Arts & Sciences Brown School McKelvey School Medicine

WashU weekly Neuroscience publications

“Regional differences in the expression of tetrodotoxin-sensitive inward Ca2+ and outward Cs+/K+ currents in mouse and human ventricles” (2019) Channels (Austin, Tex.)

Regional differences in the expression of tetrodotoxin-sensitive inward Ca2+ and outward Cs+/K+ currents in mouse and human ventricles
(2019) Channels (Austin, Tex.), 13 (1), pp. 72-87. 

Wang, W.a , Mellor, R.L.a , Nerbonne, J.M.a b , Balke, C.W.a b

a Center for Cardiovascular Research, Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
b John Cochran Veterans Administration Medical Center, St. Louis, MO, United States

Abstract
Tetrodotoxin (TTX) sensitive inward Ca2+ currents, ICa(TTX), have been identified in cardiac myocytes from several species, although it is unclear if ICa(TTX) is expressed in all cardiac cell types, and if ICa(TTX) reflects Ca2+ entry through the main, Nav1.5-encoded, cardiac Na+ (Nav) channels. To address these questions, recordings were obtained with 2 mm Ca2+ and 0 mm Na+ in the bath and 120 mm Cs+ in the pipettes from myocytes isolated from adult mouse interventricular septum (IVS), left ventricular (LV) endocardium, apex, and epicardium and from human LV endocardium and epicardium. On membrane depolarizations from a holding potential of -100 mV, ICa(TTX) was identified in mouse IVS and LV endocardial myocytes and in human LV endocardial myocytes, whereas only TTX-sensitive outward Cs+/K+ currents were observed in mouse LV apex and epicardial myocytes and human LV epicardial myocytes. The inward Ca2+, but not the outward Cs+/K+, currents were blocked by mm concentrations of MTSEA, a selective blocker of cardiac Nav1.5-encoded Na+ channels. In addition, in Nav1.5-expressing tsA-201 cells, ICa(TTX) was observed in 3 (of 20) cells, and TTX-sensitive outward Cs+/K+ currents were observed in the other (17) cells. The time- and voltage-dependent properties of the TTX-sensitive inward Ca2+ and outward Cs+/K+ currents recorded in Nav1.5-expressing tsA-201 were indistinguishable from native currents in mouse and human cardiac myocytes. Overall, the results presented here suggest marked regional, cell type-specific, differences in the relative ion selectivity, and likely the molecular architecture, of native SCN5A-/Scn5a- (Nav1.5-) encoded cardiac Na+ channels in mouse and human ventricles.

Author Keywords
interventricular septum;  Left ventricles (LV);  LV endocardium;  LV epicardium;  Nav1.5;  voltage-gated Na currents

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study” (2019) Journal of Psychiatric Research

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study
(2019) Journal of Psychiatric Research, 111, pp. 59-67. 

Greden, J.F.a , Parikh, S.V.a , Rothschild, A.J.b , Thase, M.E.c , Dunlop, B.W.d , DeBattista, C.e , Conway, C.R.f , Forester, B.P.g , Mondimore, F.M.h , Shelton, R.C.i , Macaluso, M.j , Li, J.k , Brown, K.l , Gilbert, A.k , Burns, L.k , Jablonski, M.R.k , Dechairo, B.k l

a University of Michigan Department of Psychiatry and Comprehensive Depression Center, 4250 Plymouth Rd, Ann Arbor, MI 48109, United States
b University of Massachusetts Medical School and UMass Memorial Healthcare, 55 N Lake Ave, Worcester, MA 01655, United States
c Perelman School of Medicine of the University of Pennsylvania and the Corporal Michael Crescenz VAMC, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States
d Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, 12 Executive Park Dr NE #200, Atlanta, GA 30329, United States
e Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Rd, Stanford, CA 94305, United States
f Washington University School of Medicine, Department of Psychiatry, The John Cochran Veteran’s Administration Hospital, 660 S Euclid Ave, St. Louis, MO 63110, United States
g McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, 115 Mill St, Belmont, MA 02478, United States
h Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, 1800 Orleans St, Baltimore, MD 21287, United States
i The University of Alabama at Birmingham, Department of Psychiatry and School of Medicine, 1720 2nd Ave S, Birmingham, AL, United States
j University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences, 1010 N Kansas St, Wichita, KS 67214, United States
k Assurex Health, Inc., 6960 Cintas Blvd, Mason, OH 45040, United States
l Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City, UT 84108, United States

Abstract
Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial – a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent (‘use as directed’ or ‘use with caution’ test categories) or incongruent (‘use with increased caution and with more frequent monitoring’ test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement [change in 17-item Hamilton Depression Rating Scale (HAM-D17)] at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939). © 2019

Document Type: Article
Publication Stage: Final
Source: Scopus

“Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects” (2019) AIDS (London, England)

Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects
(2019) AIDS (London, England), 33 (3), pp. 475-481. 

Pérez-Valero, I.a , Ellis, R.b , Heaton, R.b , Deutsch, R.b , Franklin, D.b , Clifford, D.B.c , Collier, A.d , Gelman, B.e , Marra, C.d , McCutchan, J.A.b , Navis, A.f , Sacktor, N.g , Simpson, D.f , Grant, I.b , Letendre, S.b

a HIV Unit – Internal Medicine Service, Hospital Universitario La Paz – IdiPAZ, Madrid, Spain
b University of California, San Diego, CA, United States
c Washington University School of Medicine, Saint Louis, MO, United States
d University of Washington School of Medicine, Seattle, WA, United States
e University of Texas, Galveston, TX, United States
f Icahn School of Medicine at Mount SinaiNY, United States
g Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
BACKGROUND: During antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed ‘CSF viral escape’. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA. METHODS: A total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression. RESULTS: CSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7). CONCLUSIONS: In this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance.

Document Type: Article
Publication Stage: Final
Source: Scopus

“A unifying hypothesis for delirium and hospital-acquired weakness as synaptic dysfunctions” (2019) Medical Hypotheses

A unifying hypothesis for delirium and hospital-acquired weakness as synaptic dysfunctions
(2019) Medical Hypotheses, 124, pp. 105-109. 

Jarquin-Valdivia, A.A.a , Major, R.J.b

a TriStar Centennial Medical Center, United States
b Washington University in St Louis, Pre-Medical School Program, United States

Abstract
In this paper, we discuss a unifying hypothesis, supported by Hebbian theory, that postulates that both delirium/toxic-metabolic encephalopathy (DTME) and hospital-acquired weakness (HAW) obey to a similar underlying anatomic site of dysfunction: the synapse. A brief historical and current state of endorsing knowledge summarizing its plausibility is presented. Both DTME and HAW are commonly encountered conditions in clinical practice. It is estimated that up to 30–70% of hospitalized patients will develop DTME and/or HAW. The currently available explanations in the pathophysiology of these conditions vary widely, and there is no consensus explanation on their etiopathogenesis. The disease state itself, inflammation, exo- and endo-toxins and decreased use of the synapse leads to their dysfunction which likely extends to other key cells in the micromilieu such as microglia, astrocytes, capillaries, Schwann cells, oligodendrocytes, and the blood brain barrier, all of which participate in the homeostasis and wellbeing of the synapses. Additional disruption of the micromilieu or presence of synaptotoxins (such as benzodiazepines, cytokines, anesthetics, and others) would allow entry into the neural tissue that could induce, aggravate or accelerate the synaptic dysfunction. As we enter the era of the connectome and synaptome, the Hebbian-endorsed synapse-centered hypothesis (heterogenous neuronal microdisconnections) attempts to unify the hypotheses of delirium/toxic-metabolic encephalopathy and hospital-acquired weakness into a single etiopathomechanism. © 2019 Elsevier Ltd

Author Keywords
Connectome;  Delirium;  Encephalopathy;  Hebbian;  Involution;  Microdisconnection;  Synapse;  Synaptome;  Synaptopathy;  Weakness

Document Type: Article
Publication Stage: Final
Source: Scopus

“A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas” (2019) Human molecular genetics

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas
(2019) Human molecular genetics, 28 (4), pp. 572-583. 

Gehlhausen, J.R.a b , Hawley, E.a b , Wahle, B.M.a , He, Y.a , Edwards, D.a b , Rhodes, S.D.a c , Lajiness, J.D.a b , Staser, K.d , Chen, S.a , Yang, X.a , Yuan, J.a , Li, X.a , Jiang, L.a , Smith, A.a , Bessler, W.a , Sandusky, G.e , Stemmer-Rachamimov, A.f , Stuhlmiller, T.J.g , Angus, S.P.g , Johnson, G.L.g , Nalepa, G.a b , Yates, C.W.h , Wade Clapp, D.a b i , Park, S.-J.a b

a Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
b Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States
d Department of Medicine, Division of Dermatology, Washington University in Saint Louis, St. Louis, MO, United States
e Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
g Department of Pharmacology, University of North Carolina, Chapel Hill, NC, United States
h Department of Otolaryngology, Indiana University School of Medicine, Indianapolis, IN, United States
i Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery the engages randomized clinical trial” (2019) JAMA – Journal of the American Medical Association

Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery the engages randomized clinical trial
(2019) JAMA – Journal of the American Medical Association, 321 (5), pp. 473-483. Cited 1 time.

Wildes, T.S.a , Mickle, A.M.a , Abdallah, A.B.a , Maybrier, H.R.a , Oberhaus, J.a , Budelier, T.P.a , Kronzer, A.a , McKinnon, S.L.a , Park, D.a , Torres, B.A.a , Graetz, T.J.a , Emmert, D.A.a , Palanca, B.J.a , Goswami, S.a , Jordan, K.a , Lin, N.b , Fritz, B.A.a , Stevens, T.W.a , Jacobsohn, E.c , Schmitt, E.M.d , Inouye, S.K.d , Stark, S.e , Lenze, E.J.f , Avidan, M.S.a

a Department of Anesthesiology, Washington University, School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, United States
b Department of Mathematics, Washington University, School of Medicine, St Louis, MO, United States
c Department of Anesthesiology, University of Manitoba, Winnipeg, Canada
d Department of Medicine, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
e Department of Occupational Therapy, Washington University, School of Medicine, St Louis, MO, United States
f Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States

Abstract
IMPORTANCE Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. OBJECTIVE To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 1232 adults aged60years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitmentwas from January 2015 toMay 2018, with follow-up until July 2018. INTERVENTIONS Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). MAIN OUTCOMES AND MEASURES The primary outcomewas incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. RESULTS Of the 1232 randomized patients (median age, 69 years [range, 60to 95]; 563women [45.7%]), 1213 (98.5%)were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604patients (26.0%)in the guided group and 140 of 609 patients (23.0%)in the usual care group (difference, 3.0%[95%CI, -2.0%to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentrationwas significantly lower in the guided group than the usual care group (0.69 vs0.80minimum alveolar concentration; difference, -0.11 [95%CI, -0.13 to -0.10), and median cumulative time with EEGsuppressionwas significantly less (7 vs 13 minutes; difference, -6.0[95%CI, -9.9 to -2.1]). Therewas no significant difference between groups in the median cumulative time with mean arterial pressure below60mmHg (7 vs 7 minutes; difference,0.0[95%CI, -1.7 to 1.7]). Undesirablemovement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group.Nopatients reported intraoperative awareness. Postoperative nausea and vomitingwas reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse eventswere reported in 124 patients (20.2%) in the guided and 130 (21.0%)in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. CONCLUSIONS AND RELEVANCE Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. © 2019 American Medical Association.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Optical coherence tomography for diagnosing optic neuritis: Are we there yet?” (2019) Neurology

Optical coherence tomography for diagnosing optic neuritis: Are we there yet?
(2019) Neurology, 92 (6), pp. 253-254. 

Saidha, S., Naismith, R.T.

From Johns Hopkins University (S.S.), Baltimore, MD; and Washington University (R.T.N.), St. Louis, MO

Document Type: Article
Publication Stage: Final
Source: Scopus

“Gene therapy targeting SARM1 blocks pathological axon degeneration in mice” (2019) The Journal of experimental medicine

Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
(2019) The Journal of experimental medicine, 216 (2), pp. 294-303. 

Geisler, S.a b , Huang, S.X.a , Strickland, A.c , Doan, R.A.a , Summers, D.W.c , Mao, X.c , Park, J.c , DiAntonio, A.b d , Milbrandt, J.b c

a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for >10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss. © 2019 Geisler et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Metabolic aspects of neuronal degeneration: From a NAD + point of view” (2019) Neuroscience Research

Metabolic aspects of neuronal degeneration: From a NAD + point of view
(2019) Neuroscience Research, 139, pp. 9-20. Cited 1 time.

Sasaki, Y.

Department of Genetics, Washington University in St. Louis, Couch Biomedical Research Building, 4515 McKinley Ave., Saint Louis, MO 63110, United States

Abstract
Cellular metabolism maintains the life of cells, allowing energy production required for building cellular constituents and maintaining homeostasis under constantly changing external environments. Neuronal cells maintain their structure and function for the entire life of organisms and the loss of neurons, with limited neurogenesis in adults, directly causes loss of complexity in the neuronal networks. The nervous system organizes the neurons by placing cell bodies containing nuclei of similar types of neurons in discrete regions. Accordingly, axons must travel great distances to connect different types of neurons and peripheral organs. The enormous surface area of neurons makes them high-energy demanding to keep their membrane potential. Distal axon survival is dependent on axonal transport that is another energy demanding process. All of these factors make metabolic stress a potential risk factor for neuronal death and neuronal degeneration often associated with metabolic diseases. This review discusses recent findings on metabolic dysregulations under neuronal degeneration and pathways protecting neurons in these conditions. © 2018 Elsevier B.V. and Japan Neuroscience Society

Author Keywords
Axon;  Axon degeneration;  Metabolism;  Neurodegeneration;  Nicotinamide adenine dinucleotide

Document Type: Review
Publication Stage: Final
Source: Scopus

“Early Sexual Trauma Exposure and Neural Response Inhibition in Adolescence and Young Adults: Trajectories of Frontal Theta Oscillations During a Go/No-Go Task” (2019) Journal of the American Academy of Child and Adolescent Psychiatry

Early Sexual Trauma Exposure and Neural Response Inhibition in Adolescence and Young Adults: Trajectories of Frontal Theta Oscillations During a Go/No-Go Task
(2019) Journal of the American Academy of Child and Adolescent Psychiatry, 58 (2), pp. 242-255.e2. Cited 1 time.

Meyers, J.a , McCutcheon, V.V.b , Pandey, A.K.a , Kamarajan, C.a , Subbie, S.a , Chorlian, D.a , Salvatore, J.c d , Pandey, G.a , Almasy, L.e , Anokhin, A.b , Bauer, L.f , Bender, A.g , Dick, D.M.c , Edenberg, H.J.h , Hesselbrock, V.f , Kramer, J.i , Kuperman, S.i , Agrawal, A.b , Bucholz, K.b , Porjesz, B.a

a State University of New York Downstate Medical Center, Brooklyn, NY, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Virginia Commonwealth University, Richmond, United States
d Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, United States
e University of Pennsylvania, Philadelphia, United States
f University of Connecticut School of Medicine, Farmington, United States
g University of Missouri, St. Louis, United States
h Indiana University School of Medicine, Indianapolis, United States
i University of Iowa, Iowa City, United States

Abstract
Objective: Trauma, particularly when experienced early in life, can alter neurophysiologic and behavioral development, thereby increasing risk for substance use disorders and related psychopathology. However, few studies have empirically examined trauma using well-characterized developmental samples that are followed longitudinally. Method: The association of assaultive, non-assaultive, and sexual assaultive experiences before 10 years of age with developmental trajectories of brain function during response inhibition was examined by measuring electrophysiologic theta and delta oscillations during no-go and go conditions in an equal probability go/no-go task. Data were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort, composed of offspring who were aged 12 through 22 years at enrollment from high-risk and comparison families, with follow-ups at 2-year intervals since 2004. In addition, other important predictors of neurophysiologic functioning (eg, substance use, impulsivity, and parental alcohol use disorders) were investigated. Moreover, associations of neurophysiologic functioning with alcohol and cannabis use disorder symptom counts and externalizing and internalizing psychopathology were examined. Results: Individuals exposed to sexual assaultive trauma before 10 years of age had slower rates of change in developmental trajectories of no-go frontal theta during response inhibition. Importantly, effects remained significant after accounting for exposure to other traumatic exposures, such as parental history of alcohol use disorder and participants’ substance use, but not measures of impulsivity. Further, slower rates of change in no-go frontal theta adolescent and young adult development were associated with increased risk for alcohol use disorder symptoms and internalizing psychopathology, but not for cannabis use disorder symptoms or externalizing psychopathology. Conclusion: Childhood sexual assault is associated with atypical frontal neurophysiologic development during response inhibition. This could reflect alterations in frontal lobe development, synaptic pruning, and/or cortical maturation involving neural circuits for inhibitory control. These same areas could be associated with increased risk for young adult alcohol use disorder symptoms and internalizing psychopathology. These findings support the hypothesis that changes in neurocognitive development related to early sexual trauma exposure could increase the risk for mental health and substance use problems in young adulthood. © 2019

Author Keywords
alcohol dependence;  event-related oscillations;  inhibition;  internalizing;  sexual abuse

Document Type: Article
Publication Stage: Final
Source: Scopus

“Reversible dementias” (2019) CONTINUUM Lifelong Learning in Neurology

Reversible dementias
(2019) CONTINUUM Lifelong Learning in Neurology, 25 (1), pp. 234-253. 

Day, G.S.

Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, School of Medicine, 4488 Forest Park Ave, St Louis, MO 63108, United States

Abstract
PURPOSE OF REVIEW This article describes the clinical features that suggest a reversible cause of dementia. RECENT FINDINGS Substantial variability exists in the presenting features and clinical course of patients with common neurodegenerative causes of dementia, but the response to available therapies and eventual outcomes are often poor. This realization has influenced the evaluation of patients with dementia, with diagnostic approaches emphasizing routine screening for a short list of potentially modifiable disorders that may exacerbate dementia symptoms or severity but rarely influence long-term outcomes. Although a standard approach to the assessment of dementia is appropriate in the vast majority of cases, neurologists involved in the assessment of patients with dementia must recognize those rare patients with reversible causes of dementia, coordinate additional investigations when required, and ensure expedited access to treatments that may reverse decline and optimize long-term outcomes. SUMMARY The potential to improve the outcome of patients with reversible dementias exemplifies the need to recognize these patients in clinical practice. Dedicated efforts to screen for symptoms and signs associated with reversible causes of dementia may improve management and outcomes of these rare patients when encountered in busy clinical practices. © Lippincott Williams & Wilkins. © 2019 American Academy of Neurology.

Document Type: Review
Publication Stage: Final
Source: Scopus

“CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis 11 Medical and Health Sciences 1107 Immunology” (2019) Journal of Neuroinflammation

CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis 11 Medical and Health Sciences 1107 Immunology
(2019) Journal of Neuroinflammation, 16 (1), art. no. 22, . 

Funk, K.E.a , Klein, R.S.a b c

a Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States
c Department of Neurosciences, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Background: Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. Methods: The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. Results: Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. Conclusions: Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor. © 2019 The Author(s).

Author Keywords
Antiviral T cells;  Colony-stimulating factor 1 receptor;  Microglia;  PLX5622;  Viral encephalitis;  West Nile virus

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“A systematic review and case series of ziprasidone for psychosis in Parkinson’s disease” (2019) Journal of Parkinson’s Disease

A systematic review and case series of ziprasidone for psychosis in Parkinson’s disease
(2019) Journal of Parkinson’s Disease, 9 (1), pp. 63-71. 

Younce, J.R.a , Davis, A.A.a , Black, K.J.a b

a Department of Neurology, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Departments of Psychiatry, Radiology, and Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The atypical antipsychotic ziprasidone has been considered inappropriate for use in patients with Parkinson’s disease (PD), as most atypical antipsychotics worsen parkinsonism. However, the current evidence for safety and efficacy of ziprasidone in PDP has not been evaluated in a systematic fashion. We review published experience with ziprasidone for treating psychosis in PD via systematic search of MEDLINE, Embase, Cochrane CENTRAL, and Clinicaltrials.gov with terms related to “ziprasidone” and “Parkinson’s disease”, inclusive of case reports and prospective studies. We also add seven cases of ziprasidone exposure in patients in our center with idiopathic PD or Lewy body dementia (DLB), selected by retrospective query of all clinical data since 1996. In our review, two prospective trials and 11 case reports or series were found, with ziprasidone found to be generally effective for treatment of psychosis and with few adverse events reported. Our case series did not support efficacy of ziprasidone; it was generally safe in PD, but two patients with DLB had adverse motor events. We conclude that, although ziprasidone occasionally can produce substantial worsening of motor signs, it usually is well tolerated, and may provide in some cases a useful alternative to quetiapine, clozapine and pimavanserin, particularly in the acute care setting. Further randomized controlled studies are needed. © 2019 IOS Press and the authors. All rights reserved.

Author Keywords
Antipsychotic drugs;  hallucinations;  lewy body disease;  Parkinson’s disease;  parkinsonism;  psychotic disorders

Document Type: Review
Publication Stage: Final
Source: Scopus

“Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry” (2019) PLoS genetics

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry
(2019) PLoS genetics, 15 (1), p. e1007808. 

Chi, C.a b , Shao, X.a , Rhead, B.a b , Gonzales, E.c , Smith, J.B.c , Xiang, A.H.c , Graves, J.d , Waldman, A.e , Lotze, T.f , Schreiner, T.g , Weinstock-Guttman, B.h , Aaen, G.i , Tillema, J.-M.j , Ness, J.k , Candee, M.l , Krupp, L.m , Gorman, M.n , Benson, L.n , Chitnis, T.o , Mar, S.p , Belman, A.m , Casper, T.C.l , Rose, J.q , Moodley, M.r , Rensel, M.s , Rodriguez, M.j , Greenberg, B.t , Kahn, L.u , Rubin, J.v , Schaefer, C.w , Waubant, E.d , Langer-Gould, A.x y , Barcellos, L.F.a

a Genetic Epidemiology and Genomics Laboratory, University of California, Berkeley, CA, United States
b Computational Biology Graduate Group, University of California, Berkeley, CA, United States
c Department of Research & Evaluation, Kaiser Permanente Southern California, Los Angeles, CA, United States
d Department of Neurology, University of California, San Francisco, CA, United States
e Leukodystrophy Center, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
f Neurology and Developmental Neuroscience Department, Texas Children’s Hospital, Houston, TX, United States
g University of Colorado School of Medicine, Aurora, CO, United States
h Department of Neurology, State University of New York, Buffalo, NY, United States
i Loma Linda University, Loma Linda, CA, United States
j Department of Neurology, Mayo Clinic, Rochester, MN, United States
k Children’s of Alabama, Birmingham, AL, United States
l Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
m Department of Neurology, NYU Langone HealthNY, United States
n Boston Children’s Hospital, Boston, MA, United States
o MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA, United States
p Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
q Department of Neurology, University of Utah, Salt Lake City, UT, United States
r Center for Pediatric Neurosciences, Cleveland Clinic, Cleveland, OH, United States
s Mellen Center, Cleveland Clinic, Cleveland, OH, United States
t Neurology & Neurotherapeutics, University of Texas Southwestern, Dallas, TX, United States
u Children’s National Medical CenterD.C, United States
v Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
w Kaiser Permanente Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
x Southern California Permanente Medical Group, Kaiser Permanente, Pasadena, CA, United States
y Los Angeles Medical Center, Neurology Department, Los Angeles, CA, United States

Abstract
Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Remembering the Presidents” (2019) Current Directions in Psychological Science

Remembering the Presidents
(2019) Current Directions in Psychological Science, . 

DeSoto, K.A.a , Roediger, H.L., IIIb

a Association for Psychological Science, Washington, DC, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, United States

Abstract
Here we report research on how important historical figures—presidents of the United States—are remembered and forgotten. When students are given 5 min to recall presidents (in order, if possible), they remember the first few, the most recent, and Lincoln and his immediate successors better than the rest. When this study is done over time, a regular forgetting curve appears, allowing us to assess the rate of forgetting for more recent presidents. Some presidents (e.g., Kennedy) are being forgotten more slowly than others (e.g., Truman). People are more accurate in recognizing presidents than in recalling them, but they also show interesting false recognitions, identifying people such as Alexander Hamilton as a former president. Together, these studies provide a window into how groups of people remember salient figures from their group’s past: its leaders. They also show that the effects derived from studying artificial materials in the lab may generalize more widely to other material with a different type of memory test. © The Author(s) 2019.

Author Keywords
collective memory;  history;  presidents;  recall;  recognition

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Pipeline Embolization of Vertebrobasilar Aneurysms—A Multicenter Case Series” (2019) World Neurosurgery

Pipeline Embolization of Vertebrobasilar Aneurysms—A Multicenter Case Series
(2019) World Neurosurgery, . 

Wallace, A.N.a b , Madaelil, T.P.c , Kamran, M.d , Miller, T.R.e , Delgado Almandoz, J.E.a , Grossberg, J.A.f , Kansagra, A.P.d g h , Gandhi, D.e , Kayan, Y.a , Cawley, C.M.f , Moran, C.J.d g , Jindal, G.i j , CreveCoeur, T.g , Howard, B.M.f , Cross, D.T.d g , Kole, M.J.j , Roy, A.K.f , Dion, J.E.c , Osbun, J.W.d g h

a Division of Neurointerventional Radiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, United States
b Department of Radiology, University of Iowa, Iowa City, IA, United States
c Department of Radiology, Emory University, Atlanta, GA, United States
d Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
e Department of Radiology, University of Maryland, Baltimore, MD, United States
f Department of Neurosurgery, Emory University, Atlanta, GA, United States
g Department of Neurosurgery, Washington University, St. Louis, MO, United States
h Department of Neurology, Washington University, St. Louis, MO, United States
i Department of Neurology, University of Maryland, Baltimore, MD, United States
j Department of Neurosurgery, University of Maryland, Baltimore, MD, United States

Abstract
Background: The Pipeline Embolization Device (PED) has been increasingly used for the treatment of posterior circulation aneurysms. The purpose of the present study was to examine the clinical and angiographic outcomes of patients with vertebrobasilar aneurysms treated with the PED. Methods: We performed a retrospective review of vertebrobasilar aneurysms treated with the PED at 4 high-volume neurovascular centers. Patient, aneurysm, and procedural data were collected, including perioperative and delayed complications. Aneurysm occlusion on follow-up imaging studies was defined as complete (100%), near-complete (>90%), or incomplete (<90%) occlusion. Results: The cohort included 35 patients with 37 vertebrobasilar aneurysms who underwent 36 treatment sessions. Of the 35 patients, 10 were men (29%), and the mean patient age was 54.1 years (range, 32–75). Eight patients (23%) underwent urgent treatment because of a ruptured aneurysm (n = 6), brainstem perforator stroke (n = 1), or post-traumatic pseudoaneurysm (n = 1). Of the 37 aneurysms, 22 arose from the vertebral artery (59%) and 15 from the basilar artery (41%). Also, 19 were saccular aneurysms (51%), with a mean size of 7.7 mm (range, 1.7–38.0); 17 were fusiform aneurysms (46%), with a mean size of 11.0 mm (range, 4.3–34); and 1 was a 2.9-mm blister aneurysm. The overall procedural complication rate was 14% (5 of 36), including 3 neurologically symptomatic complications. At a mean follow-up period of 14 months (range, 3–59), 24 of 34 aneurysms (71%) were completely occluded and 29 of 34 (85%) were completely or near-completely occluded. Conclusion: Our results show that Pipeline embolization of vertebrobasilar aneurysms is associated with acceptable occlusion and complication rates. © 2019 Elsevier Inc.

Author Keywords
Aneurysm;  Pipeline embolization;  Posterior circulation;  Vertebrobasilar

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Screening for Adolescent Alcohol Use in the Emergency Department: What Does It Tell Us About Cannabis, Tobacco, and Other Drug Use?” (2019) Substance Use and Misuse

Screening for Adolescent Alcohol Use in the Emergency Department: What Does It Tell Us About Cannabis, Tobacco, and Other Drug Use?
(2019) Substance Use and Misuse, . 

Spirito, A.a , Bromberg, J.R.a b , Casper, T.C.c , Chun, T.a b , Mello, M.J.a b , Mull, C.C.d , Shenoi, R.P.e , Vance, C.f , Ahmad, F.g , Bajaj, L.h , Brown, K.M.i , Chernick, L.S.j , Cohen, D.M.k , Fein, J.l , Horeczko, T.m , Levas, M.N.n , McAninch, B.o , Monuteaux, M.C.p , Grupp-Phelan, J.q , Powell, E.C.r , Rogers, A.s , Suffoletto, B.o , Linakis, J.G.a b , for the Pediatric Emergency Care Research Network (PECARN)t

a The Warren Alpert Medical School of Brown University, Departments of Psychiatry and Human Behavior, Pediatrics, Emergency Medicine, Providence, RI, United States
b Rhode Island Hospital, Department of Emergency Medicine, Providence, RI, United States
c University of Utah, Department of Pediatrics, Salt Lake City, Utah, United States
d Nemours/Alfred I. duPont Hospital for Children, Department of Pediatrics, Wilmington, Delaware, United States
e Baylor College of Medicine/Texas Children’s Hospital, Departments of Emergency Medicine and Pediatrics, Houston, TX, United States
f University of California, Davis, Department of Pediatrics, Davis, CA, United States
g St. Louis Children’s Hospital/Washington University, Department of Emergency Medicine, St. Louis, WA, United States
h Children’s Hospital–Colorado, Departments of Pediatric Emergency Medicine and Pediatrics, Aurora, CO, United States
i Children’s National Medical Center, Department of Emergency Medicine and Trauma Services, Washington, DC, United States
j Columbia University Medical Center, Department of Pediatric Emergency Medicine, New York, NY, United States
k Nationwide Children’s Hospital, Departments of Pediatrics and Emergency Medicine, Columbus, OH, United States
l The Children’s Hospital of Philadelphia, Departments of Pediatrics and Emergency Medicine, Philadelphia, PA, United States
m Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Department of Emergency and Pediatric Emergency Medicine, Los Angeles, CA, United States
n Medical College of Wisconsin, Department of Pediatric Emergency Medicine, Milwaukee, WI, United States
o University of Pittsburgh/Children’s Hospital of Pittsburgh of UPMC, Division of Pediatric Emergency Medicine, Pittsburgh, PA, United States
p Boston Children’s Hospital, Department of Pediatrics, Boston, MA, United States
q University of California, San Francisco, Department of Pediatric Emergency Medicine, San Francisco, CA, United States
r Lurie Children’s Hospital of Chicago, Department of Pediatric Emergency Medicine, Chicago, IL, United States
s University of Michigan, Department of Emergency Medicine, Ann Arbor, MI, United States

Abstract
Background: The pediatric emergency department (PED) represents an opportune time for alcohol and drug screening. The National Institute of Alcohol Abuse and Alcoholism (NIAAA) recommends a two-question alcohol screen for adolescents as a predictor of alcohol and drug misuse. Objective: A multi-site PED study was conducted to determine the association between the NIAAA two-question alcohol screen and adolescent cannabis use disorders (CUD), cigarette smoking, and lifetime use of other drugs. Methods: Participants included 12–17-year olds (n = 4834) treated in one of 16 participating PEDs. An assessment battery, including the NIAAA two-question screen and other measures of alcohol, tobacco and drug use, was self-administered on a tablet computer. Results: A diagnosis of CUD, lifetime tobacco use or lifetime drug use was predicted by any self-reported alcohol use in the past year, which indicates a classification of moderate risk for middle school ages and low risk for high school ages on the NIAAA two-question screen. Drinking was most strongly predictive of a CUD, somewhat weaker for lifetime tobacco use, and weakest for lifetime drug use. This same pattern held for high school and middle school students and was stronger for high school students over middle school students for all three categories. This association was also found across gender, ethnicity and race. The association was strongest for CUD for high school students, sensitivity 81.7% (95% CI, 77.0, 86.5) and specificity 70.4% (95% CI, 68.6, 72.1). Conclusions/Importance: A single question about past year alcohol use can provide valuable information about other substance use, particularly marijuana. © 2019, © 2019 Taylor & Francis Group, LLC.

Author Keywords
adolescent;  Alcohol screening;  marijuana;  other drugs;  pediatric emergency department;  tobacco

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Quantifying between-cohort and between-sex genetic heterogeneity in major depressive disorder” (2019) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

Quantifying between-cohort and between-sex genetic heterogeneity in major depressive disorder
(2019) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, . 

Trzaskowski, M.a , Mehta, D.a b , Peyrot, W.J.c , Hawkes, D.d , Davies, D.e , Howard, D.M.f , Kemper, K.E.a , Sidorenko, J.a , Maier, R.a g , Ripke, S.h i j , Mattheisen, M.k l , Baune, B.T.m , Grabe, H.J.n , Heath, A.C.o , Jones, L.p , Jones, I.q , Madden, P.A.F.o , McIntosh, A.M.f r , Breen, G.s t , Lewis, C.M.s u , Børglum, A.D.l v , Sullivan, P.F.w x y , Martin, N.G.z , Kendler, K.S.aa , Levinson, D.F.ab , Wray, N.R.a ac , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortiumad

a Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
b School of Psychology and Counselling, Queensland University of Technology, Brisbane, Australia
c Department of Psychiatry, Vrije Universiteit Medical Center and GGZ in Geest, Amsterdam, Netherlands
d AGRF, The University of Queensland, Brisbane, QLD, Australia
e Department of Psychiatry, Behavioural and Clinical Neuroscience Institute and Developmental Psychiatry, Cambridge University, Cambridge, United Kingdom
f Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
g Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
h Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
i Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
j Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany
k Department of Biomedicine, Aarhus University, Aarhus, Denmark
l iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
m Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia
n Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
o Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
p Institute of Health & Society, University of Worcester, Worcester, United Kingdom
q MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
r Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
s MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, United Kingdom
t NIHR BRC for Mental Health, King’s College London, London, United Kingdom
u Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom
v Department of Biomedicine and iSEQ-Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
w Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
x Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
y Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
z Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
aa Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
ab Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
ac Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

Abstract
Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD. © 2019 Wiley Periodicals, Inc.

Author Keywords
depression;  genetic heterogeneity;  LD score regression;  MDD;  sex differences

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Management of adrenal insufficiency risk after long-term systemic glucocorticoid therapy in duchenne muscular dystrophy: Clinical practice recommendations” (2019) Journal of Neuromuscular Diseases

Management of adrenal insufficiency risk after long-term systemic glucocorticoid therapy in duchenne muscular dystrophy: Clinical practice recommendations
(2019) Journal of Neuromuscular Diseases, 6 (1), pp. 31-41. 

Bowden, S.A.a , Connolly, A.M.b , Kinnett, K.c , Zeitler, P.S.d

a Division of Endocrinology, Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University College of Medicine, 700 Children’s Drive, Columbus, OH 43205, United States
b Department of Neurology, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
c Parent Project Muscular Dystrophy, Hackensack, NJ, United States
d Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, Aurora, CO, United States

Abstract
Long-term glucocorticoid therapy has improved outcomes in patients with Duchenne muscular dystrophy. However, the recommended glucocorticoid dosage suppresses the hypothalamic-pituitary-adrenal axis, leading to adrenal insufficiency that may develop during severe illness, trauma or surgery, and after discontinuation of glucocorticoid therapy. The purpose of this review is to highlight the risk of adrenal insufficiency in this patient population, and provide practical recommendations for management of adrenal insufficiency, glucocorticoid withdrawal, and adrenal function testing. Strategies to increase awareness among patients, families, and health care providers are also discussed. © 2019 IOS Press and the authors. All rights reserved.

Author Keywords
ACTH;  adrenal crisis;  adrenal suppression;  cortisol;  deflazacort;  Muscular dystrophy;  prednisone

Document Type: Review
Publication Stage: Final
Source: Scopus

“Presence of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease Is Associated with High Rate of Anxiety and Depression” (2019) Digestive Diseases and Sciences

Presence of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease Is Associated with High Rate of Anxiety and Depression
(2019) Digestive Diseases and Sciences, . 

Perera, L.P.a , Radigan, M.b , Guilday, C.c , Banerjee, I.d , Eastwood, D.e , Babygirija, R.f , Massey, B.T.b

a Inflammatory Bowel Disease Center, Aurora Healthcare, 975 Port Washington Rd, Grafton, WI 53024, United States
b Medical College of Wisconsin, Milwaukee, WI, United States
c Washington University, St. Louis, MO, United States
d Michigan State University, East Lansing, MI, United States
e Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, United States
f Aurora Research Institute, Milwaukee, WI, United States

Abstract
Background: Inflammatory bowel disease (IBD; Crohn’s disease, CD and Ulcerative colitis, UC) and irritable bowel syndrome (IBS) have overlapping symptoms. Few prevalence studies of IBS in quiescent IBD have used colonoscopy with histology to confirm inactive disease. The aims were (1) to determine the percentage of IBD patients in deep remission whose persistent IBS-like symptoms (IBD/IBS+) would cause them to be classified as having active disease, based on the calculation of Harvey Bradshaw Index (HBI) or UC disease activity index (UCDAI); (2) to identify demographic and disease characteristics that are associated with IBD/IBS+. Methods: This was a prospective study at a single tertiary care IBD center. 96/112 patients with colonoscopy and histology confirmed quiescent disease consented and completed Rome III criteria for IBS Survey, and the hospital anxiety and depression scale (HADS). Other demographic and disease specific data were collected. Results: 36% (28/77) and 37% (7/19) of CD and UC patients, respectively, met diagnostic criteria for IBS. Significantly higher HBI/UCDAI scores (p = 0.005) and low short inflammatory bowel disease questionnaire (SIBDQ) scores (p ≤ 0.0001) were seen in IBD/IBS+ patients. 29% of patients in deep remission were mis-categorized by HBI/UCDAI as having active disease when they fulfilled Rome III criteria for IBS. Psychiatric diagnosis (OR 3.53 95% CI 1.2–10.2) and earlier onset of IBD (OR 1.056 95% CI 1.015–1.096) were associated with IBD/IBS+. Patients fulfilling IBS criteria had higher hospital anxiety and depression scale (HADS). Conclusion: IBD/IBS+ affect scoring of IBD disease activity scales and become less useful in guiding treatment plans. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Crohn’s disease;  Disease activity measurements;  Inflammatory bowel disease;  Irritable bowel syndrome;  Ulcerative colitis

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Functional and Radiologic Assessment of the Brain after Reduced-Intensity Unrelated Donor Transplantation for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network Study 0601” (2019) Biology of Blood and Marrow Transplantation

Functional and Radiologic Assessment of the Brain after Reduced-Intensity Unrelated Donor Transplantation for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network Study 0601
(2019) Biology of Blood and Marrow Transplantation, . 

King, A.A.a , McKinstry, R.C.b , Wu, J.c , Eapen, M.d , Abel, R.e , Varughese, T.e , Kamani, N.f , Shenoy, S.g

a Dept. of Pediatrics, Division of Hematology and Oncology, Program in Occupational Therapy, Washington University School of Medicine, St. Louis Children’s Hospital, St Louis, MO, United States
b Dept. of Radiology, Section of Neuroradiology, Washington University School of Medicine, St. Louis Children’s Hospital, St Louis, MO, United States
c The Emmes Corporation, Rockville, MD, United States
d Dept. of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
e Program in Occupational Therapy, Washington University School of Medicine, St. Louis Children’s Hospital, St Louis, MO, United States
f Division of Allergy Immunology, Children’s National Medical Center, Washington, DC, United States
g Dept. of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis Children’s Hospital, St Louis, MO, United States

Abstract
Stroke and cognitive decline are hallmarks of sickle cell disease (SCD). The natural history of SCD predicts progressive loss of 1 IQ point per year attributable to disease-related pathology. Hematopoietic cell transplantation (HCT) is curative by reverting to donor-derived erythropoiesis, but evidence that HCT can positively influence disease-induced cognitive decline is lacking. The Sickle Cell Unrelated Transplant Trial prospectively evaluated cognition and brain magnetic resonance imaging (MRI) findings at 2 years after reduced-intensity conditioning followed by unrelated donor HCT. Thirteen study participants completed pre-HCT and post-HCT assessments of intelligence. The mean age of participants was 12.5 ± 3.3 years (range, 6.7 to 17.4 years). Eleven of the 13 recipients completed imaging studies at baseline and post-HCT. Seven had overt stroke pre-HCT, and 1 had an elevated transcranial Doppler velocity with abnormal MRI. The mean Full-Scale IQ was stable: 90.9 ± 13 at baseline and 91.2 ± 13 post-HCT. The mean Performance IQ was 89.9 ± 13 at baseline versus 90.9 ± 13 post-HCT, and mean Verbal IQ was 93.4 ± 13 at baseline versus 93.2 ± 13 post-HCT, respectively. Six recipients had stable MRI; 2 showed resolution of all areas of infarction. Three had additional infarcts post-HCT noted at the 2-year time point. This is the first report describing stabilization of IQ and central nervous system outcomes after unrelated donor HCT despite previous central nervous system morbidity and post-HCT posterior reversible encephalopathy syndrome. These preliminary results post-HCT suggest that HCT may stabilize the cognitive decline of SCD and should continue to be followed over the long term. © 2019 American Society for Blood and Marrow Transplantation

Author Keywords
Brain MRI;  Neurocognition;  Sickle cell disease;  Stem cell transplantation

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Anger and its consequences for judgment and behavior: Recent developments in social and political psychology” (2019) Advances in Experimental Social Psychology

Anger and its consequences for judgment and behavior: Recent developments in social and political psychology
(2019) Advances in Experimental Social Psychology, . 

Lambert, A.J.a , Eadeh, F.R.b , Hanson, E.J.a

a Washington University, St. Louis, MO, United States
b Emory University, Atlanta, GA, United States

Abstract
In the eyes of the public—and in a substantial amount of scholarly research—anger is often framed in a negative light, given its role in driving people to act in antisocial ways. However, anger also has the potential for social good, insofar as it focuses attention on, and motivates people to fix, perceived injustices. As we discuss, the foundational link between anger and a desire to rectify justice has profoundly important implications that are relevant to research and theory in a variety of different disciplines (e.g., experimental social psychology, neuroscience, political science, personality). We begin this chapter by considering the methodological and theoretical challenges involved in the measurement of this feeling state, along with its relevance to our line of research on revenge, as well as the ideological consequences of threat. In the course of this discussion, we introduce a neo-Gibsonian framework of threat which allows for the fact that different types of threats, via anger, can exert different types of ideological consequences. A key prediction of this model—one that distinguishes it from current models of threat—is that activation of anger following threat has the potential to shift political attitudes to the “right” or to the “left,” depending on the nature of the threat at hand. These and other findings provide a more comprehensive understanding of this emotion, its relation to (perceived and actual) injustice, and its role in shaping relevant political beliefs. © 2019 Elsevier Inc.

Author Keywords
Anger;  Attitudes;  Justice;  Revenge;  Threat

Document Type: Book Chapter
Publication Stage: Article in Press
Source: Scopus

“Loss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury” (2019) Translational Stroke Research

Loss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury
(2019) Translational Stroke Research, . 

Gautam, J.a , Miner, J.H.b , Yao, Y.a

a Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 240 W Green Street, Athens, GA 30602, United States
b Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Endothelial cells make laminin-411 and laminin-511. Although laminin-411 is well studied, the role of laminin-511 remains largely unknown due to the embryonic lethality of lama5−/− mutants. In this study, we generated endothelium-specific lama5 conditional knockout (α5-TKO) mice and investigated the biological functions of endothelial lama5 in blood-brain barrier (BBB) maintenance under homeostatic conditions and the pathogenesis of intracerebral hemorrhage (ICH). First, the BBB integrity of α5-TKO mice was measured under homeostatic conditions. Next, ICH was induced in α5-TKO mice and their littermate controls using the collagenase model. Various parameters, including injury volume, neuronal death, neurological score, brain edema, BBB integrity, inflammatory cell infiltration, and gliosis, were examined at various time points after injury. Under homeostatic conditions, comparable levels of IgG or exogenous tracers were detected in α5-TKO and control mice. Additionally, no differences in tight junction expression, pericyte coverage, and astrocyte polarity were found in these mice. After ICH, α5-TKO mice displayed enlarged injury volume, increased neuronal death, elevated BBB permeability, exacerbated infiltration of inflammatory cells (leukocytes, neutrophils, and mononuclear cells), aggravated gliosis, unchanged brain edema, and worse neurological function, compared to the controls. These findings suggest that endothelial lama5 is dispensable for BBB maintenance under homeostatic conditions but plays a beneficial role in ICH. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Blood-brain barrier;  Endothelial cells;  Intracerebral hemorrhage;  Laminin

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Expanding Cognition: A Brief Consideration of Technological Advances over the Past 4000 Years” (2019) Journal of Applied Research in Memory and Cognition

Expanding Cognition: A Brief Consideration of Technological Advances over the Past 4000 Years
(2019) Journal of Applied Research in Memory and Cognition, . 

Yamashiro, J.K., Roediger, H.L., III

Washington University in St. Louis, United States

Author Keywords
Cognitive technology;  Distributed cognition;  Exograms;  Extended cognition

Document Type: Note
Publication Stage: Article in Press
Source: Scopus

“Endovascular treatment of acute ischaemic stroke under conscious sedation: Predictors of poor outcomes” (2018) Indian Journal of Anaesthesia

Endovascular treatment of acute ischaemic stroke under conscious sedation: Predictors of poor outcomes
(2018) Indian Journal of Anaesthesia, 62 (12), pp. 951-957. 

Athiraman, U.a , Abdallah, A.B.a , Kansagra, A.b , Tempelhoff, R.c

a Department of Anaesthesiology, Washington University, St. Louis, MO, United States
b Department of Radiology, Neurological Surgery and Neurology, Washington University, St. Louis, MO, United States
c Department of Anaesthesiology and Neurological Surgery, Washington University, St. Louis, MO, United States

Abstract
Background and Aims: Though, many practitioners prefer conscious sedation (CS), it is unclear which factors most influence neurological outcome following mechanical thrombectomy under CS. The aim of this retrospective study is to identify these factors. Methods: After institutional review board approval, data were collected for the patients >18 years of age who underwent endovascular treatment of AIS under CS at our comprehensive stroke centre between January 2009 and June 2015. The primary outcome measure was the modified Rankin Scale (mRS) at discharge. A good outcome was defined as mRS 0–3 and poor outcome as mRS 4–6. Univariate and logistic regression analysis were performed to identify the independent predictors of poor outcomes at discharge. A P < 0.05 was considered statistically significant. Results: One hundred two patients, aged 67 ± 16 years were included. The anterior cerebral circulation was affected in 88 patients (86%), and the median National Institute of Health Stroke Scale (NIHSS) score at presentation was 17.5 (range: 1–36). Overall, 21 (21%) patients had good outcome and 81 (79%) had poor outcome. Logistic regression identified the modified treatment in cerebral ischaemia (mTICI) score [odds ratio (OR): 0.443, confidence interval (CI): 0.244–0.805], NIHSS score (OR: 1.290, CI: 1.125–1.481) and previous transient ischaemic attack (TIA) (OR: 6.988, CI: 1.342–36.380) as significant independent predictors of poor outcome at discharge. Conclusion: The outcome of patients who underwent endovascular treatment of AIS under CS depends on the mTICI score, NIHSS score and history of previous TIA. © 2018, Indian Society of Anaesthetists. All rights reserved.

Author Keywords
Acute ischaemic stroke;  Conscious sedation;  Endovascular treatment;  Outcomes

Document Type: Article
Publication Stage: Final
Source: Scopus

“The Differences in Local Translatome across Distinct Neuron Types Is Mediated by Both Baseline Cellular Differences and Post-transcriptional Mechanisms” (2018) eNeuro

The Differences in Local Translatome across Distinct Neuron Types Is Mediated by Both Baseline Cellular Differences and Post-transcriptional Mechanisms
(2018) eNeuro, 5 (6), . 

Ouwenga, R.a b c , Lake, A.M.b c , Aryal, S.a , Lagunas, T., Jra b c , Dougherty, J.D.b c d

a Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Local translation in neurites is a phenomenon that enhances the spatial segregation of proteins and their functions away from the cell body, yet it is unclear how local translation varies across neuronal cell types. Further, it is unclear whether differences in local translation across cell types simply reflect differences in transcription or whether there is also a cell type-specific post-transcriptional regulation of the location and translation of specific mRNAs. Most of the mRNAs discovered as being locally translated have been identified from hippocampal neurons because their laminar organization facilitates neurite-specific dissection and microscopy methods. Given the diversity of neurons across the brain, studies have not yet analyzed how locally translated mRNAs differ across cell types. Here, we used the SynapTRAP method to harvest two broad cell types in the mouse forebrain: GABAergic neurons and layer 5 projection neurons. While some transcripts overlap, the majority of the local translatome is not shared across these cell types. In addition to differences driven by baseline expression levels, some transcripts also exhibit cell type-specific post-transcriptional regulation. Finally, we provide evidence that GABAergic neurons specifically localize mRNAs for peptide neurotransmitters, including somatostatin and cortistatin, suggesting localized production of these key signaling molecules in the neurites of GABAergic neurons. Overall, this work suggests that differences in local translation in neurites across neuronal cell types are poised to contribute substantially to the heterogeneity in neuronal phenotypes.

Author Keywords
GABAergic interneurons;  layer 5 pyramidal neurons;  local translation;  synaptoneurosomes;  SynapTRAP;  TRAP

Document Type: Article
Publication Stage: Final
Source: Scopus