WashU weekly Neuroscience publications | Office of Neuroscience Research

"CXCR4 involvement in neurodegenerative diseases" (2018) Translational Psychiatry

CXCR4 involvement in neurodegenerative diseases
(2018) Translational Psychiatry, 8 (1), art. no. 73, .

Bonham, L.W.^a , Karch, C.M.^b , Fan, C.C.^c , Tan, C.^d , Geier, E.G.^a , Wang, Y.^e , Wen, N.^b , Broce, I.J.^d , Li, Y.^d , Barkovich, M.J.^d , Ferrari, R.^f , Hardy, J.^f , Momeni, P.^g , Höglinger, G.^h ⁱ , Müller, U.^j , Hess, C.P.^d , Sugrue, L.P.^d , Dillon, W.P.^d , Schellenberg, G.D.^k , Miller, B.L.^a , Andreassen, O.A.^e , Dale, A.M.^c ^l , Barkovich, A.J.^d , Yokoyama, J.S.^a , Desikan, R.S.^a , Hernandez, D.G.^m , Nalls, M.A.^m , Rohrer, J.D.^m , Ramasamy, A.^m , Kwok, J.B.J.^m , Dobson-Stone, C.^m , Schofield, P.R.^m , Halliday, G.M.^m , Hodges, J.R.^m , Piguet, O.^m , Bartley, L.^m , Thompson, E.^m , Haan, E.^m , Hernández, I.^m , Ruiz, A.^m , Boada, M.^m , Borroni, B.^m , Padovani, A.^m , Cruchaga, C.^m , Cairns, N.J.^m , Benussi, L.^m , Binetti, G.^m , Ghidoni, R.^m , Forloni, G.^m , Albani, D.^m , Galimberti, D.^m , Fenoglio, C.^m , Serpente, M.^m , Scarpini, E.^m , Clarimón, J.^m , Lleó, A.^m , Blesa, R.^m , Waldö, M.L.^m , Nilsson, K.^m , Nilsson, C.^m , MacKenzie, I.R.A.^m , Hsiung, G.-Y.R.^m , Mann, D.M.A.^m , Grafman, J.^m , Morris, C.M.^m , Attems, J.^m , Griffiths, T.D.^m , McKeith, I.G.^m , Thomas, A.J.^m , Pietrini, P.^m , Huey, E.D.^m , Wassermann, E.M.^m , Baborie, A.^m , Jaros, E.^m , Tierney, M.C.^m , Pastor, P.^m , Razquin, C.^m , Ortega-Cubero, S.^m , Alonso, E.^m , Perneczky, R.^m , Diehl-Schmid, J.^m , Alexopoulos, P.^m , Kurz, A.^m , Rainero, I.^m , Rubino, E.^m , Pinessi, L.^m , Rogaeva, E.^m , George-Hyslop, P.S.^m , Rossi, G.^m , Tagliavini, F.^m , Giaccone, G.^m , Rowe, J.B.^m , Schlachetzki, J.C.M.^m , Uphill, J.^m , Collinge, J.^m , Mead, S.^m , Danek, A.^m , Van Deerlin, V.M.^m , Grossman, M.^m , Trojanowski, J.Q.^m , Van Der Zee, J.^m , Cruts, M.^m , Van Broeckhoven, C.^m , Cappa, S.F.^m , Leber, I.^m , Hannequin, D.^m , Golfier, V.^m , Vercelletto, M.^m , Brice, A.^m , Nacmias, B.^m , Sorbi, S.^m , Bagnoli, S.^m , Piaceri, I.^m , Nielsen, J.E.^m , Hjermind, L.E.^m , Riemenschneider, M.^m , Mayhaus, M.^m , Ibach, B.^m , Gasparoni, G.^m , Pichler, S.^m , Gu, W.^m , Rossor, M.N.^m , Fox, N.C.^m , Warren, J.D.^m , Spillantini, M.G.^m , Morris, H.R.^m , Rizzu, P.^m , Heutink, P.^m , Snowden, J.S.^m , Rollinson, S.^m , Richardson, A.^m , Gerhard, A.^m , Bruni, A.C.^m , Maletta, R.^m , Frangipane, F.^m , Cupidi, C.^m , Bernardi, L.^m , Anfossi, M.^m , Gallo, M.^m , Conidi, M.E.^m , Smirne, N.^m , Rademakers, R.^m , Baker, M.^m , Dickson, D.W.^m , Graff-Radford, N.R.^m , Petersen, R.C.^m , Knopman, D.^m , Josephs, K.A.^m , Boeve, B.F.^m , Parisi, J.E.^m , Seeley, W.W.^m , Karydas, A.M.^m , Rosen, H.^m , Van Swieten, J.C.^m , Dopper, E.G.P.^m , Seelaar, H.^m , Pijnenburg, Y.A.L.^m , Scheltens, P.^m , Logroscino, G.^m , Capozzo, R.^m , Novelli, V.^m , Puca, A.A.^m , Franceschi, M.^m , Postiglione, A.^m , Milan, G.^m , Sorrentino, P.^m , Kristiansen, M.^m , Chiang, H.-H.^m , Graff, C.^m , Pasquier, F.^m , Rollin, A.^m , Deramecourt, V.^m , Lebouvier, T.^m , Kapogiannis, D.^m , Ferrucci, L.^m , Pickering-Brown, S.^m , Singleton, A.B.^m , International FTD-Genomics Consortium (IFGC), International Parkinson’s Disease Genetics Consortium (IPDGC), International Genomics of Alzheimer’s Project (IGAP)^m

^a Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
^b Department of Psychiatry, Washington University, St. Louis, MO, United States
^c Department of Cognitive Sciences, University of California CA, San Diego, CA, United States
^d Department of Radiology and Biomedical Imaging, Neuroradiology Section, University of California, San Francisco, San Francisco, CA, United States
^e NORMENT, Institute of Clinical Medicine, University of Oslo, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^f Department of Molecular Neuroscience, Institute of Neurology, UCL, London, United Kingdom
^g Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, United States
^h Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ⁱ Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany
^j Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
^k Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^l Department of Neurosciences and Radiology, University of California, San Diego, CA, United States

Abstract
Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases. © 2017 The Author(s).

Document Type: Article
Source: Scopus

"Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease" (2018) Neurobiology of Aging

Aerobic glycolysis and tau deposition in preclinical Alzheimer’s disease
(2018) Neurobiology of Aging, 67, pp. 95-98.

Vlassenko, A.G.^a ^c ^d , Gordon, B.A.^a ^d , Goyal, M.S.^a ^d , Su, Y.^a ^d , Blazey, T.M.^a , Durbin, T.J.^a ^d , Couture, L.E.^a , Christensen, J.J.^a ^d , Jafri, H.^a , Morris, J.C.^b ^d ^c ^d , Raichle, M.E.^a ^c ^d , Benzinger, T.L.-S.^a ^d

^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 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO2), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer’s disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO2. We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer’s disease pathology studies are needed to verify causality. © 2018 Elsevier Inc.

Author Keywords
Aging; Alzheimer’s disease; Amyloid imaging; Brain aerobic glycolysis; Cerebral metabolic rate of glucose; Cerebral metabolic rate of oxygen; Positron emission tomography; Tau imaging

Document Type: Article
Source: Scopus

"Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy" (2018) Child's Nervous System

Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy
(2018) Child’s Nervous System, 34 (5), pp. 901-910.

Shah, M.N.^a , Mitra, A.^c , Goyal, M.S.^c , Snyder, A.Z.^c ^d , Zhang, J.^a , Shimony, J.S.^c , Limbrick, D.D.^b , Raichle, M.E.^c ^d ^e ^f , Smyth, M.D.^b

^a Departments of Pediatric Surgery and Neurosurgery, McGovern Medical School at UTHealth, 6431 Fannin St, MSB 5.144, Houston, TX, 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, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Temporal lobe epilepsy (TLE) affects resting state brain networks in adults. This study aims to correlate resting state functional MRI (rsMRI) signal latency in pediatric TLE patients with their laterality. Methods: From 2006 to 2016, 26 surgical TLE patients (12 left, 14 right) with a mean age of 10.7 years (range 0.9–18) were prospectively studied. Preoperative rsMRI was obtained in patients with concordant lateralizing structural MRI, EEG, and PET studies. Standard preprocessing techniques and seed-based rsMRI analyses were performed. Additionally, the latency in rsMRI signal between each 6 mm voxel sampled was examined, compared to the global mean signal, and projected onto standard atlas space for individuals and the cohort. Results: All but one of the 26 patients improved seizure frequency postoperatively with a mean follow-up of 2.9 years (range 0–7.7), with 21 patients seizure-free. When grouped for epileptogenic laterality, the latency map qualitatively demonstrated that the right TLE patients had a relatively early signal pattern, whereas the left TLE patients had a relatively late signal pattern compared to the global mean signal in the right temporal lobe. Quantitatively, the two groups had significantly different signal latency clusters in the bilateral temporal lobes (p < 0.001). Conclusion: There are functional MR signal latency changes in medical refractory pediatric TLE patients. Qualitatively, signal latency in the right temporal lobe precedes the mean signal in right TLE patients and is delayed in left TLE patients. With larger confirmatory studies, preoperative rsMRI latency analysis may offer an inexpensive, noninvasive adjunct modality to lateralize pediatric TLE. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Default mode network; Functional magnetic resonance imaging; Pediatric epilepsy; Resting state; Temporal lobe epilepsy

Document Type: Article
Source: Scopus

"Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned" (2018) The Lancet Neurology

Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned
(2018) The Lancet Neurology, 17 (5), pp. 467-480. Cited 1 time.

^a Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^b Division of Neuroradiology and Neurophysics, UCL Institute of Neurology, Lysholm Department of Neuroradiology, London, United Kingdom
^c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML—including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis—provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis. © 2018 Elsevier Ltd

Document Type: Review
Source: Scopus

"Functional Brain Networks Are Dominated by Stable Group and Individual Factors, Not Cognitive or Daily Variation" (2018) Neuron

Functional Brain Networks Are Dominated by Stable Group and Individual Factors, Not Cognitive or Daily Variation
(2018) Neuron, 98 (2), pp. 439-452.e5. Cited 1 time.

Gratton, C.^a , Laumann, T.O.^b , Nielsen, A.N.^a , Greene, D.J.^b ^c , Gordon, E.M.^h ⁱ ^j , Gilmore, A.W.^f , Nelson, S.M.^h ⁱ ^j ^k , Coalson, R.S.^a ^c , Snyder, A.Z.^a ^c , Schlaggar, B.L.^a ^b ^c ^d ^e , Dosenbach, N.U.F.^a ^e ^g , Petersen, S.E.^a ^b ^c ^d ^f

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^g Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^h VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
ⁱ Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
^j Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
^k Department of Psychiatry, Texas A&M Health Science Center, Temple, TX, United States

Abstract
The organization of human brain networks can be measured by capturing correlated brain activity with fMRI. There is considerable interest in understanding how brain networks vary across individuals or neuropsychiatric populations or are altered during the performance of specific behaviors. However, the plausibility and validity of such measurements is dependent on the extent to which functional networks are stable over time or are state dependent. We analyzed data from nine high-quality, highly sampled individuals to parse the magnitude and anatomical distribution of network variability across subjects, sessions, and tasks. Critically, we find that functional networks are dominated by common organizational principles and stable individual features, with substantially more modest contributions from task-state and day-to-day variability. Sources of variation were differentially distributed across the brain and differentially linked to intrinsic and task-evoked sources. We conclude that functional networks are suited to measuring stable individual characteristics, suggesting utility in personalized medicine. Gratton et al. comprehensively measure individual, day-to-day, and task variance in functional brain networks, revealing that networks are dominated by stable individual factors, not cognitive content. These findings suggest utility of functional network measurements in personalized medicine. © 2018 Elsevier Inc.

Author Keywords
brain networks; fMRI; functional connectivity; individual differences

Document Type: Article
Source: Scopus

"Intrinsic mechanisms of neuronal axon regeneration" (2018) Nature Reviews Neuroscience

Intrinsic mechanisms of neuronal axon regeneration
(2018) Nature Reviews Neuroscience, pp. 1-15. Article in Press.

Mahar, M., Cavalli, V.

Department of Neuroscience, Hope Center for Neurological Disorders and Center of Regenerative Medicine, Washington University School of Medicine, St Louis, MO, United States

Abstract
Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury. © 2018 Macmillan Publishers Ltd., part of Springer Nature

Document Type: Article in Press
Source: Scopus

"Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice" (2018) Cell Reports

Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice
(2018) Cell Reports, 23 (3), pp. 866-877.

Munanairi, A.^a ^b , Liu, X.-Y.^a ^b , Barry, D.M.^a ^b , Yang, Q.^a ^b , Yin, J.-B.^a ^b ^f , Jin, H.^a ⁱ , Li, H.^a ^f , Meng, Q.-T.^a ^b ^j , Peng, J.-H.^a ^b , Wu, Z.-Y.^a ^f , Yin, J.^a ^b , Zhou, X.-Y.^a ^k , Wan, L.^a ^f ^l , Mo, P.^a ^f ^m , Kim, S.^a ⁿ , Huo, F.-Q.^a ^o , Jeffry, J.^a ^b , Li, Y.-Q.^f ^h , Bardoni, R.^g , Bruchas, M.R.^b ^e , Chen, Z.-F.^a ^b ^c ^d

^a Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Anatomy and K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an, China
^g Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
^h Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
ⁱ The First Hospital of Yunnan Province, Kunming, Yunnan, China
^j Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
^k College of Life Sciences, Wuhan University, Wuhan, Hubei, China
^l Departments of Pain Medicine, The State Key Clinical Specialty in Pain Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
^m Department of Anesthesiology, the Affiliated Nanhai Hospital of Southern Medical University, Foshan, Guangdong, China
ⁿ Center for Applied Molecular Medicine, University of Southern California, Los Angeles, CA, United States
^o Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China

Abstract
Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated Gαi signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca2+-independent protein kinase C (PKC)δ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies. Munanairi et al. show that the kappa opioid receptor (KOR) agonists inhibit nonhistaminergic itch transmission by attenuating the function of the gastrin-releasing peptide receptor (GRPR), an itch receptor in the spinal cord. KOR activation causes the translocation of PKCδ from plasma to membrane, which phosphorylates GRPR to dampen itch transmission. © 2018 The Authors

Author Keywords
GPCR cross-signaling; GRPR; itch; KOR; mouse; phosphorylation; PKC; spinal cord

Document Type: Article
Source: Scopus

"Persistence of abnormalities in white matter in children with type 1 diabetes" (2018) Diabetologia

Persistence of abnormalities in white matter in children with type 1 diabetes
(2018) Diabetologia, pp. 1-10. Article in Press.

Fox, L.A.^a , Hershey, T.^b , Mauras, N.^a , Arbeláez, A.M.^b , Tamborlane, W.V.^c , Buckingham, B.^d , Tsalikian, E.^e , Englert, K.^a , Raman, M.^f , Jo, B.^f , Shen, H.^f , Reiss, A.^d ^f ^g , Mazaika, P.^f , for the Diabetes Research in Children Network (DirecNet)^h

^a Pediatric Endocrinology, Nemours Children’s Health System, 807 Children’s Way, Jacksonville, FL, United States
^b Department of Psychiatry and Radiology, Washington University in St Louis and the St Louis Children’s Hospital, St Louis, MO, United States
^c Pediatric Endocrinology, Yale University, New Haven, CT, United States
^d Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
^e Department of Pediatric Endocrinology, The University of Iowa, Iowa City, IA, United States
^f Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
^g Department of Radiology, Stanford University School of Medicine, Stanford, CA, United States

Abstract
Aims/hypothesis: Prior studies suggest white matter growth is reduced and white matter microstructure is altered in the brains of young children with type 1 diabetes when compared with brains of non-diabetic children, due in part to adverse effects of hyperglycaemia. This longitudinal observational study examines whether dysglycaemia alters the developmental trajectory of white matter microstructure over time in young children with type 1 diabetes. Methods: One hundred and eighteen children, aged 4 to <10 years old with type 1 diabetes and 58 age-matched, non-diabetic children were studied at baseline and 18 months, at five Diabetes Research in Children Network clinical centres. We analysed longitudinal trajectories of white matter using diffusion tensor imaging. Continuous glucose monitoring profiles and HbA1c levels were obtained every 3 months. Results: Axial diffusivity was lower in children with diabetes at baseline (p = 0.022) and at 18 months (p = 0.015), indicating that differences in white matter microstructure persist over time in children with diabetes. Within the diabetes group, lower exposure to hyperglycaemia, averaged over the time since diagnosis, was associated with higher fractional anisotropy (p = 0.037). Fractional anisotropy was positively correlated with performance (p < 0.002) and full-scale IQ (p < 0.02). Conclusions/interpretation: These results suggest that hyperglycaemia is associated with altered white matter development, which may contribute to the mild cognitive deficits in this population. © 2018 Springer-Verlag GmbH Germany, part of Springer Nature

Author Keywords
Brain development; Paediatric diabetes; White matter

Document Type: Article in Press
Source: Scopus

"Smokers' unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: A focus group study" (2018) BMC Public Health

Smokers’ unprompted comments on cigarette additives during conversations about the genetic basis for nicotine addiction: A focus group study
(2018) BMC Public Health, 18 (1), art. no. 495, .

Philpott, S.E., Gehlert, S., Waters, E.A.

Division of Public Health Sciences, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States

Abstract
Background: Research designed to elicit smokers’ cognitive and affective reactions to information about chemicals that tobacco companies add to cigarettes (“additives”) found that knowledge is limited. However, little is known about smokers’ unprompted thoughts and feelings about additives. Such information could be used to shape future communication efforts. We explored the content and possible functions of spontaneous statements about cigarette additives made by smokers during a study examining reactions to learning about the genetic link to nicotine addiction. Methods: Adult smokers (N = 84) were recruited from a medium-sized Midwestern city. Focus groups (N = 13) were conducted between April-September 2012. Data were analyzed by 2 coders using thematic analysis. Results: Comments about cigarette additives arose without prompting by the focus group moderator. Three main themes were identified: (1) discussing additives helped participants navigate the conceptual link between smoking and genetics, (2) additives were discussed as an alternative mechanism for addiction to cigarettes, and (3) additives provided an alternative mechanism by which cigarette smoking exacerbates physical harm. Notably, discussion of additives contained a pervasive tone of mistrust illustrated by words like “they” and “them,” by statements of uncertainty such as “you don’t know what they’re putting into cigarettes,” and by negative affective verbalizations such as “nasty” and “disgusting”. Conclusions: Participants had distinct beliefs about cigarette additives, each of which seemed to serve a purpose. Although mistrust may complicate communication about the health risks of tobacco use, health communication experts could use smokers’ existing beliefs and feelings to better design more effective anti-smoking messages. © 2018 The Author(s).

Document Type: Article
Source: Scopus

"Judging scandal: Standards or bias in politics" (2018) Journal of Social Psychology

Judging scandal: Standards or bias in politics
(2018) Journal of Social Psychology, pp. 1-14. Article in Press.

Solomon, E.D.^a , Hackathorn, J.M.^b , Crittendon, D.^b

^a Washington University in St. Louis
^b Murray State University

Abstract
As the number of political scandals rises, we examined the circumstances that might influence how a politician would be judged as a result of a scandal. Specifically, we hypothesized that ingroup bias theory and shifting standards theory would produce different patterns of judgements. In two studies, we found support for the ingroup bias theory, such that participants rated the fictitious politician’s public approval and perceived character as higher if the politician was a member of their own political party (i.e. their ingroup) than if the politician was a member of the another political party (i.e. their outgroup). These results may explain, in part, why people may judge politicians involved in scandal more or less harshly depending on whether they are an ingroup member or outgroup member. © 2018 Taylor & Francis

Author Keywords
infidelity; ingroup bias; political scandal; shifting standards; social identity theory

Document Type: Article in Press
Source: Scopus

"Neurospheres from neural stem/neural progenitor cells (NSPCs) of non-hydrocephalic HTx rats produce neurons, astrocytes and multiciliated ependyma: the cerebrospinal fluid of normal and hydrocephalic rats supports such a differentiation" (2018) Cell and Tissue Research

Neurospheres from neural stem/neural progenitor cells (NSPCs) of non-hydrocephalic HTx rats produce neurons, astrocytes and multiciliated ependyma: the cerebrospinal fluid of normal and hydrocephalic rats supports such a differentiation
(2018) Cell and Tissue Research, pp. 1-18. Article in Press.

Henzi, R.^a ^b , Guerra, M.^a , Vío, K.^a , González, C.^a ^c , Herrera, C.^a , McAllister, P.^d , Johanson, C.^e , Rodríguez, E.M.^a

^a Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
^b Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
^c Facultad de Medicina, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt, Chile
^d Department of Neurosurgery Division of Pediatric Neurosurgery, Washington University and the Saint Louis Children’s Hospital, St. Louis, MO, United States
^e Department of Neurosurgery, Alpert Medical School at Brown University, Providence, RI, United States

Abstract
Fetal onset hydrocephalus and abnormal neurogenesis are two inseparable phenomena turned on by a cell junction pathology first affecting neural stem/progenitor cells (NSPCs) and later the multiciliated ependyma. The neurological impairment of children born with hydrocephalus is not reverted by derivative surgery. NSPCs and neurosphere (NE) grafting into the cerebrospinal fluid (CSF) of hydrocephalic fetuses thus appears as a promising therapeutic procedure. There is little information about the cell lineages actually forming the NE as they grow throughout their days in vitro (DIV). Furthermore, there is no information on how good a host the CSF is for grafted NE. Here, we use the HTx rat, a model with hereditary hydrocephalus, with the mutation expressed in about 30% of the litter (hyHTx), while the littermates develop normally (nHTx). The investigation was designed (i) to establish the nature of the cells forming 4 and 6-DIV NE grown from NSPCs collected from PN1/nHTx rats and (ii) to study the effects on these NEs of CSF collected from nHTx and hyHTx. Immunofluorescence analyses showed that 90% of cells forming 4-DIV NEs were non-committed multipotential NSPCs, while in 6-DIV NE, 40% of the NSPCs were already committed into neuronal, glial and ependymal lineages. Six-DIV NE further cultured for 3 weeks in the presence of fetal bovine serum, CSF from nHTx or CSF from hyHTx, differentiated into neurons, astrocytes and βIV-tubulin+ multiciliated ependymal cells that were joined together by adherent junctions and displayed synchronized cilia beating. This supports the possibility that ependymal cells are born from subpopulations of NSC with their own time table of differentiation. As a whole, the findings indicate that the CSF is a supportive medium to host NE and that NE grafted into the CSF have the potential to produce neurons, glia and ependyma. © 2018 Springer-Verlag GmbH Germany, part of Springer Nature

Author Keywords
Cerebrospinal fluid; Congenital hydrocephalus; Ependymogenesis; Neural stem cells; Neurospheres

Document Type: Article in Press
Source: Scopus

"Motor skill training in musculoskeletal pain: a case report in chronic low back pain" (2018) Disability and Rehabilitation

Motor skill training in musculoskeletal pain: a case report in chronic low back pain
(2018) Disability and Rehabilitation, pp. 1-9. Article in Press.

Lanier, V.M.^a , Lang, C.E.^b ^c , Van Dillen, L.R.^a

^a Department of Orthopaedic Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
^b Program in Occupational Therapy, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
^c Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

Abstract
Purpose: Low back pain is a chronic condition that limits function. The chief reason individuals with low back pain seek care is difficulty performing functional activities. A novel approach to improving performance of painful and limited functional activities is motor skill training, defined as challenging practice of activities to learn or relearn a skill. The purpose of this report is to describe the design and application of a motor skill training intervention in a 26-year-old man with a 10-year history of low back pain. Methods: A motor skill training intervention was implemented to modify the altered alignment and movement patterns he used during the performance of his painful and limited activities. Results: The patient was seen for six visits in 12 weeks. The patient reported decreased pain and medication use, as well as improved function immediately, 3-, and 9-months post-intervention. Conclusion: Individuals with low back pain report limitation in ability to perform everyday functions and demonstrate altered patterns of movement and alignment during these activities. This case report describes an innovative motor skill training intervention that directly addresses the performance of functional activities and the application of motor learning principles.Implications for rehabilitationLow back pain is a chronic condition that limits function.The chief reason individuals with chronic low back pain seek care is difficulty performing everyday functional activities.Motor skill training is a novel approach that directly addresses the performance of painful and limited functional activities through challenging practice to improve performance and decrease pain. © 2018 Informa UK Limited, trading as Taylor & Francis Group

Author Keywords
low back pain; lumbar spine; Motor learning; skill training; spine

Document Type: Article in Press
Source: Scopus

"Author Correction to: Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson’s Disease" (2018) CNS Drugs

Author Correction to: Pooled Analyses of Phase III Studies of ADS-5102 (Amantadine) Extended-Release Capsules for Dyskinesia in Parkinson’s Disease
(2018) CNS Drugs, pp. 1-2. Article in Press.

Elmer, L.W.^a , Juncos, J.L.^b , Singer, C.^c , Truong, D.D.^d , Criswell, S.R.^e , Parashos, S.^f , Felt, L.^g , Johnson, R.^g , Patni, R.^g

^a Department of Neurology, University of Toledo College of Medicine, 3120 Glendale Avenue, Toledo, OH, United States
^b Department of Neurology and Movement Disorders, Emory University School of Medicine, Atlanta, GA, United States
^c Department of Neurology, University of Miami, Miami, FL, United States
^d The Parkinson’s and Movement Disorder Institute, Fountain Valley, CA, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States
^f Struthers Parkinson’s Center, Golden Valley, MN, United States
^g Adamas Pharmaceuticals, Inc., Emeryville, CA, United States

Abstract
An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1on 12 March 2018. An error was subsequently identified in the article, and the following correction should be noted. © 2018 Springer International Publishing AG, part of Springer Nature

Document Type: Article in Press
Source: Scopus

"Cerebrovascular Events After Continuous-Flow Left Ventricular Assist Devices" (2018) Neurocritical Care

Cerebrovascular Events After Continuous-Flow Left Ventricular Assist Devices
(2018) Neurocritical Care, pp. 1-8. Article in Press.

Tahsili-Fahadan, P.^a ^b , Curfman, D.R.^c , Davis, A.A.^c , Yahyavi-Firouz-Abadi, N.^d , Rivera-Lara, L.^a ^e , Nassif, M.E.^f , LaRue, S.J.^f , Ewald, G.A.^f , Zazulia, A.R.^c ^g

^a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Medicine, Virginia Commonwealth University, INOVA Campus, Falls Church, VA, United States
^c Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus, Box 8111, St. Louis, MO, United States
^d Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^e Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^f Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Cerebrovascular events (CVE) are among the most common and serious complications after implantation of continuous-flow left ventricular assist devices (CF-LVAD). We studied the incidence, subtypes, anatomical distribution, and pre- and post-implantation risk factors of CVEs as well as the effect of CVEs on outcomes after CF-LVAD implantation at our institution.Methods: Retrospective analysis of clinical and neuroimaging data of 372 patients with CF-LVAD between May 2005 and December 2013 using standard statistical methods. Results: CVEs occurred in 71 patients (19%), consisting of 35 ischemic (49%), 26 hemorrhagic (37%), and 10 ischemic+hemorrhagic (14%) events. History of coronary artery disease and female gender was associated with higher odds of ischemic CVE (OR 2.84 and 2.5, respectively), and diabetes mellitus was associated with higher odds of hemorrhagic CVE (OR 3.12). While we found a higher rate of ischemic CVEs in patients not taking any antithrombotic medications, no difference was found between patients with ischemic and hemorrhagic CVEs. Occurrence of CVEs was associated with increased mortality (HR 1.62). Heart transplantation was associated with improved survival (HR 0.02). In patients without heart transplantation, occurrence of CVE was associated with decreased survival. Conclusions: LVADs are associated with high rates of CVE, increased mortality, and lower rates of heart transplantation. Further investigations to identify the optimal primary and secondary stroke prevention measures in post-LVAD patients are warranted. © 2018 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Author Keywords
Cardiac transplant; Heart failure; Left ventricular assist device; Stroke

Document Type: Article in Press
Source: Scopus

"Pleiotropic effects of variants in dementia genes in Parkinson disease" (2018) Frontiers in Neuroscience

Pleiotropic effects of variants in dementia genes in Parkinson disease
(2018) Frontiers in Neuroscience, 12 (APR), art. no. 230, .

Ibanez, L.^a , Dube, U.^a , Davis, A.A.^b , Fernandez, M.V.^a , Budde, J.^a , Cooper, B.^a , Diez-Fairen, M.^c ^d , Ortega-Cubero, S.^c ^e , Pastor, P.^c ^d , Perlmutter, J.S.^b ^f , Cruchaga, C.^a , Benitez, B.A.^g

^a Department of Psychiatry, Washington University, Saint Louis, MO, United States
^b Department of Neurology, Washington University, Saint Louis, MO, United States
^c Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
^d Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain
^e Department of Neurology and Neurosurgery, Hospital Universitario de Burgos, Burgos, Spain
^f Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University, Saint Louis, MO, United States
^g Department of Medicine, Washington University, Saint Louis, MO, United States

Abstract
Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10-4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects. © 2018 Ibanez, Dube, Davis, Fernandez, Budde, Cooper, Diez-Fairen, Ortega-Cubero, Pastor, Perlmutter, Cruchaga and Benitez.

Author Keywords
APP; Cognitive impairment; Dementia; GRN; Parkinson disease; PSEN1; PSEN2; Rare variants

Document Type: Article
Source: Scopus

"CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA)" (2018) Journal of Neurology

CANOMAD and other chronic ataxic neuropathies with disialosyl antibodies (CANDA)
(2018) Journal of Neurology, pp. 1-8. Article in Press.

Garcia-Santibanez, R., Zaidman, C.M., Sommerville, R.B., Lopate, G., Weihl, C.C., Pestronk, A., Bucelli, R.C.

Division of Neuromuscular Medicine, Department of Neurology, Washington University in St. Louis, 660 S Euclid Ave, Box 8111, St. Louis, MO, United States

Abstract
Introduction: CANOMAD/CANDA are syndromes characterized by ataxic neuropathy, ophthalmoplegia, monoclonal gammopathy, cold agglutinins and disialosyl antibodies. Methods: A retrospective review of our neuromuscular autoantibody panel database was performed. Anti-GD1b seropositive patients with ataxia were included. Results: Eleven patients were identified. Median age at onset was 56 years. Median disease duration was 6 years. All patients had gait disorders. Nine had ocular motility abnormalities. Most had a monoclonal protein and all had elevated serum IgM. Electrodiagnostic studies showed a mixed axonal/demyelinating pattern (6), an axonal pattern (4), or a pure demyelinating pattern (1). Ultrasounds showed nerve enlargement patterns consistent with acquired demyelination. A nerve biopsy showed near complete loss of myelinated axons with preservation of smaller axons. Rituximab was the most effective immunotherapy. Conclusion: CANOMAD/CANDA are rare and debilitating disorders with characteristic clinical and diagnostic findings. In our cohort, nerve ultrasound showed regional nerve enlargement and rituximab was the most effective immunomodulatory therapy. © 2018 Springer-Verlag GmbH Germany, part of Springer Nature

Author Keywords
Ataxic neuropathies; CANDA; CANOMAD; Disialosyl antibodies; Immune therapy; Ultrasound

Document Type: Article in Press
Source: Scopus

"Marijuana Promotion Online: an Investigation of Dispensary Practices" (2018) Prevention Science

Marijuana Promotion Online: an Investigation of Dispensary Practices
(2018) Prevention Science, pp. 1-11. Article in Press.

Cavazos-Rehg, P.A.^a , Krauss, M.J.^a , Cahn, E.^a , Lee, K.E.^a , Ferguson, E.^b , Rajbhandari, B.^a , Sowles, S.J.^a , Floyd, G.M.^a , Berg, C.^c , Bierut, L.J.^a

^a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO, United States
^b Spelman College, Atlanta, GA, United States
^c Department of Behavioral Sciences and Health Education, Rollins School of Public Health, Emory University, Atlanta, GA, United States

Abstract
Marijuana product advertising will become more common, as the use of medical and/or recreational marijuana becomes increasingly legal in the USA. In this study, we investigate the marketing tactics being used on marijuana dispensary websites in the USA that could influence substance use behaviors. One hundred dispensary websites were randomly selected from 10 states that allowed the legal use of medical or recreational marijuana and had at least 10 operational dispensaries. Three dispensaries were excluded due to non-functioning websites, leaving a sample of 97 dispensaries. Content analysis was conducted on these dispensaries’ websites, with the primary areas of focus including website age verification, marijuana effects, warnings, and promotional tactics. Among the 97 dispensaries, 75% did not include age verification. Roughly 30% offered online ordering and 21% offered delivery services. Sixty-seven percent made health claims pertaining to medical conditions that could be treated by their marijuana products, with moderate or conclusive evidence to support their claims. Less than half of the dispensaries (45%) advised consumers of possible side effects, and only 18% included warnings about contraindications. Nearly half (44%) offered reduced prices or coupons, 19% offered “buy one get one free” offers, and 16% provided giveaways or free samples. Our findings indicate that marijuana dispensary websites are easily accessible to youth. In addition, only a small amount of the websites advised consumers about possible side effects or contraindications. This study suggests the need for surveillance of marijuana commercialization and online advertising especially in the context of state policy reforms. © 2018 Society for Prevention Research

Author Keywords
Advertising; Marijuana; Online; Policy

Document Type: Article in Press
Source: Scopus

"Tau-independent Phase Analysis: A Novel Method for Accurately Determining Phase Shifts" (2018) Journal of Biological Rhythms

Tau-independent Phase Analysis: A Novel Method for Accurately Determining Phase Shifts
(2018) Journal of Biological Rhythms, . Article in Press.

Tackenberg, M.C.^a , Jones, J.R.^b , Page, T.L.^a ^c , Hughey, J.J.^c ^d

^a *Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee
^b Department of Biology, Washington University in St. Louis, St. Louis, Missouri
^c Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee
^d Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee

Abstract
Estimations of period and phase are essential in circadian biology. While many techniques exist for estimating period, comparatively few methods are available for estimating phase. Current approaches to analyzing phase often vary between studies and are sensitive to coincident changes in period and the stage of the circadian cycle at which the stimulus occurs. Here we propose a new technique, tau-independent phase analysis (TIPA), for quantifying phase shifts in multiple types of circadian time-course data. Through comprehensive simulations, we show that TIPA is both more accurate and more precise than the standard actogram approach. TIPA is computationally simple and therefore will enable accurate and reproducible quantification of phase shifts across multiple subfields of chronobiology. © 2018, The Author(s).

Author Keywords
method; period-independent; phase analysis; phase shift; tau-independent

Document Type: Article in Press
Source: Scopus

"Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma" (2018) Neuro-Oncology

Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma
(2018) Neuro-Oncology, 20 (4), pp. 472-483. Cited 1 time.

Mahlokozera, T.^a , Vellimana, A.K.^a , Li, T.^b , Mao, D.D.^a , Zohny, Z.S.^a , Kim, D.H.^a , Tran, D.D.ⁱ , Marcus, D.S.^c , Fouke, S.J.^j , Campian, J.L.^d , Dunn, G.P.^a ^d ^e ^f , Miller, C.A.^b , Kim, A.H.^a ^d ^g ^h

^a Department of Neurological Surgery, Neurology, and Developmental Biology, Washington University, School of Medicine, Box 8057 660 S. Euclid Ave, St. Louis, MO, United States
^b McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^d Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, United States
^e Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, United States
^f Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^g Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^h Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, United States
ⁱ Lillian S. Wells Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, United States
^j Department of Neurosurgery, St Luke’s Hospital, St Louis, MO, United States

Abstract
Background Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. Methods Ten newly diagnosed, isocitrate dehydrogenase 1 (IDH1) wildtype GBM tumor samples were obtained from 2 (n = 9) or 4 (n = 1) spatially distinct tumor regions. Tumor and matched blood DNA samples underwent whole-exome sequencing. Results Across all 10 tumors, 51% of mutations were clonal and 3% were subclonal and shared in different sectors, whereas 46% of mutations were subclonal and private. Two of the 10 tumors exhibited a regional hypermutator state despite being treatment naïve, and remarkably, the high mutational load was predominantly limited to one sector in each tumor. Among the canonical cancer-associated genes, only telomerase reverse transcriptase (TERT) promoter mutations were observed in the founding clone in all tumors. Reconstruction of the clonal architecture in different sectors revealed regionally divergent evolution, and integration of data from 2 sectors increased the resolution of inferred clonal architecture in a given tumor. Predicted therapeutic mutations differed in presence and frequency between tumor regions. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape. Conclusions The substantial spatial heterogeneity observed in different GBM tumor sectors, especially in spatially restricted hypermutator cases, raises important caveats to our current dependence on single-sector molecular information to guide either targeted or immune-based treatments. © 2017 The Author(s).

Author Keywords
glioblastoma; hypermutator; sequencing; spatial heterogeneity; tumor heterogeneity

Document Type: Article
Source: Scopus

"Females have the survival advantage in glioblastoma" (2018) Neuro-Oncology

Females have the survival advantage in glioblastoma
(2018) Neuro-Oncology, 20 (4), pp. 576-577.

Ostrom, Q.T.^a , Rubin, J.B.^b , Lathia, J.D.^c , Berens, M.E.^d , Barnholtz-Sloan, J.S.^a

^a Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 11100 Euclid Ave, Cleveland, OH, United States
^b Department of Pediatrics and Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^c Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
^d Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, United States

Document Type: Letter
Source: Scopus

"Psychotropic drugs and falls in older adults: What do we do now?" (2018) Psychiatric Times

Psychotropic drugs and falls in older adults: What do we do now?
(2018) Psychiatric Times, 35 (3), pp. 19-20.

Lenze, E.J.

Washington University, St Louis, MO, United States

Document Type: Short Survey
Source: Scopus

"Minimum Reporting Standards for Adult Cochlear Implantation" (2018) Otolaryngology – Head and Neck Surgery (United States)

Minimum Reporting Standards for Adult Cochlear Implantation
(2018) Otolaryngology – Head and Neck Surgery (United States), . Article in Press.

Adunka, O.F.^a ^e , Gantz, B.J.^b ^e ^e , Dunn, C.^b , Gurgel, R.K.^c ^e ^e , Buchman, C.A.^d ^e ^e

^a Department of Otolaryngology–Head and Neck Surgery, The Ohio State University, Columbus, Ohio, USA
^b Department of Otolaryngology–Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
^c Division of Otolaryngology–Head and Neck Surgery, University of Utah, Salt Lake City, Utah, USA
^d Department of Otolaryngology–Head and Neck Surgery, School of Medicine, Washington University, St Louis, Missouri, USA
^e Members of the Implantable Hearing Devices Committee and the Hearing Committee of the American Academy of Otolaryngology—Head and Neck Surgery

Abstract
This article outlines new minimum standards for reporting adult cochlear implant outcomes. These standards have been endorsed by the Implantable Hearing Devices Committee and the Hearing Committee of the American Academy of Otolaryngology—Head and Neck Surgery. The lack of a standardized method for reporting outcomes following cochlear implantation in clinical trials has hampered the ability of investigators to draw comparisons across studies. Variability in data reported in articles and presentation formats inhibits meta-analyses, making it impossible to accumulate the large patient cohorts needed for statistically significant inference. While investigators remain unrestricted in publishing their adult cochlear implant outcome data in additional formats that they believe to be valuable, they should include the presently proposed minimal data set to facilitate interstudy comparability and consistency of reporting. © 2018, American Academy of Otolaryngology—Head and Neck Surgery Foundation 2018.

Author Keywords
adult; cochlear implantation; hearing preservation; outcomes; scientific reporting

Document Type: Article in Press
Source: Scopus

"Preserved neural event segmentation in healthy older adults" (2018) Psychology and Aging

Preserved neural event segmentation in healthy older adults
(2018) Psychology and Aging, 33 (2), pp. 232-245.

Kurby, C.A.^a , Zacks, J.M.^b

^a Department of Psychology, Grand Valley State University, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, United States

Abstract
An important feature of action understanding is that comprehenders segment the perceptual stream into events. Event segmentation dynamically engages a network of brain regions that likely play a role in how events are encoded. Here, in a sample of older adults, we assessed the relationship between changes in brain dynamics during movie watching and event understanding performance. Forty healthy older adults and a comparison sample of 12 younger adults passively viewed short movies of everyday activities while their brain activity was measured with fMRI. Afterward, they segmented the movies into events and performed memory tasks for movie content. The older adults engaged a similar event segmentation network during movie watching as the younger adults. Individual differences analyses revealed that although behavioral measures of event segmentation predicted memory, activity in the segmentation network did not. Intersubject correlation analyses revealed that normative brain dynamics during viewing in the right posterior temporal sulcus and left dorsolateral prefrontal cortex predicted better segmentation performance. These data suggest that these regions play an important role in event understanding, and also that the event segmentation network is preserved in healthy aging. © 2018 American Psychological Association.

Author Keywords
Cognitive aging; Event memory; Event segmentation; FMRI; Neural synchrony

Document Type: Article
Source: Scopus

"Understanding activity participation among individuals with Wolfram syndrome" (2018) British Journal of Occupational Therapy

Understanding activity participation among individuals with Wolfram syndrome
(2018) British Journal of Occupational Therapy, . Article in Press.

Bumpus, E.^a , Hershey, T.^b , Doty, T.^c , Ranck, S.^d , Gronski, M.^e , Urano, F.^f , Foster, E.R.^g

^a Washington University School of Medicine, St. Louis, Occupational Therapy Doctoral Student, Program in Occupational Therapy, USA
^b Washington University School of Medicine, St. Louis, Associate Professor, Departments of Neurology, Psychiatry, and Radiology, USA
^c Washington University School of Medicine, St. Louis, Professional Rater III, Program in Occupational Therapy and Department of Psychiatry, USA
^d Washington University School of Medicine, St. Louis, Professional Rater III, Department of Psychiatry, USA
^e Director, Department of Occupational Therapy, Methodist University, Fayetteville, USA
^f Washington University School of Medicine, St. Louis, Professor, Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, and Department of Pathology and Immunology, USA
^g Washington University School of Medicine, St. Louis, Assistant Professor, Program in Occupational Therapy and Departments of Neurology and Psychiatry, USA

Abstract
Introduction: Wolfram syndrome is a rare genetic disease associated with a variety of progressive metabolic and neurologic impairments. Previous research has focused on Wolfram syndrome-related impairments and biomarkers for disease progression; however, information about how Wolfram syndrome impacts participation in daily activities is lacking. Method: Wolfram syndrome (n = 45; 20 children, 25 adults) participants completed an online questionnaire about activity participation. Thirty-six non-Wolfram syndrome comparison participants (11 children; 25 adults) completed a portion of the questionnaire. Symptom data from a subset of Wolfram syndrome participants (n = 20) were also examined in relation to participation data. Results: Wolfram syndrome children and adults had lower participation than non-Wolfram syndrome children and adults in almost all activity domains, and social and exercise-related activities were the most problematic. In the subset of Wolfram syndrome adults with symptom data, poorer vision, balance, gait, hearing, and overall symptom severity were related to lower participation. Conclusion: Wolfram syndrome appears to negatively impact participation in a variety of activities, and this effect may increase as people age and/or Wolfram syndrome progresses. The most functionally pertinent Wolfram syndrome symptoms are those associated with neurodegeneration, especially vision loss and walking and balance problems. This study revealed symptoms and activity domains that are most relevant for people with Wolfram syndrome and, thus, can inform current practice and treatment development research. © 2018, The Author(s) 2018.

Author Keywords
function; neurodegeneration; occupational therapy; participation; Wolfram syndrome

Document Type: Article in Press
Source: Scopus

"Validations of the OM-6 Parent-Proxy Survey for Infants/Toddlers with Otitis Media" (2018) Otolaryngology – Head and Neck Surgery (United States)

Validations of the OM-6 Parent-Proxy Survey for Infants/Toddlers with Otitis Media
(2018) Otolaryngology – Head and Neck Surgery (United States), . Article in Press.

Tao, J.^a , Schulz, K.^b , Jeffe, D.B.^c , Lieu, J.E.C.^a

^a Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USA
^b Division of Head and Neck Cancer & Communication Sciences, Duke University Medical Center, Durham, North Carolina, USA
^c Department of Medicine, Division of General Medical Sciences, Washington University School of Medicine, St Louis, Missouri, USA

Abstract
Objective: To validate the Otitis Media–6 (OM-6), a parent-proxy quality-of-life (QOL) questionnaire for infants/young children with OM, against other previously validated generic QOL questionnaires. Study Design: Multi-institutional cross-sectional study. Setting: Twenty-three otolaryngology, pediatric, and family practices across the United States. Subjects and Methods: Caregivers of 6- to 24-month-old children with a history of OM completed the OM-6, OM History Form, and Pediatric Quality of Life (PedsQL) Infant Scales survey. Principal components analysis (PCA) examined the underlying factor structure of items on the OM-6, and Cronbach’s α measured the internal consistency of items on each factor. Discriminant validity was assessed with receiver operating curves (ROCs). Results: Surveys from 1045 patients were analyzed. The overall OM-6 was strongly to moderately correlated with the PedsQL Infant Scales scores (Pearson r = −0.649 for ages 6-12 months and −0.566 for ages 13-24 months). Two underlying constructs, “Behavior and Symptoms” and “Hearing and Speech,” emerged from the PCA. Each factor and the overall OM-6 showed excellent internal consistency reliability (each Cronbach’s α >0.75). The areas under the curve on the ROC analyses were <0.65 for recurrent and chronic OM using a variety of frequency and chronicity cut-points and definitions. Conclusion: The OM-6 measures 2 underlying QOL constructs, Behavior and Symptoms and Hearing/Speech. The overall OM-6 showed acceptably high internal consistency reliability and good construct validity. However, the ability of the OM-6 to identify children who have more severe clinical recurrent or chronic OM vs milder disease was not supported by our analysis. © 2018, American Academy of Otolaryngology—Head and Neck Surgery Foundation 2018.

Author Keywords
health-related quality of life; otitis media; Otitis Media–6; validation

Document Type: Article in Press
Source: Scopus

"Endovascular Treatment of Posterior Inferior Cerebellar Artery Aneurysms with Flow Diversion" (2018) World Neurosurgery

Endovascular Treatment of Posterior Inferior Cerebellar Artery Aneurysms with Flow Diversion
(2018) World Neurosurgery, . Article in Press.

Wallace, A.N.^a ^b , Kamran, M.^c , Madaelil, T.P.^d , Kayan, Y.^a , Osbun, J.W.^c ^e ^f , Roy, A.K.^g , Almandoz, J.E.D.^a , Moran, C.J.^c ^e , Howard, B.M.^d ^g , Yasin, J.^c , Grossberg, J.A.^g

^a Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota, United States
^b Department of Radiology, University of Iowa Carver School of Medicine, Iowa City, Iowa, United States
^c Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri, United States
^d Department of Radiology, Emory University, Atlanta, Georgia, United States
^e Department of Neurosurgery, Washington University, St. Louis, Missouri, United States
^f Department of Neurology, Washington University, St. Louis, Missouri, United States
^g Department of Neurosurgery, Emory University, Atlanta, Georgia, United States

Abstract
Background: Flow diversion is a viable alternative for treatment of wide-neck and fusiform aneurysms originating from the posterior inferior cerebellar artery (PICA), but coverage of the PICA and vertebral perforating arteries may be a concern. The aim of this study was to examine procedural, clinical, and angiographic outcomes of patients with PICA aneurysms treated with the Pipeline Embolization Device. Methods: Retrospective review was performed of PICA aneurysms treated with the Pipeline device at 3 neurovascular centers, including periprocedural complications and clinical and angiographic outcomes. Results: In 16 procedures, 14 PICA aneurysms were treated with the Pipeline device. These included 11 saccular aneurysms with a mean size of 7.4 mm (range, 2.0–11.1 mm) and 3 fusiform aneurysms with a mean diameter of 6.1 mm (range, 5.0–8.0 mm) and mean length of 10.3 mm (range, 6.0–15.0 mm). One patient developed a PICA territory infarct with mild leg weakness that resolved in <7 days. Overall complication rate was 7% (1/14) per patient and 6% (1/16) per procedure. Mean duration of clinical follow-up was 13.5 months (range, 3 weeks to 61.7 months), with all patients returning to baseline functional status. Complete or near-complete aneurysm occlusion was achieved in 58% (7/12) of cases with angiographic follow-up (mean, 15 months; range, 4–61 months). All covered PICAs remained patent. Conclusions: Flow diversion of PICA aneurysms is a safe and viable treatment option when traditional endovascular options are unlikely to preserve parent vessel patency. © 2018 Elsevier Inc.

Author Keywords
Aneurysm; Angiography; Flow diverter; Hemorrhage; Stroke

Document Type: Article in Press
Source: Scopus

"Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length" (2018) Journal of Molecular Biology

Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length
(2018) Journal of Molecular Biology, . Article in Press.

Newcombe, E.A.^a , Ruff, K.M.^b , Sethi, A.^a , Ormsby, A.R.^a , Ramdzan, Y.M.^a , Fox, A.^c , Purcell, A.W.^d , Gooley, P.R.^a , Pappu, R.V.^b , Hatters, D.M.^a

^a Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneVIC, Australia
^b Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St Louis, MO, United States
^c School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia
^d Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia

Abstract
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington’s disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen–deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity. © 2018 The Authors

Author Keywords
Huntington’s disease; hydrogen–deuterium exchange; molecular simulations; NMR spectroscopy

Document Type: Article in Press
Source: Scopus
Access Type: Open Access

"Visual thalamus, 'it's complicated'" (2017) Visual neuroscience

Visual thalamus, “it’s complicated”
(2017) Visual neuroscience, 34, p. E018.

Kerschensteiner, D.^a , Guido, W.^b

^a Department of Ophthalmology and Visual Sciences,Washington University School of Medicine,Saint Louis,Missouri 63110
^b Department of Anatomical Sciences and Neurobiology,University of Louisville School of Medicine,Louisville,Kentucky 40292

Document Type: Editorial
Source: Scopus

"Use of eeg for determining propofol requirement during neuroanesthesia" (1990) Journal of Neurosurgical Anesthesiology

Use of eeg for determining propofol requirement during neuroanesthesia
(1990) Journal of Neurosurgical Anesthesiology, 2 (3), p. 233.

Department of Anesthesiology, Washington University, St. Louis, MO, United States

Document Type: Article
Source: Scopus