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, Helsinki, Finland
fe International Centre for Circulatory Health, Imperial College London, London, United Kingdom
ff Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom
fg Department of Cardiology and Cardio thoracic Surgery, Hero DMC Heart Institute, Civil Lines, Ludhiana, India
fh Department Public Health Sciences, University of Virginia, School of Medicine, 3232 West Complex, Charlottesville, VA, United States
fi Department of Psychological and Brain Sciences, Indiana University Bloomington, 1101 E. 10th Street, Bloomington, IN, United States
fj Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, Austria
fk Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
fl University of Dundee, Kirsty Semple Way, Dundee, United Kingdom
fm Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Seattle, WA, United States
fn Molecular and Cellular Therapeutics, Royal College of Surg. in Ireland, St. Stephen's Green, Dublin 2, Ireland
fo UMR INSERM U1122, IGE-PCV 'Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire', INSERM, University of Lorraine, 30 Rue Lionnois, Nancy, France
fp Institute of Medical Informatics, Biometry and Epidemiology, Department of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
fq Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, India
fr National Heart and Lung Institute, Imperial College London, Du Cane Road, London, United Kingdom
fs Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States
ft NIHR, Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester, United Kingdom
fu Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, Estonia
fv Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
fw Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
fx Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, Netherlands
fy Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
fz Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, Finland
ga Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, Australia
gb Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, India
gc Renal Unit, Department of Medicine, University of Verona, Piazzale A. Stefani 1, Verona, Italy
gd Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States
ge Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA, United States
gf Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA, United States
gg Translational Gerontology Branch, National institute on Aging, Baltimore, MD, United States
gh Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, No. 9 Edinburgh Bioquarter, 9 Little France Road, Edinburgh, United Kingdom
gi Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells Hospital, School of Medicine, Dundee, United Kingdom
gj Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
gk Faculty of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London, United Kingdom
gl Department of Medicine, University of Leipzig, Leipzig, Germany
gm Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark
gn Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, United States
go Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen, Netherlands
gp Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, Villejuif, France
gq Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, Rome, Italy
gr Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool, United Kingdom
gs Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, Helsinki, Finland
gt Vasa Central Hospital, Sandviksgatan 2-4, Vasa, Finland
gu Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, Finland
gv Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, QLD, Australia
gw Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Salt Lake City, UT, United States
gx Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh, United Kingdom
gy Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, Netherlands
gz National Institute for Health and Welfare (THL), P.O. Box 30, Mannerheimintie 166, Helsinki, Finland
ha Department of Kinesiology, Laval University, 2300 rue de la TerrasseQC, Canada
hb Department of Physiology and Biophysics, University of Mississippi, Medical Center, 2500 N. State Street, Jackson, MS, United States
hc Department of Clinical Physiology and Nuclear Medicine, University of Turku, Turku University Hospital, Turku, Finland
hd Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, Finland
he University of Groningen, University Medical, Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, Netherlands
hf Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, Sweden
hg Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, Sweden
hh Department of Genetics and Biostatistics, Washington University, School of Medicine, 4444 Forest Park Boulevard, Saint Louis, MO, United States
hi Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
hj Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, OK, United States
hk Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
hl Sidra Medical and Research Centre, Doha, Qatar
hm Mindich Child Healthand Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, United States
hn Genome Institute of Singapore, 60 Biopolis Street, 02-01 Genome, Singapore, Singapore
ho Programfor Personalised and Genomic Medicine, Department of Medicine, University of Maryland, School of Medicine, 685 Baltimore St. MSTF, Baltimore, MD, United States
hp Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, MD, United States
hq BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, United Kingdom
hr Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin Street, Chapel Hill, NC, United States
hs Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Seattle, WA, United States
ht Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Seattle, WA, United States
hu Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London, United Kingdom
hv Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, United Kingdom
hw Steno Diabetes Centre, Niels Steensens Vej 2, Gentofte, Denmark
hx Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (ASTAR), 8A Biomedical Grove, Singapore, Singapore
hy Centre for Population Health Sciences, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, United Kingdom
hz Institutes for Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
ia School of Biotechnology, Jawaharlal Nehru University, New Delhi, India


Abstract
Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10-300, 2.1 × 10-6, 2.5 × 10-10 and 1.8 × 10-10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been. © 2015 Macmillan Publishers Limited. All rights reserved.


Document Type: Article
Source: Scopus

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Grill, J.D.a e f , Bateman, R.J.b , Buckles, V.b , Oliver, A.b , Morris, J.C.b , Masters, C.L.c , Klunk, W.E.d , Ringman, J.M.a
A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease
(2015) Alzheimer's Research and Therapy, 7 (1), art. no. 50, . 

DOI: 10.1186/s13195-015-0135-0


a Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, 10911 Weyburn Ave, Ste 200, Los Angeles, CA, United States
b Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO, United States
c Mental Health Research Institute, University of Melbourne, Level 5, Kenneth Myer Building, 30 Royal Parade, Parkville, VIC, Australia
d Department of Neurology, University of Pittsburgh, Room 1422 WPIC, 3811 O'Hara Street, Pittsburgh, PA, United States
e Department of Psychiatry and Human Behavior, UCI Institute of Memory Impairments and Neurological Disorders, University of California, 3206 Biological Sciences III, Irvine, CA, United States


Abstract
Introduction: Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer's disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations. Methods: To better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer's Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate. Results: Eighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered. Conclusions: These results suggest that the availability of clinical trials to prevent ADAD can affect persons' desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required. © 2015 Grill et al.


Document Type: Article
Source: Scopus

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Estes, A.a b , Zwaigenbaum, L.c , Gu, H.d e , St. John, T.a , Paterson, S.f , Elison, J.T.g , Hazlett, H.e i , Botteron, K.j , Dager, S.R.h , Schultz, R.T.f , Kostopoulos, P.k , Evans, A.k , Dawson, G.i l , Eliason, J.c , Alvarez, S.a , Piven, J.e i
Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life
(2015) Journal of Neurodevelopmental Disorders, 7 (1), art. no. 9117, . 

DOI: 10.1186/s11689-015-9117-6


a Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
b Department of Psychology, University of Washington, Seattle, WA, United States
c Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
d Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States
e Carolina Institute for Developmental Disabilities, Chapel Hill, NC, United States
f Center for Autism Research, Department of Pediatrics, Children's Hospital of Pennsylvania, University of Pennsylvania, Philadelphia, PA, United States
g Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
h Department of Radiology, University of Washington, Seattle, WA, United States
i Department of Psychiatry, Duke University, Durham, NC, United States
j Department of Psychiatry, Washington University, St. Louis, MO, United States
k Montreal Neurological Institute, McGill University, Montreal, QB, Canada
l Autism Speaks Foundation, New York, NY, United States


Abstract
Background: To delineate the early progression of autism spectrum disorder (ASD) symptoms, this study investigated developmental characteristics of infants at high familial risk for ASD (HR), and infants at low risk (LR). Methods: Participants included 210 HR and 98 LR infants across 4 sites with comparable behavioral data at age 6, 12, and 24 months assessed in the domains of cognitive development (Mullen Scales of Early Learning), adaptive skills (Vineland Adaptive Behavioral Scales), and early behavioral features of ASD (Autism Observation Scale for Infants). Participants evaluated according to the DSM-IV-TR criteria at 24 months and categorized as ASD-positive or ASD-negative were further stratified by empirically derived cutoff scores using the Autism Diagnostic Observation Schedule yielding four groups: HR-ASD-High, HR-ASD-Moderate (HR-ASD-Mod), HR-ASD-Negative (HR-Neg), and LR-ASD-Negative (LR-Neg). Results: The four groups demonstrated different developmental trajectories that became increasingly distinct from 6 to 24 months across all domains. At 6 months, the HR-ASD-High group demonstrated less advanced Gross Motor and Visual Reception skills compared with the LR-Neg group. By 12 months, the HR-ASD-High group demonstrated increased behavioral features of ASD and decreased cognitive and adaptive functioning compared to the HR-Neg and LR-Neg groups. By 24 months, both the HR-ASD-High and HR-ASD-Moderate groups demonstrated differences from the LR- and HR-Neg groups in all domains. Conclusions: These findings reveal atypical sensorimotor development at 6 months of age which is associated with ASD at 24 months in the most severely affected group of infants. Sensorimotor differences precede the unfolding of cognitive and adaptive deficits and behavioral features of autism across the 6- to 24-month interval. The less severely affected group demonstrates later symptom onset, in the second year of life, with initial differences in the social-communication domain. © 2015 Estes et al.


Document Type: Article
Source: Scopus

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Chung, W.K.a , Martin, K.b , Jalas, C.c , Braddock, S.R.b , Juusola, J.d , Monaghan, K.G.d , Warner, B.e , Franks, S.f , Yudkoff, M.g , Lulis, L.g , Rhodes, R.H.h , Prasad, V.i , Torti, E.b , Cho, M.T.d , Shinawi, M.j
Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy
(2015) Journal of Medical Genetics, . Article in Press. 

DOI: 10.1136/jmedgenet-2015-103140


a Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA
b Genetics Division, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USA
c Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA
d GeneDx, Gaithersburg, Maryland, USA
e Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
f Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
g Division of Metabolism, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
h Department of Pathology, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
i Department of Pathology, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA
j Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA


Abstract
Background The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q<inf>10</inf> (CoQ<inf>10</inf>) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ<inf>10</inf> biosynthesis cause primary CoQ<inf>10</inf> deficiency syndromes that can be treated with oral supplementation of ubiquinone. Methods We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. Results We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. Conclusions Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ<inf>10</inf> biosynthesis. © 2015 by the BMJ Publishing Group Ltd.


Document Type: Article in Press
Source: Scopus

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McDaniel, M.A.a , Umanath, S.a , Einstein, G.O.b , Waldum, E.R.a
Dual pathways to prospective remembering
(2015) Frontiers in Human Neuroscience, 9 (JULY), art. no. 392, 12 p. 

DOI: 10.3389/fnhum.2015.00392


a Washington University in St. Louis, St. Louis, MO, United States
b Furman University, Greenville, SC, United States


Abstract
According to the multiprocess framework (McDaniel and Einstein, 2000), the cognitive system can support prospective memory (PM) retrieval through two general pathways. One pathway depends on top–down attentional control processes that maintain activation of the intention and/or monitor the environment for the triggering or target cues that indicate that the intention should be executed. A second pathway depends on (bottom–up) spontaneous retrieval processes, processes that are often triggered by a PM target cue; critically, spontaneous retrieval is assumed not to require monitoring or active maintenance of the intention. Given demand characteristics associated with experimental settings, however, participants are often inclined to monitor, thereby potentially masking discovery of bottom–up spontaneous retrieval processes. In this article, we discuss parameters of laboratory PM paradigms to discourage monitoring and review recent behavioral evidence from such paradigms that implicate spontaneous retrieval in PM. We then re-examine the neuro-imaging evidence from the lens of the multiprocess framework and suggest some critical modifications to existing neuro-cognitive interpretations of the neuro-imaging results. These modifications illuminate possible directions and refinements for further neuro-imaging investigations of PM. © 2015 McDaniel, Umanath, Einstein and Waldum.


Author Keywords
Monitoring in prospective memory;  Neuroimaging of prospective memory;  Prospective memory;  Prospective memory paradigms;  Spontaneous retrieval


Document Type: Review
Source: Scopus

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Malmstrom, T.K.a b f , Voss, V.B.c , Cruz-Oliver, D.M.b , Cummings-Vaughn, L.A.d e , Tumosa, N.d , Grossberg, G.T.a , Morley, J.E.b
The Rapid Cognitive Screen (RCS): A point-of-care screening for dementia and mild cognitive impairment
(2015) Journal of Nutrition, Health and Aging, 19 (7), pp. 741-744. 

DOI: 10.1007/s12603-015-0564-2


a Department of Neurology & Psychiatry, Saint Louis University School of Medicine, St. Louis, MO, United States
b Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
c Saint Louis University School of Medicine, St. Louis, MO, United States
d Jefferson Barracks Division, Geriatric Research Education and Clinical Center, Veterans Affairs Saint Louis Health System, St. Louis, MO, United States
e Division of Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, MO, United States
f Department of Neurology & Psychiatry, School of Medicine, Saint Louis University, 1438 South Grand Boulevard, St. Louis, MO, United States


Abstract
Objectives: There is a need for a rapid screening test for mild cognitive impairment (MCI) and dementia to be used by primary care physicians. The Rapid Cognitive Screen (RCS) is a brief screening tool (< 3 min) for cognitive dysfunction. RCS includes 3-items from the Veterans Affairs Saint Louis University Mental Status (SLUMS) exam: recall, clock drawing, and insight. Study objectives were to: 1) examine the RCS sensitivity and specificity for MCI and dementia, 2) evaluate the RCS predictive validity for nursing home placement and mortality, and 3) compare the RCS to the clock drawing test (CDT) plus recall. Methods: Patients were recruited from the St. Louis, MO Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Medical Center (VAMC) hospitals (study 1) or the Saint Louis University Geriatric Medicine and Psychiatry outpatient clinics (study 2). Study 1 participants (N=702; ages 65–92) completed cognitive evaluations and 76% (n=533/706) were followed up to 7.5 years for nursing home placement and mortality. Receiver operator characteristic (ROC) curves were computed to determine sensitivity and specificity for MCI (n=180) and dementia (n=82). Logistic regressions were computed for nursing home placement (n=31) and mortality (n=176). Study 2 participants (N=168; ages 60–90) completed the RCS and SLUMS exam. ROC curves were computed to determine sensitivity and specificity for MCI (n=61) and dementia (n=74). Results: RCS predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 5 for dementia (sensitivity=0.89, specificity=0.94) and ≤ 7 for MCI (sensitivity=0.87, specificity=0.70). The CDT plus recall predicted dementia and MCI in study 1 with optimal cutoff scores of ≤ 2 for dementia (sensitivity=0.87, specificity=0.85) and ≤ 3 for MCI (sensitivity=0.62, specificity=0.62). Higher RCS scores were protective against nursing home placement and mortality. The RCS predicted dementia and MCI in study 2. Conclusions: The 3-item RCS exhibits good sensitivity and specificity for the detection of MCI and dementia, and higher cognitive function on the RCS is protective against nursing home placement and mortality. The RCS may be a useful screening instrument for the detection of cognitive dysfunction in the primary care setting. © 2015, Serdi and Springer-Verlag France.


Author Keywords
Alzheimer’s Disease;  Cognition;  Dementia;  Mild Cognitive Impairment;  Screening


Document Type: Article
Source: Scopus

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Spadone, S.a , Della Penna, S.a , Sestieri, C.a , Betti, V.a , Tosoni, A.a , Perrucci, M.G.a , Romani, G.L.a , Corbetta, M.a b
Dynamic reorganization of human resting-state networks during visuospatial attention
(2015) Proceedings of the National Academy of Sciences of the United States of America, 112 (26), pp. 8112-8117. 

DOI: 10.1073/pnas.1415439112


a Department of Neuroscience, Imaging and Clinical Science, Institute of Advanced Biomedical Technologies, University G. d'Annunzio, Chieti, Italy
b Department of Neurology, Radiology, Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Fundamental problems in neuroscience today are understanding how patterns of ongoing spontaneous activity are modified by task performance and whether/how these intrinsic patterns influence task-evoked activation and behavior. We examined these questions by comparing instantaneous functional connectivity (IFC) and directed functional connectivity (DFC) changes in two networks that are strongly correlated and segregated at rest: the visual (VIS) network and the dorsal attention network (DAN). We measured how IFC and DFC during a visuospatial attention task, which requires dynamic selective rerouting of visual information across hemispheres, changed with respect to rest. During the attention task, the two networks remained relatively segregated, and their general pattern of within-network correlation was maintained. However, attention induced a decrease of correlation in the VIS network and an increase of the DAN→VIS IFC and DFC, especially in a top-down direction. In contrast, within the DAN, IFC was not modified by attention, whereas DFC was enhanced. Importantly, IFC modulations were behaviorally relevant. We conclude that a stable backbone of within-network functional connectivity topography remains in place when transitioning between resting wakefulness and attention selection. However, relative decrease of correlation of ongoing "idling" activity in visual cortex and synchronization between frontoparietal and visual cortex were behaviorally relevant, indicating that modulations of resting activity patterns are important for task performance. Higher order resting connectivity in the DAN was relatively unaffected during attention, potentially indicating a role for simultaneous ongoing activity as a "prior" for attention selection. © 2015, National Academy of Sciences. All rights reserved.


Author Keywords
Attention networks;  Directional connectivity;  Functional connectivity;  Resting-state networks;  Task-evoked activity


Document Type: Article
Source: Scopus

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Frontera, J.a , Ziai, W.b , O’Phelan, K.c , Leroux, P.D.d , Kirkpatrick, P.J.e , Diringer, M.N.f , Suarez, J.I.g
Regional Brain Monitoring in the Neurocritical Care Unit
(2015) Neurocritical Care, 22 (3), pp. 348-359. Cited 1 time.

DOI: 10.1007/s12028-015-0133-x


a Cerebrovascular Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland Clinic Mail Code S80, Cleveland, OH, United States
b Department of Neurology, Neurological Surgery, Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
c Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States
d Main Line Health Brain and Spine Center, Wynnewood, PA, United States
e Division of Neurosurgery, University of Cambridge, Cambridge, United Kingdom
f Section Neurological Critical Care, Department of Neurology, Neurosurgery, and Anesthesiology, Washington University, St Louis, MO, United States
g Division of Vascular Neurology and Neurocritical Care, Department of Neurology, Baylor College of Medicine, Houston, TX, United States


Abstract
Regional multimodality monitoring has evolved over the last several years as a tool to understand the mechanisms of brain injury and brain function at the cellular level. Multimodality monitoring offers an important augmentation to the clinical exam and is especially useful in comatose neurocritical care patients. Cerebral microdialysis, brain tissue oxygen monitoring, and cerebral blood flow monitoring all offer insight into permutations in brain chemistry and function that occur in the context of brain injury. These tools may allow for development of individual therapeutic strategies that are mechanistically driven and goal-directed. We present a summary of the discussions that took place during the Second Neurocritical Care Research Conference regarding regional brain monitoring. © 2015, Springer Science+Business Media New York.


Author Keywords
Brain tissue oxygenation;  Cerebral blood flow;  Microdialysis;  Neurocritical care;  Neuromonitoring


Document Type: Article
Source: Scopus

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Wallace, A.N., Greenwood, T.J., Jennings, J.W.
Radiofrequency ablation and vertebral augmentation for palliation of painful spinal metastases
(2015) Journal of Neuro-Oncology, 124 (1), pp. 111-118. 

DOI: 10.1007/s11060-015-1813-2


Siteman Cancer Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, St. Louis, MO, United States


Abstract
Radiofrequency ablation (RFA) and vertebral augmentation is an emerging combination therapy for painful osseous metastases that cannot be or are incompletely palliated with radiation therapy. Herein, we report our experience performing RFA and vertebral augmentation of spinal metastases for pain palliation. Institutional review board approval was obtained to retrospectively review our tumor ablation database for all patients who underwent RFA of osseous metastases between April 2012 and July 2014. Patient demographics, lesion characteristics, concurrent palliative therapies, and complications were recorded. Pre- and post-procedure mean worst pain scores 1 and 4 weeks after treatment were measured using the Numeric Rating Scale (10-point scale) and compared. During the study period, 72 RFA treatments of 110 spinal metastases were performed. Eighty one percent (89/110) of metastases involved the posterior vertebral body and 45 % (49/110) involved the pedicles. Vertebral augmentation was performed after 95 % (105/110) of ablations. Mean and median pre-procedure pain scores were 8.0 ± 1.9 and 8.0, respectively. Patients reported clinically significant decreased pain scores at both 1-week (mean, 3.9 ± 3.0; median, 3.25; P < 0.0001) and 4-week (mean, 2.9 ± 3.0; median, 2.75; P < 0.0001) follow-up. No major complications occurred related to RFA and there were no instances of symptomatic cement extravasation. Combination RFA and vertebral augmentation is a safe and effective therapy for palliation of painful spinal metastases, including tumor involving the posterior vertebral body and/or pedicles. © 2015, Springer Science+Business Media New York.


Author Keywords
Metastatic spine disease;  Pain palliation;  Radiofrequency ablation;  Vertebral augmentation


Document Type: Article
Source: Scopus

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Pearson, J.T.a b , Kerschensteiner, D.a c d
Ambient illumination switches contrast preference of specific retinal processing streams
(2015) Journal of Neurophysiology, 114 (1), pp. 540-550. 

DOI: 10.1152/jn.00360.2015


a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Regenerative and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Contrast, a fundamental feature of visual scenes, is encoded in a distributed manner by ~20 retinal ganglion cell (RGC) types, which stream visual information to the brain. RGC types respond preferentially to positive (ON<inf>pref</inf>) or negative (OFF<inf>pref</inf>) contrast and differ in their sensitivity to preferred contrast and responsiveness to nonpreferred stimuli. Vision operates over an enormous range of mean light levels. The influence of ambient illumination on contrast encoding across RGC types is not well understood. Here, we used large-scale multielectrode array recordings to characterize responses of mouse RGCs under lighting conditions spanning five orders in brightness magnitude. We identify three functional RGC types that switch contrast preference in a luminancedependent manner (Sw1-, Sw2-, and Sw3-RGCs). As ambient illumination increases, Sw1 and Sw2-RGCs shift from ON<inf>pref</inf> to OFF<inf>pref</inf> and Sw3-RGCs from OFF<inf>pref</inf> to ON<inf>pref</inf>. In all cases, transitions in contrast preference are reversible and track light levels. By mapping spatiotemporal receptive fields at different mean light levels, we find that changes in input from ON and OFF pathways in receptive field centers underlie shifts in contrast preference. Sw2-RGCs exhibit direction-selective responses to motion stimuli. Despite changing contrast preference, direction selectivity of Sw2-RGCs and other RGCs as well as orientation-selective responses of RGCs remain stable across light levels. © 2015 the American Physiological Society.


Author Keywords
Ambient illumination;  Contrast encoding;  Multielectrode array;  Retina;  Switch circuit


Document Type: Article
Source: Scopus

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Nemanich, S.T.a , Earhart, G.M.a b c
Prism adaptation in Parkinson disease: comparing reaching to walking and freezers to non-freezers
(2015) Experimental Brain Research, 233 (8), pp. 2301-2310. 

DOI: 10.1007/s00221-015-4299-4


a Program in Physical Therapy, Washington University School of Medicine in St. Louis, Campus Box 8502, 4444 Forest Park Blvd., St. Louis, MO, United States
b Anatomy and Neurobiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States


Abstract
Visuomotor adaptation to gaze-shifting prism glasses requires recalibration of the relationship between sensory input and motor output. Healthy individuals flexibly adapt movement patterns to many external perturbations; however, individuals with cerebellar damage do not adapt movements to the same extent. People with Parkinson disease (PD) adapt normally, but exhibit reduced after-effects, which are negative movement errors following the removal of the prism glasses and are indicative of true spatial realignment. Walking is particularly affected in PD, and many individuals experience freezing of gait (FOG), an episodic interruption in walking, that is thought to have a distinct pathophysiology. Here, we examined how individuals with PD with (PD + FOG) and without (PD − FOG) FOG, along with healthy older adults, adapted both reaching and walking patterns to prism glasses. Participants completed a visually guided reaching and walking task with and without rightward-shifting prism glasses. All groups adapted at similar rates during reaching and during walking. However, overall walking adaptation rates were slower compared to reaching rates. The PD − FOG group showed smaller after-effects, particularly during walking, compared to PD + FOG, independent of adaptation magnitude. While FOG did not appear to affect characteristics of prism adaptation, these results support the idea that the distinct neural processes governing visuomotor adaptation and storage are differentially affected by basal ganglia dysfunction in PD. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
After-effects;  Freezing of gait;  Parkinson disease;  Prism adaptation


Document Type: Article
Source: Scopus

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Brody, D.L.a , Benetatos, J.a , Bennett, R.E.a b , Klemenhagen, K.C.a c , Mac Donald, C.L.a d
The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions
(2015) Molecular and Cellular Neuroscience, 66 (PB), pp. 91-98. 

DOI: 10.1016/j.mcn.2015.02.005


a Department of Neurology, Washington University School of Medicine and Hope Center for Neurological Disorders, St Louis, MO, United States
b Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
c Department of Psychiatry, Columbia University and Research Foundation for Mental Health, New York State Psychiatric Institute, New York, NY, United States
d Department of Neurosurgery, University of Washington, Seattle, WA, United States


Abstract
In recent years, there has been an increasing interest in the pathophysiology of repetitive concussive traumatic brain injury (rcTBI) in large part due to the association with dramatic cases of progressive neurological deterioration in professional athletes, military personnel, and others. However, our understanding of the pathophysiology of rcTBI is less advanced than for more severe brain injuries. Most prominently, the mechanisms underlying traumatic axonal injury, microglial activation, amyloid-beta accumulation, and progressive tau pathology are not yet known. In addition, the role of injury to dendritic spine cytoskeletal structures, vascular reactivity impairments, and microthrombi are intriguing and subjects of ongoing inquiry. Methods for quantitative analysis of axonal injury, dendritic injury, and synaptic loss need to be refined for the field to move forward in a rigorous fashion. We and others are attempting to develop translational approaches to assess these specific pathophysiological events in both animals and humans to facilitate clinically relevant pharmacodynamic assessments of candidate therapeutics. In this article, we review and discuss several of the recent experimental results from our lab and others. We include new initial data describing the difficulty in modeling progressive tau pathology in experimental rcTBI, and results demonstrating that sertraline can alleviate social interaction deficits and depressive-like behaviors following experimental rcTBI plus foot shock stress. Furthermore, we propose a discrete set of open, experimentally tractable questions that may serve as a framework for future investigations. In addition, we also raise several important questions that are less experimentally tractable at this time, in hopes that they may stimulate future methodological developments to address them.This article is part of a Special Issue entitled "Traumatic Brain Injury". © 2015 Elsevier Inc.


Author Keywords
Amyloid-beta;  Concussion;  Depression;  Microglia;  Mouse;  Sertraline;  Social behavior;  Tau;  Traumatic axonal injury;  Traumatic brain injury


Document Type: Review
Source: Scopus

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Cradock, M.M.a , Gray, K.E.b , Kapp-Simon, K.A.c d , Collett, B.R.e f , Buono, L.A.g , Speltz, M.L.e f
Sex differences in the neurodevelopment of school-age children with and without single-suture craniosynostosis
(2015) Child's Nervous System, 31 (7), pp. 1103-1111. 

DOI: 10.1007/s00381-015-2671-0


a Department of Psychology, St Louis Children’s Hospital; Department of Pediatrics, Washington University School of Medicine, One Children’s Place 3N-14, St Louis, MO, United States
b Department of Health Services, University of Washington, Seattle, WA, United States
c Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
d Departments of Plastic Surgery and Psychology, Shriners Hospitals for Children, Chicago, IL, United States
e Center for Child Health, Behavior and Development, Seattle Children’s Research Institute, Seattle, WA, United States
f Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
g Craniofacial Team, Children’s Healthcare of Atlanta, Atlanta, GA, United States


Abstract
Purpose: Previous studies have indicated that infants and school-age children with single-suture craniosynostosis (SSC, cases) score modestly but consistently lower than unaffected children (controls) on neurodevelopmental tests. However, sex differences in these functions rarely have been examined, and it is unknown whether potential sex differences vary by case status (cases vs. controls) or location of suture fusion. Methods: We tested 182 cases and 183 demographically matched controls at a mean age of 7.4 years. We measured intellectual abilities with the Wechsler Scale of Intelligence for Children—Fourth Edition. We assessed reading, spelling, and math with a combination of the Wide Range Assessment Test—Fourth Edition, the Test of Word Reading Efficiency, and the Comprehensive Test of Phonological Processing. Results: Among both cases and controls, males scored lower on all measures than females with standard score differences ranging from −1.2 to −7.8 for controls (p values from <0.001 to 0.55) and −2.3 to −8.5 for cases (p values from <0.001 to 0.33). For all but one measure, sex differences were slightly larger for cases than controls. Among cases, males were more likely than females to have learning problems (50 vs. 30 %, respectively), with the highest level observed among males with unicoronal synostosis (86 %). Conclusions: Sex differences in neurodevelopmental abilities among children with SSC are substantial, but not a unique correlate of this disorder as similar differences were observed among controls. Girls and those with sagittal synostosis have the lowest risk for academic problems. Boys with unicoronal synostosis warrant close developmental surveillance. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
Achievement;  Cognition;  Craniosynostosis;  Gender;  Intelligence;  Sex


Document Type: Article
Source: Scopus

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Tu, Z.a , Zhang, X.a , Jin, H.a , Yue, X.a , Padakanti, P.K.a , Yu, L.a , Liu, H.a , Flores, H.P.b , Kaneshige, K.c , Parsons, S.M.c , Perlmutter, J.S.a b
Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter
(2015) Bioorganic and Medicinal Chemistry, 23 (15), pp. 4699-4709. 

DOI: 10.1016/j.bmc.2015.05.058


a Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO, United States
c Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States


Abstract
Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogs; the minus enantiomer, (-)-18a displayed high potency (VAChT K<inf>i</inf> = 0.59 ± 0.06 nM) and high selectivity for VAChT versus σ receptors (>10,000-fold). The radiosynthesis of (-)-[18F]18a was accomplished by a two-step procedure with 30-40% radiochemical yield. Preliminary biodistribution studies of (-)-[18F]18a in adult male Sprague-Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[18F]18a was 0.684 %ID/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g; evaluation of regional brain uptake showed stable levels of
0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[18F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25 mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a 90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[18F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[18F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects. © 2015 Elsevier Ltd. All rights reserved.


Author Keywords
F-18;  PET tracer;  Striatum;  VAChT;  Vesamicol


Document Type: Article
Source: Scopus

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Semenkovich, K.a b , Brown, M.E.c , Svrakic, D.M.b c , Lustman, P.J.b c
Depression in type 2 diabetes mellitus: Prevalence, impact, and treatment
(2015) Drugs, 75 (6), pp. 577-587. 

DOI: 10.1007/s40265-015-0347-4


a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Bell Street Clinic, Mental Health Service, St. Louis Veterans Administration Medical Center, St. Louis, MO, United States
c Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States


Abstract
Clinically significant depression is present in one of every four people with type 2 diabetes mellitus (T2DM). Depression increases the risk of the development of T2DM and the subsequent risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications. Conversely, a diagnosis of T2DM increases the risk of incident depression and can contribute to a more severe course of depression. This linkage reflects a shared etiology consisting of complex bidirectional interactions among multiple variables, a process that may include autonomic and neurohormonal dysregulation, weight gain, inflammation, and hippocampal structural alterations. Two recent meta-analyses of randomized controlled depression treatment trials in patients with T2DM concluded that psychotherapy and antidepressant medication (ADM) were each moderately effective for depression and that cognitive behavior therapy (CBT) had beneficial effects on glycemic control. However, the number of studies (and patients exposed to randomized treatment) included in these analyses is extremely small and limits the certainty of conclusions that can be drawn from the data. Ultimately, there is no escaping the paucity of the evidence base and the need for additional controlled trials that specifically address depression management in T2DM. Future trials should determine both the effects of treatment and the change in depression during treatment on measures of mood, glycemic control, and medical outcome. © 2015 Springer International Publishing Switzerland (outside the USA).


Document Type: Article
Source: Scopus

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Lucas, J.R.a , Vélez, A.a c , Henry, K.S.b
Habitat-related differences in auditory processing of complex tones and vocal signal properties in four songbirds
(2015) Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology, 201 (4), pp. 395-410. 

DOI: 10.1007/s00359-015-0986-7


a Department of Biological Sciences, Lilly Hall, Purdue University, 915 W. State St., West Lafayette, IN, United States
b Department of Biomedical Engineering, University of Rochester, 601 Elmwood Ave Box 603, Rochester, NY, United States
c Department of Biology, Washington University in St. Louis, St. Louis, MO, United States


Abstract
We examined temporal processing of harmonic tone complexes in two woodland species (tufted titmice and white-breasted nuthatches) and two open-habitat species (house sparrows and white-crowned sparrows). Envelope and fine-structure processing were quantified using the envelope following response (EFR) and frequency following response (FFR). We predicted stronger EFRs in the open-habitat species based on broader auditory filters and greater amplitude modulation of vocal signals in this group. We predicted stronger FFRs in woodland species based on narrower auditory filters. As predicted, EFR amplitude was generally greatest in the open habitat species. FFR amplitude, in contrast, was greatest in white-crowned sparrows with no clear difference between habitats. This result cannot be fully explained by species differences in audiogram shape and might instead reflect greater acoustic complexity of songs in the white-crowned sparrow. Finally, we observed stronger FFRs in woodland species when tones were broadcast with the next higher harmonic in the complex. Thus, species such as nuthatches that have songs with strong harmonics may process these sounds using enhanced spectral processing instead of enhanced amplitude-envelope processing. The results suggest coevolution between signal design and temporal processing of complex signals and underscore the need to study auditory processing with a diversity of signals. © 2015, Springer-Verlag Berlin Heidelberg.


Author Keywords
Amplitude envelope;  Audiogram;  Auditory evoked potential;  Hearing;  Phase-locking


Document Type: Article
Source: Scopus

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Whalen, D.J.a , Belden, A.C.a , Barch, D.a b , Luby, J.a
Emotion Awareness Predicts Body Mass Index Percentile Trajectories inYouth
(2015) Journal of Pediatrics, . Article in Press. 

DOI: 10.1016/j.jpeds.2015.06.053


a Department of Psychiatry, Washington University School of Medicine, St Louis, MO
b Department of Psychology, Washington University, St Louis, MO


Abstract
Objective: To examine the rate of change in body mass index (BMI) percentile across 3years in relation to emotion identification ability and brain-based reactivity in emotional processing regions. Study design: A longitudinal sample of 202 youths completed 3 functional magnetic resonance imaging-based facial processing tasks and behavioral emotion differentiation tasks. We examined the rate of change in the youth's BMI percentile as a function of reactivity in emotional processing brain regions and behavioral emotion identification tasks using multilevel modeling. Results: Lower correct identification of both happiness and sadness measured behaviorally predicted increases in BMI percentile across development, whereas higher correct identification of both happiness and sadness predicted decreases in BMI percentile, while controlling for children's pubertal status, sex, ethnicity, IQ score, exposure to antipsychotic medication, family income-to-needs ratio, and externalizing, internalizing, and depressive symptoms. Greater neural activation in emotional reactivity regions to sad faces also predicted increases in BMI percentile during development, also controlling for the aforementioned covariates. Conclusion: Our findings provide longitudinal developmental data demonstrating links between both emotion identification ability and greater neural reactivity in emotional processing regions with trajectories of BMI percentiles across childhood. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus

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McCall, J.G.a b c d , Al-Hasani, R.a b c , Siuda, E.R.a b c d , Hong, D.Y.a , Norris, A.J.a , Ford, C.P.e , Bruchas, M.R.a b c d
CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.07.002


a Division of Basic Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
d Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
e Department of Physiology and Biophysics, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA


Abstract
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of invivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity ofthe LC-NE system is necessary and sufficient forstress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone+ (CRH+) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. McCall etal. identify locus coeruleus (LC) neuronal activity as a critical mediator of stress-induced anxiety. Selective modulation of LC activity bidirectionally controls anxiety-like and aversive behaviors. Anatomical studies identify amygdalar CRH+ inputs that modulate LC activity and drive anxiety-like behavior. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus

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Schlaggar, B.L.a , Luna, B.b
Flux: International Congress for Integrative Developmental Cognitive Neuroscience, Pittsburgh, Pennsylvania, September 19-21, 2013: Introduction
(2015) Developmental cognitive neuroscience, 11, p. 1. 

DOI: 10.1016/j.dcn.2014.12.004


a Washington University in St. Louis School of Medicine, United States
b University of Pittsburgh, United States


Document Type: Conference Paper
Source: Scopus

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Laumann, T.O.a , Gordon, E.M.a , Adeyemo, B.a , Snyder, A.Z.a b , Joo, S.c , Chen, M.-Y.c , Gilmore, A.W.d , McDermott, K.B.b d , Nelson, S.M.e f , Dosenbach, N.U.F.a , Schlaggar, B.L.a b g h i , Mumford, J.A.j , Poldrack, R.A.c k l m , Petersen, S.E.a b d i
Functional System and Areal Organization of a Highly Sampled Individual Human Brain
(2015) Neuron, . Article in Press. 

DOI: 10.1016/j.neuron.2015.06.037


a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
c Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA
d Department of Psychology, Washington University in St. Louis, St. Louis, MO 63110, USA
e VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX 76711, USA
f Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75235, USA
g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
i Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA
j Center for Investigating Healthy Minds at the Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
k Department of Neuroscience, University of Texas at Austin, Austin, TX 78712, USA
l Imaging Research Center, University of Texas at Austin, Austin, TX 78712, USA
m Department of Psychology, Stanford University, Stanford, CA 94305, USA


Abstract
Resting state functional MRI (fMRI) has enabled description of group-level functional brain organization at multiple spatial scales. However, cross-subject averaging may obscure patterns of brain organization specific to each individual. Here, we characterized the brain organization of a single individual repeatedly measured over more than a year. We report a reproducible and internally valid subject-specific areal-level parcellation that corresponds with subject-specific task activations. Highly convergent correlation network estimates can be derived from this parcellation if sufficient data are collected-considerably more than typically acquired. Notably, within-subject correlation variability across sessions exhibited a heterogeneous distribution across the cortex concentrated in visual and somato-motor regions, distinct from the pattern of intersubject variability. Further, although the individual's systems-level organization is broadly similar to the group, it demonstrates distinct topological features. These results provide a foundation for studies of individual differences in cortical organization and function, especially for special or rare individuals. Video Abstract: Display Omitted. Resting state functional MRI allows non-invasive analysis of functional brain organization at multiple spatial scales. Laumann etal. report areal and system organization in a highly sampled human and demonstrate that an individual exhibits topological features distinct from group-level system organization. © 2015 Elsevier Inc.


Document Type: Article in Press
Source: Scopus

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Astafiev, S.V.a , Shulman, G.L.a , Metcalf, N.V.a , Rengachary, J.a , MacDonald, C.L.a f , Harrington, D.L.b , Maruta, J.c , Shimony, J.S.e , Ghajar, J.c d , Diwakar, M.b , Huang, M.-X.b , Lee, R.R.b , Corbetta, M.a
Abnormal White Matter Blood-Oxygen-Level-Dependent Signals in Chronic Mild Traumatic Brain Injury
(2015) Journal of Neurotrauma, 32 (16), pp. 1254-1271. 

DOI: 10.1089/neu.2014.3547


a Department of Neurology, Washington University in St. Louis, 660 S. Euclid Avenue, St. Louis, MO, United States
b Department of Radiology, University of California, San Diego, San Diego, CA, United States
c Brain Trauma Foundation, New York, NY, United States
d Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States
e Mallinckrodt Institute of Radiology, St. Louis, MO, United States
f Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, United States


Abstract
Concussion, or mild traumatic brain injury (mTBI), can cause persistent behavioral symptoms and cognitive impairment, but it is unclear if this condition is associated with detectable structural or functional brain changes. At two sites, chronic mTBI human subjects with persistent post-concussive symptoms (three months to five years after injury) and age- and education-matched healthy human control subjects underwent extensive neuropsychological and visual tracking eye movement tests. At one site, patients and controls also performed the visual tracking tasks while blood-oxygen-level-dependent (BOLD) signals were measured with functional magnetic resonance imaging. Although neither neuropsychological nor visual tracking measures distinguished patients from controls at the level of individual subjects, abnormal BOLD signals were reliably detected in patients. The most consistent changes were localized in white matter regions: anterior internal capsule and superior longitudinal fasciculus. In contrast, BOLD signals were normal in cortical regions, such as the frontal eye field and intraparietal sulcus, that mediate oculomotor and attention functions necessary for visual tracking. The abnormal BOLD signals accurately differentiated chronic mTBI patients from healthy controls at the single-subject level, although they did not correlate with symptoms or neuropsychological performance. We conclude that subjects with persistent post-concussive symptoms can be identified years after their TBI using fMRI and an eye movement task despite showing normal structural MRI and DTI. © Copyright 2015, Mary Ann Liebert, Inc.


Author Keywords
behavioral assessments;  diffusion tensor imaging;  MRI;  traumatic brain injury


Document Type: Article
Source: Scopus

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Ju, Y.-E.
Add ARBs to injury?
(2015) Science Translational Medicine, 7 (297), art. no. 297ec123, . 

DOI: 10.1126/scitranslmed.aac8565


Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States


Document Type: Editorial
Source: Scopus

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Milekic, M.H.a , Xin, Y.a , O'Donnell, A.b , Kumar, K.K.a , Bradley-Moore, M.a , Malaspina, D.c d , Moore, H.a , Brunner, D.a e , Ge, Y.f , Edwards, J.g , Paul, S.h , Haghighi, F.G.i , Gingrich, J.A.a
Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression
(2015) Molecular Psychiatry, 20 (8), pp. 995-1001. Cited 3 times.

DOI: 10.1038/mp.2014.84


a Department of Psychiatry, Columbia University, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, United States
b Department of Genetics and Development, Columbia University, New York, NY, United States
c Department of Psychiatry, New York University, New York, NY, United States
d Department of Psychiatry, New York University, NY OMH Creedmoor Psychiatric Center, New York, NY, United States
e PsychoGenics, New York, NY, United States
f Department of Neurology, Mount Sinai School of Medicine, New York, NY, United States
g Center for Pharmacogenomics, Department of Medicine, Washington University, St Louis, MO, United States
h Helen and Robert Appel Institute for Alzheimer's Research, Mind and Brain Institute, Weill Cornell Medical School, New York, NY, United States
i Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States


Abstract
Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring. © 2015 Macmillan Publishers Limited All rights reserved.


Document Type: Article
Source: Scopus

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Glass, J.E.a , Grant, J.D.b , Yoon, H.Y.c , Bucholz, K.K.b
Alcohol problem recognition and help seeking in adolescents and young adults at varying genetic and environmental risk
(2015) Drug and Alcohol Dependence, 153, pp. 250-257. 

DOI: 10.1016/j.drugalcdep.2015.05.006


a School of Social Work, University of Wisconsin-Madison, 1350 University Ave, Madison, WI, United States
b Department of Psychiatry and Alcoholism Research Center, Washington University School of Medicine, 660 Euclid, St. Louis, MO, United States
c Department of Journalism and Mass Communication, University of Wisconsin-Madison, 5115 Vilas Hall, 821 University Avenue, Madison, WI, United States


Abstract
Introduction: Alcohol use disorder symptoms frequently occur in adolescents and younger adults who seldom acknowledge a need for help. We identified sociodemographic, clinical, and familial predictors of alcohol problem recognition and help seeking in an offspring of twin sample. Method: We analyzed longitudinal data from the Children of Alcoholics and Twins as Parents studies, which are combinable longitudinal data sources due to their equivalent design. We analyzed respondents (n= 1073, 56.0% of the total sample) with alcohol use disorder symptoms at the baseline interview. Familial characteristics included perceptions of alcohol problems and help seeking for alcohol problems within the immediate family and a categorical variable indicating genetic and environmental risk. We used logistic regression to examine predictors of alcohol problem recognition and help seeking. Results: Approximately 25.9% recognized their alcohol problems and 26.7% sought help for drinking. In covariate-adjusted analyses, help seeking among family members predicted problem recognition, several clinical characteristics predicted both problem recognition and help seeking, and familial risk predicted help seeking. Alcohol problem recognition mediated the association between alcohol use disorder symptoms and incident help seeking. Conclusions: Facilitating the self-recognition of alcohol use disorder symptoms, and perhaps the awareness of family members' help seeking for alcohol problems, may be potentially promising methods to facilitate help seeking. © 2015 Elsevier Ireland Ltd.


Author Keywords
Adolescents;  Alcohol problem recognition;  Alcohol use disorders;  Help seeking;  Treatment utilization;  Young adults


Document Type: Article
Source: Scopus

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Franklin, E.E.a b , Perrin, R.J.a b , Vincent, B.a b , Baxter, M.a b , Morris, J.C.a b c , Cairns, N.J.a b c
Brain collection, standardized neuropathologic assessment, and comorbidity in Alzheimer's Disease Neuroimaging Initiative 2 participants
(2015) Alzheimer's and Dementia, 11 (7), pp. 815-822. Cited 1 time.

DOI: 10.1016/j.jalz.2015.05.010


a Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Introduction The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core (ADNI-NPC) facilitates brain donation, ensures standardized neuropathologic assessments, and maintains a tissue resource for research. Methods The ADNI-NPC coordinates with performance sites to promote autopsy consent, facilitate tissue collection and autopsy administration, and arrange sample delivery to the NPC, for assessment using National Institute on Aging-Alzheimer's Association neuropathologic diagnostic criteria. Results The ADNI-NPC has obtained 45 participant specimens, and neuropathologic assessments have been completed in 36 to date. Challenges in obtaining consent at some sites have limited the voluntary autopsy rate to 58%. Among assessed cases, clinical diagnostic accuracy for Alzheimer disease (AD) is 97%; however, 58% of cases show neuropathologic comorbidities. Discussion Challenges facing autopsy consent and coordination are largely resource related. The neuropathologic assessments indicate that ADNI's clinical diagnostic accuracy for AD is high; however, many AD cases have comorbidities that may impact the clinical presentation, course, and imaging and biomarker results. These neuropathologic data permit multimodal and genetic studies of these comorbidities to improve diagnosis and provide etiologic insights. © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.


Author Keywords
Alzheimer's Disease Neuroimaging Initiative;  Autopsy consent;  Comorbidity;  Lewy body;  Neuropathology;  Pathology heat map


Document Type: Article
Source: Scopus

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Luking, K.R.a , Pagliaccio, D.a , Luby, J.L.b , Barch, D.M.b
Child Gain Approach and Loss Avoidance Behavior: Relationships With Depression Risk, Negative Mood, and Anhedonia
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, 54 (8), art. no. 1224, pp. 643-651. 

DOI: 10.1016/j.jaac.2015.05.010


a Neuroscience Program, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1125, St. Louis, MO, United States
b Washington University in St. Louis, United States


Abstract
Objective Reduced reward responsiveness and altered response to loss of reward are observed in adults with major depressive disorder (MDD) and adolescents at increased risk for MDD based on family history. However, it is unclear whether altered behavioral responsiveness to reward/loss is a lifelong marker of MDD risk, which is evident before the normative adolescent increase in incentive responding. Method Healthy 7- to 10-year-old children of mothers with MDD (high risk: n = 27) or without MDD (low risk: n = 42) performed 2 signal detection tasks assessing response bias toward reward (approach) and away from loss (avoidance). Differences in approach/avoidance were related to MDD risk, child general depressive symptoms (maternal report), child-reported anhedonic symptoms, and child-reported negative mood symptoms via repeated-measures analysis of variance. Results MDD risk did not significantly relate to gain approach or loss avoidance. However, within high-risk children, higher numbers of maternal depressive episodes predicted blunted loss avoidance. Blunted gain approach was related to elevated anhedonic symptoms, whereas enhanced loss avoidance was related to elevated negative mood. Elevated negative mood was further related to blunted gain approach in high-risk children but related to enhanced gain approach in low-risk children. Conclusion In children, individual differences in specific depressive symptoms and recurrence of maternal depression significantly predicted gain approach/loss avoidance, but the presence/absence of maternal MDD did not. Child depressive symptoms characterized by low positive affect (anhedonia) were related to blunted gain responsiveness, whereas elevated depressed/negative mood was related to enhanced loss responsiveness. Findings suggest that relations between gain approach and negative mood may be an important distinction between those at high versus low risk for MDD. © 2015 American Academy of Child and Adolescent Psychiatry.


Author Keywords
anhedonia;  depression risk;  punishment;  reward


Document Type: Article
Source: Scopus

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Adam, O.a m , Mac Donald, C.L.d n , Rivet, D.a b e , Ritter, J.f , May, T.h , Barefield, M.i , Duckworth, J.j , Labarge, D.c o , Asher, D.k , Drinkwine, B.k , Woods, Y.g , Connor, M.l , Brody, D.L.d
Clinical and imaging assessment of acute combat mild traumatic brain injury in Afghanistan
(2015) Neurology, 85 (3), pp. 219-227. 

DOI: 10.1212/WNL.0000000000001758


a Division of Neurology, Naval Medical Center PortsmouthVA, United States
b Departments of Neurological Surgery, Naval Medical Center PortsmouthVA, United States
c Departments of Radiology, Naval Medical Center PortsmouthVA, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
e Department of Neurosurgery, Virginia Commonwealth University, Richmond, United States
f Department of Radiology, San Antonio Military Medical CenterTX, United States
g Department of Orthopedics and Rehabilitation, Occupational Therapy Service, San Antonio Military Medical CenterTX, United States
h Department of Sports Medicine, Naval Hospital, Camp Pendleton, CA, United States
i Department of Occupational Therapy, Naval Hospital JacksonvilleFL, United States
j Departments of Neurology, San Diego Naval Medical CenterCA, United States
k Departments of Radiology, San Diego Naval Medical CenterCA, United States
l Branch Health Clinic, Naval Air Station JacksonvilleFL, United States
m Department of Neurology, Berkshire Medical Center, Pittsfield, MA, United States
n Department of Neurological Surgery, University of Washington, Seattle, United States
o Midland Radiology Assoc.MI, United States


Abstract
Objective: To evaluate whether diffusion tensor imaging (DTI) will noninvasively reveal white matter changes not present on conventional MRI in acute blast-related mild traumatic brain injury (mTBI) and to determine correlations with clinical measures and recovery. Methods: Prospective observational study of 95 US military service members with mTBI enrolled within 7 days from injury in Afghanistan and 101 healthy controls. Assessments included Rivermead Post-Concussion Symptoms Questionnaire (RPCSQ), Post-Traumatic Stress Disorder Checklist Military (PCLM), Beck Depression Inventory (BDI), Balance Error Scoring System (BESS), Automated Neuropsychological Assessment Metrics (ANAM), conventional MRI, and DTI. Results: Significantly greater impairment was observed in participants with mTBI vs controls: RPCSQ (19.7 ± 12.9 vs 3.6 ± 7.1, p < 0.001), PCLM (32 ± 13.2 vs 20.9 ± 7.1, p < 0.001), BDI (7.4 ± 6.8 vs 2.5 ± 4.9, p < 0.001), and BESS (18.2 ± 8.4 vs 15.1 ± 8.3, p 0.01). The largest effect size in ANAM performance decline was in simple reaction time (mTBI 74.5 ± 148.4 vs control -11 ± 46.6 milliseconds, p < 0.001). Fractional anisotropy was significantly reduced in mTBI compared with controls in the right superior longitudinal fasciculus (0.393 ± 0.022 vs 0.405 ± 0.023, p < 0.001). No abnormalities were detected with conventional MRI. Time to return to duty correlated with RPCSQ (r 0.53, p < 0.001), ANAM simple reaction time decline (r 0.49, p < 0.0001), PCLM (r 0.47, p < 0.0001), and BDI (r 0.36 p 0.0005). Conclusions: Somatic, behavioral, and cognitive symptoms and performance deficits are substantially elevated in acute blast-related mTBI. Postconcussive symptoms and performance on measures of posttraumatic stress disorder, depression, and neurocognitive performance at initial presentation correlate with return-to-duty time. Although changes in fractional anisotropy are uncommon and subtle, DTI is more sensitive than conventional MRI in imaging white matter integrity in blast-related mTBI acutely. © 2015 American Academy of Neurology.


Document Type: Article
Source: Scopus

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Chung, E.J.a , Babulal, G.M.b , Monsell, S.E.c , Cairns, N.J.b , Roe, C.M.b , Morris, J.C.b
Clinical features of Alzheimer disease with and without Lewy bodies
(2015) JAMA Neurology, 72 (7), pp. 789-796. 

DOI: 10.1001/jamaneurol.2015.0606


a Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea
b Charles F. and Joanne Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, 4488 Forest Park Ave, St Louis, MO, United States
c National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, United States


Abstract
IMPORTANCE: Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings. OBJECTIVE: To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging-Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013. EXPOSURES: Standardized neuropathologic assessment and then brain autopsy after death. MAIN OUTCOMES AND MEASURES: Clinical and neuropsychiatric test scores. RESULTS: The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75-9.42] vs 5.49 [1.39] [95% CI, 2.76-8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45-1.17] vs 0.54 [0.18] [95% CI, 0.19-0.88]; P < .001) than did participants who had AD without Lewy bodies. CONCLUSIONS AND RELEVANCE: Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

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Lucero, C.d g , Campbell, M.C.a b , Flores, H.a , Maiti, B.a , Perlmutter, J.S.a b c d e , Foster, E.R.a d f
Cognitive reserve and β-amyloid pathology in Parkinson disease
(2015) Parkinsonism and Related Disorders, 21 (8), pp. 899-904. 

DOI: 10.1016/j.parkreldis.2015.05.020


a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
d Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
e Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Bethel Public Schools, Spanaway, WA, United States


Abstract
Introduction: Dementia in Parkinson disease (PD) is associated with abnormal accumulation of proteins, including β-amyloid, in cortical regions. High cognitive reserve capacity may protect cognition from β-amyloid and delay the onset of dementia. We tested the cognitive reserve theory in PD by determining whether educational attainment, a proxy for cognitive reserve, modifies the correlation between cortical β-amyloid accumulation and cognitive impairment. Methods: PD participants (N=155) underwent MRI to quantify brain volume and [11C] PiB PET imaging to quantify fibrillar β-amyloid deposition. Mean cortical binding potentials (MCBP) were calculated for each participant, with higher scores indicating more fibrillar β-amyloid. Global cognitive function was assessed using the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). Multiple linear regression analysis was used to determine whether education modified the relationship between MCBP and cognitive function after controlling for brain volume. Results: MCBP interacted with educational attainment to predict scores on each of the cognitive outcome measures (ps≤0.02). Post-hoc analysis revealed that the effect of MCBP on cognitive function changed once the level of education reached 16 years. For participants with less than16 years of education (n=68), higher MCBP correlated with worse cognitive function, with MCBP accounting for 8-30% of the variance in MMSE and CDR scores (ps≤0.02). For participants with at least 16 years of education (n=87), MCBP did not correlate with MMSE or CDR scores (R2s<0.02, ps≥0.17). Conclusion: These findings provide support for the cognitive reserve theory in PD and suggest that education may protect PD patients' cognition against cortical β-amyloid pathology. © 2015 Elsevier Ltd.


Author Keywords
Cognition;  Cognitive reserve;  Dementia;  Education;  Parkinson's disease


Document Type: Article
Source: Scopus

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Roediger, H.L., III, Abel, M.
Collective memory: A new arena of cognitive study
(2015) Trends in Cognitive Sciences, 19 (7), pp. 359-361. 

DOI: 10.1016/j.tics.2015.04.003


Department of Psychology, Washington University in St. Louis, One Brookings Drive, Box 1125, St. Louis, MO, United States


Abstract
Collective memory refers to recollection of events shared by a group. The topic has been of central interest in the humanities, but recently researchers have begun empirical studies. Topics such as how people remember a war or how quickly Americans forget their presidents can be studied objectively. © 2015 Elsevier Ltd.


Document Type: Short Survey
Source: Scopus

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Greenberg, J.K.a , Ladner, T.R.f , Olsen, M.A.d e , Shannon, C.N.f , Liu, J.c , Yarbrough, C.K.a , Piccirillo, J.F.b , Wellons, J.C., IIIf , Smyth, M.D.a , Park, T.S.a , Limbrick, D.D.a
Complications and Resource Use Associated with Surgery for Chiari Malformation Type 1 in Adults: A Population Perspective
(2015) Neurosurgery, 77 (2), pp. 261-268. Cited 1 time.

DOI: 10.1227/NEU.0000000000000777


a Department of Neurological Surgery, St. Louis Children's Hospital, One Children's Way, 4S20, St. Louis, MO, United States
b Department of Otolaryngology, United States
c Division of Biostatistics, United States
d Division of Infectious Diseases, United States
e Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States


Abstract
BACKGROUND: Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-center cohorts. OBJECTIVE: To study the complications and resource use associated with adult CM-1 surgery using administrative data. METHODS: We used a recently validated International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm to retrospectively study adult CM-1 surgeries from 2004 to 2010 in California, Florida, and New York using State Inpatient Databases. Outcomes included complications and resource use within 30 and 90 days of treatment. We used multivariable logistic regression to identify risk factors for morbidity and negative binomial models to determine risk-adjusted costs. RESULTS: We identified 1947 CM-1 operations. Surgical complications were more common than medical complications at both 30 days (14.3% vs 4.4%) and 90 days (18.7% vs 5.0%) postoperatively. Certain comorbidities were associated with increased morbidity; for example, hydrocephalus increased the risk for surgical (odds ratio [OR] 4.51) and medical (OR 3.98) complications. Medical but not surgical complications were also more common in older patients (OR 5.57 for oldest vs youngest age category) and male patients (OR 3.19). Risk-adjusted hospital costs were $22530 at 30 days and $24852 at 90 days postoperatively. Risk-adjusted 90-day costs were more than twice as high for patients experiencing surgical ($46264) or medical ($65679) complications than for patients without complications ($18880). CONCLUSION: Complications after CM-1 surgery are common, and surgical complications are more frequent than medical complications. Certain comorbidities and demographic characteristics are associated with increased risk for complications. Beyond harming patients, complications are also associated with substantially higher hospital costs. These results may help guide patient management and inform decision making for patients considering surgery. Copyright © 2015 by the Congress of Neurological Surgeons.


Author Keywords
Chiari malformation type 1;  Health services research;  Healthcare costs;  Neurosurgery;  Postoperative complications


Document Type: Review
Source: Scopus

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An, H.a , Ford, A.L.d g , Chen, Y.a , Zhu, H.b , Ponisio, R.e g , Kumar, G.d g , Shanechi, A.M.g , Khoury, N.d g , Vo, K.D.e g , Williams, J.h , Derdeyn, C.P.e g , Diringer, M.N.i , Panagos, P.f g , Powers, W.J.c , Lee, J.-M.d e g , Lin, W.a c
Defining the Ischemic Penumbra Using Magnetic Resonance Oxygen Metabolic Index
(2015) Stroke, 46 (4), pp. 982-988. 

DOI: 10.1161/STROKEAHA.114.008154


a Biomedical Research Imaging Center, Departments of Radiology, University of North Carolina at Chapel Hill, United States
b Departments of Biostatistics, University of North Carolina at Chapel Hill, United States
c Departments of Neurology, University of North Carolina at Chapel Hill, United States
d Department of Neurology, Washington University, School of Medicine, 660 South Euclid Ave, Campus Box 8111, St. Louis, MO, United States
e Department of Radiology, Washington University, St. Louis, MO, United States
f Department of Emergency Medicine, Washington University, St. Louis, MO, United States
g School of Medicine, Washington University, St. Louis, MO, United States
h Emergency Department, Barnes-Jewish Hospital, St. Louis, MO, United States


Abstract
Background and Purpose-Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography-derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. Methods-Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow×oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. Results-The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. Conclusions-OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample. © 2015 American Heart Association, Inc.


Author Keywords
magnetic resonance imaging;  reperfusion


Document Type: Article
Source: Scopus

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Barco, P.P.a , Baum, C.M.a , Ott, B.R.b , Ice, S.c , Johnson, A.d , Wallendorf, M.e , Carr, D.B.f g
Driving errors in persons with dementia
(2015) Journal of the American Geriatrics Society, 63 (7), pp. 1373-1380. 

DOI: 10.1111/jgs.13508


a Washington University, School of Medicine in St. Louis, Program in Occupational Therapy, 4444 Forest Park Blvd., St. Louis, MO, United States
b Department of Neurology, Warren Alpert Medical School, Brown University, Providence, RI, United States
c Independent Drivers, LLC, St. Louis, MO, United States
d Center for Clinical Studies, School of Medicine, Washington University, St. Louis, MO, United States
e Division of Biostatistics, School of Medicine, Washington University, St. Louis, MO, United States
f Department of Medicine, School of Medicine, Washington University, St. Louis, MO, United States
g Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States


Abstract
Objectives To differentiate driving errors in persons with dementia who fail a performance- based road test from errors in persons who pass. Design Cross-sectional. Setting Community. Participants Active drivers diagnosed with dementia (n = 60) and older adult controls (n = 32). Measurement All participants completed a standardized clinical and on-road driving assessment. The outcome variable was the number and types of driving errors according to the Record of Driving Errors (RODE), a standardized tool to record driving errors. Results Sixty-two percent (n = 37) of individuals with dementia and 3% (n = 1) of controls failed the road test. Based on the RODE, individuals with dementia made twice as many driving errors as healthy controls. Within the dementia sample, individuals who failed the road test had more difficulties driving straight and making left and right turns than during lane changes. Dangerous actions occurred most often while driving straight and making left turns. Specific driving behaviors associated with road test failure in the sample with dementia included difficulties in lane positioning and usage, stopping the vehicle appropriately, attention, decision-making, and following rules of the road. Informants of participants with dementia who failed the road test reported more impairment with cognitive functioning on the Assessing Dementia 8 Screening Interview (AD8). Conclusion This report highlights the driving errors most common in people with dementia who fail a road test. The finding that most of the dangerous actions in the sample with dementia occurred while driving straight condition is novel. Driving on straight roads has not been considered a condition of "high challenge" in prior driving studies in individuals with dementia. This finding has potential implications for future interventions related to vehicle instrumentation and driving recommendations for people with dementia. © 2015 The American Geriatrics Society.


Author Keywords
dementia;  driving errors;  driving performance;  older drivers


Document Type: Conference Paper
Source: Scopus

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Liewluck, T.a , Tian, X.b , Wong, L.-J.b , Pestronk, A.c
Dystrophinopathy mimicking metabolic myopathies
(2015) Neuromuscular Disorders, 25 (8), pp. 653-657. 

DOI: 10.1016/j.nmd.2015.04.001


a Department of Neurology, University of Colorado School of Medicine, Anschutz Medical Campus, Stop B-185, 12631 Et. 17th Avenue, Aurora, CO, United States
b Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX, United States
c Department of Neurology, Washington University School of Medicine, Campus Box8111, 660 South Euclid Avenue, St. Louis, MO, United States


Abstract
Recurrent rhabdomyolysis warrants comprehensive evaluations to search for underlying muscle diseases, including metabolic myopathies, LPIN1-myopathy, RYR1-myopathy, and less commonly muscular dystrophies. The absence of weakness and the normal or minimally elevated creatine kinase levels between attacks are typical of metabolic myopathies, LPIN1-myopathy, and RYR1-myopathy, while the presence of weakness and the highly elevated creatine kinase levels between attacks point toward muscular dystrophies. Here we report a 32-year-old man with a one-year history of recurrent rhabdomyolysis, who had normal strength, slightly elevated baseline creatine kinase level, and normal muscle histopathology. All workups for metabolic myopathies, LPIN1-myopathy and RYR1-myopathy were unrevealing. Next generation sequencing of muscular dystrophy-related genes revealed a hemizygous deletion of exons 17-34 of the dystrophin-encoding gene. Immunohistochemical study revealed absent staining for the rod domain of dystrophin. Dystrophinopathy should be considered in patients with recurrent rhabdomyolysis despite the absence of fixed weakness or highly elevated resting creatine kinase level. © 2015 Elsevier B.V.


Author Keywords
Becker muscular dystrophy;  Dystrophin;  Dystrophinopathy;  Metabolic myopathy;  Rhabdomyolysis


Document Type: Article
Source: Scopus

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Treloar, H.a , Piasecki, T.M.b d , Mccarthy, D.M.b d , Sher, K.J.b d , Heath, A.C.c d d
Ecological evidence that affect and perceptions of drink effects depend on alcohol expectancies
(2015) Addiction, 110 (9), pp. 1432-1442. 

DOI: 10.1111/add.12982


a Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States
b Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
c Washington University School of Medicine, St Louis, MO, United States
d Midwest Alcoholism Research Center, St Louis and Columbia, MO, United States


Abstract
Aims: (1) To compare affective changes over drinking and non-drinking days among frequent drinkers and (2) to evaluate whether drinkers' expectations influence affective changes and perceived pleasure and relief from drinking. Design: Observational study involving ecological momentary assessments collected via electronic diaries during the course of 3weeks. Setting: Drinkers' usual settings in Columbia, MO, USA. Participants: A total of 400 adult, frequent drinkers, aged 18-70years. Measurements: Ecological assessments included morning reports, pre-drinking random prompts, user-initiated first-drink reports and device-prompted follow-ups over drinking episodes. Participants rated positive (enthusiastic, excited, happy) and negative (distressed, sad) affect and perceived pleasure and relief from drinking in real time. A self-report questionnaire completed at baseline evaluated expectancies for enhanced sociability and tension reduction from drinking. Findings: Relative to affective changes over non-drinking days, positive affect increased prior to drinking [95% confidence interval (CI)=0.004, 0.023], and at first drink (95% CI=0.238, 0.317), whereas negative affect decreased prior to drinking (95% CI=- 0.007, 0.000) and at first drink (95% CI=- 0.154, - 0.098). Sociability expectancies augmented increases in positive affect prior to drinking (95% CI=0.009, 0.027) and at first drink (95% CI=0.017, 0.169). Sociability expectancies also enhanced perceived pleasure from first drinks (95% CI=0.046, 0.318). Tension-reduction expectancies attenuated decreases in negative affect at first drink (95% CI=- 0.133, - 0.029), but augmented perceived relief from first drinks (95% CI=0.001, 0.304). Conclusions: Although theoretical models tend to focus on negative affective outcomes of drinking, changes in positive affect prior to drinking and early in drinking episodes are important for maintaining drinking behavior. Frequent drinkers' expectations for enhanced sociability or tension reduction from drinking influence their affective experiences over drinking days and perceptions of pleasure and relief from drinking. © 2015 Society for the Study of Addiction.


Author Keywords
Alcohol;  Drink appraisals;  Ecological momentary assessment;  Expectancies;  Negative affect;  Piecewise growth model;  Positive affect;  Sociability;  Tension reduction


Document Type: Article
Source: Scopus

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Ortega, M.a , Brier, M.R.a , Ances, B.M.a b c d e
Effects of HIV and combination antiretroviral therapy on cortico-striatal functional connectivity
(2015) AIDS, 29 (6), pp. 703-712. 

DOI: 10.1097/QAD.0000000000000611


a Department of Neurology, Washington University, 660 South Euclid Ave, Saint Louis, MO, United States
b Department of Radiology, Washington University, St Louis, MO, United States
c Department of Biomedical Engineering, Washington University, St Louis, MO, United States
d Department of Microbiology, Washington University, St Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University, St Louis, MO, United States


Abstract
Objective: Determine whether HIV and combination antiretroviral therapy (cART) affect resting-state functional connectivity (rs-fc) between the striatum and the cortical regions. Methods: Forty-nine HIV-uninfected (HIV-) and 132 HIV-infected (HIV+) (65% receiving cART) patients underwent laboratory studies (current and nadir CD4+ T-cell counts, and plasma HIV viral load), neuropsychological performance testing, and neuroimaging. Rs-fc, which examines the coordination of neural activity in distant brain regions, was used to investigate the cortico-striatal functional connections. The effect of cART was assessed comparing HIV+ individuals on cART (HIV+/cART+), and HIV+ individuals not currently receiving cART (HIV+/cART+). Relationships between laboratory tests, cognitive performance, and cART on subcortical-cortical rs-fc were assessed by an analysis of variance. Results: HIV+ individuals had lower cortico-striatal functional connectivity than HIV-controls, specifically between the striatum and the default mode network (P<0.001) and ventral attention network (P<0.001). HIV+/cART+ individuals had higher functional connectivity between the striatum, and default mode network (P=0.02) and ventral attention network (P=0.01), compared to the HIV+/cART- patients. Laboratory (current and nadir CD4+ T-cell counts, plasma viral load) and neuropsychological performance was not correlated with cortico-striatal rs-fc. Conclusions: HIV was associated with disrupted cortico-striatal networks, consistent with HIV's known impact on the subcortical areas. Interestingly, within certain networks, HIV+/cART+ individuals had similar rs-fc compared to HIV- controls, suggesting possible improvements in HIV-related neural dysfunction due to medications. Rs-fc may be a sensitive biomarker of neural insult and its recovery following cART. Additional studies may show rs-fc has utility in measuring acute inflammation caused by HIV. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Author Keywords
Caudate;  Combination antiretroviral therapy;  HIV;  HIV-associated neurocognitive disorders;  Putamen;  Resting-state functional connectivity;  Striatum


Document Type: Article
Source: Scopus

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Leuchter, A.F.a , Cook, I.A.a , Feifel, D.b , Goethe, J.W.c , Husain, M.d g , Carpenter, L.L.e , Thase, M.E.f , Krystal, A.D.g , Philip, N.S.e , Bhati, M.T.f , Burke, W.J.h , Howland, R.H.i , Sheline, Y.I.f j , Aaronson, S.T.k , Iosifescu, D.V.l , O'Reardon, J.P.m , Gilmer, W.S.n , Jain, R.o , Burgoyne, K.S.p , Phillips, B.s t , Manberg, P.J.s t , Massaro, J.q , Hunter, A.M.a , Lisanby, S.H.g , George, M.S.r
Efficacy and safety of low-field synchronized transcranial magnetic stimulation (sTMS) for treatment of major depression
(2015) Brain Stimulation, 8 (4), pp. 787-794. 

DOI: 10.1016/j.brs.2015.05.005


a Department of Psychiatry and Biobehavioral Sciences, Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, Los Angeles, CA, United States
b Department of Psychiatry, UCSD School of Medicine, San Diego, CA, United States
c Institute of Living, Hartford Hospital, Hartford, CT, United States
d Department of Psychiatry, UT Southwestern Medical School, Dallas, TX, United States
e Department of Psychiatry and Human Behavior, Butler Hospital, Alpert Medical School of Brown University, Providence, RI, United States
f Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
g Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States
h Department of Psychiatry, University of Nebraska, School of Medicine, Omaha, NE, United States
i Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
j Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, United States
k Sheppard Pratt Health System, Baltimore, MD, United States
l Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
m Department of Psychiatry, Rowan University School of Osteopathic Medicine, Stratford, NJ, United States
n Chicago TMS Specialists, Chicago, IL, United States
o RD Clinical Research, Lake Jackson, TX, United States
p Harbor-UCLA Medical Center, Torrance, CA, United States
q Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
r Department of Psychiatry, Medical University of South Carolina, And the Ralph H. Johnson VA Medical Center, Charleston, SC, United States
s NeoSync, Inc., Waltham, MA, United States
t NeoSync, Inc., Newport Beach, CA, United States


Abstract
Background Transcranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events. Objective/Hypothesis To examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individual's alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD. Methods Six-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD<inf>17</inf>) ≥ 17. Results 202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (N = 59), however, had significantly greater mean decrease in HamD<inf>17</inf> than sham (N = 60) (-9.00 vs. -6.56, P = 0.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs. -4.25, P = 0.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS. Conclusions Results suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended. © 2015 Elsevier Inc. All rights reserved.


Author Keywords
Alpha oscillations;  Clinical treatment trial;  Electroencephalogram (EEG);  Individual Alpha Frequency (IAF);  Low-intensity magnetic field;  Major Depressive Disorder;  Neuromodulation;  Oscillatory synchrony;  Static magnet;  Synchronized Transcranial Magnetic Stimulation (sTMS)


Document Type: Article
Source: Scopus

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Duncan, R.P.a b , Cavanaugh, J.T.c , Earhart, G.M.a b d , Ellis, T.D.e , Ford, M.P.f , Foreman, K.B.g , Leddy, A.L.a , Paul, S.S.g i , Canning, C.G.h , Thackeray, A.g , Dibble, L.E.g
External validation of a simple clinical tool used to predict falls in people with Parkinson disease
(2015) Parkinsonism and Related Disorders, 21 (8), pp. 960-963. 

DOI: 10.1016/j.parkreldis.2015.05.008


a Washington University School of Medicine in St. Louis, Program in Physical Therapy, United States
b Washington University School of Medicine in St. Louis, Department of Neurology, United States
c University of New England, Department of Physical Therapy, United States
d Washington University School of Medicine in St. Louis, Department of Anatomy and Neurobiology, United States
e Boston University, Department of Physical Therapy and Athletic Training, United States
f University of Alabama, Birmingham School of Health Professions, Department of Physical Therapy, United States
g University of Utah, Department of Physical Therapy, United States
h The University of Sydney, Faculty of Health Sciences, Australia
i The George Institute for Global Health, The University of Sydney, Sydney Medical School, Australia


Abstract
Background: Assessment of fall risk in an individual with Parkinson disease (PD) is a critical yet often time consuming component of patient care. Recently a simple clinical prediction tool based only on fall history in the previous year, freezing of gait in the past month, and gait velocity <1.1m/s was developed and accurately predicted future falls in a sample of individuals with PD. METHODS: We sought to externally validate the utility of the tool by administering it to a different cohort of 171 individuals with PD. Falls were monitored prospectively for 6 months following predictor assessment. RESULTS: The tool accurately discriminated future fallers from non-fallers (area under the curve [AUC]=0.83; 95% CI 0.76-0.89), comparable to the developmental study. CONCLUSION: The results validated the utility of the tool for allowing clinicians to quickly and accurately identify an individual's risk of an impending fall. © 2015 Elsevier Ltd.


Author Keywords
Fall prediction;  Fall risk;  Falls;  Parkinson disease


Document Type: Article
Source: Scopus

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Bateman, R.J.a b , Morris, J.C.a b
Factors contributing to post-lumbar puncture headache: In reply
(2015) JAMA Neurology, 72 (7), p. 835. 

DOI: 10.1001/jamaneurol.2015.0691


a Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8111, St Louis, MO, United States
b Dominantly Inherited Alzheimer Network Clinical Core, Washington University School of Medicine, St Louis, MO, United States


Document Type: Letter
Source: Scopus

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Diemer, E.W.a , Grant, J.D.a b , Munn-Chernoff, M.A.a b , Patterson, D.A.c , Duncan, A.E.a b c
Gender Identity, Sexual Orientation, and Eating-Related Pathology in a National Sample of College Students
(2015) Journal of Adolescent Health, 57 (2), pp. 144-149. Cited 1 time.

DOI: 10.1016/j.jadohealth.2015.03.003


a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Midwest Alcoholism Research Center, Washington University, School of Medicine, St. Louis, MO, United States
c George Warren Brown School of Social Work, Washington University, One Brookings Drive, Campus Box 1196, St. Louis, MO, United States


Abstract
Purpose This study examined associations of gender identity and sexual orientation with self-reported eating disorder (SR-ED) diagnosis and compensatory behaviors in transgender and cisgender college students. Methods Data came from 289,024 students from 223 U.S. universities participating in the American College Health Association-National College Health Assessment II (median age, 20 years). Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were compared among transgender students (n = 479) and cisgender sexual minority (SM) male (n = 5,977) and female (n = 9,445), unsure male (n = 1,662) and female (n = 3,395), and heterosexual male (n = 91,599) and female (n = 176,467) students using chi-square tests. Logistic regression models were used to estimate the odds of eating-related pathology outcomes after adjusting for covariates. Results Rates of past-year SR-ED diagnosis and past-month use of diet pills and vomiting or laxatives were highest among transgender students and lowest among cisgender heterosexual men. Compared to cisgender heterosexual women, transgender students had greater odds of past-year SR-ED diagnosis (odds ratio [OR], 4.62; 95% confidence interval [CI], 3.41-6.26) and past-month use of diet pills (OR, 2.05; 95% CI, 1.48-2.83) and vomiting or laxatives (OR, 2.46; 95% CI, 1.83-3.30). Although cisgender SM men and unsure men and women also had elevated rates of SR-ED diagnosis than heterosexual women, the magnitudes of these associations were lower than those for transgender individuals (ORs; 1.40-1.54). Conclusions Transgender and cisgender SM young adults have elevated rates of compensatory behavior and SR-ED diagnosis. Appropriate interventions for these populations are urgently needed. © 2015 Society for Adolescent Health and Medicine.


Author Keywords
College students;  Compensatory behaviors;  Eating disorders;  Gender identity;  Sexual orientation


Document Type: Conference Paper
Source: Scopus

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Zhan, X.a b , Cao, M.a , Yoo, A.S.c , Zhang, Z.a , Chen, L.d , Crabtree, G.R.d , Wu, J.I.a
Generation of BAF53b-Cre transgenic mice with pan-neuronal Cre activities
(2015) Genesis, 53 (7), pp. 440-448. 

DOI: 10.1002/dvg.22866


a Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States
b Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, United States
c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Developmental Biology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA, United States


Abstract
Molecular and functional studies of genes in neurons in mouse models require neuron-specific Cre lines. The current available neuronal Cre transgenic or knock-in lines either result in expression in a subset of neurons or expression in both neuronal and non-neuronal tissues. Previously we identified BAF53b as a neuron-specific subunit of the chromatin remodeling BAF complexes. Using a bacteria artificial chromosome (BAC) construct containing the BAF53b gene, we generated a Cre transgenic mouse under the control of BAF53b regulatory elements. Like the endogenous BAF53b gene, we showed that BAF53b-Cre is largely neuron-specific. In both central and peripheral nervous systems, it was expressed in all developing neurons examined and was not observed in neural progenitors or glial cells. In addition, BAF53b-Cre functioned in primary cultures in a pan-neuron-specific manner. Thus, BAF53b-Cre mice will be a useful genetic tool to manipulate gene expression in developing neurons for molecular, biochemical, and functional studies. © 2015 Wiley Periodicals, Inc.


Author Keywords
Genetics;  Mammal;  Organism


Document Type: Article
Source: Scopus

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Munn-Chernoff, M.A.a e , Grant, J.D.a , Agrawal, A.a , Sartor, C.E.a b , Werner, K.B.c , Bucholz, K.K.a , Madden, P.A.F.a , Heath, A.C.a , Duncan, A.E.a d
Genetic overlap between alcohol use disorder and bulimic behaviors in European American and African American women
(2015) Drug and Alcohol Dependence, 153, pp. 335-340. 

DOI: 10.1016/j.drugalcdep.2015.05.043


a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO, United States
b Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System, 950 Campbell Ave. (151D), West Haven, CT, United States
c George Warren Brown School of Social Work, Washington University, 4560 Clayton Ave., CID 1000, St. Louis, MO, United States
d George Warren Brown School of Social Work, Washington University, One Brookings Drive, CB 1196, St. Louis, MO, United States
e Department of Psychiatry, University of North Carolina, 101Manning Drive, CB 7160, Chapel Hill, NC, United States


Abstract
Background: Despite substantial evidence that alcohol use disorder (AUD) and bulimic behaviors (i.e., binge eating and compensatory behaviors) co-occur, insufficient information exists regarding a possible shared etiology. Moreover, although numerous twin studies of European ancestry individuals have reported moderate heritability estimates for AUD and bulimic behaviors, with little evidence for shared environmental factors, research on genetic and environmental risk in African American (AA) individuals is lacking. Methods: We investigated specific and overlapping genetic and environmental influences on AUD and bulimic behaviors in 3232 European American (EA; 55.38% monozygotic) and 549 AA (42.81% monozygotic) young adult female twins from the Missouri Adolescent Female Twin Study (age range = 18-29 years). A structured clinical interview assessed lifetime DSM-5 AUD (minus craving) and bulimic behaviors. Biometrical twin modeling was conducted to generate age-adjusted estimates of genetic and environmental influences on AUD, bulimic behaviors, and their comorbidity. Results: Estimates of genetic and environmental contributions on AUD and bulimic behaviors could be equated across EA and AA women. Additive genetic effects accounted for 59% (95% CI: 50%, 66%) and 43% (33%, 52%) of the variance in AUD and bulimic behaviors, respectively, with the remainder due to non-shared environmental effects. Shared genetic factors (r<inf>g</inf>=33 (18, .49)) were solely responsible for the correlation between phenotypes; the non-shared environmental correlation was not significant (r<inf>e</inf>=10 (-05, .25)). Conclusions: Findings indicate similar magnitudes of genetic and environmental effects on AUD and bulimic behaviors for EA and AA women and implicate common genetic mechanisms underlying liability to these problem behaviors. © 2015 Elsevier Ireland Ltd.


Author Keywords
African American;  Alcohol use disorder;  DSM-5;  Eating disorders;  Heritability;  Twins


Document Type: Article
Source: Scopus

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Hohman, T.J.a b , Cooke-Bailey, J.N.a b , Reitz, C.c , Jun, G.d e f , Naj, A.g , Beecham, G.W.h i , Liu, Z.h i , Carney, R.M.h i j , Vance, J.M.h i k , Cuccaro, M.L.h i l , Rajbhandary, R.h i , Vardarajan, B.N.c , Wang, L.-S.m , Valladares, O.m , Lin, C.-F.m , Larson, E.B.n o , Graff-Radford, N.R.p q , Evans, D.r , De Jager, P.L.s t , Crane, P.K.n o , Buxbaum, J.D.u v w , Murrell, J.R.x , Raj, T.s t , Ertekin-Taner, N.p q , Logue, M.W.e f , Baldwin, C.T.e y , Green, R.C.z aa , Barnes, L.L.ab , Cantwell, L.B.m , Fallin, M.D.ac , Go, R.C.P.ad , Griffith, P.ae , Obisesan, T.O.af , Manly, J.J.c , Lunetta, K.L.f , Kamboh, M.I.ag ah , Lopez, O.L.ag ah , Bennett, D.A.ab ai , Hardy, J.aj , Hendrie, H.C.ak al , Hall, K.S.ak al , Goate, A.M.am an , Lang, R.ao , Byrd, G.S.ao , Kukull, W.A.ap , Foroud, T.M.aq , Farrer, L.A.d e f ar as , Martin, E.R.h i at , Pericak-Vance, M.A.h i k , Schellenberg, G.D.m , Mayeux, R.c , Haines, J.L.a b , Thornton-Wells, T.A.a b
Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk
(2015) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2015.02.012


a Center for Human Genetics and Research, Vanderbilt University School of Medicine, Nashville, TN, USA
b Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
c Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA
d Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
e Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
f Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
g Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
h Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA
i John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
j Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
k Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA
l Department of Psychology, College of Arts and Sciences, University of Miami, Miami, FL, USA
m Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
n Department of Medicine, University of Washington, Seattle, WA, USA
o Group Health Research Institute, Group Health, Seattle, WA, USA
p Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
q Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
r Department of Internal Medicine, Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, USA
s Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA
t Program in Medical and Population Genetics, The Broad Institute, Cambridge, MA, USA
u Department of Psychiatry, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
v Department of Genetics and Genomic Sciences, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
w Department of Neuroscience, The Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
x Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
y Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA
z Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
aa Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
ab Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
ac Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
ad School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
ae Division of Neurology, Department of Medicine, Morehouse School of Medicine, Atlanta, GA, USA
af Division of Geriatrics, Howard University Hospital, Washington, DC, USA
ag Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
ah Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA
ai Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
aj Department of Molecular Neuroscience, Institute of Neurology, University College of London, London, UK
ak Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA
al Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
am Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
an Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA
ao Department of Biology, North Carolina A and T State University, Greensboro, NC, USA
ap National Alzheimer's Coordinating Center and Department of Epidemiology, University of Washington, Seattle, WA, USA
aq Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
ar Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA
as Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA
at Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA


Abstract
African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses. © 2015 The Alzheimer's Association.


Author Keywords
Admixture mapping;  African-American;  Alzheimer's disease;  Genome-wide association analysis (GWAS);  Local admixture;  Local ancestry


Document Type: Article in Press
Source: Scopus

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Weiner, M.W.a b c d e , Veitch, D.P.a , Aisen, P.S.f , Beckett, L.A.g , Cairns, N.J.h i , Cedarbaum, J.j , Donohue, M.C.k , Green, R.C.l , Harvey, D.g , Jack, C.R., Jr.m , Jagust, W.n , Morris, J.C.i , Petersen, R.C.o , Saykin, A.J.p , Shaw, L.q , Thompson, P.M.r , Toga, A.W.s , Trojanowski, J.Q.t u v w
Impact of the Alzheimer's Disease Neuroimaging Initiative, 2004 to 2014
(2015) Alzheimer's and Dementia, 11 (7), pp. 865-884. Cited 3 times.

DOI: 10.1016/j.jalz.2015.04.005


a Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, United States
b Department of Radiology, University of California San Francisco, San Francisco, CA, United States
c Department of Medicine, University of California San Francisco, San Francisco, CA, United States
d Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States
e Department of Neurology, University of California San Francisco, San Francisco, CA, United States
f Department of Neurosciences, University of California San Diego, San Diego, CA, United States
g Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Davis, CA, United States
h Department of Neurology, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
i Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
j Neurology Early Clinical Development, Biogen Idec, Cambridge, MA, United States
k Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA, United States
l Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
m Department of Radiology, Mayo Clinic, Rochester, MN, United States
n Helen Wills Neuroscience Institute, School of Public Health, University of California Berkeley, Berkeley, CA, United States
o Department of Neurology, Mayo Clinic, Rochester, MN, United States
p Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
q Department of Pathology, Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
r Imaging Genetics Center, Institute for Neuroimaging and Informatics, University of Southern California, Marina Del Rey, CA, United States
s Laboratory of Neuroimaging, Institute of Neuroimaging and Informatics, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
t Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
u Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
v Alzheimer's Disease Core Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
w Udall Parkinson's Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States


Abstract
Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer's disease (AD) by validating biomarkers for AD clinical trials. Methods We searched for ADNI publications using established methods. Results ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post-traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data-sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public-private partnerships developing biomarkers for Parkinson's disease and multiple sclerosis. Discussion ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials. © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.


Author Keywords
AD biomarker signature;  Alzheimer's disease;  Amyloid phenotyping;  Clinical trial biomarkers;  Data-sharing;  Tau imaging;  Worldwide ADNI


Document Type: Article
Source: Scopus

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Few, L.R.a , Lynam, D.R.b , Miller, J.D.c
Impulsivity-related traits and their relation to DSM-5 section II and III personality disorders
(2015) Personality Disorders: Theory, Research, and Treatment, 6 (3), pp. 261-266. 

DOI: 10.1037/per0000120


a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Psychological Sciences, Purdue UniversityIN, United States
c Department of Psychology, University of GeorgiaGA, United States


Abstract
Difficulties with impulse control are considered a core feature of personality disorders (PDs) as assessed by the Diagnostic and Statistical Manual of Mental Disorders (5th edition [DSM-5]; American Psychiatric Association, 2013). Despite this, there has been relatively little examination of the manner in which DSM-5 PDs are characterized by multidimensional models of impulsivity that parse this broad umbrella construct into smaller, more unidimensional constructs. Using the UPPS model and measure of impulsivity (Whiteside & Lynam, 2001), the relations between 4 impulsivity-related traits and interview-rated scores on both DSM-5 Section II and III PDs and PD traits were examined in a community sample of individuals currently receiving psychological or psychiatric care (N = 106). As expected, the UPPS traits manifested correlations with the new Section III trait model that were generally consistent with the assertion that this new DSM-5 trait model reflects a pathological variant of the Five-Factor Model (FFM; e.g., UPPS traits associated with FFM conscientiousness were most strongly related to DSM-5 disinhibition traits). Overall, the UPPS traits accounted best for variance in DSM-5 Section II and III Cluster B PDs, consistent with these PDs being characterized, in part, by emotionally and cognitively based forms of impulsivity. © 2015 APA, all rights reserved.


Author Keywords
DSM-5;  impulsivity;  personality disorders;  UPPS


Document Type: Article
Source: Scopus

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Johnson, E.O.a , Hancock, D.B.b , Levy, J.L.c , Gaddis, N.C.c , Page, G.P.d , Glasheen, C.b , Saccone, N.L.e , Bierut, L.J.f , Kral, A.H.g
KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex
(2015) Addiction Biology, . Article in Press. 

DOI: 10.1111/adb.12286


a Fellow Program and Behavioral Health and Criminal Justice Division RTI International Research Triangle Park, NC USA
b Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division RTI International Research Triangle Park, NC USA
c Research Computing Division RTI International Research Triangle Park, NC USA
d Fellow Program, Center for Genomics in Public Health and Medicine, and Genomics, Statistical Genetics, and Environmental Research Program RTI International Atlanta, GA USA
e Department of Genetics Washington University School of Medicine St. Louis, MO USA
f Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
g Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division RTI International San Francisco, CA USA


Abstract
Drug abuse is a common and heritable set of disorders, but the underlying genetic factors are largely unknown. We conducted genome-wide association studies of drug abuse using 7 million imputed single nucleotide polymorphisms (SNPs) and insertions/deletions in African Americans (AAs; n=3742) and European Americans (EAs; n=6845). Cases were drawn from the Urban Health Study of street-recruited people, who injected drugs and reported abusing opioids, cocaine, marijuana, stimulants and/or other drugs 10 or more times in the past 30days, and were compared with population controls. Independent replication testing was conducted in 755 AAs and 1131 EAs from the Genetic Association Information Network. An intronic SNP (rs9829896) in the K(lysine) acetyltransferase 2B (KAT2B) gene was significantly associated with drug abuse in AAs (P=4.63×10-8) and independently replicated in AAs (P=0.0019). The rs9829896-C allele (frequency=12%) had odds ratios of 0.68 and 0.53 across the AA cohorts: meta-analysis P=3.93×10-10. Rs9829896-C was not associated with drug abuse across the EA cohorts: frequency=36% and meta-analysis P=0.12. Using dorsolateral prefrontal cortex data from the BrainCloud cohort, we found that rs9829896-C was associated with reduced KAT2B expression in AAs (n=113, P=0.050) but not EAs (n=110, P=0.39). KAT2B encodes a transcriptional regulator in the cyclic adenosine monophosphate and dopamine signaling pathways, and rs9829896-C was associated with expression of genes in these pathways: reduced CREBBP expression (P=0.011) and increased OPRM1 expression (P=0.016), both in AAs only. Our study identified the KAT2B SNP rs9829896 as having novel and biologically plausible associations with drug abuse and gene expression in AAs but not EAs, suggesting ancestry-specific effects. © 2015 Society for the Study of Addiction.


Author Keywords
African American;  Gene expression;  GWAS;  KAT2B and substance abuse


Document Type: Article in Press
Source: Scopus

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Pita-Thomas, W.
Magnetic nanotechnology to study and promote axon growth
(2015) Neural Regeneration Research, 10 (7), pp. 1037-1039. 

DOI: 10.4103/1673-5374.160067


Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States


Document Type: Note
Source: Scopus

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Grucza, R.A.a , Hur, M.a , Agrawal, A.a , Krauss, M.J.a , Plunk, A.D.c , Cavazos-Rehg, P.A.a , Chaloupka, F.J.d , Bierut, L.J.b
Medical marijuana laws and suicide
(2015) American Journal of Public Health, 105 (8), p. e3. 

DOI: 10.2105/AJPH.2015.302745


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Siteman Cancer Center, Washington University School of Medicine, United States
c Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
d Department of Economics, Health Policy Center, University of Illinois, Chicago, IL, United States


Document Type: Letter
Source: Scopus

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De Moor, M.H.M.a b c , Van Den Berg, S.M.d , Verweij, K.J.H.e f , Krueger, R.F.g , Luciano, M.h i , Arias Vasquez, A.j k l m , Matteson, L.K.g , Derringer, J.n , Esko, T.o , Amin, N.p , Gordon, S.D.f , Hansell, N.K.f , Hart, A.B.q , Seppälä, I.r , Huffman, J.E.s , Konte, B.t , Lahti, J.u v , Lee, M.w , Miller, M.g , Nutile, T.x , Tanaka, T.y , Teumer, A.z , Viktorin, A.aa , Wedenoja, J.ab , Abecasis, G.R.ac , Adkins, D.E.ad , Agrawal, A.ae , Allik, J.af ag , Appel, K.ah , Bigdeli, T.B.w , Busonero, F.ai , Campbell, H.aj , Costa, P.T.ak , Davey Smith, G.al , Davies, G.h i , De Wit, H.am , Ding, J.y , Engelhardt, B.E.an , Eriksson, J.G.u ao ap aq , Fedko, I.O.c , Ferrucci, L.y , Franke, B.k l m , Giegling, I.t , Grucza, R.ae , Hartmann, A.M.t , Heath, A.C.ae , Heinonen, K.v , Henders, A.K.f , Homuth, G.ar , Hottenga, J.-J.c , Iacono, W.G.g , Janzing, J.l , Jokela, M.v , Karlsson, R.aa , Kemp, J.P.al as , Kirkpatrick, M.G.am , Latvala, A.ab aq , Lehtimäki, T.r , Liewald, D.C.h i , Madden, P.A.F.ae , Magri, C.at , Magnusson, P.K.E.aa , Marten, J.s , Maschio, A.ai , Medland, S.E.f , Mihailov, E.o au , Milaneschi, Y.av , Montgomery, G.W.f , Nauck, M.aw , Ouwens, K.G.c , Palotie, A.ax ay , Pettersson, E.aa , Polasek, O.az , Qian, Y.y , Pulkki-Råback, L.v , Raitakari, O.T.ba bb , Realo, A.af , Rose, R.J.bc , Ruggiero, D.x , Schmidt, C.O.z , Slutske, W.S.bd , Sorice, R.x , Starr, J.M.h be , St Pourcain, B.al bf bg , Sutin, A.R.y bh , Timpson, N.J.al , Trochet, H.s , Vermeulen, S.m bi , Vuoksimaa, E.ab , Widen, E.ay , Wouda, J.c d , Wright, M.J.f , Zgaga, L.aj bj , Porteous, D.bk , Minelli, A.at , Palmer, A.A.q am , Rujescu, D.t , Ciullo, M.x , Hayward, C.s bl , Rudan, I.aj , Metspalu, A.o ag , Kaprio, J.ab aq ay , Deary, I.J.h i , Räikkönen, K.v , Wilson, J.F.aj , Keltikangas-Järvinen, L.v , Bierut, L.J.ae , Hettema, J.M.w , Grabe, H.J.ah bm , Van Duijn, C.M.p , Evans, D.M.al as , Schlessinger, D.y , Pedersen, N.L.x , Terracciano, A.u bh , McGue, M.g bn , Penninx, B.W.J.H.av , Martin, N.G.f , Boomsma, D.I.c
Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder
(2015) JAMA Psychiatry, 72 (7), pp. 642-650. 

DOI: 10.1001/jamapsychiatry.2015.0554


a Department of Clinical Child and Family Studies, VU University Amsterdam, Van der Boechorststraat 1, Amsterdam, Netherlands
b Department of Methods, VU University Amsterdam, Amsterdam, Netherlands
c Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
d Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, Netherlands
e Department of Developmental Psychology, EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, Netherlands
f QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia
g Department of Psychology, University of Minnesota, Minneapolis, United States
h Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
i Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
j Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
k Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, Netherlands
l Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
m Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
n Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, United States
o Estonian Genome Center, University of Tartu, Tartu, Estonia
p Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
q Department of Human Genetics, University of Chicago, Chicago, IL, United States
r Department of Clinical Chemistry, Fimlab Laboratories, School of Medicine, University of Tampere, Tampere, Finland
s Medical Research Council Human Genetics, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
t Department of Psychiatry, University of Halle, Halle, Germany
u Folkhälsan Research Center, Helsinki, Finland
v Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
w Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, United States
x Institute of Genetics and Biophysics A. Buzzati-Traverso, National Research Council of Italy, Naples, Italy
y National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
z Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
aa Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
ab Department of Public Health, University of Helsinki, Helsinki, Finland
ac Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, United States
ad Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, United States
ae Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
af Department of Psychology, University of Tartu, Tartu, Estonia
ag Estonian Academy of Sciences, Tallinn, Estonia
ah Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
ai Istituto di Ricerca Genetica e Biomedica, National Research Council of Italy, Monserrato, Italy
aj Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
ak Behavioral Medicine Research Center, Duke University School of Medicine, Durham, NC, United States
al Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
am Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
an Department of Computer Science, Princeton University, Princeton, NJ, United States
ao Department of General Practice and Primary Health Care, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
ap Vasa Central Hospital, Vasa, Finland
aq National Institute for Health and Welfare, Helsinki, Finland
ar Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
as University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia
at Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
au Department of Biotechnology, University of Tartu, Tartu, Estonia
av Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands
aw Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
ax Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
ay Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
az Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
ba Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
bb Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
bc Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States
bd Department of Psychological Sciences, Missouri Alcoholism Research Center, University of Missouri, Columbia, United States
be Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom
bf School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom
bg School of Experimental Psychology, University of Bristol, Bristol, United Kingdom
bh College of Medicine, Florida State University, Tallahassee, United States
bi Department for Health Evidence, Radboud University Medical Center, Nijmegen, Netherlands
bj Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
bk Medical Genetics Section, University of Edinburgh, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom
bl Generation Scotland, University of Edinburgh, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom
bm Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, Stralsund, Germany
bn Institute of Public Health, University of Southern Denmark, Odense, Denmark


Abstract
IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15%of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P <.05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism. Copyright 2015 American Medical Association. All rights reserved.


Document Type: Article
Source: Scopus

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Petersen, S.C.a , Monk, K.R.a b
Neurobiology: Myelin Goes Where the Action is
(2015) Current Biology, 25 (13), pp. R562-R565. 

DOI: 10.1016/j.cub.2015.04.054


a Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO, United States


Abstract
There is increasing evidence that neuronal activity modulates how axons are wrapped in myelin. Two recent studies demonstrate that activity-dependent vesicle release from neurons regulates myelination in vivo. © 2015 Elsevier Ltd All rights reserved.


Document Type: Article
Source: Scopus

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Govindarajan, R.a , Iyadurai, S.J.b , Connolly, A.a , Zaidman, C.a
Selective response to rituximab in a young child with MuSK-associated myasthenia gravis
(2015) Neuromuscular Disorders, 25 (8), pp. 651-652. 

DOI: 10.1016/j.nmd.2015.03.014


a Division of Neuromuscular Medicine, Washington University in St. Louis School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
b Department of Neurology and Psychiatry, Neuromuscular Medicine, Saint Louis University, Monteleone Hall, 1438 South Grand Blvd., St. Louis, MO, United States


Abstract
Neuromuscular junction disorders in children are either genetic, such as congenital myasthenic syndrome, or autoimmune with circulating antibodies most commonly against acetylcholine receptors. There is limited experience recognizing and treating children with myasthenia associated with muscle-specific tyrosine kinase antibodies. We report a seven-year-old child with intermittent esotropia since age 3 months, and two years of progressive and severe diplopia, dysarthria, dysphagia, and facial weakness. Acetylcholine receptor antibodies and genetic testing for congenital myasthenic syndrome were negative. Muscle specific tyrosine kinase antibodies were significantly elevated. Ophthalmoplegia and bulbar weakness were refractory to treatment with acetylcholinesterase inhibitors, corticosteroids and IVIg but completely resolved following treatment with rituximab. Her neurologic examination remained normal at the most recent follow-up, 15 months after initiation of rituximab. Children with MuSK myasthenia, like adults, can respond to rituximab despite long standing disease and failure to improve on other immunosuppressant medications. © 2015 Elsevier B.V.


Author Keywords
Diplopia;  Dysarthria;  Muscle specific tyrosine kinase;  Myasthenia gravis;  Rituximab


Document Type: Article
Source: Scopus

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Shahim, P.a , Mattsson, N.a b , Macy, E.M.c , Crimmins, D.L.c , Ladenson, J.H.c , Zetterberg, H.a d , Blennow, K.a , Tegner, Y.e
Serum visinin-like protein-1 in concussed professional ice hockey players
(2015) Brain Injury, 29 (7-8), pp. 872-876. 

DOI: 10.3109/02699052.2015.1018324


a Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Mölndal, Sweden
b Department of Veterans Affairs Medical Center, University of California San Francisco, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, United States
c Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Molecular Neuroscience, Reta Lila Weston Laboratories, UCL Institute of Neurology, London, United Kingdom
e Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden


Abstract
Primary objective: Visinin-like protein-1 (VILIP-1) has shown potential utility as a biomarker for neuronal injury in cerebrospinal fluid. This study investigated serum VILIP-1 as a diagnostic and prognostic marker in sports-related concussion. Methods: This multi-centre prospective cohort study involved the 12 teams of the professional ice hockey league in Sweden. A total of 288 players consented to participate in the study. Thirty-five players sustained concussions, of whom 28 underwent repeated blood samplings at 1, 12, 36 and 144 hours after the trauma or when the player returned to play (7-90 days). Main outcomes and results: The highest levels of VILIP-1 were measured 1 hour after concussion and the levels decreased during rehabilitation, reaching a minimum level at the 36-hour sampling. However, the levels of serum VILIP-1 at 1 hour after concussion were not significantly higher than pre-season baseline values. Serum levels of VILIP-1 1 hour post-concussion did not correlate with the number of days for the concussion symptoms to resolve. Further, serum levels of VILIP-1 increased after a friendly game in players who were not concussed. Conclusions: These results provide evidence that serum VILIP-1 may not be a useful biomarker for diagnosis and prognosis of sports-related concussion. © 2015 Informa UK Ltd. All rights reserved.


Author Keywords
Biomarker;  Brain injury;  Concussion;  Ice hockey;  VILIP-1


Document Type: Article
Source: Scopus

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Kharasch, E.D.a , Hollmann, M.W.b
Steroid anesthesia revisited: Again
(2015) Anesthesia and Analgesia, 120 (5), pp. 983-984. 

DOI: 10.1213/ANE.0000000000000667


a Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St. Louis, 660 S Euclid Ave., St. Louis, MO, United States
b Department of Anesthesiology, Academic Medical Center Amsterdam, Amsterdam, Netherlands


Document Type: Editorial
Source: Scopus

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Raichle, M.E.
The Brain's Default Mode Network
(2015) Annual Review of Neuroscience, 38, pp. 433-447. Cited 1 time.

DOI: 10.1146/annurev-neuro-071013-014030


Washington University School of Medicine, St. Louis, MO, United States


Abstract
The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its discovery was an unexpected consequence of brain-imaging studies first performed with positron emission tomography in which various novel, attention-demanding, and non-self-referential tasks were compared with quiet repose either with eyes closed or with simple visual fixation. The default mode network consistently decreases its activity when compared with activity during these relaxed nontask states. The discovery of the default mode network reignited a longstanding interest in the significance of the brain's ongoing or intrinsic activity. Presently, studies of the brain's intrinsic activity, popularly referred to as resting-state studies, have come to play a major role in studies of the human brain in health and disease. The brain's default mode network plays a central role in this work. © 2015 by Annual Reviews. All rights reserved.


Author Keywords
Activation;  Attention;  Baseline;  Functional connectivity;  Intrinsic activity;  Memory;  Resting state;  Self


Document Type: Article
Source: Scopus

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Beebe, K.a , Park, D.b , Taghert, P.H.b , Micchelli, C.A.a
The Drosophila prosecretory transcription factor dimmed is dynamically regulated in adult enteroendocrine cells and protects against Gram-negative infection
(2015) G3: Genes, Genomes, Genetics, 5 (7), pp. 1517-1524. 

DOI: 10.1534/g3.115.019117


a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
The endocrine system employs peptide hormone signals to translate environmental changes into physiological responses. The diffuse endocrine system embedded in the gastrointestinal barrier epithelium is one of the largest and most diverse endocrine tissues. Furthermore, it is the only endocrine tissue in direct physical contact with the microbial environment of the gut lumen. However, it remains unclear how this sensory epithelium responds to specific pathogenic challenges in a dynamic and regulated manner. We demonstrate that the enteroendocrine cells of the adult Drosophila melanogaster midgut display a transient, sensitive, and systemic induction of the prosecretory factor dimmed (dimm) in response to the Gram-negative pathogen Pseudomonas entomophila (Pe). In enteroendocrine cells, dimm controls the levels of the targets Phm, dcat-4, and the peptide hormone, Allatostatin A. Finally, we identify dimm as a host factor that protects against Pe infection and controls the expression of antimicrobial peptides. We propose that dimm provides "gain" in enteroendocrine output during the adaptive response to episodic pathogen exposure. © 2015 Beebe et al.


Author Keywords
Dimmed;  Drosophila;  Enteroendocrine;  Immunity;  Midgut


Document Type: Article
Source: Scopus

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Duma, A.a b , Cartmill, C.a , Blood, J.a , Sharma, A.a , Kharasch, E.D.a , Nagele, P.a
The hematological effects of nitrous oxide anesthesia in pediatric patients
(2015) Anesthesia and Analgesia, 120 (6), pp. 1325-1330. 

DOI: 10.1213/ANE.0000000000000642


a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, 660 S. Euclid Ave., St. Louis, MO, United States
b Department of Anesthesiology and Intensive Care, Medical University of Vienna, Vienna, Austria


Abstract
BACKGROUND: Prolonged administration of nitrous oxide causes an increase in plasma homocysteine in children via vitamin B<inf>12</inf> inactivation. However, it is unclear whether nitrous oxide doses used in clinical practice cause adverse hematological effects in pediatric patients. METHODS: This retrospective study included 54 pediatric patients undergoing elective spinal surgery: 41 received nitrous oxide throughout anesthesia (maintenance group), 9 received nitrous oxide for induction and/or emergence (induction/emergence group), and 4 did not receive nitrous oxide (nitrous oxide-free group). Complete blood counts obtained before and up to 4 days after surgery were assessed for anemia, macrocytosis/microcytosis, anisocytosis, hyperchromatosis/hypochromatosis, thrombocytopenia, and leukopenia. The change (Δ) from preoperative to the highest postoperative value was calculated for mean corpuscular volume (MCV) and red cell distribution width (RDW). RESULTS: No pancytopenia was present in any patient after surgery. All patients had postoperative anemia, and none had macrocytosis. Postoperative MCV (mean [99% confidence interval]) peaked at 86 fL (85-88 fL), 85 fL (81-89 fL), and 88 fL (80-96 fL) and postoperative RDW at 13.2% (12.8-13.5%), 13.3% (12.7-13.8%), and 13.0% (11.4-14.6%) for the maintenance group, the induction/emergence group, and the nitrous oxide-free group. Two patients in the maintenance group (5%) developed anisocytosis (RDW >14.6%), but none in the induction/emergence group or in the nitrous oxide-free group (P = 0.43). Both ΔMCV (P = 0.52) and ΔRDW (P = 0.16) were similar across all groups. CONCLUSIONS: Nitrous oxide exposure for up to 8 hours is not associated with megaloblastic anemia in pediatric patients undergoing major spinal surgery. © 2015 International Anesthesia Research Society.


Document Type: Article
Source: Scopus

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Finnerup, N.B.a , Haroutounian, S.b , Nikolajsen, L.c
The sodium-channel blocker lidocaine in subanesthetic concentrations reduces spontaneous and evoked pain in human painful neuroma
(2015) Scandinavian Journal of Pain, 8, pp. 45-46. 

DOI: 10.1016/j.sjpain.2015.05.003


a Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Norrebrogade 44, Aarhus C, Denmark
b Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
c Department of Anesthesiology, Aarhus University Hospital, Denmark


Document Type: Note
Source: Scopus

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Bai, Y.a b , Xuan, B.b , Liu, H.a , Zhong, J.c , Yu, D.d e , Qian, Z.b
Tuberous Sclerosis complex protein 2-independent activation of mTORC1 by human cytomegalovirus pUL38
(2015) Journal of Virology, 89 (15), pp. 7625-7635. 

DOI: 10.1128/JVI.01027-15


a Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
b Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Xuhui District, Shanghai, China
c Unit of Viral Hepatitis, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Xuhui District, Shanghai, China
d Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
e Novartis Vaccines, Cambridge, MA, United States


Abstract
The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and anabolic metabolism and is a critical host factor activated by human cytomegalovirus (HCMV) for successful infection. The multifunctional HCMV protein pUL38 previously has been reported to activate mTORC1 by binding to and antagonizing tuberous sclerosis complex protein 2 (TSC2) (J. N. Moorman et al., Cell Host Microbe 3:253-262, 2008, http://dx.doi.org/10.1016/j.chom.2008.03.002). pUL38 also plays a role in blocking endoplasmic reticulum stress-induced cell death during HCMV infection. In this study, we showed that a mutant pUL38 lacking the N-terminal 24 amino acids (pHA-UL38<inf>25-331</inf>) was fully functional in suppressing cell death during infection. Interestingly, pHA-UL38<inf>25-331</inf> lost the ability to interact with TSC2 but retained the ability to activate mTORC1, although to a lesser extent than full-length pHA-UL38. Recombinant virus expressing pHA-UL38<inf>25-331</inf> replicated with ~10-fold less efficiency than the wild-type virus at a low multiplicity of infection (MOI), but it grew similarly well at a high MOI, suggesting an MOIdependent importance of pUL38-TSC2 interaction in supporting virus propagation. Site-directed mutational analysis identified a TQ motif at amino acid residues 23 and 24 as critical for pUL38 interaction with TSC2. Importantly, when expressed in isolation, the TQ/AA substitution mutant pHA-UL38 TQ/AA was capable of activating mTORC1 just like pHA-UL38<inf>25-331</inf>. We also created TSC2-null U373-MG cell lines by CRISPR genome editing and showed that pUL38 was capable of further increasing mTORC1 activity in TSC2-null cells. Therefore, this study identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners. © 2015, American Society for Microbiology.


Document Type: Article
Source: Scopus

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Randerath, J.a b , Valyear, K.F.b , Hood, A.c , Frey, S.H.b
Two Routes to the Same Action: An Action Repetition Priming Study
(2015) Journal of Motor Behavior, 47 (2), pp. 142-152. Cited 1 time.

DOI: 10.1080/00222895.2014.961891


a Department of Psychology, Clinical Neuropsychology, University of Konstanz, PB 905, Konstanz, Germany
b Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
c Department of Psychology, Washington University, St. Louis, MO, United States


Abstract
Action selection can be influenced by preceding movements. The authors investigated how retrospective factors may interact with plan- versus rule-based action selection. Participants completed 2 tasks, both of which involved selecting a pronated or supinated posture. In the plan task, they chose the most comfortable hand orientation. In the rule task, they followed a learned prescription. Trials in both tasks comprised prime-probe pairs that were identical, or differed in the visual stimulus or required motor response. Both tasks showed a response-time advantage for probes that were preceded by identical primes. This effect was greater for the plan task suggesting that plan-based action selection is especially susceptible to recent history, fortifying the idea that differential mechanisms underlie a rule- versus plan-based approach to the same action. Copyright © Taylor & Francis Group, LLC 2015.


Author Keywords
action planning;  action repetition priming;  action selection;  motor history;  rule-based action


Document Type: Article
Source: Scopus

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Greenberg, J.K.a , Ladner, T.R.f , Olsen, M.A.d e , Shannon, C.N.f , Liu, J.c , Yarbrough, C.K.a , Piccirillo, J.F.b , Wellons, J.C., IIIf , Smyth, M.D.a , Park, T.S.a , Limbrick, D.D.a
Validation of an International Classification of Diseases, Ninth Revision Code Algorithm for Identifying Chiari Malformation Type 1 Surgery in Adults
(2015) Neurosurgery, 77 (2), pp. 269-273. Cited 1 time.

DOI: 10.1227/NEU.0000000000000778


a Department of Neurological Surgery, St. Louis Children's Hospital, One Children's Way, 4S20, St. Louis, MO, United States
b Department of Otolaryngology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Division of Infectious Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States


Abstract
BACKGROUND: The use of administrative billing data may enable large-scale assessments of treatment outcomes for Chiari Malformation type I (CM-1). However, to utilize such data sets, validated International Classification of Diseases, Ninth Revision (ICD-9-CM) code algorithms for identifying CM-1 surgery are needed. OBJECTIVE: To validate 2 ICD-9-CM code algorithms identifying patients undergoing CM-1 decompression surgery. METHODS: We retrospectively analyzed the validity of 2 ICD-9-CM code algorithms for identifying adult CM-1 decompression surgery performed at 2 academic medical centers between 2001 and 2013. Algorithm 1 included any discharge diagnosis code of 348.4 (CM-1), as well as a procedure code of 01.24 (cranial decompression) or 03.09 (spinal decompression, or laminectomy). Algorithm 2 restricted this group to patients with a primary diagnosis of 348.4. The positive predictive value (PPV) and sensitivity of each algorithm were calculated. RESULTS: Among 340 first-time admissions identified by Algorithm 1, the overall PPV for CM-1 decompression was 65%. Among the 214 admissions identified by Algorithm 2, the overall PPV was 99.5%. The PPV for Algorithm 1 was lower in the Vanderbilt (59%) cohort, males (40%), and patients treated between 2009 and 2013 (57%), whereas the PPV of Algorithm 2 remained high (≥99%) across subgroups. The sensitivity of Algorithms 1 (86%) and 2 (83%) were above 75% in all subgroups. CONCLUSION: ICD-9-CM code Algorithm 2 has excellent PPV and good sensitivity to identify adult CM-1 decompression surgery. These results lay the foundation for studying CM-1 treatment outcomes by using large administrative databases. Copyright © 2015 by the Congress of Neurological Surgeons.


Author Keywords
Administrative data research;  Chiari malformation type 1;  Health services research;  Neurosurgery;  Validation studies


Document Type: Article
Source: Scopus

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Herrick, R.a , Horton, W.a , Olsen, T.b , McKay, M.a , Archie, K.A.a , Marcus, D.S.a
XNAT Central: Open sourcing imaging research data
(2015) NeuroImage, . Article in Press. 

DOI: 10.1016/j.neuroimage.2015.06.076


a Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
b Deck5 Consulting, Normal, IL, USA


Abstract
XNAT Central is a publicly accessible medical imaging data repository based on the XNAT open-source imaging informatics platform. It hosts a wide variety of research imaging data sets. The primary motivation for creating XNAT Central was to provide a central repository to host and provide access to a wide variety of neuroimaging data. In this capacity, XNAT Central hosts a number of data sets from research labs and investigative efforts from around the world, including the OASIS Brains imaging studies, the NUSDAST study of schizophrenia, and more. Over time, XNAT Central has expanded to include imaging data from many different fields of research, including oncology, orthopedics, cardiology, and animal studies, but continues to emphasize neuroimaging data. Through the use of XNAT's DICOM metadata extraction capabilities, XNAT Central provides a searchable repository of imaging data that can be referenced by groups, labs, or individuals working in many different areas of research. The future development of XNAT Central will be geared towards greater ease of use as a reference library of heterogeneous neuroimaging data and associated synthetic data. It will also become a tool for making data available supporting published research and academic articles. © 2015 Elsevier Inc.


Author Keywords
Data sharing;  Neuroinformatics databases;  Open access;  Open source;  XNAT;  XNAT Central

 


Document Type: Article in Press
Source: Scopus