“Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases” (2022) Neural Regeneration Research
Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases
(2022) Neural Regeneration Research, 17 (4), pp. 867-874.
Li, H., Knight, W., Xu, J.
Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of β-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer’s Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). © 2022 Wolters Kluwer Medknow Publications. All rights reserved.
Author Keywords
Alzheimer disease; Disease progression; Lewy body diseases; Microglia; Neurodegeneration; Oxidative damage; Striatum; Survival
Funding details
National Institutes of HealthNIHP30AG06644, R01NS092865
Document Type: Article
Publication Stage: Final
Source: Scopus
“SARS-CoV-2 screening testing in schools for children with intellectual and developmental disabilities” (2021) Journal of Neurodevelopmental Disorders
SARS-CoV-2 screening testing in schools for children with intellectual and developmental disabilities
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 31, .
Sherby, M.R.a , Walsh, T.J.b , Lai, A.M.c , Neidich, J.A.d , Balls-Berry, J.E.e , Morris, S.M.a , Head, R.f , Prener, C.G.g , Newland, J.G.b , Gurnett, C.A.a , Baldenweck, M.h , Bono, K.h , Brodsky, V.B.h , Caburnay, C.A.h , Constantino, J.N.h , Dougherty, N.L.h , Dubois, J.M.h , Fritz, S.A.h , Gotto, G.S., IVh , Imbeah, A.h , Kalb, L.G.h , Liu, J.h , Maricque, B.B.h , McKay, V.R.h , Myers, L.S.h , Poor, T.J.h , Powell, B.J.h , Mueller, N.B.h , Schlaggar, B.L.h , Schmidt, A.h , Snider, E.h , Traughber, M.C.h , van Stone, M.h , Vestal, L.h , Wilcher-Roberts, M.h , for the COMPASS-T Study Grouph
a Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University in St. Louis, 660 S. Euclid Avenue Campus, Box 8111, St. Louis, MO 63110, United States
b Department of Pediatrics, Division of Pediatric Infectious Diseases, Washington University in St. Louis, St. Louis, MO, United States
c Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, Division of Memory and Aging, Washington University in St. Louis, St. Louis, MO, United States
f Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
g Department of Sociology and Anthropology, Saint Louis University, St. Louis, MO, United States
Abstract
Background: Transmission of SARS-CoV-2 in schools primarily for typically developing children is rare. However, less is known about transmission in schools for children with intellectual and developmental disabilities (IDD), who are often unable to mask or maintain social distancing. The objectives of this study were to determine SARS-CoV-2 positivity and in-school transmission rates using weekly screening tests for school staff and students and describe the concurrent deployment of mitigation strategies in six schools for children with IDD. Methods: From November 23, 2020, to May, 28, 2021, weekly voluntary screening for SARS-CoV-2 with a high sensitivity molecular-based saliva test was offered to school staff and students. Weekly positivity rates were determined and compared to local healthcare system and undergraduate student screening data. School-based transmission was assessed among participants quarantined for in-school exposure. School administrators completed a standardized survey to assess school mitigation strategies. Results: A total of 59 students and 416 staff participated. An average of 304 school staff and students were tested per week. Of 7289 tests performed, 21 (0.29%) new SARS-CoV-2 positive cases were identified. The highest weekly positivity rate was 1.2% (n = 4) across all schools, which was less than community positivity rates. Two cases of in-school transmission were identified, each among staff, representing 2% (2/103) of participants quarantined for in-school exposure. Mitigation strategies included higher than expected student mask compliance, reduced room capacity, and phased reopening. Conclusions: During 24 weeks that included the peak of the COVID-19 pandemic in winter 2020-21, we found lower rates of SARS-CoV-2 screening test positivity among staff and students of six schools for children with IDD compared to community rates. In-school transmission of SARS-CoV-2 was low among those quarantined for in-school exposure. However, the impact of the emerging SARS-CoV-2 Delta variant on the effectiveness of these proven mitigation strategies remains unknown. Trial registration: Prior to enrollment, this study was registered at ClinicalTrials.gov on September 25, 2020, identifier NCT04565509, titled Supporting the Health and Well-being of Children with Intellectual and Developmental Disability During COVID-19 Pandemic. © 2021, The Author(s).
Author Keywords
Children with IDD; COVID-19; COVID-19 School tests; Intellectual and developmental disabilities; SARS-CoV-2 testing
Funding details
National Institutes of HealthNIH3P50HD103525-01S1
National Center for Advancing Translational SciencesNCATS
Washington University in St. LouisWUSTL
University of WashingtonUW
Institute of Clinical and Translational SciencesICTSUL1TR002345
University of Missouri-Kansas CityUMKC
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
“Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus” (2021) NeuroToxicology
Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus
(2021) NeuroToxicology, 87, pp. 43-50.
Calsbeek, J.J.a , González, E.A.a , Boosalis, C.A.a , Zolkowska, D.b , Bruun, D.A.a , Rowland, D.J.c , Saito, N.H.d , Harvey, D.J.d , Chaudhari, A.J.c , Rogawski, M.A.b , Garbow, J.R.e , Lein, P.J.a
a Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, United States
b Department of Neurology, University of California, Davis, School of Medicine, Davis, CA 95616, United States
c Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA 95616, United States
d Department of Public Health Sciences, University of California, Davis, School of Medicine, DavisCA 95616, United States
e Biomedical Magnetic Resonance Laboratory, Mallinckrodt Institute of Radiology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
Abstract
Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury. © 2021 The Author(s)
Author Keywords
MRI; Neurodegeneration; Neuroinflammation; PET; Tetramine
Funding details
R25 GM5676520
NIH Office of the DirectorOD
National Institute of Neurological Disorders and StrokeNINDSU54 NS079202
Silicon Valley Community FoundationSVCF2019-198156
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50 HD103526
School of Veterinary Medicine, University of California, DavisF31 NS110522
Chan Zuckerberg InitiativeCZI
Document Type: Article
Publication Stage: Final
Source: Scopus
“Partitioning of gene expression among zebrafish photoreceptor subtypes” (2021) Scientific Reports
Partitioning of gene expression among zebrafish photoreceptor subtypes
(2021) Scientific Reports, 11 (1), art. no. 17340, .
Ogawa, Y., Corbo, J.C.
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
Abstract
Vertebrate photoreceptors are categorized into two broad classes, rods and cones, responsible for dim- and bright-light vision, respectively. While many molecular features that distinguish rods and cones are known, gene expression differences among cone subtypes remain poorly understood. Teleost fishes are renowned for the diversity of their photoreceptor systems. Here, we used single-cell RNA-seq to profile adult photoreceptors in zebrafish, a teleost. We found that in addition to the four canonical zebrafish cone types, there exist subpopulations of green and red cones (previously shown to be located in the ventral retina) that express red-shifted opsin paralogs (opn1mw4 or opn1lw1) as well as a unique combination of cone phototransduction genes. Furthermore, the expression of many paralogous phototransduction genes is partitioned among cone subtypes, analogous to the partitioning of the phototransduction paralogs between rods and cones seen across vertebrates. The partitioned cone-gene pairs arose via the teleost-specific whole-genome duplication or later clade-specific gene duplications. We also discovered that cone subtypes express distinct transcriptional regulators, including many factors not previously implicated in photoreceptor development or differentiation. Overall, our work suggests that partitioning of paralogous gene expression via the action of differentially expressed transcriptional regulators enables diversification of cone subtypes in teleosts. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHEY030075
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Japan Society for the Promotion of ScienceKAKEN202060618
Document Type: Article
Publication Stage: Final
Source: Scopus
“Hierarchical modelling of functional brain networks in population and individuals from big fMRI data” (2021) NeuroImage
Hierarchical modelling of functional brain networks in population and individuals from big fMRI data
(2021) NeuroImage, 243, art. no. 118513, .
Farahibozorg, S.-R.a , Bijsterbosch, J.D.b , Gong, W.a , Jbabdi, S.a , Smith, S.M.a , Harrison, S.J.a c d , Woolrich, M.W.a e
a FMRIB, Wellcome Centre for Integrative Neuroimaging, Nuffield Dept. of Clinical Neuroscience, Oxford University, Oxford, United Kingdom
b Department of Radiology, Washington University in St Louis, St. Louis, United States
c Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and ETH ZurichZurich, Switzerland
d New Zealand Brain Research Institute, University of Otago, Christchurch, New Zealand
e OHBA, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, Oxford University, Oxford, United Kingdom
Abstract
A major goal of large-scale brain imaging datasets is to provide resources for investigating heterogeneous populations. Characterisation of functional brain networks for individual subjects from these datasets will have an enormous potential for prediction of cognitive or clinical traits. We propose for the first time a technique, Stochastic Probabilistic Functional Modes (sPROFUMO), that is scalable to UK Biobank (UKB) with expected 100,000 participants, and hierarchically estimates functional brain networks in individuals and the population, while allowing for bidirectional flow of information between the two. Using simulations, we show the model’s utility, especially in scenarios that involve significant cross-subject variability, or require delineation of fine-grained differences between the networks. Subsequently, by applying the model to resting-state fMRI from 4999 UKB subjects, we mapped resting state networks (RSNs) in single subjects with greater detail than has been possible previously in UKB (>100 RSNs), and demonstrate that these RSNs can predict a range of sensorimotor and higher-level cognitive functions. Furthermore, we demonstrate several advantages of the model over independent component analysis combined with dual-regression (ICA-DR), particularly with respect to the estimation of the spatial configuration of the RSNs and the predictive power for cognitive traits. The proposed model and results can open a new door for future investigations into individualised profiles of brain function from big data. © 2021
Author Keywords
Big data fMRI; Cognition prediction; Hierarchical network modelling; Resting state networks; Single subject connectivity; sPROFUMO; Stochastic inference
Funding details
2017-403
National Institutes of HealthNIH1 R34 NS118618-01
McDonnell Center for Systems Neuroscience1U01AG052564–01, 1U01MH109589–01, 203139/Z/16/Z, 221933/Z/20/Z
Wellcome TrustWT098369/Z/12/Z, 215573/Z/19/Z
Medical Research CouncilMRCMC_PC_17215
National Institute for Health ResearchNIHR203141/Z/16/Z.
Eidgenössische Technische Hochschule ZürichETH
Biomedical Research CouncilBMRC
NIHR Oxford Biomedical Research CentreOxBRC106183/Z/14/Z
Document Type: Article
Publication Stage: Final
Source: Scopus
“Modulation in cortical excitability disrupts information transfer in perceptual-level stimulus processing.” (2021) NeuroImage
Modulation in cortical excitability disrupts information transfer in perceptual-level stimulus processing.
(2021) NeuroImage, 243, art. no. 118498, .
Moheimanian, L.a b , Paraskevopoulou, S.E.a , Adamek, M.a c , Schalk, G.a b , Brunner, P.a b d e
a National Center for Adaptive Neurotechnologies, Albany, NY, United States
b Department of Biomedical Sciences, State University of New York at Albany, Albany, NY, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Albany Medical College, Albany, NY, United States
e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Despite significant interest in the neural underpinnings of behavioral variability, little light has been shed on the cortical mechanism underlying the failure to respond to perceptual-level stimuli. We hypothesized that cortical activity resulting from perceptual-level stimuli is sensitive to the moment-to-moment fluctuations in cortical excitability, and thus may not suffice to produce a behavioral response. We tested this hypothesis using electrocorticographic recordings to follow the propagation of cortical activity in six human subjects that responded to perceptual-level auditory stimuli. Here we show that for presentations that did not result in a behavioral response, the likelihood of cortical activity decreased from auditory cortex to motor cortex, and was related to reduced local cortical excitability. Cortical excitability was quantified using instantaneous voltage during a short window prior to cortical activity onset. Therefore, when humans are presented with an auditory stimulus close to perceptual-level threshold, moment-by-moment fluctuations in cortical excitability determine whether cortical responses to sensory stimulation successfully connect auditory input to a resultant behavioral response. © 2021
Author Keywords
Alpha oscillations; Broadband gamma activity; Electrocorticography (ECoG); Instantaneous voltage; Perception threshold; Stimulus detection
Funding details
National Institutes of HealthNIHP41-EB018783, P50-MH109429, R01-EB026439, U01-NS108916, U24-NS109103
Army Research OfficeAROW911NF-14-1-0440
Document Type: Article
Publication Stage: Final
Source: Scopus
“Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly” (2021) Clinical Genetics
Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly
(2021) Clinical Genetics, 100 (4), pp. 386-395.
Uguen, K.a b , Krysiak, K.c , Audebert-Bellanger, S.a , Redon, S.a b , Benech, C.b , Viora-Dupont, E.d , Tran Mau-Them, F.e f , Rondeau, S.g , Elsharkawi, I.h , Granadillo, J.L.h , Neidich, J.c , Soares, C.A.i j , Tkachenko, N.i , M. Amudhavalli, S.k , Engleman, K.k , Boland, A.l , Deleuze, J.-F.l , Bezieau, S.m , Odent, S.n , Toutain, A.o , Bonneau, D.p , Gilbert-Dussardier, B.q , Faivre, L.d f , Rio, M.g , Le Marechal, C.a b , Ferec, C.a b , Repnikova, E.r , Cao, Y.c
a Service de Génétique Médicale, CHRU de Brest, Brest, France
b University Brest, Inserm, EFS, Brest, France
c Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’Enfants, Dijon, France
e Unité Fonctionnelle 6254 d’Innovation en Diagnostic Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France
f Inserm – Université de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Dijon, France
g Fédération de Génétique Médicale, AP-HP, Hôpital Necker-Enfants Malades, Paris, France
h Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
i Serviço de Genética Médica, Centro de Genética Médica Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal
j Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar/Universidade do Porto, Porto, Portugal
k Department of Clinical Genetics, Children’s Mercy Hospital, Kansas City, MO, United States
l Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
m Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France; INSERM, CNRS, UNIV Nantes, Nantes, France
n Service de Génétique Clinique, Centre Référence Déficiences Intellectuelles de Causes Rares, Centre de Référence Anomalies du Développement, Centre Labellisé pour les Anomalies du Développement (CLAD) Ouest, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France; Institut de Génétique et Développement de Rennes, UMR 6290, Université de Rennes, Rennes, France
o Service de Génétique, Centre Hospitalier Universitaire de Tours, Université de Tours, Tours, France
p Centre Hospitalier Universitaire de Angers, Département de Biochimie et Génétique, Mitochondrial and Cardiovascular Pathophysiology (MITOVASC), Unité mixte de Recherche, Centre National de la Recherche Scientifique 6015, Angers, France
q Centre Hospitalier Universitaire de Poitiers, Service de Génétique, Université Poitiers, Poitiers, France
r Department of Pathology, Children’s Mercy Hospital/University of Missouri Kansas City Medical School, Kansas City, MO, United States
Abstract
13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome. © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Author Keywords
developmental disabilities; dysmorphic features; HMGB1; loss of function mutation
Document Type: Article
Publication Stage: Final
Source: Scopus
“Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice” (2021) Life Science Alliance
Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice
(2021) Life Science Alliance, 4 (10), art. no. e202101040, .
Davidson, C.D.a , Gibson, A.L.a , Gu, T.a , Baxter, L.L.a , Deverman, B.E.b , Beadle, K.b , Incao, A.A.a , Rodriguez-Gil, J.L.a , Fujiwara, H.c , Jiang, X.c , Chandler, R.J.d , Ory, D.S.c , Gradinaru, V.b , Venditti, C.P.d , Pavan, W.J.a
a Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
b Division of Biology and Biological Engineering, California Institutes of Technology, Pasadena, CA, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
Abstract
Niemann–Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors. © 2021 Davidson et al.
Funding details
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRI1ZIAHG000068-15
Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign
School of Medicine and Public Health, University of Wisconsin-MadisonUWSMPH3T32GM008692
Ara Parseghian Medical Research FundAPMRFDP1OD025535
Document Type: Article
Publication Stage: Final
Source: Scopus
“Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation” (2021) The Journal of General Physiology
Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation
(2021) The Journal of General Physiology, 153 (9), .
Angsutararux, P.a , Kang, P.W.a , Zhu, W.b , Silva, J.R.a
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO
b Department of Medicine, Brigham and Women’s Hospital, MA, Boston
Abstract
Voltage-gated Na+ (NaV) channels underlie the initiation and propagation of action potentials (APs). Rapid inactivation after NaV channel opening, known as open-state inactivation, plays a critical role in limiting the AP duration. However, NaV channel inactivation can also occur before opening, namely closed-state inactivation, to tune the cellular excitability. The voltage-sensing domain (VSD) within repeat IV (VSD-IV) of the pseudotetrameric NaV channel α-subunit is known to be a critical regulator of NaV channel inactivation. Yet, the two processes of open- and closed-state inactivation predominate at different voltage ranges and feature distinct kinetics. How inactivation occurs over these different ranges to give rise to the complexity of NaV channel dynamics is unclear. Past functional studies and recent cryo-electron microscopy structures, however, reveal significant inactivation regulation from other NaV channel components. In this Hypothesis paper, we propose that the VSD of NaV repeat III (VSD-III), together with VSD-IV, orchestrates the inactivation-state occupancy of NaV channels by modulating the affinity of the intracellular binding site of the IFMT motif on the III-IV linker. We review and outline substantial evidence that VSD-III activates in two distinct steps, with the intermediate and fully activated conformation regulating closed- and open-state inactivation state occupancy by altering the formation and affinity of the IFMT crevice. A role of VSD-III in determining inactivation-state occupancy and recovery from inactivation suggests a regulatory mechanism for the state-dependent block by small-molecule anti-arrhythmic and anesthetic therapies. © 2021 Angsutararux et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
“COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay” (2021) American Journal of Human Genetics
COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay
(2021) American Journal of Human Genetics, 108 (9), pp. 1710-1724.
Marom, R.a b , Burrage, L.C.a b , Venditti, R.c , Clément, A.d , Blanco-Sánchez, B.d , Jain, M.a , Scott, D.A.a b e , Rosenfeld, J.A.a , Sutton, V.R.a b , Shinawi, M.f , Mirzaa, G.g , DeVile, C.h , Roberts, R.h , Calder, A.D.h , Allgrove, J.h , Grafe, I.a , Lanza, D.G.a , Li, X.a , Joeng, K.S.a , Lee, Y.-C.a , Song, I.-W.a , Sliepka, J.M.a , Batkovskyte, D.a , Washington, M.a , Dawson, B.C.a , Jin, Z.a , Jiang, M.-M.a , Chen, S.a , Chen, Y.a , Tran, A.A.a , Emrick, L.T.a b i , Murdock, D.R.a j , Hanchard, N.A.a b k , Zapata, G.E.k , Mehta, N.R.k , Weis, M.A.l , Scott, A.A.m , Tremp, B.A.d , Phillips, J.B.d , Wegner, J.d , Taylor-Miller, T.h , Gibbs, R.A.a j , Muzny, D.M.j , Jhangiani, S.N.j , Hicks, J.b n , Stottmann, R.W.o , Dickinson, M.E.a e , Seavitt, J.R.a , Heaney, J.D.a , Eyre, D.R.l , Westerfield, M.d , De Matteis, M.A.c p , Lee, B.a b , Undiagnosed Diseases Networkq
a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
b Texas Children’s Hospital, Houston, TX 77030, United States
c Telethon Institute of Genetics and Medicine, Naples, 80078, Italy
d Institute of Neuroscience, University of Oregon, Eugene, OR 97403, United States
e Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, United States
f Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
g Center for Integrative Brain Research, Seattle Children’s Research Institute, and Department of Pediatrics, University of Washington, and Brotman Baty Institute for Precision Medicine, Seattle, WA 98105, United States
h Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK WC1N 3JH, United Kingdom
i Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
j Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, United States
k Laboratory for Translational Genomics, ARS/USDA Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, United States
l Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, United States
m Division of Genetic Medicine, Seattle Children’s Hospital, Seattle, WA 98105, United States
n Department of Pathology, Texas Children’s Hospital, and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States
o Division of Human Genetics, and Division of Developmental Biology, and Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
p Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Naples, 80078, Italy
Abstract
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects’ fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/− mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/− mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/− mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis. © 2021 American Society of Human Genetics
Author Keywords
coatopathy; collagen trafficking; COPB2; COPI complex; juvenile osteoporosis
Funding details
National Institutes of HealthNIH
National Institute of General Medical SciencesNIGMSK08 DK106453, P01 HD070394, T32GM007526, U01HG007709, U54 AR068069, U54NS093793, UM1HG006348
National Institute of Neurological Disorders and StrokeNINDSK08NS092898
National Institute of Dental and Craniofacial ResearchNIDCR5UM1HG006542, R03DE026233
Burroughs Wellcome FundBWF
Università degli Studi di Napoli Federico IIUNINAMFAG2020-25174, STAR2017 Linea1
Intellectual and Developmental Disabilities Research CenterIDDRC
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54HD083092
European Research CouncilERC670881
Fondazione TelethonFTTGM11CB1
Associazione Italiana per la Ricerca sul CancroAIRCIG2013_14761
Document Type: Article
Publication Stage: Final
Source: Scopus
“Femoral nerve decompression and sartorius-to-quadriceps nerve transfers for partial femoral nerve injury: A cadaveric study and early case series” (2021) Journal of Neurosurgery
Femoral nerve decompression and sartorius-to-quadriceps nerve transfers for partial femoral nerve injury: A cadaveric study and early case series
(2021) Journal of Neurosurgery, 135 (3), pp. 904-911.
McInnes, C.W.a , Ha, A.Y.b , Power, H.A.c , Tung, T.H.b , Moore, A.M.d
a Department of Surgery, Division of Plastic Surgery, Fraser Health Authority/University of British Columbia, New Westminster, BC, Canada
b Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in St. LouisMO, United States
c Department of Surgery, Division of Plastic Surgery, University of Alberta, Edmonton, AB, Canada
d Department of Plastic and Reconstructive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
Abstract
OBJECTIVE Partial femoral nerve injuries cause significant disability with ambulation. Due to their more proximal and superficial location, sartorius branches are often spared in femoral nerve injuries. In this article, the authors report the benefits of femoral nerve decompression, demonstrate the feasibility of sartorius-to-quadriceps nerve transfers in a cadaveric study, describe the surgical technique, and report clinical results. METHODS Four fresh-frozen cadaveric lower limbs were dissected for anatomical analysis of the sartorius nerve. In addition, a retrospective review of patients with partial femoral nerve injuries treated with femoral nerve decompression and sartorius-to-quadriceps nerve transfers was conducted. Pre- and postoperative knee extension Medical Research Council (MRC) grades and pain scores (visual analog scale) were collected. RESULTS Up to 6 superficial femoral branches innervate the sartorius muscle just distal to the inguinal ligament. Each branch yielded an average of 672 nerve fibers (range 99-1850). Six patients underwent femoral nerve decompression and sartorius-to-quadriceps nerve transfers. Four patients also had concomitant obturator-to-quadriceps nerve transfers. At final follow-up (average 13.4 months), all patients achieved MRC grade 4-/5 or greater knee extension. The average preoperative pain score was 5.2, which decreased to 2.2 postoperatively (p = 0.03). CONCLUSIONS Femoral nerve decompression and nerve transfer using sartorius branches are a viable tool for restoring function in partial femoral nerve injuries. Sartorius branches serve as ideal donors in quadriceps nerve transfers because they are expendable, are close to their recipients, and have an adequate supply of nerve fibers. © 2021 American Association of Neurological Surgeons. All rights reserved.
Author Keywords
Cadaveric study; Femoral nerve injury; Nerve decompression; Nerve to sartorius; Nerve transfer; Peripheral nerve
Document Type: Article
Publication Stage: Final
Source: Scopus
“Amyloidosis: Multisystem spectrum of disease with pathologic correlation” (2021) Radiographics
Amyloidosis: Multisystem spectrum of disease with pathologic correlation
(2021) Radiographics, 41 (5), pp. 1454-1474.
Sugi, M.D.a , Kawashima, A.b , Salomao, M.A.c , Bhalla, S.d , Venkatesh, S.K.e , Pickhardt, P.J.f
a Department of Radiology and Biomedical Imaging, University of California, 505 Parnassus Ave, 3rd Floor, M391, Box 0628, San Francisco, CA 94143, United States
b Departments of Radiology, Mayo Clinic Arizona, Scottsdale, AZ, United States
c Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, United States
f Department of Radiology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States
Abstract
Amyloidosis is a group of conditions defined by extracellular deposition of insoluble proteins that can lead to multiorgan dysfunction and failure. The systemic form of the disease is often associated with a plasma cell dyscrasia but may also occur in the setting of chronic inflammation, long-term dialysis, malignancy, or multiple hereditary conditions. Localized forms of the disease most often involve the skin, tracheobronchial tree, and urinary tract and typically require tissue sampling for diagnosis, as they may mimic many conditions including malignancy at imaging alone. Advancements in MRI and nuclear medicine have provided greater specificity for the diagnosis of amyloidosis involving the central nervous system and heart, potentially obviating the need for biopsy of the affected organ in certain circumstances. Specifically, a combination of characteristic findings at noninvasive cardiac MRI and skeletal scintigraphy in patients without an underlying plasma cell dyscrasia is diagnostic for cardiac transthyretin amyloidosis. Histologically, the presence of amyloid is denoted by staining with Congo red and a characteristic apple green birefringence under polarized light microscopy. The imaging features of amyloid vary across each organ system but share some common patterns, such as soft-tissue infiltration and calcification, that may suggest the diagnosis in the appropriate clinical context. The availability of novel therapeutics that target amyloid protein fibrils such as transthyretin highlights the importance of early diagnosis. © RSNA, 2021.
Document Type: Article
Publication Stage: Final
Source: Scopus
“A representational similarity analysis of cognitive control during color-word Stroop” (2021) Journal of Neuroscience
A representational similarity analysis of cognitive control during color-word Stroop
(2021) Journal of Neuroscience, 41 (35), .
Freund, M.C.a , Bugg, J.M.a , Braver, T.S.a b c
a Department of Psychological and Brain Sciences, Washington University in St. Louis, STL, MO 63130, United States
b Department of Radiology, Washington University in St. Louis School of Medicine, STL, MO 63110, United States
c Department of Neuroscience, Washington University in St. Louis School of Medicine, STL, MO 63110, United States
Abstract
Progress in understanding the neural bases of cognitive control has been supported by the paradigmatic color-word Stroop task, in which a target response (color name) must be selected over a more automatic, yet potentially incongruent, distractor response (word). For this paradigm, models have postulated complementary coding schemes: dorsomedial frontal cortex (DMFC) is proposed to evaluate the demand for control via incongruency-related coding, whereas dorsolateral prefrontal cortex (DLPFC) is proposed to implement control via goal and target-related coding. Yet, mapping these theorized schemes to measured neural activity within this task has been challenging. Here, we tested for these coding schemes relatively directly, by decomposing an event-related color-word Stroop task via representational similarity analysis (RSA). Three neural coding models were fit to the similarity structure of multi-voxel patterns of human fMRI activity, acquired from 65 healthy, young-adult males and females. Incongruency coding was predominant in DMFC, whereas both target and incongruency coding were present with indistinguishable strength in DLPFC. In contrast, distractor coding was strongly encoded within early visual cortex. Further, these coding schemes were differentially related to behavior: individuals with stronger DLPFC (and lateral posterior parietal cortex) target coding, but weaker DMFC incongruency coding, exhibited less behavioral Stroop interference. These results highlight the utility of the RSA framework for investigating neural mechanisms of cognitive control and point to several promising directions to extend the Stroop paradigm. Copyright © 2021 the authors
Funding details
National Institutes of HealthNIH1S10OD018091-01, 1S10RR022984-01A1, R37 MH066078
Technology Strategy BoardTSB
Document Type: Article
Publication Stage: Final
Source: Scopus
“Glial-specific deletion of Med12 results in rapid hearing loss via degradation of the stria vascularis” (2021) Journal of Neuroscience
Glial-specific deletion of Med12 results in rapid hearing loss via degradation of the stria vascularis
(2021) Journal of Neuroscience, 41 (34), pp. 7171-7181.
Huang, T.-W.a , Iyer, A.A.c f , Manalo, J.M.d , Woo, J.a , Bosquez Huerta, N.A.a e , McGovern, M.M.b , Schrewe, H.g , Pereira, F.A.h i , Groves, A.K.b c e f , Ohlemiller, K.K.j , Deneen, B.a b e k
a Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, United States
b Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
d Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030, United States
e Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, United States
f Program in Genetics and Genomics, Baylor College of Medicine, Houston, TX 77030, United States
g Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany
h Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, United States
i Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, United States
j Department of Otolaryngolgy, Central Institute for the Deaf, Fay and Carl Simons Center for Biology of Hearing and Deafness, Washington University in St. Louis, St. Louis, MO 63110, United States
k Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
Abstract
Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regulates auditory function in the adult by preserving the structural integrity of the stria vascularis. Copyright © 2021 the authors
Author Keywords
Astrocyte; Hearing loss; Mediator complex; Stria vascularis
Funding details
National Institutes of HealthNIHDC-014832, NS-071153, NS-096096
National Multiple Sclerosis SocietyFG-1607-25417
Cullen Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
“Molecular Characterization of Microbiota in Cerebrospinal Fluid From Patients With CSF Shunt Infections Using Whole Genome Amplification Followed by Shotgun Sequencing” (2021) Frontiers in Cellular and Infection Microbiology
Molecular Characterization of Microbiota in Cerebrospinal Fluid From Patients With CSF Shunt Infections Using Whole Genome Amplification Followed by Shotgun Sequencing
(2021) Frontiers in Cellular and Infection Microbiology, 11, art. no. 699506, .
Hodor, P.a , Pope, C.E.b , Whitlock, K.B.c , Hoffman, L.R.a b , Limbrick, D.L.d , McDonald, P.J.e , Hauptman, J.S.a b , Ojemann, J.G.a b , Simon, T.D.f g , Cerebrospinal FLuId MicroBiota in Shunts Study (CLIMB) Grouph
a Seattle Children’s Hospital, Seattle, WA, United States
b Department of Pediatrics, University of Washington, Seattle, WA, United States
c New Harmony Statistical Consulting LLC, Clinton, WA, United States
d Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
e Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
f Children’s Hospital Los Angeles, Los Angeles, CA, United States
g Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Abstract
Understanding the etiology of cerebrospinal fluid (CSF) shunt infections and reinfections requires detailed characterization of associated microorganisms. Traditionally, identification of bacteria present in the CSF has relied on culture methods, but recent studies have used high throughput sequencing of 16S rRNA genes. Here we evaluated the method of shotgun DNA sequencing for its potential to provide additional genomic information. CSF samples were collected from 3 patients near the beginning and end of each of 2 infection episodes. Extracted total DNA was sequenced by: (1) whole genome amplification followed by shotgun sequencing (WGA) and (2) high-throughput sequencing of the 16S rRNA V4 region (16S). Taxonomic assignments of sequences from WGA and 16S were compared with one another and with conventional microbiological cultures. While classification of bacteria was consistent among the 3 approaches, WGA provided additional insights into sample microbiological composition, such as showing relative abundances of microbial versus human DNA, identifying samples of questionable quality, and detecting significant viral load in some samples. One sample yielded sufficient non-human reads to allow assembly of a high-quality Staphylococcus epidermidis genome, denoted CLIMB1, which we characterized in terms of its MLST profile, gene complement (including putative antimicrobial resistance genes), and similarity to other annotated S. epidermidis genomes. Our results demonstrate that WGA directly applied to CSF is a valuable tool for the identification and genomic characterization of dominant microorganisms in CSF shunt infections, which can facilitate molecular approaches for the development of better diagnostic and treatment methods. © Copyright © 2021 Hodor, Pope, Whitlock, Hoffman, Limbrick, McDonald, Hauptman, Ojemann and Simon.
Author Keywords
cerebrospinal fluid; CSF shunt infection; high throughput DNA sequencing; microbiota; Staphylococcus epidermidis CLIMB1
Funding details
Cosmetic Surgery FoundationCSF
Document Type: Article
Publication Stage: Final
Source: Scopus
“Validation of Trifluoromethylphenyl Diazirine Cholesterol Analogues As Cholesterol Mimetics and Photolabeling Reagents” (2021) ACS Chemical Biology
Validation of Trifluoromethylphenyl Diazirine Cholesterol Analogues As Cholesterol Mimetics and Photolabeling Reagents
(2021) ACS Chemical Biology, 16 (8), pp. 1493-1507.
Krishnan, K.a , Qian, M.a , Feltes, M.d , Chen, Z.-W.b , Gale, S.d , Wang, L.b , Sugasawa, Y.b , Reichert, D.E.e , Schaffer, J.E.d , Ory, D.S.d , Evers, A.S.a b d , Covey, D.F.a b c
a Department of Developmental Biology, The Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
b Department of Anesthesiology, The Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, The Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
d Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
e Department of Radiology, The Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
Abstract
Aliphatic diazirine analogues of cholesterol have been used previously to elaborate the cholesterol proteome and identify cholesterol binding sites on proteins. Cholesterol analogues containing the trifluoromethylphenyl diazirine (TPD) group have not been reported. Both classes of diazirines have been prepared for neurosteroid photolabeling studies and their combined use provided information that was not obtainable with either diazirine class alone. Hence, we prepared cholesterol TPD analogues and used them along with previously reported aliphatic diazirine analogues as photoaffinity labeling reagents to obtain additional information on the cholesterol binding sites of the pentameric Gloeobacter ligand-gated ion channel (GLIC). We first validated the TPD analogues as cholesterol substitutes and compared their actions with those of previously reported aliphatic diazirines in cell culture assays. All the probes bound to the same cholesterol binding site on GLIC but with differences in photolabeling efficiencies and residues identified. Photolabeling of mammalian (HEK) cell membranes demonstrated differences in the pattern of proteins labeled by the two classes of probes. Collectively, these date indicate that cholesterol photoaffinity labeling reagents containing an aliphatic diazirine or TPD group provide complementary information and will both be useful tools in future studies of cholesterol biology. © 2021 American Chemical Society.
Funding details
National Institutes of HealthNIHF31 HL142167, R01 GM108799, R01 HL067773, R01 MH110550, T32 HL134635
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
“Amyloid β-Binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu Positron Emission Tomography Imaging in Alzheimer’s Disease” (2021) Inorganic Chemistry
Amyloid β-Binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu Positron Emission Tomography Imaging in Alzheimer’s Disease
(2021) Inorganic Chemistry, 60 (16), pp. 12610-12620.
Wang, Y.a , Huynh, T.T.b c , Cho, H.-J.a , Wang, Y.-C.a , Rogers, B.E.b , Mirica, L.M.a d
a Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
b Department of Radiation Oncology, Washington University, School of Medicine, St. Louis, MO 63108, United States
c Department of Chemistry, Washington University, St. Louis, MO 63130, United States
d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable 64Cu-radiolabeled complexes. Among the five compounds tested, the 64Cu-YW-7 and 64Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log Doct) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis. © 2021 American Chemical Society.
Funding details
National Institutes of HealthNIHR01GM114588
Document Type: Article
Publication Stage: Final
Source: Scopus
“Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy” (2021) Pain Medicine (Malden, Mass.)
Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy
(2021) Pain Medicine (Malden, Mass.), 22 (8), pp. 1850-1856.
Diaz, M.M.a , Keltner, J.R.b c , Simmons, A.N.b c , Franklin, D.c , Moore, R.C.c , Clifford, D.d , Collier, A.C.e , Gelman, B.B.f , Marra, P.D.C.e , McCutchan, J.A.g , Morgello, S.h , Sacktor, N.i , Best, B.j , Notestine, C.F.c , Weibel, S.G.g , Grant, I.c , Marcotte, T.D.c , Vaida, F.k , Letendre, S.c g , Heaton, R.c , Ellis, R.J.a c
a Department of Neurosciences, University of California, La Jolla, San Diego, CA, Mexico
b Center of Excellence in Stress and Mental Health, San Diego Veterans Health System, San Diego, CA, Mexico
c Department of Psychiatry, University of California, La Jolla, San Diego, CA, Mexico
d Washington University, St. Louis, MO, United States
e University of Washington, Seattle, WA, United States
f University of Texas Medical Branch, Galveston, TX, United States
g Department of Medicine, University of California, La Jolla, San Diego, CA, Mexico
h Icahn School of Medicine at Mount SinaiNY
i Johns Hopkins University, Baltimore, MD, United States
j Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, San Diego, CA, Mexico
k Department of Family Medicine and Public Health, University of California, La Jolla, San Diego, CA, United States
Abstract
OBJECTIVE: Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. METHODS: This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. RESULTS: Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). CONCLUSIONS: Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain. © The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
CHARTER Study; HIV; Neuropathy; Pain; Paresthesia
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neonatal Brain Response to Deviant Auditory Stimuli and Relation to Maternal Trait Anxiety” (2021) The American Journal of Psychiatry
Neonatal Brain Response to Deviant Auditory Stimuli and Relation to Maternal Trait Anxiety
(2021) The American Journal of Psychiatry, 178 (8), pp. 771-778.
Sylvester, C.M., Myers, M.J., Perino, M.T., Kaplan, S., Kenley, J.K., Smyser, T.A., Warner, B.B., Barch, D.M., Pine, D.S., Luby, J.L., Rogers, C.E., Smyser, C.D.
Department of Psychiatry (Sylvester, Myers, Perino, T.A. Smyser, Barch, Luby, Rogers), Department of Neurology (Kaplan, Kenley, C.D. Smyser), Department of Pediatrics (Warner, Rogers, C.D. Smyser), Department of Radiology (Barch, C.D. Smyser), and Department of Psychological and Brain Sciences (Barch), Washington University, St. Louis; Emotion and Development Branch, NIMH, Bethesda, Md. (Pine)
Abstract
OBJECTIVE: Excessive response to unexpected or “deviant” stimuli during infancy and early childhood represents an early risk marker for anxiety disorders. However, research has yet to delineate the specific brain regions underlying the neonatal response to deviant stimuli near birth and the relation to risk for anxiety disorders. The authors used task-based functional MRI (fMRI) to delineate the neonatal response to deviant stimuli and its relationship to maternal trait anxiety. METHODS: The authors used fMRI to measure brain activity evoked by deviant auditory stimuli in 45 sleeping neonates (mean age, 27.8 days; 60% female; 64% African American). In 41 of the infants, neural response to deviant stimuli was examined in relation to maternal trait anxiety on the State-Trait Anxiety Inventory, a familial risk factor for offspring anxiety. RESULTS: Neonates manifested a robust and widespread neural response to deviant stimuli that resembles patterns found previously in adults. Higher maternal trait anxiety was related to higher responses within multiple brain regions, including the left and right anterior insula, the ventrolateral prefrontal cortex, and multiple areas within the anterior cingulate cortex. These areas overlap with brain regions previously linked to anxiety disorders and other psychiatric illnesses in adults. CONCLUSIONS: The neural architecture sensitive to deviant stimuli robustly functions in newborns. Excessive responsiveness of some circuitry components at birth may signal risk for anxiety and other psychiatric disorders.
Author Keywords
Anxiety Disorders; Child/Adolescent Psychiatry; Development; Neuroimaging
Document Type: Article
Publication Stage: Final
Source: Scopus
“Efficient CRISPR/Cas9 mutagenesis for neurobehavioral screening in adult zebrafish” (2021) G3: Genes, Genomes, Genetics
Efficient CRISPR/Cas9 mutagenesis for neurobehavioral screening in adult zebrafish
(2021) G3: Genes, Genomes, Genetics, 11 (8), art. no. jkab089, .
Shaw, D.K.a b , Mokalled, M.H.a b
a Department of Developmental Biology, Washington University, School of Medicine, Saint Louis, MO 63110, United States
b Center of Regenerative Medicine, Washington University, School of Medicine, Saint Louis, MO 63110, United States
Abstract
Adult zebrafish are widely used to interrogate mechanisms of disease development and tissue regeneration. Yet, the prospect of large-scale genetics in adult zebrafish has traditionally faced a host of biological and technical challenges, including inaccessibility of adult tissues to high-throughput phenotyping and the spatial and technical demands of adult husbandry. Here, we describe an experimental pipeline that combines high-efficiency CRISPR/Cas9 mutagenesis with functional phenotypic screening to identify genes required for spinal cord repair in adult zebrafish. Using CRISPR/Cas9 dual-guide ribonucleic proteins, we show selective and combinatorial mutagenesis of 17 genes at 28 target sites with efficiencies exceeding 85% in adult F0 “crispants”. We find that capillary electrophoresis is a reliable method to measure indel frequencies. Using a quantifiable behavioral assay, we identify seven single- or duplicate-gene crispants with reduced functional recovery after spinal cord injury. To rule out off-target effects, we generate germline mutations that recapitulate the crispant regeneration phenotypes. This study provides a platform that combines high-efficiency somatic mutagenesis with a functional phenotypic readout to perform medium- to large-scale genetic studies in adult zebrafish. © The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.
Author Keywords
CRISPR/Cas9; Genetic screen; Regeneration; Spinal cord injury; Zebrafish
Funding details
National Institutes of HealthNIHR01 NS113915
University of MissouriMU
Central Washington UniversityCWU
Document Type: Article
Publication Stage: Final
Source: Scopus
“The updated neuroradiology milestones: Synapsing from 1.0 to 2.0” (2021) American Journal of Neuroradiology
The updated neuroradiology milestones: Synapsing from 1.0 to 2.0
(2021) American Journal of Neuroradiology, 42 (8), pp. E48-E52.
Bhatt, A.A.a , Kurtz, R.M.b , Kennedy, T.A.c , Miller-Thomas, M.M.d , Anderson, J.C.e , Edgar, L.f , Wood, C.P.g
a Department of Radiology, Mayo Clinic Jacksonville, Jacksonville, FL, United States
b Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
c School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
d Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Radiology, Oregon Health & Science University, Portland, OR, United States
f Milestones Development, Accreditation Council for Graduate Medical Education, Chicago, IL, United States
g Department of Radiology, Mayo Clinic Rochester, Rochester, MN, United States
Abstract
The Accreditation Council for Graduate Medical Education is currently in the process of specialty-by-specialty revision of the Milestones. As a result, the Neuroradiology Milestones 2.0 Workgroup was created to refine a system of competency-based assessments for fellow educational growth and development. Strengths of the new Milestones include decreased complexity and uniformity within a subcompetency as it relates to a specific educational development trajectory. The Supplemental Guide serves to decrease clutter in the Milestones 2.0 document and provides a more practical resource for guidance. This article serves to review the history of the Neuroradiology Milestones, followed by a summary of the timeline of events and discussions of the workgroup for development of Neuroradiology Milestones 2.0 and a synopsis of major changes. The plan is for the updated Neuroradiology Milestones to take effect in 2021 or 2022 based on public commentary. © 2021 American Society of Neuroradiology. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
“A comparison of prediction approaches for identifying prodromal Parkinson disease” (2021) PLoS ONE
A comparison of prediction approaches for identifying prodromal Parkinson disease
(2021) PLoS ONE, 16 (8 August), art. no. e0256592, .
Warden, M.N.a , Nielsen, S.S.a , Camacho-Soto, A.a , Garnett, R.b , Racette, B.A.a c
a Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
b Department of Computer Science and Engineering, Washington University in Saint Louis, Saint Louis, MO, United States
c Faculty of Health Sciences, School of Public Heath, University of the Witwatersrand, Johannesburg, South Africa
Abstract
Identifying people with Parkinson disease during the prodromal period, including via algorithms in administrative claims data, is an important research and clinical priority. We sought to improve upon an existing penalized logistic regression model, based on diagnosis and procedure codes, by adding prescription medication data or using machine learning. Using Medicare Part D beneficiaries age 66-90 from a population-based case-control study of incident Parkinson disease, we fit a penalized logistic regression both with and without Part D data. We also built a predictive algorithm using a random forest classifier for comparison. In a combined approach, we introduced the probability of Parkinson disease from the random forest, as a predictor in the penalized regression model. We calculated the receiver operator characteristic area under the curve (AUC) for each model. All models performed well, with AUCs ranging from 0.824 (simplest model) to 0.835 (combined approach). We conclude that medication data and random forests improve Parkinson disease prediction, but are not essential. © 2021 Warden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Six-minute walking test performance relates to neurocognitive abilities in preschoolers” (2021) Journal of Clinical Medicine
Six-minute walking test performance relates to neurocognitive abilities in preschoolers
(2021) Journal of Clinical Medicine, 10 (4), art. no. 584, pp. 1-17.
Keye, S.A.a , Walk, A.M.b , Cannavale, C.N.c , Iwinski, S.d , McLoughlin, G.M.e f , Steinberg, L.G.a , Khan, N.A.a c g
a Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
b Department of Psychology, Eastern Illinois University, Charleston, IL 61920, United States
c University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
d Department of Human Development and Family Studies, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
e Implementation Science Center for Cancer Control and Prevention Research Center, Brown School, Washington University in St. Louis, St. Louis, MO 63130, United States
f Department of Surgery (Division of Public Health Sciences), Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63130, United States
g Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
Abstract
This study investigated the relationship between six-minute walking test (6MWT) distance walked and preschool-aged children’s academic abilities, and behavioral and event-related potentials (ERP) indices of cognitive control. There were 59 children (25 females; age: 5.0 ± 0.6 years) who com-pleted a 6MWT (mean distance: 449.6 ± 82.0 m) to estimate cardiorespiratory fitness. The Woodcock Johnson Early Cognitive and Academic Development Test evaluated academic abilities. A mod-ified Eriksen flanker, hearts and flowers task, and auditory oddball task eliciting ERPs (N2, P3) assessed cognitive control. After adjusting for adiposity, diet, and demographics, linear regressions resulted in positive relationships between 6MWT distance and General Intellectual Ability (β = 0.25, Adj R2 = 0.04, p = 0.04) and Expressive Language (β = 0.30, Adj R2 = 0.13, p = 0.02). 6MWT distance was positively correlated with congruent accuracy (β = 0.29, Adj R2 = 0.18, p < 0.01) and negatively with incongruent reaction time (β = −0.26, Adj R2 = 0.05, p = 0.04) during the flanker task, and positively with homogeneous (β = 0.23, Adj R2 = 0.21, p = 0.04) and heterogeneous (β = 0.26, Adj R2 = 0.40, p = 0.02) accuracy on the hearts and flowers task. Higher fit children showed faster N2 latencies and greater P3 amplitudes to target stimuli; however, these were at the trend level following the adjustment of covariates. These findings indicate that the positive influence of cardiorespiratory fitness on cognitive function is evident in 4–6-year-olds. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Academic achievement; Cardiorespiratory fitness; Children; Event-related potentials; Executive function
Document Type: Article
Publication Stage: Final
Source: Scopus
“Early Vital Sign Differences in Very Low Birth Weight Infants with Severe Intraventricular Hemorrhage” (2021) American Journal of Perinatology
Early Vital Sign Differences in Very Low Birth Weight Infants with Severe Intraventricular Hemorrhage
(2021) American Journal of Perinatology, .
Zanelli, S.A.a , Abubakar, M.a , Andris, R.a , Patwardhan, K.b , Fairchild, K.D.a , Vesoulis, Z.A.b
a Department of Pediatrics, University of Virginia, Charlottesville, VA, United States
b Department of Pediatrics, Division of Newborn Medicine, Washington University, St. Louis, MO, United States
Abstract
Objective Severe intraventricular hemorrhage (sIVH, grades 3 and 4) is a serious complication for very low birth weight (VLBW) infants and is often clinically silent requiring screening cranial ultrasound (cUS) for detection. Abnormal vital sign (VS) patterns might serve as biomarkers to identify risk or occurrence of sIVH. Study Design This retrospective study was conducted in VLBW infants admitted to two level-IV neonatal intensive care units (NICUs) between January 2009 and December 2018. Inclusion criteria were: birth weight <1.5 kg and gestational age (GA) <32 weeks, at least 12 hours of systemic oxygen saturation from pulse oximetry (SpO 2) data over the first 24 hours and cUS imaging. Infants were categorized as early sIVH (sIVH identified in the first 48 hours), late sIVH (sIVH identified after 48 hours and normal imaging in the first 48 hours), and no IVH. Infants with grades 1 and 2 or unknown timing IVH were excluded. Mean heart rate (HR), SpO 2, mean arterial blood pressure (MABP), number of episodes of bradycardia (HR < 100 bpm), and desaturation (SpO 2< 80%) were compared. Results A total of 639 infants (mean: 27 weeks’ gestation) were included (567 no IVH, 34 early sIVH, and 37 late sIVH). In the first 48 hours, those with sIVH had significantly higher HR compared with those with no IVH. Infants with sIVH also had lower mean SpO 2and MABP and more desaturations <80%. No significant differences in VS patterns were identified in early versus late sIVH. Logistic regression identified higher HR and greater number of desaturations <80% as independently associated with sIVH. Conclusion VLBW infants who develop sIVH demonstrate VS differences with significantly lower SpO 2and higher mean HR over the first 48 hours after birth compared with VLBW infants with no IVH. Abnormalities in early VS patterns may be a useful biomarker for sIVH. Whether VS abnormalities predict or simply reflect sIVH remains to be determined. Key Points A higher HR in the first 48 hours is seen in infants with severe IVH. Infants with sIVH have lower blood pressure in the first 48 hours. Infants with sIVH have more oxygen desaturations in the first 48 hours. © 2021 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
biomarker; intraventricular hemorrhage; preterm infant; very low birth weight; vital signs
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Direct synaptic excitation between hilar mossy cells revealed with a targeted voltage sensor” (2021) Hippocampus
Direct synaptic excitation between hilar mossy cells revealed with a targeted voltage sensor
(2021) Hippocampus, .
Ma, Y.a d , Bayguinov, P.O.b , McMahon, S.M.a , Scharfman, H.E.c , Jackson, M.B.a
a Department of Neuroscience, University of Wisconsin–Madison, Madison, WI, United States
b Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, United States
c New York University Langone Health and the Nathan Kline Institute for Psychiatric Research, Orangeburg, NJ, United States
d Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
Abstract
The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of excitatory neuron strategically located in the hilus of the dentate gyrus where they can contribute to this processing through networks of synapses with inhibitory neurons and dentate granule cells. Some prior work has suggested that MCs can form excitatory synapses with other MCs, but the role of these synapses in the network activity of the dentate gyrus has received little attention. Here, we investigated synaptic inputs to MCs in mouse hippocampal slices using a genetically encoded hybrid voltage sensor (hVOS) targeted to MCs by Cre-lox technology. This enabled optical recording of voltage changes from multiple MCs simultaneously. Stimulating granule cells and CA3 pyramidal cells activated well-established inputs to MCs and elicited synaptic responses as expected. However, the weak blockade of MC responses to granule cell layer stimulation by DCG-IV raised the possibility of another source of excitation. To evaluate synapses between MCs as this source, single MCs were stimulated focally. Stimulation of one MC above its action potential threshold evoked depolarizing responses in neighboring MCs that depended on glutamate receptors. Short latency responses of MCs to other MCs did not depend on release from granule cell axons. However, granule cells did contribute to the longer latency responses of MCs to stimulation of other MCs. Thus, MCs transmit their activity to other MCs both through direct synaptic coupling and through polysynaptic coupling with dentate granule cells. MC–MC synapses can redistribute information entering the dentate gyrus and thus shape and modulate the electrical activity underlying hippocampal functions such as navigation and memory, as well as excessive excitation during seizures. © 2021 Wiley Periodicals LLC
Author Keywords
dentate gyrus; excitatory synapse; glutamate receptors; hilus; voltage imaging
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction” (2021) Nature Neuroscience
Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction
(2021) Nature Neuroscience, .
Karlsson Linnér, R.a , Mallard, T.T.b , Barr, P.B.c , Sanchez-Roige, S.d e , Madole, J.W.b , Driver, M.N.f , Poore, H.E.g , de Vlaming, R.a , Grotzinger, A.D.b , Tielbeek, J.J.h , Johnson, E.C.i , Liu, M.j , Rosenthal, S.B.k , Ideker, T.l , Zhou, H.m n , Kember, R.L.o p , Pasman, J.A.q , Verweij, K.J.H.r , Liu, D.J.s t , Vrieze, S.j , Porjesz, B.ac , Hesselbrock, V.ad , Foroud, T.M.ae , Agrawal, A.af , Edenberg, H.J.ae , Nurnberger Jr, J.I.ae , Liu, Y.ae , Kuperman, S.ag , Kramer, J.ag , Meyer, J.L.ac , Kamarajan, C.ac , Pandey, A.K.ac , Bierut, L.af , Rice, J.af , Bucholz, K.K.af , Schuckit, M.A.ah , Tischfield, J.ai , Brooks, A.ai , Hart, R.P.ai , Almasy, L.aj , Dick, D.M.c f , Salvatore, J.E.ai , Goate, A.ak , Kapoor, M.ak , Slesinger, P.ak , Scott, D.M.al , Bauer, L.ad , Wetherill, L.ae , Xuei, X.ae , Lai, D.ae , O’Connor, S.J.ae , Plawecki, M.H.ae , Lourens, S.ae , Acion, L.ag , Chan, G.ad ag , Chorlian, D.B.ac , Zhang, J.ac , Kinreich, S.ac , Pandey, G.ac , Chao, M.J.ak , Anokhin, A.P.af , McCutcheon, V.V.af , Saccone, S.af , Aliev, F.am , Barr, P.B.c , Chin, H.an , Parsian, A.an , Kranzler, H.R.o p , Gelernter, J.m n u v , Harris, K.M.w x , Tucker-Drob, E.M.b y , Waldman, I.D.g z , Palmer, A.A.d aa , Harden, K.P.b y , Koellinger, P.D.a ab , Dick, D.M.c f , COGA Collaboratorsao
a Department of Economics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
b Department of Psychology, University of Texas at Austin, Austin, TX, United States
c Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
d Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
e Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
f Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
g Department of Psychology, Emory University, Atlanta, GA, United States
h Department of Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
i Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
j Department of Psychology, University of Minnesota, Minneapolis, MN, United States
k Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, La Jolla, CA, United States
l Department of Medicine, University of California San Diego, La Jolla, CA, United States
m Department of Psychiatry, Yale University School of Medicine, West Haven, CT, United States
n Department of Psychiatry, VA CT Healthcare System, West Haven, CT, United States
o Center for Studies of Addiction, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
p Mental Illness Research Education and Clinical Center, Crescenz VA Medical Center, Philadelphia, PA, United States
q Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, Netherlands
r Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
s Department of Public Health Sciences, Penn State University, Hershey, PA, United States
t Institute of Personalized Medicine, Penn State University, Hershey, PA, United States
u Department of Genetics, Yale University School of Medicine, West Haven, CT, United States
v Department of Neuroscience, Yale University School of Medicine, West Haven, CT, United States
w Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
x Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
y Population Research Center, University of Texas at Austin, Austin, TX, United States
z Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, United States
aa Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States
ab La Follette School of Public Affairs, University of Wisconsin–Madison, Madison, WI, United States
ac SUNY Downstate, Brooklyn, NY, United States
ad University of Connecticut, Farmington, CT, United States
ae Indiana University, Indianapolis, IN, United States
af Washington University in St. Louis, St. Louis, MO, United States
ag University of Iowa, Iowa City, IA, United States
ah University of California San Diego, San Diego, CA, United States
ai Rutgers University, Newark, NJ, United States
aj Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
ak Icahn School of Medicine at Mount Sinai, New York, NY, United States
al Howard University, Washington, DC, United States
am Virginia Commonwealth University, Richmond, VA, United States
an National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
Abstract
Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
28IR-0070, T29KT0526
R01HD060726, R01HD073342
National Institutes of HealthNIH
National Institute on Drug AbuseNIDAK02AA018755, P50AA022527, R01DA050721, U10AA008401
National Institute on Alcohol Abuse and AlcoholismNIAAAR01AA015416
Brain and Behavior Research FoundationBBRF27676
University of North Carolina at Chapel HillUNC-CHP01HD031921
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD083613, R01HD092548
National Alliance for Research on Schizophrenia and DepressionNARSAD
Vanderbilt University Medical CenterVUMCP50GM115305, R01HD074711, R01NS032830, RC2GM092618, RC2MH089924, RC2MH089983, U01HG004798, U01HG006378, U19HL065962, phs000607
European Research CouncilERC647648 EdGe
Jacobs FoundationP50DA037844, R01AA026281
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“A computational Monte Carlo simulation strategy to determine the temporal ordering of abnormal age onset among biomarkers of Alzheimers disease” (2021) IEEE ACM Transactions on Computational Biology and Bioinformatics
A computational Monte Carlo simulation strategy to determine the temporal ordering of abnormal age onset among biomarkers of Alzheimers disease
(2021) IEEE/ACM Transactions on Computational Biology and Bioinformatics, .
Guo, X.a , Chen, K.b , Chen, Y.c , Xiong, C.d , Su, Y.e , Yao, L.f , Reiman, E.g
a School of Artificial Intelligence, Beijing Normal University, 47836 Beijing, Beijing, China, (e-mail: gxj@bnu.edu.cn)
b Department of Mathematics and Statistics, Arizona State University, 7864 Tempe, Arizona, United States, (e-mail: Kewei.Chen@bannerhealth.com)
c Banner Alzheimers Institute, Phoenix, Arizona, United States, (e-mail: yinghua.chen@bannerhealth.com)
d Division of Biostatistics, Washington University School of Medicine in Saint Louis, 12275 Saint Louis, Missouri, United States, (e-mail: chengjie@wubios.wustl.edu)
e Banner Alzheimers Institute, Banner Health, Phoenix, Arizona, United States, (e-mail: yi.su@bannerhealth.com)
f School of Artificial Intelligence, Beijing Normal University, Beijing, Beijing, China, (e-mail: yaoli@bnu.edu.cn)
g Division of Neurogenomics, Translational Genomics Research Institute, 10897 Phoenix, Arizona, United States, (e-mail: Eric.Reiman@bannerhealth.com)
Abstract
To quantitatively determining the temporal ordering of abnormal age onsets (AAO) among various biomarkers for Alzheimers disease (AD), we introduced a computational Monte-Carlo simulation (CMCS) to statistically examine such ordering of an AAO pair or over all AAOs. The CMCS 1) simulates longitudinal data, estimates AAO for each iteration, and finally assesses the type-I error of an AAO pair or all AAO ordering. Using hippocampus volume (V<sub>HC</sub>), cerebral glucose hypometabolic convergence index (HCI), plasma neurofilament light (NfL), mini-mental state exam (MMSE), the auditory verbal learning test-long term memory (AVLT-LTM), short term memory (AVLT-STM) and clinical-dementia rating sum of box scale (CDR-SOB) from 382 mild cognitive impairment converters and non-converters, the CMCS estimated type-I error for the earlier AAO of V<sub>HC</sub>, AVLT_STM and AVLT_LTM each than MMSE was significant (p<0.002). The type-I error for the overall AAO temporal ordering of V<sub>HC</sub> AVLT_STM AVLT_LTM < HCI MMSE CDR-SOB NfL was p = 0.012. These findings showed that our CMCS is capable of providing statistical inferences for quantifying AAO ordering which has important implications in advancing our understanding of AD. IEEE
Author Keywords
abnormal age onset; Alzheimer’s disease; Alzheimer’s disease; Biological system modeling; biomarker; Biomarkers; Brain modeling; Diseases; Human computer interaction; linear mixed effects; Monte Carlo simulation; temporal ordering; Trajectory
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Meaningful boundaries create boundary conditions for control” (2021) Psychological Research
Meaningful boundaries create boundary conditions for control
(2021) Psychological Research, .
Colvett, J.S., Bugg, J.M.
Department of Psychological and Brain Sciences, Washington University in St. Louis, Campus Box 1125, St. Louis, MO 63130, United States
Abstract
Recent research demonstrated that control states learned via experience in inducer locations were retrieved in novel, unbiased (i.e., diagnostic) locations positioned nearby. Such transfer has been observed even in the presence of a visual boundary (a line) separating inducer and diagnostic locations. One aim of the present study was to assess whether a meaningful boundary might disrupt retrieval of control states in diagnostic locations. Supporting this possibility, in Experiment 1 learned control states did not transfer from inducer locations superimposed on a university’s quad to diagnostic locations superimposed on buildings outside the quad. Similarly, in Experiment 2 transfer was not observed for diagnostic locations positioned on a track outside of the field where inducer locations were positioned; however, transfer was also not observed for diagnostic locations on the field (inside the boundary). The latter finding helped motivate Experiments 3a and 3b, which tackled the second aim by examining whether a meaningful boundary might attenuate learning of control states for inducer locations within the boundary. Consistent with this hypothesis, a CSPC effect was observed only when a meaningful boundary was not present. Taken together, the findings provide evidence that meaningful boundaries influence how conflict experiences are organized during a task thereby impacting learning and transfer of context-specific control states. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Funding details
National Institutes of HealthNIHAG057937
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“The pubertal stress recalibration hypothesis: Potential neural and behavioral consequences” (2021) Child Development Perspectives
The pubertal stress recalibration hypothesis: Potential neural and behavioral consequences
(2021) Child Development Perspectives, .
DePasquale, C.E.a , Herzberg, M.P.a b , Gunnar, M.R.a
a Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Recent research has suggested that the pubertal period provides an opportunity for recalibrating the stress-responsive systems in youth whose responses to stress have been altered by early adversity. Such recalibration may have cascading effects that affect brain and behavioral development. In this article, we consider a large, cross-species literature to demonstrate the potential importance of pubertal stress recalibration for understanding the development of psychopathology following early deprivation by caregivers. We review the evidence for recalibration of the hypothalamic-pituitary-adrenal axis in humans, examine research on rodents that has established mechanisms through which stress hormones affect brain structure and function, and summarize the literature on human neuroimaging to assess how these mechanisms may translate into changes in human behavior. Finally, we suggest ideas for elucidating the consequences of pubertal stress recalibration that will improve our understanding of adaptive and maladaptive adolescent behavior following early adversity. © 2021 The Authors. Child Development Perspectives © 2021 Society for Research in Child Development.
Author Keywords
cortisol; early life stress; pubertal stress recalibration
Funding details
National Institutes of HealthNIHR01 HD095904, T32 MH015755, T32 MH100019, TL1 TR002493
National Center for Advancing Translational SciencesNCATS
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus” (2021) Epilepsia
Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus
(2021) Epilepsia, .
Sheehan, T.a , Amengual-Gual, M.a b , Vasquez, A.a c , Abend, N.S.d , Anderson, A.e , Appavu, B.f , Arya, R.g , Barcia Aguilar, C.a h , Brenton, J.N.i , Carpenter, J.L.j , Chapman, K.E.k , Clark, J.a , Farias-Moeller, R.l , Gaillard, W.D.j , Gaínza-Lein, M.a m , Glauser, T.A.g , Goldstein, J.L.n , Goodkin, H.P.i , Guerriero, R.M.o , Huh, L.p , Jackson, M.a , Kapur, K.q , Kahoud, R.r s , Lai, Y.-C.t , McDonough, T.L.u , Mikati, M.A.v , Morgan, L.A.w , Novotny, E.J.w , Ostendorf, A.P.x , Payne, E.T.y , Peariso, K.g , Piantino, J.z , Reece, L.a , Riviello, J.J.e , Sands, T.T.u , Sannagowdara, K.l , Shellhaas, R.aa , Smith, G.aa , Tasker, R.C.ab , Tchapyjnikov, D.v ac , Topjian, A.A.ad , Wainwright, M.S.w , Wilfong, A.f , Williams, K.f , Zhang, B.q , Loddenkemper, T.a , the Pediatric Status Epilepticus Research Groupae
a Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
b Pediatric Neurology Unit, Department of Pediatrics, Son Espases University Hospital, University of the Balearic Islands, Palma, Spain
c Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, United States
d Division of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
e Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
f Department of Pediatrics, University of Arizona College of Medicine and Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
g Division of Neurology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, United States
h Department of Child Neurology, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain
i Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, VA, United States
j Center for Neuroscience, Children’s National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
k Departments of Pediatrics and Neurology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
l Department of Neurology, Division of Pediatric Neurology, Children’s Hospital of Wisconsin, Medical College of Wisconsin, MilwaukeeWI, United States
m Faculty of Medicine, Austral University of Chile, Valdivia, Chile
n Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
o Division of Pediatric and Developmental Neurology, Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
p Division of Neurology, Department of Paediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
q Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
r Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mayo Clinic, Rochester, MN, United States
s Department of Neurology, Mayo Clinic, Rochester, MN, United States
t Section of Pediatric Critical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
u Division of Child Neurology, Department of Neurology, Columbia University Medical Center, Columbia University, New YorkNY, United States
v Division of Pediatric Neurology, Duke University Medical Center, Duke University, DurhamNC, United States
w Departments of Neurology and Pediatrics, Division of Pediatric Neurology, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
x Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States
y Division of Neurology, Department of Pediatrics, Alberta Children’s Hospital, Calgary, AB, Canada
z Division of Neurology, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR, United States
aa Department of Pediatrics, Division of Pediatric Neurology, University of Michigan, Ann Arbor, MI, United States
ab Division of Critical Care, Departments of Neurology, Anesthesiology, and Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
ac Department of Pediatrics, Montana Children’s Hospital, Kalispell Regional Medical Center, Kalispell, MT, United States
ad Critical Care and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
Abstract
Objective: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). Methods: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. Results: We included 293 patients with a median (interquartile range) age of 3.8 (1.3–9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] =.998, 95% confidence interval [CI] =.997–.999 per minute, p =.01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73–3.46, p <.0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40–6.03, p <.0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01–2.06, p =.04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. Significance: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
Author Keywords
benzodiazepine; epilepsy; pediatric; seizure; status epilepticus; treatment
Funding details
National Institutes of HealthNIH2U01‐NS045911, R01‐LM011124, R01‐NS043209, R01‐NS062756, U10‐NS077311
U.S. Department of JusticeDOJ
Epilepsy FoundationEFEF‐ 213583
Pfizer
Patient-Centered Outcomes Research InstitutePCORI
University of MichiganU-M
Fundación Alfonso Martín Escudero
Sunovion
Pediatric Epilepsy Research FoundationPERF
American Clinical Neurophysiology SocietyACNS
School of Public Health, University of California BerkeleyUCB
Zogenix
Eisai
H. Lundbeck A/S
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Gut microbiome is associated with multiple sclerosis activity in children” (2021) Annals of Clinical and Translational Neurology
Gut microbiome is associated with multiple sclerosis activity in children
(2021) Annals of Clinical and Translational Neurology, .
Horton, M.K.a , McCauley, K.b , Fadrosh, D.b , Fujimura, K.b , Graves, J.c , Ness, J.d , Wheeler, Y.d , Gorman, M.P.e , Benson, L.A.e , Weinstock-Guttman, B.f , Waldman, A.g , Rodriguez, M.h , Tillema, J.-M.h , Krupp, L.i , Belman, A.i , Mar, S.j , Rensel, M.k , Chitnis, T.l , Casper, T.C.m , Rose, J.m , Hart, J.n , Shao, X.a , Tremlett, H.o , Lynch, S.V.b , Barcellos, L.F.a , Waubant, E.n , the U.S. Network of Pediatric MS Centersp
a Division of Epidemiology, University of California, Berkeley, Berkeley, CA, United States
b Department of Medicine- Gastroenterology, University of California, San Francisco, San Francisco, CA, United States
c Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
d Division of Pediatric Neurology, University of Alabama, Birmingham, AL, United States
e Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
f Department of Neurology, State University of New York, Buffalo, NY, United States
g Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
h Department of Neurology, Mayo Clinic, Rochester, MN, United States
i Pediatric Multiple Sclerosis Center, New York University Langone Medical Center, New York, NY, United States
j Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
k Department of Neurology, Cleveland Clinic, Cleveland, OH, United States
l Division of Child Neurology, Massachusetts General Hospital, Boston, MA, United States
m School of Medicine, University of Utah School, Salt Lake City, UT, United States
n Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
o Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Abstract
Objective: To identify features of the gut microbiome associated with multiple sclerosis activity over time. Methods: We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric-onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice-Williams-Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium-enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease-modifying therapies. Results: Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co-occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium-enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. Interpretation: Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association
Funding details
National Institute of Neurological Disorders and StrokeNINDSF13NS108668, R01NS071463
National Multiple Sclerosis SocietyHC150906233, RG4861A13
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Patient-reported neurocognitive symptoms influence instrumental activities of daily living in sickle cell disease” (2021) American Journal of Hematology
Patient-reported neurocognitive symptoms influence instrumental activities of daily living in sickle cell disease
(2021) American Journal of Hematology, .
Longoria, J.N.a , Pugh, N.L.b , Gordeuk, V.c , Hsu, L.L.d , Treadwell, M.e , King, A.A.f , Gibson, R.g , Kayle, M.h , Crego, N.i , Glassberg, J.j , Melvin, C.L.k , Hankins, J.S.l , Porter, J.a
a Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
b Center for Clinical Research Network Coordination, RTI International, Research Triangle Park, NC, United States
c Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
d Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, United States
e Department of Pediatrics, University of California San Francisco Benioff Children’s Hospital Oakland, San Francisco, CA, United States
f Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, St. Louis, MO, United States
g Department of Emergency Medicine and Hospitalist Services, Augusta University, Augusta, GA, United States
h Clinical Health Systems and Analytics Division, Duke University, Durham, NC, United States
i Women, Children and Families Division, Duke University School of Nursing, Durham, New Caledonia
j Department of Emergency Medicine, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
k Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States
l Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
Abstract
Individuals with sickle cell disease (SCD) experience neurocognitive decline, low medication adherence, increased unemployment, and difficulty with instrumental activities of daily living (IADL). The relationship between self-perceived cognitive difficulties and IADLs, including employment, school enrollment, independence, engagement in leisure activities, and medication adherence is unknown. We hypothesized that self-reported difficulties across neurocognitive areas would predict lower IADL skills. Adolescent and adult participants of the multi-site Sickle Cell Disease Implementation Consortium (SCDIC) (n = 2436) completed patient-reported outcome (PRO) measures of attention, executive functioning, processing speed, learning, and comprehension. Cognitive symptoms were analyzed as predictors in multivariable modeling. Outcome variables included 1) an IADL composite that consisted of employment, participation in school, reliance on others, and leisure pursuits, and 2) hydroxyurea adherence. Participants reported cognitive difficulty across areas of attention (55%), executive functioning (51%), processing speed (57%), and reading comprehension (65%). Executive dysfunction (p < 0.001) and sometimes or often experiencing learning difficulties (p < 0.001 and p = 0.04) and poor comprehension (p = 0.000 and p = 0.001), controlled for age (p < 0.001), pain (p < 0.001), and hydroxyurea use (p = 0.001), were associated with poor IADL skills. Executive functioning difficulties (p = 0.021), controlled for age (p = 0.013 for ages 25–34), genotype (p = 0.001), and hemoglobin (p = 0.004), predicted hydroxyurea non-adherence. Analysis of PRO measures indicated that cognitive dysfunction is prevalent in adolescents and adults with SCD. Cognitive dysfunction translated into clinically meaningful outcomes. PRO of cognitive symptoms can be used as an important adjunct clinical tool to monitor symptoms that impact functional skills, including engagement in societal activities and medication adherence. © 2021 Wiley Periodicals LLC.
Funding details
National Heart, Lung, and Blood InstituteNHLBIK01 HL125495
National Institute on Minority Health and Health DisparitiesNIMHD
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Safety and tolerability of srx246, a vasopressin 1a antagonist, in irritable huntington’s disease patients—a randomized phase 2 clinical trial” (2020) Journal of Clinical Medicine
Safety and tolerability of srx246, a vasopressin 1a antagonist, in irritable huntington’s disease patients—a randomized phase 2 clinical trial
(2020) Journal of Clinical Medicine, 9 (11), art. no. 3682, pp. 1-14.
Brownstein, M.J.a , Simon, N.G.a b , Long, J.D.c , Yankey, J.c , Maibach, H.T.a , Cudkowicz, M.d , Coffey, C.c , Conwit, R.A.e , Lungu, C.e , Anderson, K.E.f , Hersch, S.M.d g , Ecklund, D.J.c , Damiano, E.M.a , Itzkowitz, D.E.a , Lu, S.a b , Chase, M.K.d , Shefner, J.M.h i j , McGarry, A.k , Thornell, B.d , Gladden, C.d , Costigan, M.c , O’suilleabhain, P.l , Marshall, F.J.m , Chesire, A.M.m , Deritis, P.m , Adams, J.L.m , Hedera, P.n , Lowen, K.n , Diana Rosas, H.d , Hiller, A.L.o , Quinn, J.o , Keith, K.o , Duker, A.P.p , Gruenwald, C.p , Molloy, A.p , Jacob, C.p , Factor, S.q , Sperin, E.q , Bega, D.r , Brown, Z.R.r , Seeberger, L.C.s , Sung, V.W.t , Benge, M.t , Kostyk, S.K.u , Daley, A.M.u , Perlman, S.v , Suski, V.w , Conlon, P.w , Barrett, M.J.x , Lowenhaupt, S.x , Quigg, M.x , Perlmutter, J.S.y , Wright, B.A.z , Most, E.y , Schwartz, G.J.aa , Lamb, J.aa , Chuang, R.S.ab , Singer, C.ac , Marder, K.ad , Moran, J.A.ad , Singleton, J.R.ae , Zorn, M.ae , Wall, P.V.ae , Dubinsky, R.M.af , Gray, C.af , Drazinic, C.ag
a Azevan Pharmaceuticals, Inc., Bethlehem, PA 18015, United States
b Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, United States
c Department of Biostatistics, University of Iowa, Iowa City, IA 52242, United States
d Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
e National Institutes of Health, NINDS, Bethesda, MD 20852, United States
f Department of Neurology, Medstar Georgetown University Hospital, Washington, DC 20007, United States
g Voyager Therapeutics Inc., Cambridge, MA 02139, United States
h Barrow Neurological Institute, Phoenix, AZ 85013, United States
i Department of Neurology, College of Medicine, The University of Arizona, Phoenix, AZ 85004, United States
j Department of Neurology, College of Medicine, Creighton University, Phoenix, AZ 85013, United States
k Department of Neurology, Cooper University Hospital, Camden, NJ 08103, United States
l Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, United States
m Department of Neurology, University of Rochester Medical Center, Rochester, NY 14618, United States
n Department of Neurology, Vanderbilt University, Nashville, TN 37212, United States
o Department of Neurology, Oregon Health and Science University, Portland, OR 97239, United States
p Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, United States
q Department of Neurology, Emory University, Atlanta, GA 30322, United States
r Department of Neurology, Northwestern University, Chicago, IL 60611, United States
s Department of Neurology, University of Colorado Denver, Aurora, CO 80045, United States
t Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL 35233, United States
u Department of Neurology, Ohio State University, Columbus, OH 43210, United States
v Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, United States
w Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States
x Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, United States
y Department of Neurology, Washington University, Saint Louis, MO 63110, United States
z Department of Neurosciences, University of California San Diego, La JollaCA 92121, United States
aa Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, United States
ab Department of Neurology, Swedish Medical Center, Seattle, WA 98122, United States
ac Department of Neurology, University of Miami, Miami, FL 33136, United States
ad Department of Neurology, Columbia University, New York, NY 10032, United States
ae Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, United States
af Department of Neurology, University of Kansas, Medical Center, Kansas City, KS 66160, United States
ag Department of Clinical Sciences, Florida State University, Tallahassee, FL 32306, United States
Abstract
SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood‐brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple‐ascending dose clinical trials. The present study was a 3‐arm, multicenter, randomized, placebo‐controlled, double‐blind, 12‐week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty‐two out of 106 subjects randomized completed the trial on their assigned dose of drug. One‐sided exact‐method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Huntington’s disease; Safety; Tolerability; Vasopressin 1a receptor antagonist
Document Type: Article
Publication Stage: Final
Source: Scopus