WashU weekly Neuroscience publications

Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering
(2024) Nature Communications, 15 (1), art. no. 354, . 

Yang, Z.^a b , Wen, J.^a c , Abdulkadir, A.^d , Cui, Y.^a , Erus, G.^a , Mamourian, E.^a , Melhem, R.^a , Srinivasan, D.^a , Govindarajan, S.T.^a , Chen, J.^a , Habes, M.^e , Masters, C.L.^f , Maruff, P.^f , Fripp, J.^g , Ferrucci, L.^h , Albert, M.S.ⁱ , Johnson, S.C.^j , Morris, J.C.^k , LaMontagne, P.^l , Marcus, D.S.^l , Benzinger, T.L.S.^k l , Wolk, D.A.^m , Shen, L.ⁿ , Bao, J.ⁿ , Resnick, S.M.^o , Shou, H.ⁿ , Nasrallah, I.M.^a p , Davatzikos, C.^a

^a Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Graduate Group in Applied Mathematics and Computational Science, University of Pennsylvania, Philadelphia, PA, United States
^c Laboratory of AI and Biomedical Science (LABS), Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
^d Laboratory for Research in Neuroimaging, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
^e Biggs Alzheimer’s Institute, University of Texas San Antonio Health Science Center, San Antonio, TX, United States
^f The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
^g CSIRO Health and Biosecurity, Australian e-Health Research Centre CSIRO, Brisbane, QLD, Australia
^h Translational Gerontology Branch, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital, 3001 S. Hanover Street, Baltimore, MD, United States
ⁱ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^k Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^l Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, United States
^o Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, United States
^p Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN – a multi-view, weakly-supervised deep clustering method – which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer’s disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes. © 2024, The Author(s).

Funding details
National Institutes of HealthNIH191026, 1U24AG074855-01, 206795, HHSN271201600059C, U01AG068057, U19-AG033655
National Institute on AgingNIARF1 AG054409
National Institute of Biomedical Imaging and BioengineeringNIBIB
University of Southern CaliforniaUSC
Alzheimer’s Disease Neuroimaging InitiativeADNI
Northern California Institute for Research and EducationNCIRE
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF35148

Document Type: Article
Publication Stage: Final
Source: Scopus

Postnatal meningeal CSF transport is primarily mediated by the arachnoid and pia maters and is not altered after intraventricular hemorrhage-posthemorrhagic hydrocephalus
(2024) Fluids and Barriers of the CNS, 21 (1), art. no. 4, . 

Pan, S., Koleske, J.P., Koller, G.M., Halupnik, G.L., Alli, A.-H.O., Koneru, S., DeFreitas, D., Ramagiri, S., Strahle, J.M.

Department of Neurosurgery, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Background: CSF has long been accepted to circulate throughout the subarachnoid space, which lies between the arachnoid and pia maters of the meninges. How the CSF interacts with the cellular components of the developing postnatal meninges including the dura, arachnoid, and pia of both the meninges at the surface of the brain and the intracranial meninges, prior to its eventual efflux from the cranium and spine, is less understood. Here, we characterize small and large CSF solute distribution patterns along the intracranial and surface meninges in neonatal rodents and compare our findings to meningeal CSF solute distribution in a rodent model of intraventricular hemorrhage-posthemorrhagic hydrocephalus. We also examine CSF solute interactions with the tela choroidea and its pial invaginations into the choroid plexuses of the lateral, third, and fourth ventricles. Methods: 1.9-nm gold nanoparticles, 15-nm gold nanoparticles, or 3 kDa Red Dextran Tetramethylrhodamine constituted in aCSF were infused into the right lateral ventricle of P7 rats to track CSF circulation. 10 min post-1.9-nm gold nanoparticle and Red Dextran Tetramethylrhodamine injection and 4 h post-15-nm gold nanoparticle injection, animals were sacrificed and brains harvested for histologic analysis to identify CSF tracer localization in the cranial and spine meninges and choroid plexus. Spinal dura and leptomeninges (arachnoid and pia) wholemounts were also evaluated. Results: There was significantly less CSF tracer distribution in the dura compared to the arachnoid and pia maters in neonatal rodents. Both small and large CSF tracers were transported intracranially to the arachnoid and pia mater of the perimesencephalic cisterns and tela choroidea, but not the falx cerebri. CSF tracers followed a similar distribution pattern in the spinal meninges. In the choroid plexus, there was large CSF tracer distribution in the apical surface of epithelial cells, and small CSF tracer along the basolateral surface. There were no significant differences in tracer intensity in the intracranial meninges of control vs. intraventricular hemorrhage-posthemorrhagic hydrocephalus (PHH) rodents, indicating preserved meningeal transport in the setting of PHH. Conclusions: Differential CSF tracer handling by the meninges suggests that there are distinct roles for CSF handling between the arachnoid-pia and dura maters in the developing brain. Similarly, differences in apical vs. luminal choroid plexus CSF handling may provide insight into particle-size dependent CSF transport at the CSF-choroid plexus border. © 2024, The Author(s).

Funding details
National Institutes of HealthNIHOD021694, R01 NS110793
Washington University in St. LouisWUSTL
Children’s Discovery InstituteCDI
McDonnell Center for Systems Neuroscience
Rudi Schulte Research InstituteRSRI
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
Hydrocephalus AssociationHA

Document Type: Article
Publication Stage: Final
Source: Scopus

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
(2024) Nature Communications, 15 (1), art. no. 396, . 

Hamel, A.R.^a b c , Yan, W.^d , Rouhana, J.M.^a b c , Monovarfeshani, A.^d , Jiang, X.^e f , Mehta, P.A.^a b c , Advani, J.^g , Luo, Y.^a b c , Liang, Q.^h , Rajasundaram, S.^b i j , Shrivastava, A.^a b c , Duchinski, K.^a b c k , Mantena, S.^a l , Wang, J.^a b c , van Zyl, T.^d m , Pasquale, L.R.ⁿ , Swaroop, A.^g , Gharahkhani, P.^o , Khawaja, A.P.^p , MacGregor, S.^o , Hewitt, A.W.^q r , Schuster, A.K.^s , Viswanathan, A.C.^t u v , Lotery, A.J.^w x , Cree, A.J.^x , Pang, C.P.^y , Brandl, C.^z aa , Klaver, C.C.W.^{ab ac ad ae} , Hayward, C.^e , Khor, C.C.^af , Cheng, C.-Y.^ag ah ai , Hammond, C.J.^aj , van Duijn, C.^ak al , Mackey, D.A.^am , Stefansson, E.^an , Vithana, E.N.^ao , Pasutto, F.^ap , Jonansson, F.^aq , Thorleifsson, G.^ar , Koh, J.^as , Wilson, J.F.^e at , Craig, J.E.^au , Vergroesen, J.E.^ab ac , Fingert, J.H.^av aw , Jonas, J.B.^{ag ax ay az} , Stefánsson, K.^ar , Burdon, K.P.^q , Chen, L.J.^y , Kass, M.^ba , Jansonius, N.M.^bb bc bd , Pfeiffer, N.^af , Polašek, O.^be , Foster, P.J.^p , Mitchell, P.^bf , Hysi, P.G.^aj , Wojciechowski, R.^bg , Driessen, S.J.^ab ac , Tompson, S.W.J.^bh , Young, T.L.^bh , Wong, T.Y.^ag ah , Aung, T.^ag ah ai , Thorsteinsdottir, U.^aq ar , de Vries, V.A.^ab ac , Ramdas, W.D.^ab , Wang, Y.X.^bi , Chen, R.^h , Vitart, V.^e , Sanes, J.R.^d , Wiggs, J.L.^a b c , Segrè, A.V.^a b c

^a Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, United States
^b Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
^c Broad Institute of Harvard and MIT, Cambridge, MA, United States
^d Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, United States
^e MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, United Kingdom
^f Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom
^g Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, United States
^h Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
ⁱ Centre for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom
^j Faculty of Medicine, Imperial College London, London, United Kingdom
^k Bioinformatics and Integrative Genomics (BIG) PhD Program, Harvard Medical School, Boston, MA, United States
^l Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, United States
^m Department of Ophthalmology and Visual Sciences, Yale School of Medicine, New Haven, CT, United States
ⁿ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^o QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
^p NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
^q Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
^r Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia
^s Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany
^t National Institute for Health Research Biomedical Research Centre, London, United Kingdom
^u Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
^v UCL Institute of Ophthalmology, London, United Kingdom
^w University Hospital Southampton NHS Foundation Trust, London, United Kingdom
^x Faculty of Medicine, University of Southampton, Southampton, United Kingdom
^y Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong
^z Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany
^aa Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
^ab Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
^ac Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
^ad Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands
^ae Institute for Molecular and Clinical Ophthalmology, Basel, Switzerland
^af Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore
^ag Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
^ah Ophthalmology & Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
^ai Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
^aj Departments of Ophthalmology and Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
^ak Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^al Department of Genetic Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
^am University of Western Australia, Centre for Ophthalmology and Vision Science, Lions Eye Institute, Nedlands, WA, Australia
^an Faculty of Medicine, University of Iceland, Reykjavik, Iceland
^ao Singapore Eye Research Institute, Singapore, Singapore
^ap Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
^aq Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
^ar deCODE genetics/Amgen Inc., Reykjavik, Iceland
^as Singapore National Eye Centre, Singapore, Singapore
^at Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
^au Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia
^av Department of Ophthalmology, Carver College of Medicine, lowa, IA, United States
^aw Institute for Vision Research, University of Iowa, lowa, IA, United States
^ax Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
^ay Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
^az Privatpraxis Prof Jonas und Dr Panda-Jonas, Heidelberg, Germany
^ba Washington University, St Louis, MO, United States
^bb Faculty of Medical Sciences, University of Groningen, Groningen, Netherlands
^bc Department of Ophthalmology, University of Groningen, Groningen, Netherlands
^bd University Medical Center Groningen, Groningen, Netherlands
^be School of Medicine, University of Split, Split, Croatia
^bf Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
^bg Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^bh Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, United States
^bi Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China

Abstract
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis. © 2024, The Author(s).

Funding details
National Institutes of HealthNIH
National Eye InstituteNEICZF2019-002425, P30 EY014104, R01 EY022305, R01 EY031424, R01 EY032559, ZIAEY000546
National Institute of General Medical SciencesNIGMST32GM144273
Research to Prevent BlindnessRPB
Glaucoma FoundationTGF
Helsingin YliopistoHY
Alcon Research InstituteARI
Memphis Research ConsortiumMRCMC_UU_00007/10)
National Youth Council SingaporeNYC
University of EdinburghED
National Health and Medical Research CouncilNHMRC1173390, APP1150144
UCL Institute of Ophthalmology, University College London

Document Type: Article
Publication Stage: Final
Source: Scopus

Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease
(2024) Molecular Neurodegeneration, 19 (1), art. no. 1, . 

Wang, L.^a b , Nykänen, N.-P.^a b , Western, D.^a b , Gorijala, P.^a b , Timsina, J.^a b , Li, F.^c , Wang, Z.^a b , Ali, M.^a b , Yang, C.^a b , Liu, M.^a b , Brock, W.^a b , Marquié, M.^d e , Boada, M.^d e , Alvarez, I.^f , Aguilar, M.^f , Pastor, P.^g , Ruiz, A.^d e , Puerta, R.^d e , Orellana, A.^d e , Rutledge, J.^h , Oh, H.^h , Greicius, M.D.^h , Le Guen, Y.^h , Perrin, R.J.ⁱ , Wyss-Coray, T.^h , Jefferson, A.^j , Hohman, T.J.^j , Graff-Radford, N.^k , Mori, H.^l , Goate, A.^m , Levin, J.ⁿ , Sung, Y.J.^a b o , Cruchaga, C.^a b p

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
^e Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
^f Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain
^g Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
^h Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
ⁱ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^j Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, United States
^k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^l Nagaoka Sutoku University, Osaka, Japan
^m Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁿ Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
^o Division of Biostatistics, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave, Box 8134, St. Louis, MO 63110, United States
^p Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States

Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. © 2024, The Author(s).

Funding details
115975, 115985, PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI22/01403
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG066444, R01AG044546, RF1AG053303, RF1AG058501, RF1AG074007, U01 AG024904, U01AG058922
U.S. Department of DefenseDODLI- W81XWH2010849, W81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAIIRG-08-88733, SG-20-690363-DIAN, ZEN-22-848604
Washington University in St. LouisWUSTL
Alzheimer’s Disease Neuroimaging InitiativeADNI
Takeda Pharmaceuticals U.S.A.TPUSA
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
EU Joint Programme – Neurodegenerative Disease ResearchJPNDAC19/00097, FI20/00215
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
European Research CouncilERC681712, R01-AG059716
Korea Health Industry Development InstituteKHIDI
VetenskapsrådetVR2018-02532
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
European Regional Development FundERDFAC17/00100, JCT2017
Servier
Fleni

Document Type: Article
Publication Stage: Final
Source: Scopus

Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
(2024) Nature Communications, 15 (1), art. no. 25, . 

Dalal, V.^a , Arcario, M.J.^a , Petroff, J.T., II^a , Tan, B.K.^a , Dietzen, N.M.^a , Rau, M.J.^b , Fitzpatrick, J.A.J.^b , Brannigan, G.^c d , Cheng, W.W.L.^a

^a Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
^b Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO, United States
^c Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, United States
^d Department of Physics, Rutgers University, Camden, NJ, United States

Abstract
Lipid nanodiscs have become a standard tool for studying membrane proteins, including using single particle cryo-electron microscopy (cryo-EM). We find that reconstituting the pentameric ligand-gated ion channel (pLGIC), Erwinia ligand-gated ion channel (ELIC), in different nanodiscs produces distinct structures by cryo-EM. The effect of the nanodisc on ELIC structure extends to the extracellular domain and agonist binding site. Additionally, molecular dynamic simulations indicate that nanodiscs of different size impact ELIC structure and that the nanodisc scaffold directly interacts with ELIC. These findings suggest that the nanodisc plays a crucial role in determining the structure of pLGICs, and that reconstitution of ion channels in larger nanodiscs may better approximate a lipid membrane environment. © 2024, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses
(2024) Nature Communications, 15 (1), art. no. 246, . 

Ma, H.^a , Adams, L.J.^b , Raju, S.^a b , Sariol, A.^a , Kafai, N.M.^a , Janova, H.^a b , Klimstra, W.B.^c , Fremont, D.H.^b d e , Diamond, M.S.^{a b e f g}

^a Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, United States
^d Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease. © 2024, The Author(s).

Funding details
National Institutes of HealthNIHAI201800001, F30AI164842, R01 AI141436, R01AI095436, U19 AI142790
National Institute of Allergy and Infectious DiseasesNIAID
Defense Threat Reduction AgencyDTRAMCDC2103-11

Document Type: Article
Publication Stage: Final
Source: Scopus

Absolute quantification of nicotinamide mononucleotide in biological samples by double isotope-mediated liquid chromatography-tandem mass spectrometry (dimeLC-MS/MS)
(2024) npj Aging, 10 (1), art. no. 2, . 

Unno, J.^a b , Mills, K.F.^b , Ogura, T.^c , Nishimura, M.^d , Imai, S.-I.^b

^a Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan
^b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Innovation Center, Shimadzu Scientific Instruments, Inc., Columbia, MD, United States
^d New Strategy Department, Shimadzu Scientific Instruments, Inc., Columbia, MD, United States

Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite for fundamental biological phenomena, including aging. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that has been extensively tested as an effective NAD+-boosting compound in mice and humans. However, the accurate measurement of NMN in biological samples has long been a challenge in the field. Here, we have established an accurate, quantitative methodology for measuring NMN by using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) with double isotopic NMN standards. In this new methodology, the matrix effects of biological samples were properly adjusted, and the fate of NMN could be traced during sample processing. We have demonstrated that this methodology can accurately quantitate NMN levels in mouse plasma and confirmed quick, direct NMN uptake into blood circulation and cells. This double isotope-mediated LC-MS/MS (dimeLC-MS/MS) can easily be expanded to other NAD+-related metabolites as a reliable standard methodology for NAD+ biology. © 2024, The Author(s).

Funding details
University of WashingtonUW
Shimadzu

Document Type: Article
Publication Stage: Final
Source: Scopus

Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy
(2024) Journal of Pediatrics, 266, art. no. 113853, . 

Rao, R.^a , Comstock, B.A.^b , Wu, T.-W.^c , Mietzsch, U.^b , Mayock, D.E.^b , Gonzalez, F.F.^d , Wood, T.R.^b , Heagerty, P.J.^b , Juul, S.E.^b , Wu, Y.W.^d

^a Division of Newborn Medicine, Department of Pediatrics, Washington University in St Louis, St. Louis, MO, United States
^b Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, United States
^c Division of Neonatology, Department of Pediatrics, University of Southern California, Los Angeles, CA, United States
^d Division of Neonatology, Department of Pediatrics, University of California, San Francisco, CA, United States

Abstract
Objective: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE). Study design: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2. Results: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, −2.8 [95% CI, −6.1 to 0.5], language −3.3 [95% CI, −7.4 to 0.8], and motor −3.5 [95% CI, −7.3 to 0.3]). Conclusions: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. Trial Registration: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta.clinicaltrials.gov/study/NCT02811263. © 2023 Elsevier Inc.

Author Keywords
age at target temperature;  hypoxia-ischemia;  neonatal encephalopathy

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

Genome-Wide Association Studies of 3 Distinct Recovery Phenotypes in Mild Ischemic Stroke
(2024) Neurology, 102 (3), p. e208011. 

Aldridge, C.M., Braun, R., Lohse, K., de Havenon, A., Cole, J.W., Cramer, S.C., Lindgren, A.G., Keene, K.L., Hsu, F.-C., Worrall, B.B.

From the Department of Neurology (C.M.A., B.B.W.), University of Virginia, Charlottesville; Department of Neurology (R.B., J.W.C.), University of Maryland, Baltimore; Program in Physical Therapy (K.L.), Washington University; Department of Neurology (K.L.), Washington University, St. Louis, MO; Department of Neurology (A.H.), Center for Brain and Mind Health, Yale University, New Haven, CT; Department of Neurology (S.C.C.), University of California Los Angeles; California Rehabilitation Institute (S.C.C.), Los Angeles; Department of Clinical Sciences Lund, Neurology (A.G.L.), Lund University; Department of Neurology (A.G.L.), Skane University Hospital, Sweden; Department of Public Health Sciences (K.L.K., B.B.W.); Center for Health Equity and Precision Public Health (K.L.K.), University of Virginia, Charlottesville; and Department of Biostatistics (F.-C.H.), School of Medicine, Wake Forest University, Winston-Salem, NC

Abstract
BACKGROUND AND OBJECTIVES: Stroke genetic research has made substantial progress in the past decade. Its recovery application, however, remains behind, in part due to its reliance on the modified Rankin Scale (mRS) score as a measure of poststroke outcome. The mRS does not map well to biological processes because numerous psychosocial factors drive much of what the mRS captures. Second, the mRS contains multiple disparate biological events into a single measure further limiting its use for biological discovery. This led us to investigate the effect of distinct stroke recovery phenotypes on genetic variation associations with Genome-Wide Association Studies (GWASs) by repurposing the NIH Stroke Scale (NIHSS) and its subscores. METHODS: In the Vitamin Intervention for Stroke Prevention cohort, we estimated changes in cognition, motor, and global impairments over 2 years using specific measures. We included genotyped participants with a total NIHSS score greater than zero at randomization and excluded those with recurrent stroke during the trial. A GWAS linear mixed-effects model predicted score changes, with participant as a random effect, and included initial score, age, sex, treatment group, and the first 5 ancestry principal components. RESULTS: In total, 1,270 participants (64% male) were included with a median NIHSS score of 2 (interquartile range [IQR] 1-3) and median age 68 (IQR 59-75) years. At randomization, 20% had cognitive deficits (NIHSS Cog-4 score >0) and 70% had ≥1 motor deficits (impairment score >1). At 2 years, these percentages improved to 7.2% with cognitive deficits and 30% with motor deficits. GWAS identified novel suggestive gene-impairment associations (p < 5e-6) for cognition (CAMK2D, EVX2, LINC0143, PTPRM, SGMS1, and SMAD2), motor (ACBD6, KDM4B, MARK4, PTPRS, ROBO1, and ROBO2), and global (MSR1 and ROBO2) impairments. DISCUSSION: Defining domain-specific stroke recovery phenotypes and using longitudinal clinical trial designs can help detect novel genes associated with chronic recovery. These data support the use of granular endpoints to identify genetic associations related to stroke recovery.

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples
(2024) Developmental Cognitive Neuroscience, 65, art. no. 101333, . 

Burrows, C.A.^a , Lasch, C.^b , Gross, J.^c , Girault, J.B.^c , Rutsohn, J.^d , Wolff, J.J.^e , Swanson, M.R.^f , Lee, C.M.^a , Dager, S.R.^g , Cornea, E.^j , Stephens, R.^h , Styner, M.^h , John, T.S.ⁱ , Pandey, J.^j , Deva, M.^h , Botteron, K.N.^k , Estes, A.M.^i l , Hazlett, H.C.^c , Pruett, J.R., Jr.^k , Schultz, R.T.^j , Zwaigenbaum, L.^m , Gilmore, J.H.^h , Shen, M.D.^c h , Piven, J.^c , Elison, J.T.^a b , for the IBIS Networkⁿ

^a Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
^b Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
^c Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
^d Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^e Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
^f School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
^g Deptartment of Radiology, University of Washington Medical Center, Seattle, WA, United States
^h Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
ⁱ University of Washington Autism Center, University of Washington, Seattle, WA, United States
^j Center for Autism Research, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^k Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^l Deptartment of Speech and Hearing Science, University of Washington, Seattle, WA, United States
^m Deptartment of Pediatrics, University of Alberta, Edmonton, AB, Canada

Abstract
Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6–12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups. © 2023 The Authors

Author Keywords
Amygdala;  Anxiety;  Autism spectrum disorder (ASD);  Magnetic resonance imaging (MRI);  Reproducibility

Funding details
National Science FoundationNSF
National Institutes of HealthNIHID 8084, K12-HD055887, K23-HD112507, P50-HD103573, R01-HD055741, R01-MH118362–01, U54-HD079124, U54-HD086984
National Institute of Mental HealthNIMHT32 MH015755
Autism SpeaksAS
Simons FoundationSF140209
University of MinnesotaUMN

Document Type: Article
Publication Stage: Final
Source: Scopus

The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients
(2024) Brain, Behavior, and Immunity, 116, pp. 362-369. 

Lutgendorf, S.K.^a b c , Telles, R.M.^a , Whitney, B.^a , Thaker, P.H.^d , Slavich, G.M.^e f , Goodheart, M.J.^b c , Penedo, F.J.^g , Noble, A.E.^a , Cole, S.W.^e f h , Sood, A.K.ⁱ , Corn, B.W.^j k

^a Department of Psychological & Brain Sciences, University of Iowa, Iowa City, IA, United States
^b Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States
^c Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
^d Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States
^e Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, CA, United States
^f Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
^g Departments of Psychology and Medicine and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
^h Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
ⁱ Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
^j Shaare Zedek Medical Center, Jerusalem, Israel
^k Hebrew University, Faculty of Medicine, Jerusalem, Israel

Abstract
Introduction: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers. Method: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression. Results: Greater hope was significantly related to a steeper cortisol slope, β = −0.193, p = 0.046, and lower night cortisol, β = −0.227, p = 0.018, plasma IL-6, β = −0.142, p = 0.033, and ascites IL-6, β = −0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol β = −0.233, p = 0.017 and ascites IL-6, β = −0.282, p = 0.003, and between hopelessness and a flatter cortisol slope, β = 0.211, p = 0.031. Conclusions: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope. © 2023 Elsevier Inc.

Author Keywords
Diurnal cortisol;  Hope;  Hopelessness;  Inflammation;  Interleukin-6;  Ovarian cancer;  Positive psychology

Funding details
National Institutes of HealthNIHCA109298, CA140933, CA193249, CA209904, CA246540, P30CA086862
American Cancer SocietyACSOPR21101

Document Type: Article
Publication Stage: Final
Source: Scopus

Assessing Needs and Perceptions of Research Participation in Pediatric-Onset Multiple Sclerosis: A Multistakeholder Survey
(2024) Pediatric Neurology, 151, pp. 115-120. 

Gambrah-Lyles, C.^a b , Kannan, V.^c , Lotze, T.^c , Abrams, A.^d , Schreiner, T.^e , Rodriguez, M.^f , Casper, T.C.^g , Rose, J.W.^h , Gorman, M.P.ⁱ , Chitnis, T.^j , Loud, S.^k , Wheeler, Y.^l , Mar, S.^m , US Network of Pediatric MS Centersⁿ

^a Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
^b Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
^c Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine at Texas Children’s Hospital, Houston, Texas, United States
^d Cleveland Clinic, Center for Pediatric Neurosciences and Mellen Center for MS, Neurologic Institute, Cleveland, Ohio, United States
^e Departments of Pediatrics and Neurology, Children’s Hospital Colorado, University of Colorado, Aurora, Colorado, United States
^f Department of Pediatrics, Mayo Clinic Pediatric MS Center, Rochester, Minnesota, United States
^g Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States
^h Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, United States
ⁱ Department of Neurology, Boston Children’s Hospital, Pediatric Multiple Sclerosis and Related Diseases Program, Boston, Massachusetts, United States
^j Department of Neurology, Brigham and Women’s Hospital, Pediatric Multiple Sclerosis Center, Boston, Massachusetts, United States
^k Accelerated Cure Project, Inc. and iConquerMS, Waltham, Massachusetts, United States
^l Department of Pediatrics, Center for Pediatric Onset Demyelinating Disease, University of Alabama at Birmingham, Birmingham, Alabama, United States
^m Department of Neurology, Washington University in Saint Louis, St. Louis, Missouri, United States

Abstract
Background: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey. Methods: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS). Results: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs. Conclusions: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation. © 2023 Elsevier Inc.

Author Keywords
Multiple sclerosis;  Patient engagement;  Patient perspective;  Pediatric multiple sclerosis;  Survey

Funding details
National Multiple Sclerosis SocietyNMSSSI-2110-38420
Patient-Centered Outcomes Research InstitutePCORI20262-ACPMS

Document Type: Article
Publication Stage: Final
Source: Scopus

Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development
(2024) Immunity, 57 (1), pp. 86-105.e9. Cited 1 time.

Tagliatti, E.^a b , Desiato, G.^a , Mancinelli, S.^c , Bizzotto, M.^a c , Gagliani, M.C.^d , Faggiani, E.^a , Hernández-Soto, R.^a , Cugurra, A.^a , Poliseno, P.^a , Miotto, M.^a , Argüello, R.J.^e , Filipello, F.^a f , Cortese, K.^d , Morini, R.^a , Lodato, S.^a c , Matteoli, M.^a g

^a IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, Milan, 20089, Italy
^b Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
^c Humanitas University, Department of Biomedical Sciences, Via Levi Montalicini 4, Pieve Emanuele, Milan, 20072, Italy
^d Cellular Electron Microscopy Laboratory, Department of Experimental Medicine (DIMES), Human Anatomy, Università di Genova, Via Antonio de Toni 14, Genova, 16132, Italy
^e Aix Marseille Univ, CNRS, INSERM, CIML, Centre d’Immunologie de Marseille-Luminy, Marseille, France
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^g Institute of Neuroscience – National Research Council, Milan, 20139, Italy

Abstract
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer’s disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner. © 2023 The Authors

Author Keywords
hippocampus;  metabolism;  microglia;  mitochondria;  neurodevelopment;  TREM2

Funding details
European Research CouncilERC101055323
Fondazione TelethonFT

Document Type: Article
Publication Stage: Final
Source: Scopus

DGIdb 5.0: rebuilding the drug-gene interaction database for precision medicine and drug discovery platforms
(2024) Nucleic Acids Research, 52 (D1), pp. D1227-D1235. 

Cannon, M.^a , Stevenson, J.^a , Stahl, K.^a , Basu, R.^a , Coffman, A.^b , Kiwala, S.^b , McMichael, J.F.^b , Kuzma, K.^a , Morrissey, D.^b , Cotto, K.^b , Mardis, E.R.^a c , Griffith, O.L.^b , Griffith, M.^b , Wagner, A.H.^a c

^a Steve and Cindy Rasmussen Institute for Genomic Medicine ,Nationwide Children’s Hospital, Columbus, United States
^b Department of Medicine, Washington University, St Louis, MO 63110, United States
^c Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH 43210, United States

Abstract
The Drug-Gene Interaction Database (DGIdb, https://dgidb.org) is a publicly accessible resource that aggregates genes or gene products, drugs and drug-gene interaction records to drive hypothesis generation and discovery for clinicians and researchers. DGIdb 5.0 is the latest release and includes substantial architectural and functional updates to support integration into clinical and drug discovery pipelines. The DGIdb service architecture has been split into separate client and server applications, enabling consistent data access for users of both the application programming interface (API) and web interface. The new interface was developed in ReactJS, and includes dynamic visualizations and consistency in the display of user interface elements. A GraphQL API has been added to support customizable queries for all drugs, genes, annotations and associated data. Updated documentation provides users with example queries and detailed usage instructions for these new features. In addition, six sources have been added and many existing sources have been updated. Newly added sources include ChemIDplus, HemOnc, NCIt (National Cancer Institute Thesaurus), Drugs@FDA, HGNC (HUGO Gene Nomenclature Committee) and RxNorm. These new sources have been incorporated into DGIdb to provide additional records and enhance annotations of regulatory approval status for therapeutics. Methods for grouping drugs and genes have been expanded upon and developed as independent modular normalizers during import. The updates to these sources and grouping methods have resulted in an improvement in FAIR (findability, accessibility, interoperability and reusability) data representation in DGIdb. © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

Document Type: Article
Publication Stage: Final
Source: Scopus

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity
(2024) Brain: A Journal of Neurology, 147 (1), pp. 186-200. 

Hakon, J.^a , Quattromani, M.J.^a , Sjölund, C.^a , Talhada, D.^a , Kim, B.^b , Moyanova, S.^c , Mastroiacovo, F.^c , Di Menna, L.^c , Olsson, R.^d , Englund, E.^e , Nicoletti, F.^c f , Ruscher, K.^a , Bauer, A.Q.^b , Wieloch, T.^a

^a Division of Neurosurgery, Department of Clinical Sciences, Laboratory for Experimental Brain Research, Lund University, Lund, 221 84, Sweden
^b Department of Radiology, Washington UniversitySaint Louis MO 63110, United States
^c Department of Molecular Pathology, IRCCS Neuromed, Pozzilli, 86077, Italy
^d Department of Experimental Medical Sciences, Chemical Biology & Therapeutics, Lund University, Lund, 221 84, Sweden
^e Division of Pathology, Department of Clinical Sciences, Lund University, Lund, 221 84, Sweden
^f Department of Physiology and Pharmacology, University of Rome La Sapienza, Rome, 00185, Italy

Abstract
Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
long term depression;  pharmacological therapy;  plasticity;  resting-state functional connectivity;  stroke recovery

Document Type: Article
Publication Stage: Final
Source: Scopus

Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma
(2024) Cell, 187 (1), pp. 149-165.e23. 

Kirschenbaum, D.^a , Xie, K.^a , Ingelfinger, F.^a , Katzenelenbogen, Y.^a , Abadie, K.^a , Look, T.^b , Sheban, F.^a , Phan, T.S.^a , Li, B.^a , Zwicky, P.^a , Yofe, I.^a , David, E.^a , Mazuz, K.^a , Hou, J.^c , Chen, Y.^c , Shaim, H.^d , Shanley, M.^d , Becker, S.^e , Qian, J.^f , Colonna, M.^c , Ginhoux, F.^f g , Rezvani, K.^d , Theis, F.J.^e , Yosef, N.^a h i , Weiss, T.^b , Weiner, A.^a , Amit, I.^a

^a Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
^b Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
^e Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^f Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
^g Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, 138648, Singapore
^h Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, United States
ⁱ Center for Computational Biology, University of California, Berkeley, CA, United States

Abstract
Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies. © 2023 Elsevier Inc.

Author Keywords
cancer;  computational biology;  dynamics;  glioblastoma;  immunology;  immunotherapy;  single-cell biology;  systems immunology;  temporal transcriptomics;  tumor-associated-macrophages

Funding details
101055341-TROJAN-Cell
607/20
Howard Hughes Medical InstituteHHMI
European Molecular Biology OrganizationEMBO
Deutsche ForschungsgemeinschaftDFG259373024
Israel Science FoundationISF1944/22
Azrieli Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Sensory neurons promote immune homeostasis in the lung
(2024) Cell, 187 (1), pp. 44-61.e17. 

Tamari, M.^{a b c d e f} , Del Bel, K.L.^g , Ver Heul, A.M.^h , Zamidar, L.^a b c d , Orimo, K.^f , Hoshi, M.^i j , Trier, A.M.^k , Yano, H.^l m n , Yang, T.-L.^k , Biggs, C.M.^g , Motomura, K.^f , Shibuya, R.^a b c d , Yu, C.D.^o p , Xie, Z.^a b d , Iriki, H.^a b c d , Wang, Z.^a b c d , Auyeung, K.^a b c d , Damle, G.^q r , Demircioglu, D.^q r , Gregory, J.K.^s , Hasson, D.^q r t u , Dai, J.^v w , Chang, R.B.^o p x , Morita, H.^f y , Matsumoto, K.^f , Jain, S.^i j , Van Dyken, S.ⁱ , Milner, J.D.^z , Bogunovic, D.^{c q t aa ab ac ad} , Hu, H.^a b d , Artis, D.^{l m n x ae} , Turvey, S.E.^g , Kim, B.S.^{a b c d x}

^a Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^b Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^c Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^d Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^e Department of Pediatrics, Jikei University School of Medicine, Minato-ku, Tokyo, 1058471, Japan
^f Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, 1578535, Japan
^g Department of Pediatrics, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada
^h Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^k Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, United States
^m Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, United States
ⁿ Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10021, United States
^o Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, United States
^p Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, United States
^q Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^r Skin Biology and Disease Resource-based Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^s Digital and Technology Partners, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^t Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^u Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^v Department of Pharmacological Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^w Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^x Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, United States
^y Allergy Center, National Center for Child Health and Development, Setagaya-ku, Tokyo, 1578535, Japan
^z Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, United States
^aa Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^ab Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^ac Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^ad Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^ae Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY 10021, United States

Abstract
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future. © 2023 The Authors

Author Keywords
AAV;  afferent nerves;  allergic lung inflammation;  atopic disorders;  CGRP;  ILC2;  JAK1;  neuropeptide;  sensory neurons;  vagus nerve

Funding details
National Institutes of HealthNIHS10OD026880
National Institute on Alcohol Abuse and AlcoholismNIAAAAA027065, AR080219, AT012041
National Cancer InstituteNCIAR079200, CA196521
National Institute of Allergy and Infectious DiseasesNIAIDAI167047, AI167933
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKAR077183, DK103901
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSAR070116, AR077007, AR080392
Doris Duke Charitable FoundationDDCF
Icahn School of Medicine at Mount SinaiISMMS
National Center for Child Health and DevelopmentNCCHD2022B-11
Crohn’s and Colitis FoundationCCF20H01622, 937437, AI007163, AI154912

Document Type: Article
Publication Stage: Final
Source: Scopus

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication
(2024) Cell Metabolism, . 

Tokizane, K.^a , Brace, C.S.^a , Imai, S.-I.^a b

^a Departments of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control. © 2023 The Author(s)

Author Keywords
aging;  DMH;  dorsomedial hypothalamus;  eNAMPT;  longevity;  PKG;  Ppp1r17;  protein kinase G;  sympathetic nervous system;  white adipose tissue

Funding details
National Institute on AgingNIAAG037457, AG047902
American Federation for Aging ResearchAFAR
Glenn Foundation for Medical ResearchGFMR
University of WashingtonUW
Washington University School of Medicine in St. LouisWUSM

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

The Perceived Meaning of Traumatic Brain Injury for Older Adults: A Longitudinal-Multiple Case Study
(2024) Rehabilitation Nursing: The Official Journal of the Association of Rehabilitation Nurses, 49 (1), pp. 14-23. 

Jung, W.^a , Vogel, M.^b , Figuracion, K.C.F.^c , Byun, E.^d , Thompson, H.^e

^a RESILIENCE Center, School of Nursing, Johns Hopkins University, Baltimore, MD, United States
^b Center for Public Health Systems Science, Institute for Clinical and Translational Science, Brown School, Washington University in St. Louis, St Louis, MO, United States
^c School of Nursing, Alvord Brain Tumor Center, Department of Radiation Oncology, University of Washington, Seattle, WA, United States
^d Department of Biobehavioral Nursing & Health Informatics, School of Nursing, University of Washington, Seattle, WA, United States
^e Department of Biobehavioral Nursing & Health Informatics, School of Nursing, Harborview Injury Prevention and Research Center, University of Washington, Seattle, WA, United States

Abstract
PURPOSE: The aim of this study was to explore the perceived meaning of traumatic brain injury (TBI) over the first-year postinjury among older adults and to explore if and how meaning changes. DESIGN: A longitudinal multiple-case study design was used. METHODS: Semistructured face-to-face interviews were completed at 1 week and 1, 3, 6, and 12 months postinjury. Transcripts were analyzed using inductive thematic analysis. RESULTS: Fifty-five interviews were conducted with 12 participants. Four themes were identified: gratitude, vulnerability and dependence, slowing down and being more careful, and a chance for reflecting on life. Most participants’ perceptions of their TBI remained either consistently positive or negative over the first-year postinjury. CLINICAL RELEVANCE: Nurses should elicit and support patients’ positive illness perceptions regarding their brain injury, which can contribute to a higher quality of life. For those patients with negative illness perceptions, nurses should provide resources in order to support coping and resilience following brain injury. CONCLUSIONS: This study is the first study to explore individual perceptions over time of the meaning made from experiencing TBI among older adults. Findings can serve as a foundation for tailored supportive interventions among older adults following TBI to maximize quality of life. Copyright © 2023 Association of Rehabilitation Nurses.

Document Type: Article
Publication Stage: Final
Source: Scopus

Responsive Neurostimulation for People With Drug-Resistant Epilepsy and Autism Spectrum Disorder
(2024) Journal of Clinical Neurophysiology: Official Publication of the American Electroencephalographic Society, 41 (1), pp. 64-71. Cited 3 times.

Fields, M.C.^a , Marsh, C.^a , Eka, O.^a , Johnson, E.A.^b , Marcuse, L.V.^a , Kwon, C.-S.^a c , Young, J.J.^a , LaVega-Talbott, M.^a , Kurukumbi, M.^d , Von Allmen, G.^e , Zempel, J.^f , Friedman, D.^g , Jette, N.^a , Singh, A.^a , Yoo, J.Y.^a , Blank, L.^a , Panov, F.^c , Ghatan, S.^c

^a Department of Neurology, Icahn School of Medicine at Mount SinaiNY, United States
^b Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, Icahn School of Medicine at Mount SinaiNY, United States
^d Department of Neurology, Inova Fairfax HospitalVA, United States
^e Division of Pediatric Epilepsy, McGovern Medical School, UTHealth, Houston, TX, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, U.S.A. ; and
^g Department of Neurology, New York University Langone Medical CenterNY, United States

Abstract
PURPOSE: Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System. METHODS: This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis. RESULTS: Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a >50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction >90%). For the super responders, two of the four patients had the device implanted for >2 years. The response rate was 70% for those in whom the device was implanted for >2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported. CONCLUSIONS: Based on the authors’ experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Clinical Neurophysiology Society.

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations Between Coordination and Wearable Sensor Variables Vary by Recording Context but Not Assessment Type
(2024) Journal of Motor Behavior, . 

Konrad, J.D.^a , Marrus, N.^b , Lohse, K.R.^a , Thuet, K.M.^a , Lang, C.E.^a c d

^a Washington University School of Medicine, Mail Stop Code: 8502-66-1101, 4444 Forest Park, St. Louis, MO 63108, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
^c Program in Occupational Therapy, Washington University School of Medicine, St. Louis, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, United States

Abstract
Motor coordination is an important driver of development and improved coordination assessments could facilitate better screening, diagnosis, and intervention for children at risk of developmental disorders. Wearable sensors could provide data that enhance the characterization of coordination and the clinical utility of that data may vary depending on how sensor variables from different recording contexts relate to coordination. We used wearable sensors at the wrists to capture upper-limb movement in 85 children aged 6–12. Sensor variables were extracted from two recording contexts. Structured recordings occurred in the lab during a unilateral throwing task. Unstructured recordings occurred during free-living activity. The objective was to determine the influence of recording context (unstructured versus structured) and assessment type (direct vs. indirect) on the association between sensor variables and coordination. The greatest associations were between six sensor variables from the structured context and the direct measure of coordination. Worse coordination scores were associated with upper-limb movements that had higher peak magnitudes, greater variance, and less smoothness. The associations were consistent across both arms, even though the structured task was unilateral. This finding suggests that wearable sensors could be paired with a simple, structured task to yield clinically informative variables that relate to motor coordination. © 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.

Author Keywords
accelerometry;  developmental coordination disorder;  motor coordination;  wearable sensors

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

Avoidance and fear day by day in social anxiety disorder
(2024) Psychotherapy Research, . 

Rodebaugh, T.L.^a b , Grossman, J.T.^a , Tonge, N.A.^c , Shin, J.^a , Frumkin, M.R.^a , Rodriguez, C.R.^a , Ortiz, E.G.^a , Piccirillo, M.L.^d

^a Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, United States
^b Department of Psychology and Neuroscience, The University of North Carolina at Chapel Hill, Chapel Hill, United States
^c Department of Psychology, George Mason University, Fairfax, United States
^d Department of Psychology, University of Washington, Seattle, United States

Abstract
Objective: Theories assert that avoidance maintains maladaptive anxiety over time, yet a clear prospective test of this effect in the day-by-day lives of people with social anxiety disorder (SAD) is lacking. Method: We used intensive longitudinal data to test prospective relationships between social fear and social avoidance in 32 participants with SAD who reported on a total of 4256 time points. Results: Results suggested that avoidance strongly predicted future anxiety, but only in a minority of people with SAD. Relationships between anxiety and avoidance varied considerably across individuals. Pre-registered tests found that the strength of autocorrelation for social fear is a good target for future testing of prediction of exposure response. Participants with lower autocorrelations were less likely to show between-session habituation. Conclusions: Overall, results suggest avoidance maintains fear in SAD for at least some individuals, but also indicates considerable variability. Further intensive longitudinal data is needed to examine individuals with SAD across varying time courses. © 2024 Society for Psychotherapy Research.

Author Keywords
avoidance;  cognitive behavioral models;  exposure;  idiographic models;  social anxiety disorder

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

Helmet Therapy for the Management of Deformational Plagiocephaly in Pediatric Patients with Shunted Hydrocephalus
(2024) Cleft Palate Craniofacial Journal, . 

Johnson, E.A.^a , Koller, G.M.^a , Jafrani, R.^a , Patel, K.^b , Naidoo, S.^b , Strahle, J.M.^a

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Plastics & Reconstructive Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Objective: To evaluate the safety and efficacy of helmet therapy for deformational plagiocephaly in patients with shunted hydrocephalus. Design: Retrospective chart review. Setting: Institutional, tertiary-care hospital. Patients: All patients at St. Louis Children’s Hospital between 2014 and 2021 with shunted hydrocephalus who underwent helmet therapy for deformational plagiocephaly. Interventions: Helmet therapy. Main Outcome Measures: Cranial vault asymmetry (CVA), cranial vault asymmetry index (CVAI), and cephalic index (CI) were measured before and after completion of helmet therapy. Results: There were 37 patients with shunted hydrocephalus and documented deformational plagiocephaly. Twelve were managed with helmet therapy. Average age at helmeting initiation and time between shunt placement and helmeting initiation was 5.8 and 4.6 months, respectively. Average CVA, CVAI, and CI at helmeting initiation and termination was 11.6, 7.98, and 85.2, and 6.95, 4.49, and 83.7, respectively. Average duration of helmeting was 3.7 months. CVA and CVAI were significantly lower after helmeting (P =.0028 and.0021) and 11/12 patients had overall improvement in plagiocephaly. Conclusions: Helmet therapy appears to be a safe and efficacious management strategy for deformational plagiocephaly in patients with shunted hydrocephalus. Despite the occasional need for additional fittings and surveillance beyond the normal schedule, in all cases appropriately fitting helmets were achieved and no major adverse events occurred. This cohort represents a proof of principle for the safety and efficacy of helmet therapy in patients with shunted hydrocephalus. Further work in larger prospective cohorts is needed to confirm these initial findings. © 2024, American Cleft Palate Craniofacial Association.

Author Keywords
cranial molding orthosis;  deformational plagiocephaly;  helmeting;  hydrocephalus;  ventriculoperitoneal shunt

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

Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement
(2024) Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine, 20 (1), pp. 121-125. 

Rishi, M.A.^a , Cheng, J.Y.^b , Strang, A.R.^c , Sexton-Radek, K.^d , Ganguly, G.^e , Licis, A.^f , Flynn-Evans, E.E.^g , Berneking, M.W.^h , Bhui, R.ⁱ , Creamer, J.^j , Kundel, V.^k , Namen, A.M.^l , Spector, A.R.^m , Olaoye, O.ⁿ , Hashmi, S.D.^o , Abbasi-Feinberg, F.^p , Abreu, A.R.^q , Gurubhagavatula, I.^r s , Kapur, V.K.^t , Kuhlmann, D.^u , Martin, J.^v w , Olson, E.^x , Patil, S.^y z , Rowley, J.^aa , Shelgikar, A.^ab , Trotti, L.M.^ac , Wickwire, E.M.^ad ae , Sullivan, S.S.^af

^a Indiana University School of Medicine, Indianapolis, IN, United States
^b Eisai, Inc., Nutley, NJ, United States
^c Division of Pulmonary and Sleep Medicine, Nemours Children’s Hospital, Wilmington, DE, United States
^d Department of Psychology, Elmhurst University, Elmhurst, IL, United States
^e Neurology Consultants Medical Group, Whittier, CA, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Fatigue Countermeasures Laboratory, Human Systems Integration Division, NASA Ames Research
^h Kalamazoo, MI, United States
ⁱ University of British Columbia, Vancouver, BC, Canada
^j Sleep Disorders Center at Walter Reed National Military Medical Center, Bethesda, MD, Liberia
^k Division of Pulmonary, Critical Care, Sleep Medicine, Icahn School of Medicine at Mount SinaiNY, United States
^l Wake Forest Baptist Health, Winston-SalemNC, United States
^m Department of Neurology, Duke University School of Medicine, Durham, NC, United States
ⁿ Ascent Sleep & Weight Disorders CenterTX, United States
^o American Academy of Sleep Medicine, Darien, Illinois
^p Sleep Medicine, Millennium Physician Group, Fort Myers, FL, Puerto Rico
^q Miller School of Medicine/Universisty of Miami UHealth Sleep Program, Miami, FL, Puerto Rico
^r Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^s Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
^t Division of Pulmonary Critical Care and Sleep Medicine, University of Washington, Seattle, WA, United States
^u Sleep Medicine, Bothwell Regional Health Center, Sedalia, MO, United States
^v Geriatric Research, Education and Clinical Center, Veteran Affairs Greater Los Angeles Healthcare System, North HillsCA, United States
^w David Geffen School of Medicine at the University of California, Los Angeles, CA, United States
^x Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^y Sleep Medicine Program, University Hospitals of Cleveland, Cleveland, OH, United States
^z Case Western Reserve University School of Medicine, Cleveland, OH, United States
^aa Rush University Medical Center, Chicago, IL, United States
^ab University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, MI, United States
^ac Emory Sleep Center and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
^ad Sleep Disorders Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, Liberia
^ae Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, Liberia
^af Division of Pulmonary, Asthma, Sleep Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States

Abstract
The period of the year from spring to fall, when clocks in most parts of the United States are set one hour ahead of standard time, is called daylight saving time, and its beginning and ending dates and times are set by federal law. The human biological clock is regulated by the timing of light and darkness, which then dictates sleep and wake rhythms. In daily life, the timing of exposure to light is generally linked to the social clock. When the solar clock is misaligned with the social clock, desynchronization occurs between the internal circadian rhythm and the social clock. The yearly change between standard time and daylight saving time introduces this misalignment, which has been associated with risks to physical and mental health and safety, as well as risks to public health. In 2020, the American Academy of Sleep Medicine (AASM) published a position statement advocating for the elimination of seasonal time changes, suggesting that evidence best supports the adoption of year-round standard time. This updated statement cites new evidence and support for permanent standard time. It is the position of the AASM that the United States should eliminate seasonal time changes in favor of permanent standard time, which aligns best with human circadian biology. Evidence supports the distinct benefits of standard time for health and safety, while also underscoring the potential harms that result from seasonal time changes to and from daylight saving time. CITATION: Rishi MA, Cheng JY, Strang AR, et al. Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2024;20(1):121-125. © 2024 American Academy of Sleep Medicine.

Author Keywords
daylight saving time;  standard time

Document Type: Article
Publication Stage: Final
Source: Scopus

Laser interstitial thermal therapy compared with open resection for treating subependymal giant cell astrocytoma
(2024) Journal of Neurosurgery. Pediatrics, 33 (1), pp. 95-104. 

Aum, D.J.^a , Reynolds, R.A.^b , McEvoy, S.D.^a , Wong, M.^c , Roland, J.L.^a , Smyth, M.D.^b

^a 2Department of Neurological Surgery, Washington University in St. Louis, Missouri; and
^b 1Division of Pediatric Neurosurgery, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, Puerto Rico
^c Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE: Subependymal giant cell astrocytomas (SEGAs) are WHO grade 1 tumors associated with tuberous sclerosis that classically arise from the ventricular wall near the caudate groove and foramen of Monro. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique, which works by heating a stereotactically placed laser fiber to ablative temperatures under MRI thermometry monitoring. In this paper, the authors present LITT as a surgical alternative to open resection of SEGAs. METHODS: Twelve patients with SEGAs who underwent 16 procedures between 2007 and 2022 at a single institution were retrospectively reviewed. These patients underwent either open resection or LITT. Clinical data, imaging, recurrence rate, further treatments, and related complications were analyzed. RESULTS: Among the 16 procedures, 9 were open resection and 7 were LITT. An external ventricular drain was placed in 66% (6/9) of open procedures and 57.1% (4/7) of LITT cases. A septostomy was performed in 56% (5/9) of open procedures and 29% (2/7) of LITT cases. Complication rates were higher in open cases than in LITT procedures (44% vs 0%, p < 0.05). Complications included hydrocephalus, transient venous ischemia, wound infection, and bone flap migration. The median length of hospital stay was 4 days (IQR 3.3-5.5 days) for open cases and 4 days (IQR 3.0-7.0 days) for LITT procedures. Recurrence or progression occurred after 3 open cases and 2 LITT cases (33% vs 33%, p = 0.803). For the recurrences, 2 open cases underwent stereotactic radiosurgery, 1 open case underwent LITT, and 1 LITT case underwent repeat LITT. Among the LITT cases, only the patients with no decrease in tumor size by 6 months experienced tumor progression afterward. The 2 LITT cases with progression were the only ones with calcification present on preoperative imaging. The median follow-up times for cases assessed for progression were 8.4 years (IQR 3.8-14.4 years) for open resection and 3.9 years (IQR 3.4-5.1 years) for LITT. CONCLUSIONS: The small size of this case series limits generalizability or adequate comparison of safety. However, this series adds to the literature supporting LITT as a less invasive surgical alternative to open resection of SEGAs and demonstrates that LITT has similar recurrence and/or progression rates to open resection. Additional studies with more data are necessary for comprehensive comparisons between open resection and LITT for treating SEGA.

Author Keywords
laser interstitial thermal therapy;  LITT;  SEGA;  subependymal giant cell astrocytoma;  tuberous sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

Impact of environment on pediatric and adult brain tumors: The 2023 Brain Tumor Epidemiology Consortium meeting report
(2024) Clinical Neuropathology, 43 (1), pp. 29-35. 

Johnson, K.J.^a , Bauchet, L.^b , McKean-Cowdin, R.^c , Kruchko, C.^d , Lau, C.C.^e , Ostrom, Q.T.^f , Scheurer, M.E.^g , Villano, J.^h , Yuan, Y.ⁱ

^a Brown School Master of Public Health Program, Washington University, St. Louis, MO, United States
^b Montpellier University Hospital, Montpellier, France
^c University of Southern California, Los Angeles, CA, United States
^d Central Brain Tumor Registry of the United States, Chicago, IL, United States
^e The Jackson Laboratory for Genomic Medicine in Farmington, CT, Connecticut Children’s Medical Center, Hartford, CT, United States
^f Department of Neurosurgery, Duke Cancer Institute, The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, NC, United States
^g Baylor College of Medicine, Department of Pediatrics, Division of Hematology, Oncology Texas Children’s Hospital, Cancer and Hematology Centers, Houston, TX, United States
^h University of Kentucky School of Medicine, Lexington, KY, United States
ⁱ University of Alberta, School of Public Health & Women and Children’s Health Research Institute, Canada

Abstract
The Brain Tumor Epidemiology Consortium (BTEC) is an international organization with membership of individuals from the scientific community with interests related to brain tumor epidemiology including surveillance, classification, methodology, etiology, and factors associated with morbidity and mortality. The 2023 annual BTEC meeting entitled “Impact of Environment on Pediatric and Adult Brain Tumors” was held in Lexington, KY, USA on May 22 – 24, 2023. The meeting gathered scientists from the United States, Canada, Australia, and Europe and included four keynote sessions covering genomic, epigenomic, and metabolomic considerations in brain tumor epidemiology, cancer clusters, environmental risk factors, and new approaches to cancer investigation. The meeting also included three abstract sessions and a brainstorming session. A summary of the meeting content is included in this report. © 2024 Dustri-Verlag Dr. Karl Feistle. All rights reserved.

Author Keywords
brain tumors;  epidemiology

Funding details
American Brain Tumor AssociationABTA

Document Type: Article
Publication Stage: Final
Source: Scopus

Sleep restores an optimal computational regime in cortical networks
(2024) Nature Neuroscience, . 

Xu, Y.^a , Schneider, A.^a , Wessel, R.^b , Hengen, K.B.^a

^a Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Physics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Sleep is assumed to subserve homeostatic processes in the brain; however, the set point around which sleep tunes circuit computations is unknown. Slow-wave activity (SWA) is commonly used to reflect the homeostatic aspect of sleep; although it can indicate sleep pressure, it does not explain why animals need sleep. This study aimed to assess whether criticality may be the computational set point of sleep. By recording cortical neuron activity continuously for 10–14 d in freely behaving rats, we show that normal waking experience progressively disrupts criticality and that sleep functions to restore critical dynamics. Criticality is perturbed in a context-dependent manner, and waking experience is causal in driving these effects. The degree of deviation from criticality predicts future sleep/wake behavior more accurately than SWA, behavioral history or other neural measures. Our results demonstrate that perturbation and recovery of criticality is a network homeostatic mechanism consistent with the core, restorative function of sleep. © 2024, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHR01NS118442
Washington University in St. LouisWUSTL

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

A neural mechanism for conserved value computations integrating information and rewards
(2024) Nature Neuroscience, 27 (1), pp. 159-175. 

Bromberg-Martin, E.S.^a , Feng, Y.-Y.^a b , Ogasawara, T.^a , White, J.K.^a , Zhang, K.^a b , Monosov, I.E.^{a b c d e}

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Electrical Engineering, Washington University, St. Louis, MO, United States
^e Pain Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Behavioral and economic theory dictate that we decide between options based on their values. However, humans and animals eagerly seek information about uncertain future rewards, even when this does not provide any objective value. This implies that decisions are made by endowing information with subjective value and integrating it with the value of extrinsic rewards, but the mechanism is unknown. Here, we show that human and monkey value judgements obey strikingly conserved computational principles during multi-attribute decisions trading off information and extrinsic reward. We then identify a neural substrate in a highly conserved ancient structure, the lateral habenula (LHb). LHb neurons signal subjective value, integrating information’s value with extrinsic rewards, and the LHb predicts and causally influences ongoing decisions. Neurons in key input areas to the LHb largely signal components of these computations, not integrated value signals. Thus, our data uncover neural mechanisms of conserved computations underlying decisions to seek information about the future. © 2024, The Author(s).

Funding details
National Institute of Mental HealthNIMHF30MH130103, OCD MH106435, R01MH110594, R01MH116937
Army Research OfficeARO78259-NS-MUR

Document Type: Article
Publication Stage: Final
Source: Scopus

Spatiotemporal jump detection during continuous film viewing: Insights from a flicker paradigm
(2024) Attention, Perception, and Psychophysics, . 

Upadhyayula, A.^a , Henderson, J.M.^b c

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, CB 1125, One Brookings Drive, St. Louis, MO 63130-4899, United States
^b Center for Mind and Brain, University of California, Davis, United States
^c Department of Psychology, University of California, Davis, United States

Abstract
We investigated how sensitive visual processing is to spatiotemporal disruptions in ongoing visual events. Prior work has demonstrated that participants often miss spatiotemporal disruptions in videos presented in the form of scene edits or disruptions during saccades. Here, we asked whether this phenomenon generalizes to spatiotemporal disruptions that are not tied to saccades. In two flicker paradigm experiments, participants were instructed to identify spatiotemporal disruptions created when videos either jumped forward or backward in time. Participants often missed the jumps, and forward jumps were reported less frequently compared with backward jumps, demonstrating that a flicker paradigm produces effects similar to a saccade contingent disruption paradigm. These results suggest that difficulty detecting spatiotemporal disruptions is a general phenomenon that extends beyond trans-saccadic events. © 2024, The Psychonomic Society, Inc.

Author Keywords
Change blindness;  Film comprehension;  Flicker paradigm;  Spatiotemporal disruptions;  Visual cognition

Funding details
National Science FoundationNSF

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

Caregiver descriptions of dystonia in cerebral palsy
(2024) Annals of Clinical and Translational Neurology, . 

Jaleel, F.^a , Rust, A.^a , Cheung, S.^a , Pearson, T.S.^a b , Ueda, K.^a , Robichaux-Viehoever, A.^a , Leger, K.^a , Chintalapati, K.^a , Guez-Barber, D.^c d , Shusterman, M.^e , Aravamuthan, B.^a

^a Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Neurology, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States
^c Division of Child Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^d Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e The Cerebral Palsy Research Network, Salt Lake City, UT, United States

Abstract
Objective: To determine how caregivers describe dystonia in people with cerebral palsy (CP). Methods: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis. Results: 113 caregivers responded on behalf of 56 people with and 57 people without dystonia. If caregivers noted that both voluntary movement and tactile stimulation triggered involuntary movements, that had a 92% positive predictive value for a dystonia diagnosis. Movement features exclusively described in people with CP and dystonia included: (1) stiffening, tensing, or tightening (15% of respondents); (2) involvement of the head (10%), torso (5%), or feet (5%); and (3) triggers of stretching (12.5%), excitement (5%), or transfers (5%). Interpretation: In addition to a thorough exam, asking caregivers of people with CP to describe involuntary movements triggered by voluntary movement or tactile stimulation may inform clinical dystonia diagnosis. © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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

Germline BRCA2 pathogenic variants in pediatric ganglioglioma: Case report and review of the literature
(2024) Child’s Nervous System, . 

Gupta, A.^a , Lechpammer, M.^b , Brossier, N.M.^a

^a Departments of Pediatrics, Washington University School of Medicine, Box 8208, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Foundation One Medicine, Cambridge, United States

Abstract
Background: BRCA1 and BRCA2 are tumor suppressor genes associated with increased risk of breast and ovarian cancer in adulthood. Patients with germline pathogenic variants in these genes have also been reported to develop brain tumors, although it is unclear whether these syndromes are associated with significant increased risk of brain tumor formation. Results: Here, we report a case of a child with germline BRCA2 pathogenic variant presenting with a symptomatic ganglioglioma. To our knowledge, this is the first such patient to be reported. We discuss prior cases of brain tumors in BRCA1/2 patients and evidence for a potential role for BRCA1/2 pathogenic variants in brain tumor formation. Conclusion: BRCA2 germline variants may increase the risk of developing some types of pediatric brain tumors, but further study is needed to determine its effect on low-grade glioma formation. © 2024, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
BRCA2;  Ganglioglioma;  Germline pathogenic variant;  Pediatric;  Tumor suppressor gene

Funding details
FDN20231203

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

Collective overclaiming is related to collective narcissism and numeracy
(2024) Memory and Cognition, . 

Putnam, A.L.^a , Yamashiro, J.K.^b , Tekin, E.^c , Roediger, H.L., III^c

^a Furman University, Greenville, SC 29613, United States
^b University of California, Santa Cruz, CA, United States
^c Washington University in St. Louis, St. Louis, MO, United States

Abstract
When asked to estimate how much their state or nation has contributed to history, people typically provide unreasonably large estimates, claiming that their group has contributed much more to history than nongroup members would estimate, demonstrating collective overclaiming. Why does such overclaiming occur? In the current study we examined factors that might predict collective overclaiming. Participants from 12 U.S. states estimated how much their home state contributed to U.S. history, completed measures of collective narcissism and numeracy, and rated the importance of 60 specific historical events. There was a positive relationship between collective overclaiming and collective narcissism, a negative relationship between collective overclaiming and numeracy, and a positive relationship between collective overclaiming and the importance ratings of the specific events. Together, these results indicate that overclaiming is partially and positively related to collective narcissism and negatively related to people’s ability to work with numbers. We conclude that collective overclaiming is likely determined by several factors, including the availability heuristic and ego protection mechanisms, in addition to collective narcissism and relative innumeracy. © 2023, The Psychonomic Society, Inc.

Author Keywords
Collective memory;  Collective narcissism;  Collective overclaiming;  Numeracy

Funding details
James S. McDonnell FoundationJSMF

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

Age-related alterations in the oscillatory dynamics serving verbal working memory processing
(2023) Aging, 15 (24), pp. 14574-14590. 

Springer, S.D.^a b , Okelberry, H.J.^a b , Willett, M.P.^a b , Johnson, H.J.^a b , Meehan, C.E.^a c , Schantell, M.^a b , Embury, C.M.^a , Rempe, M.P.^a b , Wilson, T.W.^a b d

^a Institute for Human Neuroscience, Boys Town National Research Hospital, Boys Town, NE 68010, USA
^b College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Pharmacology and Neuroscience, Creighton University, Omaha, NE 68131, USA

Abstract
Working memory (WM) is a foundational cognitive function involving the temporary storage of information. Unfortunately, WM is also one of the most sensitive cognitive functions to the detrimental effects of aging. Expanding the field’s understanding of age-related WM changes is critical to advancing the development of strategies to mitigate age-related WM declines. In the current study, we investigated the neural mechanisms serving WM function in seventy-eight healthy aging adults (range: 20.2-65.2 years) using magnetoencephalography (MEG) and a Sternberg WM task with letter stimuli. Neural activity during the different phases of the WM task (i.e., encoding, maintenance, and retrieval) were imaged using a time-frequency resolved beamformer and whole-brain statistics were performed. We found stronger increases in theta activity and stronger decreases in alpha and beta activity (i.e., more negative relative to baseline) as a function of healthy aging. Specifically, age-related increases in theta activity were detected during the encoding period in the primary visual and left prefrontal cortices. Additionally, alpha and beta oscillations were stronger (i.e., more negative) during both encoding and maintenance in the left prefrontal cortex in older individuals. Finally, alpha and beta oscillations during the retrieval phase were stronger (i.e., more negative) in older participants within the prefrontal, parietal, and temporal cortices. Together, these results indicate that healthy aging strongly modulates the neural oscillatory dynamics serving WM function.

Author Keywords
aging;  alpha;  magnetoencephalography;  MEG;  oscillation;  theta

Document Type: Article
Publication Stage: Final
Source: Scopus

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study
(2023) The Journal of Clinical Psychiatry, 85 (1), . 

Cutler, A.J.^a b , Mattingly, G.W.^c , Kornstein, S.G.^d , Aaronson, S.T.^e , Lasser, R.^f , Zhang, H.^f , Rana, N.^f , Brown, C.^f , Levin, S.^g , Miller, C.^g , Kotecha, M.^g , Forrestal, F.^g , Doherty, J.^f

^a Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, United States
^b Corresponding Author: Andrew J. Cutler, 8429 Lorraine Rd #350, FL 34202 ()MD, Liberia
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
^e Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Baltimore, MD, Liberia
^f Sage Therapeutics, Cambridge, MA, United States
^g Biogen Inc., Cambridge, MA, United States

Abstract
Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported. Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s). Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]). Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses. Trial Registration: ClinicalTrials.gov identifier: NCT03864614. © Copyright 2023 Physicians Postgraduate Press, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

GPCR-G protein selectivity revealed by structural pharmacology
(2023) FEBS Journal, . 

Bernhard, S.M.^a b , Han, J.^a b , Che, T.^a b

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, St. Louis, MO, United States

Abstract
Receptor-G protein promiscuity is frequently observed in class A G protein-coupled receptors (GPCRs). In particular, GPCRs can couple with G proteins from different families (Gαs, Gαq/11, Gαi/o, and Gα12/13) or the same family subtypes. The molecular basis underlying the selectivity/promiscuity is not fully revealed. We recently reported the structures of kappa opioid receptor (KOR) in complex with the Gi/o family subtypes [Gαi1, GαoA, Gαz, and Gustducin (Gαg)] determined by cryo-electron microscopy (cryo-EM). The structural analysis, in combination with pharmacological studies, provides insights into Gi/o subtype selectivity. Given the conserved sequence identity and activation mechanism between different G protein families, the findings within Gi/o subtypes could be likely extended to other families. Understanding the KOR-Gi/o or GPCR-G protein selectivity will facilitate the development of more precise therapeutics targeting a specific G protein subtype. © 2023 Federation of European Biochemical Societies.

Author Keywords
bias signaling;  G protein;  GPCR;  selectivity;  structural pharmacology

Funding details
National Institutes of HealthNIHR35 GM143061

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

Disparate Dementia Risk Factors Are Associated with Cognitive Impairment and Rates of Decline in African Americans
(2023) Annals of Neurology, . 

Lachner, C.^a b , Craver, E.C.^c , Babulal, G.M.^d , Lucas, J.A.^b , Ferman, T.J.^b , White, R.O.^e f , Graff-Radford, N.R.^a , Day, G.S.^a

^a Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
^b Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, United States
^c Department of Quantitative Health Sciences, Mayo Clinic Florida, Jacksonville, FL, United States
^d Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^e Division of Community Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, United States
^f Mayo Center for Health Equity and Community Engaged Research, Jacksonville, FL, United States

Abstract
Objective: This study was undertaken to evaluate the frequency of modifiable dementia risk factors and their association with cognitive impairment and rate of decline in diverse participants engaged in studies of memory and aging. Methods: Modifiable dementia risk factors and their associations with cognitive impairment and cognitive decline were determined in community-dwelling African American (AA; n = 261) and non-Hispanic White (nHW; n = 193) participants who completed ≥2 visits at the Mayo Clinic Alzheimer Disease Research Center in Jacksonville, Florida. Risk factors and their associations with cognitive impairment (global Clinical Dementia Rating [CDR] ≥ 0.5) and rates of decline (CDR Sum of Boxes) in impaired participants were compared in AA and nHW participants, controlling for demographics, APOE ɛ4 status, and Area Deprivation Index. Results: Hypertension, hypercholesterolemia, obesity, and diabetes were overrepresented in AA participants, but were not associated with cognitive impairment. Depression was associated with increased odds of cognitive impairment in AA (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 2.13–8.67) and nHW participants (OR = 2.79, 95% CI = 1.21–6.44) but uniquely associated with faster decline in AA participants (β = 1.71, 95% CI = 0.69–2.73, p = 0.001). Fewer AA participants reported antidepressant use (9/49, 18%) than nHW counterparts (57/78, 73%, p < 0.001). Vitamin B12 deficiency was also associated with an increased rate of cognitive decline in AA participants (β = 2.65, 95% CI = 0.38–4.91, p = 0.023). Interpretation: Modifiable dementia risk factors are common in AA and nHW participants, representing important risk mitigation targets. Depression was associated with dementia in AA and nHW participants, and with accelerated declines in cognitive function in AA participants. Optimizing depression screening and treatment may improve cognitive trajectories and outcomes in AA participants. ANN NEUROL 2024. © 2023 American Neurological Association.

Funding details
National Institute on AgingNIAK23 AG064029, P30 AG062677

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

The Saint Louis bridges program: A mental health network of more than one hundred churches and the mental health community
(2023) Journal of the National Medical Association, . 

Hong, B.^a , Scribner, S.^b , Downs, D.^a , Jackson-Beavers, R.^b , Wright, T.^b , Orson, W.^b , Rice, B.^c , Wilson, K.^b , Poirier, R.^d

^a Washington University School of Medicine Department of Psychiatry, 660 South Euclid Avenue, St. Louis, MO 63110-1010, United States
^b Behavioral Health Network of Greater St. Louis, 2 Campbell Plaza, St. Louis, MO 63139-1779, United States
^c New Horizon Seventh Day Christian Church, 206 Emerling Drive, St. Louis, MO 63121, United States
^d Washington University School of Medicine Department of Emergency Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1010, United States

Abstract
This article describes the history and development of a faith-based mental health network of over one hundred Black churches in North St Louis City and County. The Bridges to Care and Recovery (BCR) program is a joint effort of the Black faith community, three community hospitals, local universities, a school of medicine and funding from the city /state departments of mental health. The mission of BCR is to improve the fragmented mental health services to the Black community and to address the stigma of mental illness. This innovative program provides a blueprint for other metropolitan areas to emulate. The present paper is a detailed description of the key elements and services of the Bridges program. © 2023 National Medical Association

Author Keywords
Black church;  Clergy;  Faith-based;  Mental health network;  Mental health referral

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

Bidirectional temporal associations between sleep and affect and cognitive symptoms among community-dwelling stroke survivors: An ecological momentary assessment study
(2023) PM and R, . 

Lau, S.C.L.^a b c , Hall, M.L.^d , Terhorst, L.^a , Skidmore, E.R.^a

^a Department of Occupational Therapy, School of Health and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States
^b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Introduction: Sleep plays a critical role in daily functioning and stroke recovery but receives little attention in stroke rehabilitation. Sleep disturbances are linked to affective and cognitive impairments, but temporal associations between sleep and affect and cognitive symptoms are less clear. Understanding these temporal associations may inform new directions in intervention and prevention to support continued stroke recovery. Objective: To examine the bidirectional temporal associations between sleep and affect and cognitive symptoms among community-dwelling stroke survivors. Design: A secondary analysis of a longitudinal observational study involving 7 days of ecological momentary assessment (EMA), during which participants completed eight EMA surveys and a sleep diary per day. Multilevel modeling was used to analyze data. Setting: Community. Participants: Community-dwelling stroke survivors (N = 40). Interventions: Not applicable. Main Outcome Measures: EMA measures of depressed affect, cheerful affect, and cognitive symptoms. Sleep quality and duration as measured using a sleep diary. Results: Between-person sleep quality was negatively associated with next-day depressed affect (B = −.16; p =.028) and positively associated with next-day cheerful affect (B =.63; p <.001). Inversely, between-person depressed affect was negatively associated with next night sleep quality (B = −.77; p =.015), and vice versa for cheerful affect (between-person: B =.45; p <.001; within-person: B =.09; p =.008). Long sleep (>9 hours) was positively associated with next-day cognitive symptoms (B =.13; p =.002), whereas cognitive symptoms were associated with a higher odds of long sleep the following night (odds ratio [OR] = 0.25; p =.047). Conclusions: This study identified the bidirectional associations of sleep with affect and cognitive symptoms in the context of the everyday life of stroke survivors. The findings suggest that interventions addressing sleep quality and duration may impact affect and cognitive symptoms, and vice versa. © 2023 American Academy of Physical Medicine and Rehabilitation.

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

Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo
(2023) Frontiers in Molecular Neuroscience, 16, art. no. 1320182, . 

Vemula, P., Schoch, K.M., Miller, T.M.

Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Many preclinical and clinical studies support the use of antisense oligonucleotides (ASOs) as effective therapeutic strategies. However, acquiring ASOs for research purposes may be limited by partnerships with the pharmaceutical companies. Our lab previously developed an effective ASO strategy to lower human tau and reverse pathology in aged tauopathy model mice. Testing the efficacy of purchased tau lowering ASOs would provide support for these reagents as broad research tools. Purchased mouse and human tau lowering ASOs were infused or injected intracerebroventricularly into wildtype and tau transgenic mice. Following treatment, brain tissue evaluated for ASO distribution and levels of tau mRNA, protein, and phosphorylated tau. We show that purchased ASOs enter cell types of the brain and effectively decrease mouse or human tau mRNA and protein levels. Human tau lowering ASO treatment in PS19 mice decreased phosphorylated tau and gliosis relative to saline-treated PS19 mice, consistent with our previous study using a non-commercial tau lowering ASO. The results of this study demonstrate the efficacy of purchased tau targeting ASOs in vivo to support their broad use by researchers. Copyright © 2023 Vemula, Schoch and Miller.

Author Keywords
Alzheimer’s disease;  antisense oligonucleotides;  human tau mouse model;  tau protein;  tauopathies

Funding details
National Institutes of HealthNIH
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
University of WashingtonUWS10 RR027552
Tau Consortium
Office of Research Infrastructure ProgramsORIP, NIHOD021629
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

High intensity interval training exercise increases dopamine D2 levels and modulates brain dopamine signaling
(2023) Frontiers in Public Health, 11, art. no. 1257629, . 

Tyler, J.^a b , Podaras, M.^a c , Richardson, B.^a d , Roeder, N.^a d , Hammond, N.^a , Hamilton, J.^a , Blum, K.^e , Gold, M.^f , Baron, D.A.^e , Thanos, P.K.^a d

^a Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
^b Department of Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
^c Department of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United States
^d Department of Psychology, University at Buffalo, Buffalo, NY, United States
^e Center for Sports, Exercsie and Mental Health, Western University of Health Sciences, Pomona, CA, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [3H] SCH 23390 and [3H] spiperone autoradiography, and TH-immunoreactive optical density values. Methods: Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min). Results: Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression. Conclusion: These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior. Copyright © 2023 Tyler, Podaras, Richardson, Roeder, Hammond, Hamilton, Blum, Gold, Baron and Thanos.

Author Keywords
addiction;  autoradiography;  dopamine;  exercise;  reward deficiency;  running;  tyrosine

Funding details
RIAQ1094
University at BuffaloUB

Document Type: Article
Publication Stage: Final
Source: Scopus