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Neuroscience Publications Archive - June 2016

June 10, 2016

Mill, R.D.a , O'Connor, A.R.b , Dobbins, I.G.c
Pupil dilation during recognition memory: Isolating unexpected recognition from judgment uncertainty
(2016) Cognition, 154, pp. 81-94. 

DOI: 10.1016/j.cognition.2016.05.018

a Center for Molecular and Behavioral Neuroscience, Rutgers University, United States
b School of Psychology and Neuroscience, University of St Andrews, United Kingdom
c Department of Psychological and Brain Sciences, Washington University in Saint Louis, United States

Optimally discriminating familiar from novel stimuli demands a decision-making process informed by prior expectations. Here we demonstrate that pupillary dilation (PD) responses during recognition memory decisions are modulated by expectations, and more specifically, that pupil dilation increases for unexpected compared to expected recognition. Furthermore, multi-level modeling demonstrated that the time course of the dilation during each individual trial contains separable early and late dilation components, with the early amplitude capturing unexpected recognition, and the later trailing slope reflecting general judgment uncertainty or effort. This is the first demonstration that the early dilation response during recognition is dependent upon observer expectations and that separate recognition expectation and judgment uncertainty components are present in the dilation time course of every trial. The findings provide novel insights into adaptive memory-linked orienting mechanisms as well as the general cognitive underpinnings of the pupillary index of autonomic nervous system activity. © 2016 Elsevier B.V.

Author Keywords
Decision-making;  Orienting;  Pupillometry;  Recognition memory;  Uncertainty

Document Type: Article
Source: Scopus


Nguyen, T.-V.a , Gower, P.b , Albaugh, M.D.c , Botteron, K.N.d e , Hudziak, J.J.c e , Fonov, V.S.f , Collins, L.f , Ducharme, S.f g , McCracken, J.T.e h
The developmental relationship between DHEA and visual attention is mediated by structural plasticity of cortico-amygdalar networks
(2016) Psychoneuroendocrinology, 70, pp. 122-133. 

DOI: 10.1016/j.psyneuen.2016.05.003

a Department of Psychiatry and Department of Obstetrics-Gynecology, McGill University Health Center (Royal Victoria Hospital at the Glen site), McGill University, Montreal, QC, Canada
b Department of Psychology, McGill University, Montreal, QC, Canada
c University of Vermont, College of Medicine, Burlington, VT, United States
d Washington University School of Medicine, St. Louis, MO, United States
e Brain Development Cooperative Group, Canada
f McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
g McGill University Health Centre, Department of Psychiatry and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
h Department of Child and Adolescent Psychiatry, University of California in Los Angeles, Los Angeles, CA, United States

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention. Here we examined associations between DHEA, structural covariance of the amygdala with whole-brain cortical thickness, and tests of visual attention, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DHEA predicted covariance between amygdalar volume and the left occipital pole, right somatosensory parietal cortex and right anterior cingulate cortex. Amygdala-occipital covariance predicted visual awareness; amygdala-parietal covariance predicted visuo-motor dexterity and processing speed; amygdala-prefrontal covariance predicted global attentional impairment. Further, effects of DHEA were above and beyond those of age and sex, as well as distinct from those of pubertal stage, estradiol and testosterone. These findings support the notion that DHEA may play a unique role in shaping amygdala-dependent cortical plasticity and in regulating 'bottom-up' visual attention processes from childhood to young adulthood. © 2016 Elsevier Ltd.

Author Keywords
Adolescents;  Adrenarche;  Androgen;  Human brain;  Visual awareness;  Visuo-motor dexterity

Document Type: Article
Source: Scopus


Ben-David, V.
Substance-abusing parents and their children in termination of parental rights cases in Israel
(2016) Children and Youth Services Review, 66, pp. 94-100. 

DOI: 10.1016/j.childyouth.2016.05.001

School of social work, Washington University, St. Louis, MO, United States

Parental substance abuse significantly increases the risk of child maltreatment and loss of custody. If parental capacity due to substance abuse cannot be rehabilitated within a limited time period and if the child cannot be safely returned to his/her home, the state, in various jurisdictions, is empowered to initiate termination of parental rights proceedings. Despite the connection between substance abuse and termination of parental rights, the research literature in this area is limited. Based on a sample of 212 rulings in favor of termination of parental rights by Israeli courts, the present study examines factors that differentiate substance-abusing from non-substance-abusing parents. The findings indicate that substance-abusing parents constitute a unique high-risk group among parents whose parental rights were terminated. This group is characterized by a higher cumulative risk that includes mental health issues with an emphasis on personality disorders and emotional problems, criminal records, child neglect and maternal single parenthood. All these factors, as well as the overall number of risk factors in a particular case, were found to predict substance-abusing parenthood. A discussion of the findings and their implications for social work practice with families involved in the child welfare system follows. © 2016 Elsevier Ltd.

Author Keywords
Child maltreatment;  Court decisions;  Substance abuse;  Termination of parental rights

Document Type: Article
Source: Scopus


Yu, A.B.a b , Zacks, J.M.b
How are bodies special? Effects of body features on spatial reasoning
(2016) Quarterly Journal of Experimental Psychology, 69 (6), pp. 1210-1226. 

DOI: 10.1080/17470218.2015.1079225

a Army Research Laboratory, Aberdeen Proving GroundMD, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Embodied views of cognition argue that cognitive processes are influenced by bodily experience. This implies that when people make spatial judgments about human bodies, they bring to bear embodied knowledge that affects spatial reasoning performance. Here, we examined the specific contribution to spatial reasoning of visual features associated with the human body. We used two different tasks to elicit distinct visuospatial transformations: object-based transformations, as elicited in typical mental rotation tasks, and perspective transformations, used in tasks in which people deliberately adopt the egocentric perspective of another person. Body features facilitated performance in both tasks. This result suggests that observers are particularly sensitive to the presence of a human head and body, and that these features allow observers to quickly recognize and encode the spatial configuration of a figure. Contrary to prior reports, this facilitation was not related to the transformation component of task performance. These results suggest that body features facilitate task components other than spatial transformation, including the encoding of stimulus orientation. © 2015 The Experimental Psychology Society.

Author Keywords
Mental imagery;  Perspective taking;  Spatial transformations

Document Type: Article
Source: Scopus


Massaro, A.N.a , Murthy, K.b c , Zaniletti, I.d , Cook, N.e , DiGeronimo, R.f , Dizon, M.L.V.b , Hamrick, S.E.G.g , McKay, V.J.h , Natarajan, G.i , Rao, R.j , Richardson, T.d , Smith, D.k , Mathur, A.M.j , Dykes, F.l , Piazza, A.l , Sysyn, G.l , Coghill, C.l , Dhanireddy, R.l , Hansen, A.l , Hossain, T.l , Reber, K.l , Savani, R.l , Brion, L.l , Grover, T.l , Chi, A.l , Johnson, Y.l , Suresh, G.l , Pallotto, E.l , Rodgers, B.l , Lyle, R.l , Chin, S.l , Joe, P.l , D'Harlingue, A.l , Evans, J.l , Padula, M.l , Brozanski, B.l , Speziale, M.l , Short, B.l , Sullivan, K.l , Di Geronimo, R.l , Uhing, M.l , Meskin, K.l , Jentsch, L.l , Grebe, J.l , Wadhawan, R.l , Jacobson, E.l , Asselin, J.l , Durand, D.l , Short, B.L.l
Intercenter cost variation for perinatal hypoxic-ischemic encephalopathy in the era of therapeutic hypothermia
(2016) Journal of Pediatrics, 173, pp. 76-83.e1. Cited 1 time.

DOI: 10.1016/j.jpeds.2016.02.033

a Children's National Health System, Department of Pediatrics, George Washington University School of Medicine, Washington, DC, United States
b Ann and Robert H. Lurie Children's Hospital of Chicago, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
c Children's Hospitals Neonatal Consortium, Inc, United States
d Children's Hospitals Association, Overland Park, KS, United States
e Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
f Department of Pediatrics, University of Utah, Primary Children's Medical Center, Salt Lake City, UT, United States
g Department of Pediatrics, Children's Healthcare of Atlanta at Egleston, Emory University, Atlanta, GA, United States
h All Children's Hospital, St Petersburg, FL, United States
i Department of Pediatrics, Wayne State University, Children's Hospital of Michigan, Detroit, MI, United States
j Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States
k Children's Hospital of Colorado, Department of Pediatrics, University of Colorado, Aurora, CO, United States

Objective To quantify intercenter cost variation for perinatal hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia across children's hospitals. Study design Prospectively collected data from the Children's Hospitals Neonatal Database and Pediatric Health Information Systems were linked to evaluate intercenter cost variation in total hospitalization costs after adjusting for HIE severity, mortality, length of stay, use of extracorporeal support or nitric oxide, and ventilator days. Secondarily, costs for intensive care unit bed, electroencephalography (EEG), and laboratory and neuroimaging testing were also evaluated. Costs were contextualized by frequency of favorable (survival with normal magnetic resonance imaging) and adverse (death or need for gastric tube feedings at discharge) outcomes to identify centers with relative low costs and favorable outcomes. Results Of the 822 infants with HIE treated with therapeutic hypothermia at 19 regional neonatal intensive care units, 704 (86%) survived to discharge. The median cost/case for survivors was $58 552 (IQR $32 476-$130 203) and nonsurvivors $29 760 (IQR $16 897-$61 399). Adjusting for illness severity and select interventions, intercenter differences explained 29% of the variation in total hospitalization costs. The widest cost variability across centers was EEG use, although low cost and favorable outcome centers ranked higher with regards to EEG costs. Conclusions There is marked intercenter cost variation associated with treating HIE across regional children's hospitals. Our investigation may help establish references for cost and enhance quality improvement and resource utilization projects related to HIE. © 2016 Elsevier Inc. All rights reserved.

Author Keywords
cost;  hypothermia;  intercenter variation;  neonatal intensive care unit;  newborn

Document Type: Article
Source: Scopus


Chang, R.O.a , Marshall, B.K.a , Yahyavi, N.b , Sharma, A.b , Huecker, J.a , Gordon, M.O.a , McClelland, C.a , Van Stavern, G.P.a
Neuroimaging Features of Idiopathic Intracranial Hypertension Persist After Resolution of Papilloedema
(2016) Neuro-Ophthalmology, pp. 1-6. Article in Press. 

DOI: 10.1080/01658107.2016.1179767

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA

Papilloedema is a key clinical finding in the diagnosis of idiopathic intracranial hypertension (IIH). However, newly proposed criteria allow diagnosis without papilloedema only if certain neuroimaging features are present. It is currently unclear if these findings persist upon resolution of papilloedema and IIH. A retrospective chart review identified three groups of patients (six per group) who had received orbital imaging within 4 weeks of fundoscopic examination: (1) IIH patients without active papilloedema, (2) IIH patients with active papilloedema, and (3) patients with no history of IIH or papilloedema. All magnetic resonance imaging (MRI) scans were graded by a neuroradiologist who was blinded to clinical status. Neuroimaging features were compared by using the Kruskal-Wallis one-way analysis of variance. Measurements of sellar and optic nerve configuration showed a statistical trend with papilloedema status. For the control group versus the active papilloedema group, the values were 0.0597 and 0.0621, respectively. For the control group versus the resolved papilloedema group, the values were 0.0485 and 0.0512, respectively. However, globe and sellar p values for the resolved papilloedema group versus the active papilloedema group were 1.000 and 0.6023, respectively, and not significant. Sellar and globe configuration suggest that a statistical trend for persistence after papilloedema has resolved and intracranial pressure (ICP) has normalised. Careful clinical correlation and fundus examination are essential because some of these neuroimaging features can be seen in normal patients and those with resolved IIH, and their presence on MRI may not necessarily indicate active disease or elevated ICP. © 2016 Taylor & Francis

Author Keywords
Globe configuration;  idiopathic intracranial hypertension;  papilloedema;  sellar configuration

Document Type: Article in Press
Source: Scopus


Salimi, H.a , Cain, M.D.a , Klein, R.S.a b c
Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis
(2016) Neurotherapeutics, pp. 1-21. Article in Press. 

DOI: 10.1007/s13311-016-0443-5

a Department of Internal Medicine, 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 Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus- and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause. © 2016 The American Society for Experimental NeuroTherapeutics, Inc.

Author Keywords
Arbovirus;  Blood-brain barrier;  Innate immunity;  Viral encephalitis

Document Type: Article in Press
Source: Scopus


Taylor, J.J.a , Grant, K.E.b , Zulauf, C.A.c , Fowler, P.J.d , Meyerson, D.A.e , Irsheid, S.f
Exposure to Community Violence and the Trajectory of Internalizing and Externalizing Symptoms in a Sample of Low-Income Urban Youth
(2016) Journal of Clinical Child and Adolescent Psychology, pp. 1-15. Article in Press. 

DOI: 10.1080/15374416.2016.1152553

a Assessment and Continuous Improvement, Collaborative for Academic, Social, and Emotional Learning
b Department of Psychology, DePaul University
c Department of Psychology, University of Illinois at Chicago
d George Warren Brown School of Social Work, Washington University in St. Louis
e PROMISE Program, Columbia University Medical Center
f Harlem Children’s Zone – Promise Academy Charter School

This study examined trajectories of psychopathology in a sample of low-income urban youth and tested exposure to community violence as a predictor of these trajectories. Self-report and parent-report survey measures of psychological problems and exposure to community violence were collected annually over 3 years from a sample of 364 fifth- to ninth-grade low-income urban youth (64% female; 95% youth of color). Linear growth models showed that youth experienced declines in both internalizing and externalizing symptoms across adolescence. Exposure to community violence was more strongly associated with externalizing symptoms than with internalizing symptoms but predicted declines in both types of symptoms. Results also indicated that youth reported more internalizing and externalizing symptoms than their parents reported for them. Exposure to community violence may explain unique trajectories of mental health problems among low-income urban youth. In addition, youth efforts to adopt a tough façade in the face of community violence could lead to higher rates of externalizing problems relative to internalizing problems, whereas desensitization processes may better explain reductions in both types of symptoms over time. Finally, youth report may be more valid than parent report in the context of urban poverty. © 2016, Routledge. All rights reserved.

Document Type: Article in Press
Source: Scopus


Fernandez, K.C.a , Gordon, E.A.b , Rodebaugh, T.L.a , Heimberg, R.G.b
Exploring linguistic correlates of social anxiety in romantic stories
(2016) Cognitive Behaviour Therapy, pp. 1-16. Article in Press. 

DOI: 10.1080/16506073.2016.1184711

a Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA
b Department of Psychology, Temple University, Philadelphia, PA, USA

The current study used computerized linguistic analysis of stories about either going on a date or taking a walk down a street to examine linguistic correlates of social anxiety in a sample of undergraduate students. In general, linguistic analysis revealed associations of social anxiety with several linguistic variables, including negative emotion, affect, and anxiety words. Participants higher in social anxiety wrote fewer affect words. The relationship between social anxiety and anxiety words depended on gender, whereas the relationship between social anxiety and negative emotion words depended on both gender and the nature of primes (supraliminal vs. subliminal) received. Overall, our findings highlight the potential utility and benefits of using linguistic analysis as another source of information about how individuals higher in social anxiety process romantic stimuli. © 2016 Swedish Association for Behaviour Therapy

Author Keywords
Linguistic analysis;  LIWC;  romantic;  social anxiety;  subliminal priming

Document Type: Article in Press
Source: Scopus


Reynolds, M.R., Haydon, D.H., Caird, J., Leonard, J.R.
Radiation-Induced Moyamoya Syndrome after Proton Beam Therapy in the Pediatric Patient: A Case Series
(2016) Pediatric Neurosurgery, . Article in Press. 

DOI: 10.1159/000446075

aDepartment of Neurological Surgery, Washington University School of Medicine, St. Louis, Mo., and bDepartment of Neurological Surgery, The Ohio State University, Columbus, Ohio, USA; cDepartment of Neurological Surgery, National Centre for Neurosurgery, Beaumont Hospital, Dublin, Republic of Ireland

Minimizing normal-tissue radiation exposure is especially important in the pediatric population as children appear to be particularly sensitive to postradiation vasculopathies after conventional photon radiotherapy. Given the limited scattering effect and low-dose radiation delivery to the surrounding tissues with proton beam radiotherapy, this modality is considered to be an effective treatment for pediatric skull-base tumors compared to conventional radiotherapy, and to have fewer adverse side effects. We report 2 cases of radiation-induced moyamoya syndrome following proton beam therapy in pediatric patients. To our knowledge, only a few other reported cases of radiation-induced moyamoya syndrome following proton beam therapy exist in the current literature. While rare, radiation-induced moyamoya syndrome can occur in the pediatric population with newer techniques like proton beam radiotherapy. Accordingly, patients and their families should be informed about this potential complication prior to all forms of radiation treatment. © 2016 S. Karger AG, Basel

Author Keywords
Ischemic stroke;  Moyamoya syndrome;  Neurofibromatosis type 1;  Proton beam;  Radiation therapy

Document Type: Article in Press
Source: Scopus


Yuan, P.a b , Condello, C.a i , Keene, C.D.c , Wang, Y.d , Bird, T.D.e , Paul, S.M.f , Luo, W.f , Colonna, M.d , Baddeley, D.g h , Grutzendler, J.a b
TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
(2016) Neuron, 90 (4), pp. 724-739. 

DOI: 10.1016/j.neuron.2016.05.003

a Department of Neurology, Yale University, New Haven, CT, United States
b Department of Neuroscience, Yale University, New Haven, CT, United States
c Department of Pathology, University of Washington, Seattle, WA, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, University of Washington, Seattle, WA, United States
f The Helen and Robert Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
g Department of Cell Biology, Yale University, New Haven, CT, United States
h Nanobiology Institute, Yale University, West Haven, CT, United States
i Department of Neurology, Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, United States

Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD. © 2016 Elsevier Inc.

Document Type: Article
Source: Scopus


Luby, J.L.a , Belden, A.a , Harms, M.P.a , Tillman, R.a , Barch, D.M.a b c
Preschool is a sensitive period for the influence of maternal support on the trajectory of hippocampal development
(2016) Proceedings of the National Academy of Sciences of the United States of America, 113 (20), pp. 5742-5747. 

DOI: 10.1073/pnas.1601443113

a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Building on well-established animal data demonstrating the effects of early maternal support on hippocampal development and adaptive coping, a few longitudinal studies suggest that early caregiver support also impacts human hippocampal development. How caregiving contributes to human hippocampal developmental trajectories, whether there are sensitive periods for these effects, as well as whether related variation in hippocampal development predicts later childhood emotion functioning are of major public health importance. The current study investigated these questions in a longitudinal study of preschoolers assessed annually for behavioral and emotional development, including observed caregiver support. One hundred and twenty-seven children participated in three waves of magnetic resonance brain imaging through school age and early adolescence. Multilevel modeling of the effects of preschool and school-age maternal support on hippocampal volumes across the three waves was conducted. Hippocampal volume increased faster for those with higher levels of preschool maternal support. Subjects with support 1 SD above the mean had a 2.06 times greater increase in total hippocampus volume across the three scans than those with 1 SD below the mean (2.70% vs. 1.31%). No effect of school-age support was found. Individual slopes of hippocampus volume were significantly associated with emotion regulation at scan 3. The findings demonstrate a significant effect of early childhood maternal support on hippocampal volume growth across school age and early adolescence and suggest an early childhood sensitive period for these effects. They also show that this growth trajectory is associated with later emotion functioning.

Author Keywords
Emotions;  Hippocampus;  Maternal support;  Preschool;  Sensitive period

Document Type: Article
Source: Scopus


Glass, J.a , Won, M.b , Schultz, C.J.c , Brat, D.d , Bartlett, N.L.e , Suh, J.H.f , Werner-Wasik, M.a , Fisher, B.J.g , Liepman, M.K.h , Augspurger, M.i , Bokstein, F.j , Bovi, J.A.c , Solhjem, M.C.k , Meh, M.P.l
Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227
(2016) Journal of Clinical Oncology, 34 (14), pp. 1620-1625. 

DOI: 10.1200/JCO.2015.64.8634

a Department of Neurologic Surgery, Thomas Jefferson University, 909 Walnut St, Philadelphia, PA, United States
b NRG Oncology Statistics and Data Management Center, Philadelphia, PA, United States
c Medical College of Wisconsin, Milwaukee, WI, United States
d Emory University, Atlanta, GA, United States
e Washington University School of Medicine, St Louis, MO, United States
f Cleveland Clinic, Cleveland, OH, United States
g London Regional Cancer Program, London, ON, Canada
h Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI, United States
i Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL, United States
j Tel-Aviv SouraskyMedical Center, Tel Aviv, Israel
k Columbia River CCOP, Portland, OR, United States
l University of Maryland Medical Systems, Baltimore, MD, United States

Purpose This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life. Patients and Methods The phase I study increased TMZ doses from 100 to 150 to 200 mg/m2. Patients were treated with rituximab 375 mg/m2 3 days before cycle 1; methotrexate 3.5 g/m2 with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m2 daily for 5 days every 28 days on weeks 14 to 50. Results Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m2. Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT. Conclusion This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies. © 2016 by American Society of Clinical Oncology.

Document Type: Article
Source: Scopus


Jiang, X.a , Sidhu, R.a , Mydock-McGrane, L.b , Hsu, F.-F.c , Covey, D.F.b , Scherrer, D.E.a , Earley, B.a , Gale, S.E.a , Farhat, N.Y.d , Porter, F.D.d , Dietzen, D.J.e , Orsini, J.J.f , Berry-Kravis, E.g , Zhang, X.h , Reunert, J.i , Marquardt, T.i , Runz, H.j k , Giugliani, R.l , Schaffer, J.E.a , Ory, D.S.a
Development of a bile acid-based newborn screen for Niemann-Pick disease type C
(2016) Science Translational Medicine, 8 (337), . 

DOI: 10.1126/scitranslmed.aaf2326

a Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f New York State Department of Health, Wadsworth Center, Albany, NY, United States
g Rush University Medical Center, Chicago, IL, United States
h Genzyme, 500 Kendall Street, Cambridge, MA, United States
i Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Padiatrie, Universitatsklinikum Münster, Albert-Schweitzer-Campus 1, Gebaude A1, Münster, Germany
j Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, Germany
k Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, United States
l Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, Brazil

Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3β, 5aα, 6β trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β, 5aα, 6β-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry-based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs.

Document Type: Article
Source: Scopus


Kharade, S.V.a , Nichols, C.c , Denton, J.S.a b d
The shifting landscape of KATP channelopathies and the need for 'sharper' therapeutics
(2016) Future Medicinal Chemistry, 8 (7), pp. 789-802. 

DOI: 10.4155/fmc-2016-0005

a Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
c Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University, St. Louis, MO, United States
d Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN, United States

ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators. © 2016 Future Science Ltd.

Author Keywords
Cantu syndrome;  chemical chaperone;  diabetes;  high-throughput screening;  insulin;  KATP channels;  pancreas;  thallium flux;  trafficking

Document Type: Review
Source: Scopus


Orr, C.A.a , Albaugh, M.D.a , Watts, R.b f , Garavan, H.c d , Andrews, T.b e f , Nickerson, J.P.b f , Gonyea, J.f , Hipko, S.f , Zweber, C.a , Logan, K.a , Hudziak, J.J.a g h i
Neuroimaging biomarkers of a history of concussion observed in asymptomatic young athletes
(2016) Journal of Neurotrauma, 33 (9), pp. 803-810. 

DOI: 10.1089/neu.2014.3721

a Vermont Center for Children, Youth, and Families, University of Vermont, Burlington, VT, United States
b Department of Radiology, University of Vermont, Burlington, VT, United States
c Department of Psychiatry, University of Vermont, Burlington, VT, United States
d Department of Psychology, University of Vermont, Burlington, VT, United States
e Philips Healthcare, Cleveland, OH, United States
f MRI Center for Biomedical Imaging, University of Vermont, Burlington, VT, United States
g Erasmus University, Sophia Children's Hospital, Rotterdam, Netherlands
h Department of Child Psychiatry, Washington University, St. Louis, MO, United States
i Vermont Center for Children, Youth, and Families, University of Vermont, College of Medicine, 1 South Prospect Street, Burlington, VT, United States

Participation in contact sports places athletes at elevated risk for repeated head injuries and is associated with negative mental health outcomes later in life. The current study identified changes observable on neuroimaging that persisted beyond the apparent resolution of acute symptoms of concussion. Sixteen young adult ice hockey players with a remote history of concussion but no subjective complaints were compared against 13 of their teammates with no history of concussion. Participants completed a detailed phenotypic assessment and a neuroimaging battery including diffusion kurtosis imaging and resting-state functional magnetic resonance imaging. Athletes with a history of concussion performed no differently from those without on phenotypic assessment, but showed significantly elevated fractional anisotropy (FA) in the left genu and anterior corona radiata relative to those without. Post hoc analyses revealed that elevated FA was associated with increased microstructural complexity perpendicular to the primary axon (radial kurtosis). Athletes with concussion history also showed significant differences in the organization of the default mode network (DMN) characterized by stronger temporal coherence in posterior DMN, decreased temporal coherence in anterior DMN, and increased functional connectivity outside the DMN. In the absence of deficits on detailed phenotypic assessment, athletes with a history of concussion displayed changes to the microstructural architecture of the cerebral white matter and to the functional connectivity of the brain at rest. Some of these changes are consistent with those previously associated with persisting deficits and complaints, but we also report novel, complementary changes that possibly represent compensatory mechanisms. © Mary Ann Liebert, Inc. 2016.

Author Keywords
cognitive function;  head trauma, MRI;  neuroplasticity

Document Type: Article
Source: Scopus


Huang, J., Bonni, A.
A decade of the anaphase-promoting complex in the nervous system
(2016) Genes and Development, 30 (6), pp. 622-638. 

DOI: 10.1101/gad.274324.115

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

Control of protein abundance by the ubiquitin–proteasome system is essential for normal brain development and function. Just over a decade ago, the first post-mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology. © 2016 Huang and Bonni.

Author Keywords
Anaphase-promoting complex;  E3 ubiquitin ligase;  Ubiquitin–proteasome system

Document Type: Review
Source: Scopus


Ohlemiller, K.K.a , Kiener, A.L.b , Gagnon, P.M.a
QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice
(2016) JARO - Journal of the Association for Research in Otolaryngology, pp. 1-22. Article in Press. 

DOI: 10.1007/s10162-016-0558-8

a Department of Otolaryngology, Central Institute for the Deaf at Washington University School of Medicine, Fay and Carl Simons Center for Hearing and Deafness, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO, United States
b Department of Speech and Hearing Science, Ohio State University, Columbus, OH, United States

We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10–26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht’s strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45–58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40–50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1–CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1–3 h after broadband noise (4–45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47–53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall. © 2016 Association for Research in Otolaryngology

Author Keywords
cochlea;  genetics;  lateral wall;  noise-induced hearing loss;  recombinant inbred;  stria vascularis

Document Type: Article in Press
Source: Scopus


Liu, H., Jin, H., Yue, X., Luo, Z., Liu, C., Rosenberg, A.J., Tu, Z.
PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis
(2016) Molecular Imaging and Biology, pp. 1-9. Article in Press. 

DOI: 10.1007/s11307-016-0944-y

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

Purpose: Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [11C]TZ3321. Procedures: MicroPET imaging studies of [11C]TZ3321 were performed to measure uptake of [11C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers. Results: MicroPET imaging demonstrated a 20–30 % increase in [11C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35–60 min post injection. The increased uptake of [11C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration. Conclusions: MicroPET imaging modality with a specific radioligand [11C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases. © 2016 World Molecular Imaging Society

Document Type: Article in Press
Source: Scopus


Kim, J.H.a , Song, S.-K.a , Haldar, J.P.b
Signal-to-noise ratio-enhancing joint reconstruction for improved diffusion imaging of mouse spinal cord white matter injury
(2016) Magnetic Resonance in Medicine, 75 (2), pp. 852-858. 

DOI: 10.1002/mrm.25691

a Department of Radiology, Washington University, St. Louis, MO, United States
b Departments of Electrical Engineering and Biomedical Engineering, University of Southern California, University Park Campus, Hughes Aircraft Electrical Engineering Center (EEB), 3740 S. McClintock Avenue, #442, M/C 2564, Los Angeles, CA, United States

Purpose To assess the capability of signal-to-noise ratio enhancing reconstruction (SER) to reduce the acquisition time for quantitative white matter injury assessment. Methods Four single-average diffusion tensor imaging (DTI) datasets were acquired for each animal from four mouse cohorts: two models of spinal cord injury and two control groups. Quantitative parameters (apparent diffusion coefficient, relative anisotropy, axial and radial diffusivities) were computed from (I) single-average data with traditional reconstruction; (II) single-average data with SER; (III) four-average data with traditional reconstruction; and (IV) single-average data with optimized multicomponent nonlocal means (OMNLM) denoising. These approaches were compared based on coefficients of variation (COVs) and whether estimated diffusion parameters were sensitive to injury. Results SER yielded better COVs for diffusivity and anisotropy than traditional reconstruction of single-average data, and yielded comparable COVs to that achieved with four-average data. In addition, diffusion parameters obtained using SER with single-average data had comparable injury sensitivity to those obtained from four-average data, while diffusion parameters obtained from OMNLM and traditional reconstruction of single-average data had limited sensitivity. Conclusion A four-fold reduction in the number of averages for quantitative diffusion imaging of small animal white matter injury is feasible using SER. Our results also underscore the need to validate nonlinear methods using task-based measures on an application-by-application basis. © 2015 Wiley Periodicals, Inc.

Author Keywords
denoising;  diffusion tensor imaging;  signal-to-noise ratio

Document Type: Article
Source: Scopus


Werner, K.B.a , McCutcheon, V.V.b , Challa, M.c , Agrawal, A.b , Lynskey, M.T.d , Conroy, E.e , Statham, D.J.f , Madden, P.A.F.b , Henders, A.K.g , Todorov, A.A.b , Heath, A.C.b , Degenhardt, L.g , Martin, N.G.f , Bucholz, K.K.b , Nelson, E.C.b
The association between childhood maltreatment, psychopathology, and adult sexual victimization in men and women: Results from three independent samples
(2016) Psychological Medicine, 46 (3), pp. 563-573. 

DOI: 10.1017/S0033291715002056

a George Warren Brown School of Social Work, Washington University in St Louis, 4560 Clayton Ave., 1000 CID, St Louis, MO, United States
b Alcoholism Research Center, Washington University School of Medicine, St Louis, MO, United States
c University of Illinois-Chicago School of Medicine, Chicago, IL, United States
d Institute of Psychiatry, Psychology and Neuroscience, King's College, London, United Kingdom
e Centre for Health Research, University of Western Sydney, Sydney, Australia
f QIMR Berghofer Medical Research Institute, Brisbane, Australia
g National Drug and Alcohol Research Center, University of New South Wales, Sydney, Australia

Background Childhood maltreatment (CM) has consistently been linked with adverse outcomes including substance use disorders and adult sexual revictimization. Adult sexual victimization itself has been linked with psychopathology but has predominately been studied in women. The current investigation examines the impact of CM and co-occurring psychopathology on adult sexual victimization in men and women, replicating findings in three distinct samples. Method We investigated the association between continuous CM factor scores and adult sexual victimization in the Childhood Trauma Study (CTS) sample (N = 2564). We also examined the unique relationship between childhood sexual abuse (CSA) and adult sexual victimization while adjusting for co-occurring substance dependence and psychopathology. We replicated these analyses in two additional samples: the Comorbidity and Trauma Study (CATS; N = 1981) and the Australian Twin-Family Study of Alcohol Use Disorders (OZ-ALC; N = 1537). Results Analyses revealed a significant association with CM factor scores and adult sexual victimization for both men and women across all three samples. The CSA factor score was strongly associated with adult sexual victimization after adjusting for substance dependence and psychopathology; higher odds ratios were observed in men (than women) consistently across the three samples. Conclusions A continuous measure of CSA is independently associated with adult sexual trauma risk across samples in models that included commonly associated substance dependence and psychopathology as covariates. The strength of the association between this CSA measure and adult sexual victimization is higher in magnitude for men than women, pointing to the need for further investigation of sexual victimization in male community samples. © Cambridge University Press 2015.

Author Keywords
childhood sexual abuse;  childhood trauma;  Key words Adult sexual revictimization;  psychopathology;  sex disparities

Document Type: Article
Source: Scopus


Horner, C.C.a , Dula, C.b , Bacharier, L.B.a , Garbutt, J.M.a c , Gonzalez, C.c , Deych, E.c , Shannon, W.D.c , Strunk, R.C.a
Daily global stress is associated with nocturnal asthma awakenings in school-age children
(2016) Journal of Allergy and Clinical Immunology, . Article in Press. 

DOI: 10.1016/j.jaci.2016.01.054

a Department of Pediatrics, Washington University School of Medicine and St Louis Children's Hospital, St Louis, Mo
b Department of Neurology, Washington University School of Medicine, St Louis, Mo
c Department of Medicine, Washington University School of Medicine, St Louis, Mo

Document Type: Article in Press
Source: Scopus


Holtzman, D.M.a , Carrillo, M.C.b , Hendrix, J.A.b , Bain, L.J.c , Catafau, A.M.d , Gault, L.M.e , Goedert, M.f , Mandelkow, E.g , Mandelkow, E.-M.g , Miller, D.S.h , Ostrowitzki, S.i , Polydoro, M.j , Smith, S.k , Wittmann, M.l , Hutton, M.m
Tau: From research to clinical development
(2016) Alzheimer's and Dementia, . Article in Press. 

DOI: 10.1016/j.jalz.2016.03.018

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA
b Medical and Scientific Relations, Alzheimer's Association, Chicago, IL, USA
c Independent Science Writer, Elverson, PA, USA
d Piramal Imaging GmbH, Berlin, Germany
e AbbVie, North Chicago, IL, USA
f Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
g German Center for Neurodegenerative Diseases (DZNE), CAESAR Research Center, Bonn, Germany
h Bracket Global, Wayne, PA, USA
i F. Hoffmann-La Roche Ltd, Neuroscience, Basel, Switzerland
j Novartis Institute of Biomedical Research, Cambridge, MA, USA
k Merck, West Point, PA, USA
l Biogen, Cambridge, MA, USA
m Eli Lilly, Inc, Windlesham, Surrey, UK

Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials. © 2016 Alzheimer's Association.

Author Keywords
Alzheimer's disease;  Biomarkers;  Neurofibrillary tangles;  Tau;  Tauopathies

Document Type: Article in Press
Source: Scopus


Lin, C.-C.a , Bradstreet, T.R.a , Schwarzkopf, E.A.a , Jarjour, N.N.a , Chou, C.a , Archambault, A.S.b , Sim, J.c , Zinselmeyer, B.H.a , Carrero, J.A.a , Wu, G.F.a b d , Taneja, R.e , Artyomov, M.N.a , Russell, J.H.c , Edelson, B.T.a
IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation
(2016) Journal of Experimental Medicine, 213 (2), pp. 251-271. 

DOI: 10.1084/jem.20150568

a Department of Pathology and Immunology, 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 Developmental Biology, 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
e Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

The features that define autoreactive T helper (Th) cell pathogenicity remain obscure. We have previously shown that Th cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40 reporter mice and analyzing both polyclonal and TCR transgenic Th cells, we found that Bhlhe40 expression was heterogeneous after EAE induction, with Bhlhe40-expressing cells displaying marked production of IFN-γ, IL-17A, and granulocyte-macrophage colony-stimulating factor. In adoptive transfer EAE models, Bhlhe40-deficient Th1 and Th17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical co-adjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in Th cells. Furthermore, PTX co-adjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized Th17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by Th cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic Th cells and defines a PTX-IL-1-Bhlhe40 pathway active in EAE. © 2016 Lin et al.

Document Type: Article
Source: Scopus


Cooper, P.E.a b , Sala-Rabanal, M.a b , Lee, S.J.a b , Nichols, C.G.a b
Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel
(2015) Journal of General Physiology, 146 (6), pp. 527-540. 

DOI: 10.1085/jgp.201511495

a Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, United States
b Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, United States

Cantú syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium (86Rb+) efflux assays, we show that KATP channels formed with P429L, A475V, or C1039Y mutants enhance KATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive KATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation. © 2015 Cooper et al.

Document Type: Article
Source: Scopus


Choi, I.a , Piccio, L.b , Childress, P.c , Bollman, B.b , Ghosh, A.d , Brandhorst, S.a , Suarez, J.a , Michalsen, A.e , Cross, A.H.b , Morgan, T.E.a , Wei, M.a , Paul, F.f g , Bock, M.f g , Longo, V.a d h i
A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms
(2016) Cell Reports, . Article in Press. 

DOI: 10.1016/j.celrep.2016.05.009

a Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
b Department of Neurology and Neurosurgery and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
c Global Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
d Department of Neuroscience, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA
e Institute of Social Medicine, Epidemiology and Health Economics, Charité University Medicine Berlin, 10117 Berlin, Germany
f NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité University Medicine Berlin, 10117 Berlin, Germany
g Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, 10117 Berlin, Germany
h Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
i IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355). Choi et al. show that cycles of a fasting mimicking diet (FMD) ameliorate disease severity by suppressing autoimmunity and stimulating remyelination via oligodendrocyte regeneration in multiple sclerosis (MS) mouse models. They also show that a similar FMD is a safe, feasible, and possibly a potentially effective treatment for patients with relapsing-remitting MS. © 2016 The Author(s).

Document Type: Article in Press
Source: Scopus


Onal, S.a , Adeshina, A.a , Dabil-Karacal, H.b
A machine learning approach to improve the diagnosis of diabetic retinopathy using fundus image
(2015) IIE Annual Conference and Expo 2015, pp. 447-455. 

a Department of Mechanical and Industrial Engineering, Southern Illinois University-Edwardsville, Edwardsville, IL, United States
b School of Medicine, Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States

Diabetic retinopathy is the most common diabetic eye disease. There are more than 29 million people with diabetes mellitus (DM) as of 2012 in the U.S and approximately 40% of the patients with DM have at least mild diabetic retinopathy. Diabetic retinopathy is diagnosed through comprehensive eye exams where blood vessels are examined on fundus images. However, assessment of blood vessels on colored fundus images is a very time consuming and subjective process. In this research, we present an automated blood vessel segmentation algorithm to facilitate the evaluation of diabetic retinopathy through assessment of blood vessel abnormalities. The blood vessels are extracted using random forest based classification model combined with wavelet based features and local binary pattern (LBP) based texture information. Discriminant analysis is modified and adopted for selection of the significant features to train the proposed classification model. Results demonstrate that the proposed method achieves higher blood vessel segmentation accuracy compared to other supervised based methods. The main advantage of the proposed model is to provide robust and computationally efficient classification of the diabetic retinopathy.

Author Keywords
Blood vessel segmentation;  Diabetic retinopathy;  Feature selection;  Fundus image;  Random forest


Document Type: Conference Paper
Source: Scopus


 June 3, 2016 

Vos, S.J.B.a , Gordon, B.A.b c , Su, Y.b c , Visser, P.J.a d , Holtzman, D.M.c e f , Morris, J.C.c e f g , Fagan, A.M.c e f , Benzinger, T.L.S.b c f h
NIA-AA staging of preclinical Alzheimer disease: Discordance and concordance of CSF and imaging biomarkers
(2016) Neurobiology of Aging, 44, pp. 1-8. 

DOI: 10.1016/j.neurobiolaging.2016.03.025

a Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
b Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
c Knight Alzheimer's Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Neurology, Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands
e Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
f Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, United States
g Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
h Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States

The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (β-amyloidosis) or preclinical AD stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures. © 2016 Elsevier Inc.

Author Keywords
Aging;  Alzheimer's disease;  Amyloid;  Biomarkers;  Cerebrospinal fluid;  Comorbidities;  Diagnosis;  MRI;  Neuroimaging;  Neuronal injury;  PET;  Prognosis

Document Type: Article
Source: Scopus


Chartier, K.G.a b , Dick, D.M.c , Almasy, L.d , Chan, G.e , Aliev, F.c f , Schuckit, M.A.g , Scott, D.M.h , Kramer, J.i , Bucholz, K.K.j , Bierut, L.J.j , Nurnberger, J., Jr.k , Porjesz, B.l , Hesselbrock, V.M.e
Interactions between alcohol metabolism genes and religious involvement in association with maximum drinks and alcohol dependence symptoms
(2016) Journal of Studies on Alcohol and Drugs, 77 (3), pp. 393-404. 

DOI: 10.15288/jsad.2016.77.393

a Virginia Commonwealth University School of Social Work, Richmond, VA, United States
b Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
c Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
d South Texas Diabetes and Obesity Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
e Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
f Faculty of Business, Karabuk University, Karabuk, Turkey
g Department of Psychiatry, University of San Diego School of Medicine, La Jolla, CA, United States
h Departments of Pediatrics and Human Genetics, Howard University, Washington, DC, United States
i Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
j Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
k Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
l Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, United States

Objective: Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes. Method: Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1B-rs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance. Results: Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement. Conclusions: This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms. © 2016, Alcohol Research Documentation Inc. All rights reserved.

Document Type: Article
Source: Scopus


Woolsey, T.A.
Re: Woolsey TA, van der Loos H. 1970. The structural organization of layer IV in the somatosensory region (S I) of mouse cerebral cortex. Brain Res. 17: 205-242
(2016) Brain Research, . Article in Press. 

DOI: 10.1016/j.brainres.2016.04.029

Biology, Neurosurgery, Neurology, Anatomy and Neurobiology, Biomedical Engineering , Washington University in St. Louis, United States

Axoplasmically transported proteins synthesized in neuronal somata labeled by radioactively labeled amino acids (tritium), following local targeted injections for tracing of pathways in the central nervous system using autoradiography. Results from a number of neuronal systems, including: the rat olfactory bulb; cortico-thalamic projections in the mouse; commissural connections of the rat hippocampus; and retinal projections in the monkey and chick are documented. Pathway origins are clear, as the number and distribution of the labeled cells and the normal structure of the injection site is preserved.Light and electron microscopic autoradiography shows that proteins are transported, at two rates: rapid transport (>100. mm/day) of fewer proteins accumulating in axon terminals; and, slow transport (1-5. mm/day) of the bulk of labeled proteins distributed along the length of axons. Different survival times can be selected to evaluate terminal projection field(s) or pathways from origin to termination. The clarity of autoradiographic labeling of pathways and their terminations is comparable to other techniques (such as the Nauta-Gygax and the Fink-Heimer methods and the electron microscopy of terminal degeneration). Labeled amino acids do not label molecules in fibers of passage and there is no retrograde transport of labeled material from the axon terminals. The functional polarity of fiber pathways can be easily established. We summarize the merits of this technique is based upon an established physiological properties of neurons that are summarized in contrast to currently used techniques dependent upon pathological changes in neurons, axons, or axonal terminals. The cytoarchitecture of layer IV in mouse SmI cerebral cortex was examined in.formalin-fixed, Nissl-stained and Cox-fixed, Golgi-Nissl-stained sections cut coronally and tangentially to the pia, A multicellular cytoarchitectonic unit is described in layer IV, roughly cylindrical, 100-400. um in diameter, and perpendicular to the pia. Because of their characteristic shape we call these structures barrels. Each barrel is a ring of neurons, the side, which surrounds a less cellular hollow. The nearly acellular reigion surrounding each barrel and separating adjacent barrels is the septum. Barrels are discussed in relation to observations reported in several earlier papers on the mouse cortex. The barrel field (all barrels) has remarkable constancy by all measures: from one hemisphere to the next and from one specimen to the next. A consistent part of the barrel field is the postero-medial barrel subield (PMBSF). Barrels in the PMBSF are larger, elliptical in shape, organized into five distinct rows and their numbers are constant. It is postulated that each barrel in the PMBSF is the cortical correlate of a contralateral mystacial vibrissa (whisker). On the basis of counts of barrels and of all facial sinus hairs a 'one barrel-one vibrissa' hypothesis is proposed. The general hypothesis is that barrels are the morphological manifestation in layer IV of the functional cortical columns discovered by physiologists. The barrels offer excellent opportunities for integrated studies of sensory cerebral cortex at a degree of resolution previously not possible. This article is part of a Special Issue entitled SI:50th Anniversary Issue. © 2016.

Document Type: Article in Press
Source: Scopus


Hannaford, K.E.a , Stout, M.J.a , Smyser, C.D.b , Mathur, A.c , Cahill, A.G.a
Evaluating the Sensitivity of Electronic Fetal Monitoring Patterns for the Prediction of Intraventricular Hemorrhage
(2016) American Journal of Perinatology, . Article in Press. 

DOI: 10.1055/s-0036-1584140

a Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri
b Departments of Neurology and Pediatrics, Washington University, St. Louis, Missouri
c Division of Newborn Medicine, Department of Pediatrics, Washington University, St. Louis, Missouri

Objective We evaluated electronic fetal (heart rate) monitoring (EFM) patterns among very preterm infants with and without intraventricular hemorrhage (IVH) to evaluate the test characteristics of EFM for the prediction of IVH. Study Design We performed a case-control study of preterm infants born ≤ 30 weeks' gestation over a 6-year period. We evaluated differences in EFM patterns between those (cases) with and without IVH (controls). The relative odds ratio of observing differences in EFM patterns between cases and controls was calculated. Regression models were adjusted based on confounding variables. The sensitivity, specificity, and positive and negative predictive values of EFM characteristics were evaluated for the diagnosis of IVH. Results Total 79 very preterm infants underwent cranial ultrasound, 24 of whom had IVH. Infants with IVH were more likely to be males and delivered at earlier gestational ages. Moderate variability was seen in all infants with normal cranial ultrasounds and 83% of infants with IVH. Minimal variability has a sensitivity of 17% in the prediction of IVH. Conclusion While minimal variability was observed more frequently in fetuses that developed IVH, it is poorly predictive of IVH. EFM patterns are not discriminating in identifying very preterm infants at risk for developing IVH. Copyright © 2016, Thieme Medical Publishers. All rights reserved.

Author Keywords
electronic fetal monitoring;  intraventricular hemorrhage;  neuroimaging;  prematurity

Document Type: Article in Press
Source: Scopus


Bansal, A., Wall, L.B., Goldfarb, C.A.
Cerebral Palsy Tendon Transfers. Flexor Carpi Ulnaris to Extensor Carpi Radialis Brevis and Extensor Pollicis Longus Reroutement
(2016) Hand Clinics, . Article in Press. 

DOI: 10.1016/j.hcl.2016.03.010

Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA

The flexor carpi ulnaris to extensor carpi radialis brevis transfer and extensor pollicis longus rerouting combined with thenar release are 2 successful surgical interventions for children with spastic cerebral palsy. The goal of both procedures is to improve quality of life for patients who have previously failed conservative management, and the degree of expected improvement is predicated on several patient variables, making careful patient selection crucial for ensuring successful outcomes. Here, surgical technique is described; risk factors are discussed, and outcomes related to both procedures are presented. © 2016 Elsevier Inc.

Author Keywords
Cerebral palsy;  EPL tendon reroutement;  FCU tendon transfer

Document Type: Article in Press
Source: Scopus


Wang, Y.a e , Ulland, T.K.a , Ulrich, J.D.b c d , Song, W.a , Tzaferis, J.A.e , Hole, J.T.e , Yuan, P.f , Mahan, T.E.b c d , Shi, Y.b c d , Gilfillan, S.a , Cella, M.a , Grutzendler, J.f , DeMattos, R.B.e , Cirrito, J.R.b c d , Holtzman, D.M.b c d , Colonna, M.a
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
(2016) Journal of Experimental Medicine, 213 (5), pp. 667-675. 

DOI: 10.1084/jem.20151948

a Department of Pathology and Immunology, 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 Knight Alzheimer's Disease Research Center, 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
e Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, United States
f Department of Neurology, Yale University, New Haven, CT, United States

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid ß (Aß) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aß deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aß accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aß accumulation, we examined Aß plaques in the 5XFAD model of AD at the onset of Aß-related pathology. At this early time point, Aß accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aß plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aß plaque structure, thereby limiting neuritic damage. © 2016 Wang et al.

Document Type: Article
Source: Scopus


Yuede, C.M.a , Lee, H.a , Restivo, J.L.a , Davis, T.A.a , Hettinger, J.C.a , Wallace, C.E.a , Young, K.L.a , Hayne, M.R.a , Bu, G.b , Li, C.-Z.c , Cirrito, J.R.a
Rapid in vivo measurement of ß-amyloid reveals biphasic clearance kinetics in an Alzheimer's mouse model
(2016) Journal of Experimental Medicine, 213 (5), pp. 677-685. 

DOI: 10.1084/jem.20151428

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
c Nanobioengineering/Bioelectronics Laboratory, Department of Biomedical Engineering, Florida International University, Miami, FL, United States

Findings from genetic, animal model, and human studies support the observation that accumulation of the ß-amyloid (Aß) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer's disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aß clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aß clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aß levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aß levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aß40 in the ISF are relatively stable and begin to decline within minutes of blocking Aß production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood-brain barrier transport of Aß, resulted in significant prolongation of Aß40 half-life, but only in the latter phase of Aß clearance from the ISF. © 2016 Yuede et al.

Document Type: Article
Source: Scopus


Smyser, C.D.a b c , Dosenbach, N.U.F.a , Smyser, T.A.d , Snyder, A.Z.a c , Rogers, C.E.d , Inder, T.E.e , Schlaggar, B.L.a b c d f , Neil, J.J.g
Prediction of brain maturity in infants using machine-learning algorithms
(2016) NeuroImage, . Article in Press. 

DOI: 10.1016/j.neuroimage.2016.05.029

a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, USA
b Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, USA
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, USA
d Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, USA
e Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
f Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110-1093, USA
g Department of Neurology, Boston Children's Hospital, 333 Longwood Avenue, Boston, MA 02115, USA

Recent resting-state functional MRI investigations have demonstrated that much of the large-scale functional network architecture supporting motor, sensory and cognitive functions in older pediatric and adult populations is present in term- and prematurely-born infants. Application of new analytical approaches can help translate the improved understanding of early functional connectivity provided through these studies into predictive models of neurodevelopmental outcome. One approach to achieving this goal is multivariate pattern analysis, a machine-learning, pattern classification approach well-suited for high-dimensional neuroimaging data. It has previously been adapted to predict brain maturity in children and adolescents using structural and resting state-functional MRI data. In this study, we evaluated resting state-functional MRI data from 50 preterm-born infants (born at 23-29. weeks of gestation and without moderate-severe brain injury) scanned at term equivalent postmenstrual age compared with data from 50 term-born control infants studied within the first week of life. Using 214 regions of interest, binary support vector machines distinguished term from preterm infants with 84% accuracy (p. <. 0.0001). Inter- and intra-hemispheric connections throughout the brain were important for group categorization, indicating that widespread changes in the brain's functional network architecture associated with preterm birth are detectable by term equivalent age. Support vector regression enabled quantitative estimation of birth gestational age in single subjects using only term equivalent resting state-functional MRI data, indicating that the present approach is sensitive to the degree of disruption of brain development associated with preterm birth (using gestational age as a surrogate for the extent of disruption). This suggests that support vector regression may provide a means for predicting neurodevelopmental outcome in individual infants. © 2016 Elsevier Inc.

Author Keywords
Developmental neuroimaging;  Functional MRI;  Infant;  Multivariate pattern analysis;  Prematurity

Document Type: Article in Press
Source: Scopus


Pe, M.L.a , Kircanski, K.b , Thompson, R.J.c , Bringmann, L.F.a , Tuerlinckx, F.a , Mestdagh, M.a , Mata, J.d , Jaeggi, S.M.e , Buschkuehl, M.f , Jonides, J.g , Kuppens, P.a , Gotlib, I.H.b
Emotion-Network Density in Major Depressive Disorder
(2015) Clinical Psychological Science, 3 (2), pp. 292-300. 

DOI: 10.1177/2167702614540645

a Department of Psychology, KU Leuven, Belgium
b Department of Psychology, Stanford University, United States
c Department of Psychology, Washington University in St. Louis, United States
d Max Planck Institute for Human Development, Germany
e School of Education, University of California, Irvine, United States
f MIND Research Institute, Irvine, CA, United States
g Department of Psychology, University of Michigan, Ann Arbor, United States

Major depressive disorder (MDD) is a prevalent disorder involving disturbances in mood. There is still much to understand regarding precisely how emotions are disrupted in individuals with MDD. In this study, we used a network approach to examine the emotional disturbances underlying MDD. We hypothesized that compared with healthy control individuals, individuals diagnosed with MDD would be characterized by a denser emotion network, thereby indicating that their emotion system is more resistant to change. Indeed, results from a 7-day experience sampling study revealed that individuals with MDD had a denser overall emotion network than did healthy control individuals. Moreover, this difference was driven primarily by a denser negative, but not positive, network in MDD participants. These findings suggest that the disruption in emotions that characterizes depressed individuals stems from a negative emotion system that is resistant to change. © 2014, © The Author(s) 2014.

Author Keywords
affective disorders;  depression;  emotion

Document Type: Article
Source: Scopus