WashU weekly Neuroscience publications

Small near-infrared photochromic protein for photoacoustic multi-contrast imaging and detection of protein interactions in vivo
(2018) Nature Communications, 9 (1), art. no. 2734, . 

Li, L.^a , Shemetov, A.A.^b , Baloban, M.^b , Hu, P.^c , Zhu, L.^{c d} , Shcherbakova, D.M.^b , Zhang, R.^c , Shi, J.^d , Yao, J.^e , Wang, L.V.^{a d} , Verkhusha, V.V.^{b f}

^a Caltech Optical Imaging Laboratory, Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, United States
^b Department of Anatomy and Structural Biology, Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^d Caltech Optical Imaging Laboratory, Andrew and Peggy Cherng Department of Medical Engineering, California Institute of Technology, Pasadena, CA, United States
^e Department of Biomedical Engineering, Duke University, Durham, NC, United States
^f Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland

Abstract
Photoacoustic (PA) computed tomography (PACT) benefits from genetically encoded probes with photochromic behavior, which dramatically increase detection sensitivity and specificity through photoswitching and differential imaging. Starting with a DrBphP bacterial phytochrome, we have engineered a near-infrared photochromic probe, DrBphP-PCM, which is superior to the full-length RpBphP1 phytochrome previously used in differential PACT. DrBphP-PCM has a smaller size, better folding, and higher photoswitching contrast. We have imaged both DrBphP-PCM and RpBphP1 simultaneously on the basis of their unique signal decay characteristics, using a reversibly switchable single-impulse panoramic PACT (RS-SIP-PACT) with a single wavelength excitation. The simple structural organization of DrBphP-PCM allows engineering a bimolecular PA complementation reporter, a split version of DrBphP-PCM, termed DrSplit. DrSplit enables PA detection of protein-protein interactions in deep-seated mouse tumors and livers, achieving 125-μm spatial resolution and 530-cell sensitivity in vivo. The combination of RS-SIP-PACT with DrBphP-PCM and DrSplit holds great potential for noninvasive multi-contrast deep-Tissue functional imaging. © 2018 The Author(s).

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

Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam
(2018) Scientific Reports, 8 (1), art. no. 10341, . 

Cao, L.Q.^a , Montana, M.C.^a , Germann, A.L.^a , Shin, D.J.^a , Chakrabarti, S.^a , Mennerick, S.^{b d} , Yuede, C.M.^c , Wozniak, D.F.^{b d} , Evers, A.S.^{a d} , Akk, G.^{a d}

^a Departments of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Many GABAergic drugs are in clinical use as anesthetics, sedatives, or anxiolytics. We have investigated the actions of the combinations of the neuroactive steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with the intravenous anesthetic propofol or the benzodiazepine diazepam. The goal of the study was to determine whether coapplication of alfaxalone reduces the effective doses and concentrations of propofol and diazepam. Behavioral effects of alfaxalone, propofol, diazepam, and the combinations of the drugs were evaluated during a 30-min activity test in mice. Functional effects of the individual drugs and drug combinations were tested by measuring the decay times of spontaneous inhibitory postsynaptic currents in rat hippocampal neurons, and peak current responses from heterologously expressed concatemeric α1β2γ2L GABAA receptors. Co-Administration of alfaxalone increased the sedative actions of propofol and diazepam in mice. The combination of alfaxalone with propofol or diazepam increased the decay times of sIPSCs and shifted the concentration-response relationships for GABA-Activated receptors to lower transmitter concentrations. We infer that alfaxalone acts as a co-Agonist to enhance the GABAergic effects of propofol and diazepam. We propose that co-Administration of alfaxalone, and possibly other neuroactive steroids, can be employed to reduce dosage requirements for propofol and diazepam. © 2018 The Author(s).

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

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood
(2018) Pediatric Blood and Cancer, 65 (9), art. no. e27228, . 

Hankins, J.S.^{a s} , Estepp, J.H.^a , Hodges, J.R.^a , Villavicencio, M.A.^a , Robison, L.L.^b , Weiss, M.J.^a , Kang, G.^c , Schreiber, J.E.^d , Porter, J.S.^d , Kaste, S.C.^{e f g} , Saving, K.L.^h , Bryant, P.C.ⁱ , Deyo, J.E.^j , Nottage, K.A.^k , King, A.A.^l , Brandow, A.M.^m , Lebensburger, J.D.ⁿ , Adesina, O.^o , Chou, S.T.^p , Zemel, B.S.^q , Smeltzer, M.P.^r , Wang, W.C.^a , Gurney, J.G.^r

^a Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^e Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^f Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, United States
^g Department of Radiology, University of Tennessee Health Science Center, Memphis, TN, United States
^h OSF Healthcare Children’s Hospital of Illinois, University of Illinois College of Medicine, Peoria, IL, United States
ⁱ Department of Pediatric Hematology and Oncology, Novant Health Hemby Children’s Hospital, Charlotte, NC, United States
^j Department of Pediatric Hematology/Oncology, Our Lady of the Lake Children’s Hospital, Baton Rouge, LA, United States
^k Janssen Research & Development, Raritan, NJ, United States
^l Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^m Section of Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
ⁿ Department of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
^o Division of Hematology, University of Washington, Seattle, WA, United States
^p Division of Hematology and the Apheresis Program, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^q Department of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^r School of Public Health, University of Memphis, Memphis, TN, United States
^s Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Abstract
Background: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children’s Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. Procedures: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. Results: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7–30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0-thalassemia, 25.7% HbSC, 8.4% HbsB+-Thalassemia, 1.7% HbS/HPFH, and 1.2% other. Conclusions: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD. © 2018 Wiley Periodicals, Inc.

Author Keywords
disease-modifying therapy;  natural history;  sickle cell anemia

Document Type: Article
Source: Scopus

The Prescription of Benzodiazepines for Panic Disorder: Time for an Evidence-Based Educational Approach
(2018) Journal of Clinical Psychopharmacology, 38 (4), pp. 283-285. 

Nardi, A.E.^a , Cosci, F.^b , Balon, R.^c , Weintraub, S.J.^{d e} , Freire, R.C.^a , Krystal, J.H.^{f g h i} , Roth, T.^j , Silberman, E.K.^k , Sonino, N.^l , Fava, G.A.^{m n} , Starcevic, V.^o , Dubovsky, S.L.^p , Salzman, C.^q , Rickels, K.^r , Greenblatt, D.J.^s , Shader, R.I.^t , Chouinard, G.^u

^a Institute of Psychiatry, Federal University of Rio de Janeiro, Rua Visconde de Piraja 407/702, Rio de Janeiro, Brazil
^b Department of Health Sciences, University of Florence, Florence, Italy
^c Departments of Psychiatry and Behavioral Neurosciences and Anesthesiology, Wayne State University School of Medicine, Detroit, MI, United States
^d Division of Hospital Medicine, Department of Medicine, Saint Louis Veterans Affairs Medical Center, United States
^e Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^f Department of Psychiatry, United States
^g Department of Neuroscience, Child Study Center, Yale University School of Medicine, United States
^h Psychiatry and Behavioral Health Services, Yale-New Haven Hospital, New Haven, United States
ⁱ Clinical Neuroscience Division, National Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
^j Henry Ford Sleep Research Center, Henry Ford Hospital, Detroit, MI, United States
^k Department of Psychiatry, Tufts Medical Center, Boston, MA, United States
^l University of Padova, Padova, Italy
^m Department of Psychology, University of Bologna, Italy
ⁿ Department of Psychiatry, University of Buffalo, Buffalo, NY, United States
^o Sydney Medical School-Nepean, University of Sydney, Sydney, Australia
^p Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, United States
^q Harvard Medical School, Beth Israel Deaconess Medical Center, Massachusetts Mental Health Center, Boston, MA, United States
^r Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
^s Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, United States
^t Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
^u Clinical Pharmacology and Toxicology Program, McGill University and Researcher Emeritus, Mental Health Institute of Montreal Fernand Seguin Research Centre, University of Montreal, Montreal, QC, Canada

Document Type: Editorial
Source: Scopus

Understanding Mechanisms of Genetic Risk for Adolescent Internalizing and Externalizing Problems: The Mediating Role of Parenting and Personality
(2018) Twin Research and Human Genetics, 21 (4), pp. 310-321. 

Su, J.^a , Kuo, S.I.-C.^a , Bucholz, K.K.^b , Edenberg, H.J.^c , Kramer, J.R.^d , Schuckit, M.^e , Dick, D.M.^{a f}

^a Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^b Department of Psychiatry, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Biochemistry and Molecular Biology, Indiana University, Bloomington, IN, United States
^d Department of Psychiatry, University of Iowa, Iowa City, IA, United States
^e Department of Psychiatry, University of California at San Diego, San Diego, CA, United States
^f Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Genetic predispositions play an important role in the development of internalizing and externalizing behaviors. Understanding the mechanisms through which genetic risk unfolds to influence these developmental outcomes is critical for developing prevention and intervention efforts, capturing key elements of Irv’s research agenda and scientific legacy. In this study, we examined the role of parenting and personality in mediating the effect of genetic risk on adolescents’ major depressive disorder and conduct disorder symptoms. Longitudinal data were drawn from a sample of 709 European American adolescents and their mothers from the Collaborative Studies on Genetics of Alcoholism. Results from multivariate path analysis indicated that adolescents’ depressive symptoms genome-wide polygenic scores (DS-GPS) predicted lower parental knowledge, which in turn was associated with more subsequent major depressive disorder and conduct disorder symptoms. Adolescents’ DS-GPS also had indirect effects on these outcomes via personality, with a mediating effect via agreeableness but not via other dimensions of personality. Findings revealed that the pattern of associations was similar across adolescent gender. Our findings emphasize the important role of evocative gene-environment correlation processes and intermediate phenotypes in the pathways of risk from genetic predispositions to complex adolescent outcomes. © The Author(s) 2018.

Author Keywords
conduct problems;  depression;  genes;  parenting;  personality

Document Type: Article
Source: Scopus

Discovery and validation of autosomal dominant Alzheimer’s disease mutations
(2018) Alzheimer’s Research and Therapy, 10 (1), art. no. 67, . Cited 1 time.

Hsu, S.^a , Gordon, B.A.^b , Hornbeck, R.^b , Norton, J.B.^a , Levitch, D.^c , Louden, A.^a , Ziegemeier, E.^c , Laforce, R., Jr.^d , Chhatwal, J.^e , Day, G.S.^c , McDade, E.^c , Morris, J.C.^c , Fagan, A.M.^c , Benzinger, T.L.S.^{b f} , Goate, A.M.^g , Cruchaga, C.^a , Bateman, R.J.^c , Karch, C.M.^a

^a Department of Psychiatry, Washington University, School of Medicine, 425 S. Euclid Ave, Campus Box 8134, St. Louis, MO, United States
^b Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^d Clinique Interdisciplinaire de Mémoire du CHU de Québec, Département des Sciences Neurologiques, Faculté de Médecine, Université Laval, Québec City, QC, Canada
^e Massachusetts General Hospital, Martinos Center for Biomedical Imaging, 149 13th Street, Charlestown, MA, United States
^f Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^g Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States

Abstract
Background: Alzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes. © 2018 The Author(s).

Author Keywords
APP;  Autosomal dominant Alzheimer’s disease;  Cell-based assays;  Pathogenicity algorithm;  PSEN1;  PSEN2

Document Type: Article
Source: Scopus

TREM2-dependent effects on microglia in Alzheimer’s Disease
(2018) Frontiers in Aging Neuroscience, 10 (JUL), art. no. 202, . 

Zhou, Y., Ulland, T.K., Colonna, M.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Alzheimer’s disease (AD) is a late-onset dementia characterized by the deposition of amyloid plaques and formation of neurofibrillary tangles (NFTs) which lead to neuronal loss and cognitive deficits. Abnormal protein aggregates in the AD brain are also associated with reactive microglia and astrocytes. Whether this glial response is beneficial or detrimental in AD pathology is under debate. Microglia are the resident innate immune cells in the central nervous system (CNS) that survey the surrounding environment. Genome-wide association studies (GWAS) have identified the R47H variant of triggering receptor expressed on myeloid cell 2 (TREM2) as a risk factor for late-onset AD (LOAD) with an odds ratio of 4.5. TREM2 is an immunoreceptor primarily present on microglia in the CNS that binds to polyanionic molecules. The transmembrane domain of TREM2 signals through DAP12, an adaptor protein that contains an immunoreceptor tyrosine-based activation motif (ITAM), which mediates TREM2 signaling and promotes microglial activation and survival. In mouse models of AD, Trem2 haplodeficiency and deficiency lead to reduced microglial clustering around amyloid β (Aβ) plaques, suggesting TREM2 is required for plaque-associated microglial responses. Recently, TREM2 has been shown to enhance microglial metabolism through the mammalian target of rapamycin (mTOR) pathway. Although aberrant metabolism has long been associated with AD, not much was known regarding how metabolism in microglia might affect disease progression. In this review, we discuss the role of TREM2 and metabolism in AD pathology, highlighting how TREM2-mediated microglial metabolism modulates AD pathogenesis. © 2018 Zhou, Ulland and Colonna.

Author Keywords
Alzheimer’s disease;  Autophagy;  Metabolism;  Microglia;  TREM2

Document Type: Short Survey
Source: Scopus
Access Type: Open Access

AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease)
(2018) Human Gene Therapy, 29 (7), pp. 785-801. 

Bradbury, A.M.^a , Rafi, M.A.^b , Bagel, J.H.^a , Brisson, B.K.^a , Marshall, M.S.^c , Pesayco Salvador, J.^d , Jiang, X.^e , Swain, G.P.^a , Prociuk, M.L.^a , Odonnell, P.A.^a , Fitzgerald, C.^a , Ory, D.S.^e , Bongarzone, E.R.^{c f} , Shelton, G.D.^d , Wenger, D.A.^b , Vite, C.H.^a

^a University of Pennsylvania, School of Veterinary Medicine, 208 Rosenthal Building, 3800 Spruce Street, Philadelphia, PA, United States
^b Department of Neurology, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA, United States
^c Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, Chicago, IL, United States
^d Department of Pathology, School of Medicine, Comparative Neuromuscular Laboratory, University of California, San Diego, San Diego, CA, United States
^e Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, United States
^f Departamento de Química Biologica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina

Abstract
Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase. Most commonly, deficits of galactosylceramidase result in widespread central and peripheral nervous system demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem-cell transplantation is the current standard of care in children diagnosed prior to symptom onset. However, disease correction is incomplete. Herein, the first adeno-associated virus (AAV) gene therapy experiments are presented in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients. Adapted from studies in twitcher mice, GLD dogs were treated by combination intravenous and intracerebroventricular injections of AAVrh10 to target both the peripheral and central nervous systems. Combination of intravenous and intracerebroventricular AAV gene therapy had a clear dose response and resulted in delayed onset of clinical signs, extended life-span, correction of biochemical defects, and attenuation of neuropathology. For the first time, therapeutic effect has been established in the canine model of GLD by targeting both peripheral and central nervous system impairments with potential clinical implications for GLD patients. © Copyright 2018, Mary Ann Liebert, Inc. 2018.

Author Keywords
AAV gene therapy;  canine model;  globoid cell leukodystrophy (Krabbe disease);  leukodystrophy;  lysosomal storage disorder;  neurodegenerative disease

Document Type: Article
Source: Scopus

High and low levels of an NTRK2-driven genetic profile affect motor- and cognition-associated frontal gray matter in prodromal Huntington’s disease
(2018) Brain Sciences, 8 (7), art. no. 116, . 

Ciarochi, J.A.^a , Liu, J.^b , Calhoun, V.^{b c} , Johnson, H.^d , Misiura, M.^e , Bockholt, H.J.^{b l} , Espinoza, F.A.^b , Caprihan, A.^b , Plis, S.^b , Turner, J.A.^{a e} , Paulsen, J.S.^{d f g} , Long, J.D.^{l aq} , Johnson, H.J.^{l aq} , Brashers-Krug, T.^{l aq} , Danzer, P.^aq , Miller, A.^{p aq aq} , Montross, K.^aq , Harrington, D.^h , Westervelt, H.ⁱ , Aylward, E.^j , Rao, S.^{k ap} , Moser, D.J.^l , Williams, J.^l , Downing, N.^l , Magnotta, V.A.^l , Vaidya, J.^l , O’Leary, D.^l , Kim, E.Y.^l , Kim, J.-I.^l , Lourens, S.^l , Zhang, Y.^m , Lu, W.^m , Erwin, C.ⁿ , Nance, M.^o , Evans, J.^l , Zschiegner, R.^l , Chiu, E.^q , Loi, S.^q , Chua, P.^r , Raymond, L.^s , Ross, C.A.^t , Mallonee, W.M.^u , Samii, A.^v , Jones, R.^w , Barker, R.A.^x , McCusker, E.^y , Loy, C.^y , Orth, M.^z , Süßmuth, S.^z , Quaid, K.^aa , Guttman, M.^ab , Perlman, S.^ac , Geschwind, M.D.^ad , Sha, S.^ad , Warner, T.^ae , Rosser, A.^af , Marshall, F.^ag , Panegyres, P.^ah , Lee, J.^ah , Perlmutter, J.^ai , Miedzybrodzka, Z.^aj , Craufurd, D.^ak , Mazzoni, P.^al , Marder, K.^al , Kumar, R.^am , Wheelock, V.^an , Martin, W.^ao , Suchowersky, O.^ao , Ahmed, A.^ap , De Soriano, I.^p , Shadrick, C.^p , Preston, J.^q , Goh, A.^q , Antonopoulos, S.^q , Komiti, A.^r , Decolongon, J.^s , Fan, M.^s , Coleman, A.^s , Varvaris, M.^t , Ong, M.^t , Yoritomo, N.^t , Suter, G.^u , Freney, E.P.^v , Macaraeg, A.^v , Wood-Siverio, C.^w , Factor, S.A.^w , Mason, S.^x , Guzman, N.V.^x , Griffith, J.^y , McMillan, J.^y , Gunn, D.^y , Barth, K.^z , Trautmann, S.^z , Schwenk, D.^z , Eschenbach, C.^z , Wesson, M.^aa , Wojcieszek, J.^aa , Sheinberg, A.^ab , Law, A.^ab , Karmalkar, I.^ab , Clemente, B.^ac , Winer, J.^ad , Satris, G.^ad , Burrows, M.^ae , Price, K.^af , Hunt, S.^af , Chesire, A.^ag , Wodarski, M.^ag , Hickey, C.^ag , Tedesco, M.^ah , Maxwell, B.^ah , Barton, S.^ai , Smith, S.^ai , Rae, D.^aj , Vaughan, V.^aj , D’Alessandro, M.^aj , Bek, J.^ak , Howard, E.^ak , Wasserman, P.^al , Erickson, D.^am , Reeves, C.^am , Nickels, B.^am , Kjer, L.^an , Martin, A.^{p an} , Farias, S.^an , King, P.^ao , Wieler, M.^ao , Sran, S.^ao , Reece, C.^ap , Bura, A.^ap , Mourany, L.^ap , PREDICT-HD Investigators and Coordinators of the Huntington^aq

^a Neuroscience Institute, Georgia State University, Atlanta, GA, United States
^b The Mind Research Network, Albuquerque, NM, United States
^c Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, United States
^d Iowa Mental Health Clinical Research Center, Department of Psychiatry, University of Iowa, Iowa City, IA, United States
^e Department of Psychology, Georgia State University, Atlanta, GA, United States
^f Department of Neurology, University of Iowa, Iowa City, IA, United States
^g Department of Psychology, University of Iowa, Iowa City, IA, United States
^h University of California, San Diego, United States
ⁱ Rhode Island Hospital/Alpert Medical School of Brown University, United States
^j Seattle Children’s Research Institute, United States
^k Cleveland Clinic, United States
^l University of Iowa, United States
^m University of Indiana, United States
ⁿ Texas Tech University Health Sciences Center, United States
^o University of Minnesota, United States
^p University of Iowa, Iowa City, IA, United States
^q St. Vincent’s Hospital, The University of Melbourne, Kew, VIC, Australia
^r The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia
^s University of British Columbia, Vancouver, BC, Canada
^t Johns Hopkins University, Baltimore, MD, United States
^u Hereditary Neurological Disease Centre, Wichita, KS, United States
^v University of Washington and VA Puget Sound Health Care System, Seattle, WA, United States
^w Emory University School of Medicine, Atlanta, GA, United States
^x John van Geest Centre for Brain Repair, Cambridge, United Kingdom
^y Westmead Hospital, Sydney, Australia
^z University of Ulm, Ulm, Germany
^aa Indiana University School of Medicine, Indianapolis, IN, United States
^ab Centre for Addiction and Mental Health, University of Toronto, Markham, ON, Canada
^ac UCLA Medical Center, Los Angeles, CA, United States
^ad University of California, San Francisco, CA, United States
^ae National Hospital for Neurology and Neurosurgery, London, United Kingdom
^af Cardiff University, Cardiff, United Kingdom
^ag University of Rochester, Rochester, NY, United States
^ah Neurosciences Unit, Graylands, Selby-Lemnos & Special Care Health Services, Perth, Australia
^ai Washington University, St. Louis, MO, United States
^aj Clinical Genetics Centre, Aberdeen, United Kingdom
^ak University of Manchester, Manchester, United Kingdom
^al Columbia University Medical Center, New York, NY, United States
^am Colorado Neurological Institute, Englewood, CO, United States
^an University of California, Davis, Sacramento, CA, United States
^ao University of Alberta, Edmonton, AB, Canada
^ap Cleveland Clinic Foundation, Cleveland, OH, United States

Abstract
This study assessed how BDNF (brain-derived neurotrophic factor) and other genes involved in its signaling influence brain structure and clinical functioning in pre-diagnosis Huntington’s disease (HD). Parallel independent component analysis (pICA), a multivariate method for identifying correlated patterns in multimodal datasets, was applied to gray matter concentration (GMC) and genomic data from a sizeable PREDICT-HD prodromal cohort (N = 715). pICA identified a genetic component highlighting NTRK2, which encodes BDNF’s TrkB receptor, that correlated with a GMC component including supplementary motor, precentral/premotor cortex, and other frontal areas (p < 0.001); this association appeared to be driven by participants with high or low levels of the genetic profile. The frontal GMC profile correlated with cognitive and motor variables (Trail Making Test A (p = 0.03); Stroop Color (p = 0.017); Stroop Interference (p = 0.04); Symbol Digit Modalities Test (p = 0.031); Total Motor Score (p = 0.01)). A top-weighted NTRK2 variant (rs2277193) was protectively associated with Trail Making Test B (p = 0.007); greater minor allele numbers were linked to a better performance. These results support the idea of a protective role of NTRK2 in prodromal HD, particularly in individuals with certain genotypes, and suggest that this gene may influence the preservation of frontal gray matter that is important for clinical functioning. © 2018 by the authors.

Author Keywords
Brain-derived neurotrophic factor;  Huntington’s disease;  Independent component analysis;  Supplementary motor;  Tropomyosin receptor kinase B

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

Preoperative electrophysiological characterization of patients with primary macula-involving rhegmatogenous retinal detachment
(2018) Journal of Ophthalmic and Vision Research, 13 (3), pp. 241-248. Cited 1 time.

Lin, J.B.^a , Sein, J.^a , Van Stavern, G.P.^a , Apte, R.S.^{a b c}

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

Abstract
Purpose: To determine 1) which components of retinal function are impaired after rhegmatogenous retinal detachment, 2) which outer retinal pathways (rod- or cone-driven) are more severely affected, and 3) whether there is concomitant inner retinal dysfunction. Methods: We conducted a prospective observational study in a large academic institution. We performed preoperative electroretinography on eight patients to assess outer and inner retinal function. In all cases, a comparison between the eye with the detached retina and the control fellow eye was made. Results: Eyes with a detached retina had significantly lower a-wave and b-wave amplitudes with respect to both rod- and cone-dominated testing parameters (P < 0.05) and reduced 30 Hz flicker responses compared to fellow eyes (P < 0.05); the effect size was similar for all significantly reduced parameters (r~0.6). There were no significant differences between eyes with detached retinas and control fellow eyes with respect to b/a-wave ratios, a-wave latencies, or b-wave latencies. Conclusion: Patients with rhegmatogenous retinal detachment have preoperative outer retinal dysfunction equally affecting both rod- and cone-driven pathways, and they have minimal inner retinal dysfunction. © 2018 Medknow Publications.All Rights Reserved.

Author Keywords
Clinical Electrophysiology;  Electroretinography;  Retinal Detachment

Document Type: Article
Source: Scopus

Progressive multifocal leukoencephalopathy: Are you aware of it?
(2018) Neurology, 90 (6), pp. 255-256. 

Clifford, D.B.^a , Berger, T.^b

^a Departments of Neurology and Medicine, Washington University in St. LouisMO, United States
^b Clinical Department of Neurology, Medical University of Innsbruck, Austria

Document Type: Editorial
Source: Scopus

Hospital case-volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage
(2018) International Journal of Stroke, . Article in Press. 

Lindgren, A.^{a b} , Burt, S.^c , Bragan Turner, E.^c , Meretoja, A.^{d e} , Lee, J.-M.^f , Hemmen, T.M.^g , Alberts, M.^h , Lemmens, R.^{i j k} , Vergouwen, M.D.I.^a , Rinkel, G.J.E.^a

^a Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, Netherlands
^b Department of Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland
^c Dr Foster Ltd, London, United Kingdom
^d Department of Neurology, Helsinki University Hospital, Helsinki, Finland
^e Department of Medicine at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
^f Department of Neurology, and the Hope Center for Neurological disorders, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurosciences, University of California, San Diego, CA, United States
^h Department of Neurology, Hartford Hospital, Hartford, CT, United States
ⁱ Department of Neurosciences, Experimental Neurology, Leuven Institute for Neuroscience and Disease, University of (LIND), KU Leuven, Leuven, Leuven, Belgium
^j VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium
^k Department of Neurology, University Hospitals Leuven, Leuven, Belgium

Abstract
Background: Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. Aims: To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods: We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007–2014. Hospitals were categorized by annual case-volume (low volume: <41/year; intermediate: 41–70/year; high: >70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. Results: We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high-volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2–11.7%), for intermediate volume 7.0% (95% CI 6.2–7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47–0.85)) and for high volume 5.4% (95% CI 4.6–6.3%; adjusted OR 0.50 (95% CI 0.33–0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30–0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25–0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55–1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36–0.87) with high case-volume. Conclusions: Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers. © 2018 World Stroke Organization.

Author Keywords
epidemiology;  hospital volume;  intracranial aneurysm;  outcome;  stroke;  Subarachnoid hemorrhage

Document Type: Article in Press
Source: Scopus

Children’s third-party understanding of communicative interactions in a foreign language
(2018) Collabra: Psychology, 4 (1), art. no. 2, . 

Afshordi, N.^{a b} , Sullivan, K.R.^{a c} , Markson, L.^a

^a Washington University, Saint Louis, United States
^b Harvard University, Cambridge, MA, United States
^c US Department of Health and Human Services, United States

Abstract
Two studies explored young children’s understanding of the role of shared language in communication by investigating how monolingual English-speaking children interact with an English speaker, a Spanish speaker, and a bilingual experimenter who spoke both English and Spanish. When the bilingual experimenter spoke in Spanish or English to request objects, four-year-old children, but not three-year-olds, used her language choice to determine whom she addressed (e.g. requests in Spanish were directed to the Spanish speaker). Importantly, children used this cue – language choice – only in a communicative context. The findings suggest that by four years, monolingual children recognize that speaking the same language enables successful communication, even when that language is unfamiliar to them. Three-year-old children’s failure to make this distinction suggests that this capacity likely undergoes significant development in early childhood, although other capacities might also be at play. © 2018 The Author(s).

Author Keywords
Communication;  Conventionality;  Metalinguistic awareness

Document Type: Article
Source: Scopus

Topology of functional connectivity and hub dynamics in the beta band as temporal prior for natural vision in the human brain
(2018) Journal of Neuroscience, 38 (15), pp. 3858-3871. 

Betti, V.^{a b} , Corbetta, M.^{c d} , de Pasquale, F.^e , Wens, V.^f , Penna, S.D.^g

^a Department of Psychology, Sapienza University of RomeRome, Italy
^b Fondazione Santa Lucia, Istituto Di Ricovero e Cura a Carattere ScientificoRome, Italy
^c Department of Neuroscience and Padova Neuroscience Center, University of Padua, Padua, Italy
^d Department of Neurology, Radiology and Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
^e Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
^f Laboratoire de Cartographie fonctionnelle du Cerveau, UNI-ULB Neurosciences Institute, Université libre de Bruxelles (ULB) and Magnetoencephalography Unit, Department of Functional Neuroimaging Service of Nuclear Medicine CUB-Hôpital Erasme, Brussels, Belgium
^g Department of Neuroscience, Imaging and Clinical Sciences and Institute for Advanced Biomedical Technologies, G d’Annunzio University Chieti-Pescara, Chieti, Italy

Abstract
Networks hubs represent points of convergence for the integration of information across many different nodes and systems. Although a great deal is known on the topology of hub regions in the human brain, little is known about their temporal dynamics. Here, we examine the static and dynamic centrality of hub regions when measured in the absence of a task (rest) or during the observation of natural or synthetic visual stimuli. We used Magnetoencephalography (MEG) in humans (both sexes) to measure static and transient regional and network-level interaction in α- and β-band limited power (BLP) in three conditions: visual fixation (rest), viewing of movie clips (natural vision), and time-scrambled versions of the same clips (scrambled vision). Compared with rest, we observed in both movie conditions a robust decrement of α-BLP connectivity. Moreover, both movie conditions caused a significant reorganization of connections in the α band, especially between networks. In contrast, β-BLP connectivity was remarkably similar between rest and natural vision. Not only the topology did not change, but the joint dynamics of hubs in a core network during natural vision was predicted by similar fluctuations in the resting state. We interpret these findings by suggesting that slow-varying fluctuations of integration occurring in higher-order regions in the β band may be a mechanism to anticipate and predict slow-varying temporal patterns of the visual environment. © 2018 the authors.

Author Keywords
Brain rhythms;  Centrality;  Functional connectivity;  Magnetoencephalography;  Natural stimulation;  Resting-state networks

Document Type: Article
Source: Scopus

From genes to treatments: A systematic review of the pharmacogenetics in smoking cessation
(2018) Pharmacogenomics, 19 (10), pp. 861-871. 

Salloum, N.C.^a , Buchalter, E.L.^a , Chanani, S.^a , Espejo, G.^a , Ismail, M.S.^a , Laine, R.O.^b , Nageeb, M.^a , Srivastava, A.B.^a , Trapp, N.^a , Trillo, L.^a , Vance, E.^a , Wenzinger, M.^a , Hartz, S.M.^a , David, S.P.^c , Chen, L.-S.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^c Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, United States

Abstract
Smoking cessation treatment outcomes may be heavily influenced by genetic variations among smokers. Therefore, identifying specific variants that affect response to different pharmacotherapies is of major interest to the field. In the current study, we systematically review all studies published in or after the year 1990 which examined one or more gene-drug interactions for smoking cessation treatment. Out of 644 citations, 46 articles met the inclusion criteria for the systematic review. We summarize evidence on several genetic polymorphisms (CHRNA5-A3-B4, CYP2A6, DBH, CHRNA4, COMT, DRD2, DRD4 and CYP2B6) and their potential moderating pharamacotherarpy effects on patient cessation efficacy rates. These findings are promising and call for further research to demonstrate the effectiveness of genetic testing in personalizing treatment decision-making and improving outcome. © 2018 Future Medicine Ltd.

Author Keywords
nicotine replacement therapy;  pharmacogenetics;  precision medicine;  smoking cessation

Document Type: Review
Source: Scopus

Four-year-old children align their preferences with those of their peers
(2017) Collabra: Psychology, 3 (1), art. no. 14, . 

Hennefield, L., Markson, L.

Washington University in, St Louis, United States

Abstract
Children express preferences for a wide range of options, such as objects, and frequently observe the preferences that others express towards these things. However, little is know about how these initial preferences develop. The present research investigated whether one particular type of social information – other children’s preferences – influences children’s own preferences. Four-year-old children observed, via video, two boys and two girls display the same preference for one of two stickers. Each child (peer) expressed liking for one sticker and dislike for the other. Then children completed two rounds of the Dictator Game, a classic resource distribution task. In each round, children distributed either 10 liked stickers or 10 disliked stickers (counterbalanced) between themselves and another child who was not present. If the preferences expressed by their peers influenced children’s own preferences, children should keep more of the liked than disliked stickers for themselves. In line with this prediction, more children kept more liked than disliked stickers, indicating their distribution patterns were influenced by their peers’ preferences. This finding suggests that children extracted informational content about the value of the stickers from their peers and used that information to guide their own preferences. Children might also have aligned their preferences with those of their peers to facilitate social bonding and group membership. This research demonstrates the strong influence of peers on children’s developing preferences, and reveals the effect of peer influence via video – a medium that young children are frequently exposed to but often struggle to learn from in other contexts. © 2017 The Author(s).

Author Keywords
Dictator game;  Peer influence;  Preferences;  Preschoolers;  Video deficit

Document Type: Article
Source: Scopus