WashU weekly Neuroscience publications | Office of Neuroscience Research

“Equivalent learning, but unequal participation: Male bumble bees learn comparably to females, but participate in cognitive assessments at lower rates” (2021) Behavioural Processes

Equivalent learning, but unequal participation: Male bumble bees learn comparably to females, but participate in cognitive assessments at lower rates
(2021) Behavioural Processes, 193, art. no. 104528, .

Manning, T.H.^a ^b , Austin, M.W.^a ^b ^c , MuseMorris, K.^a , Dunlap, A.S.^a ^b

^a Department of Biology, University of Missouri, St. Louis, St. Louis, MO, United States
^b Whitney R. Harris World Ecology Center, St. Louis, MO, United States
^c Living Earth Collaborative, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Sex-specific cognitive abilities are well documented. These can occur when sexes engage in different ecological contexts. Less known is whether different ecological contexts can also drive sex-specific participation rates in behavioral tests. Here, we explore this question in bumble bees, a group of eusocial insects where worker females and males exhibit stark socioecological differences. Among myriad colony maintenance tasks, workers forage for themselves and developing brood, while males forage only for themselves while mate-searching. Following upon previous studies suggesting no sex differences in bumble bee learning, we test the hypothesis that despite having equivalent associative learning abilities, males participate in cognitive assessments offering nutritional rewards at lower rates. Testing > 500 bees from nine colonies in a differential conditioning protocol, we find support for our hypothesis. An equivalent proportion of workers and males successfully completed our cognitive assessment, while a significantly lower proportion of males participated in the entire protocol. Unequal participation is a perennial issue in the behavioral sciences, limiting sample size and potentially biasing results. Our results suggest that to understand the true range of variation in cognition, sex-differences in participation must be accounted for. © 2021 Elsevier B.V.

Author Keywords
Bombus; Free-moving proboscis extension response; Motivation; Participation; Sexual dimorphism; Social insects

Document Type: Article
Publication Stage: Final
Source: Scopus

“BRAF mutations may identify a clinically distinct subset of glioblastoma” (2021) Scientific Reports

BRAF mutations may identify a clinically distinct subset of glioblastoma
(2021) Scientific Reports, 11 (1), art. no. 19999, .

McNulty, S.N.^a , Schwetye, K.E.^a , Ferguson, C.^a , Storer, C.E.^b , Ansstas, G.^c ^d , Kim, A.H.^d ^e , Gutmann, D.H.^f , Rubin, J.B.^d ^g ^h , Head, R.D.^b , Dahiya, S.^a ^d

^a Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
^b Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
^c Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM. © 2021, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Gene-Targeted Therapies in Pediatric Neurology: Challenges and Opportunities in Diagnosis and Delivery” (2021) Pediatric Neurology

Gene-Targeted Therapies in Pediatric Neurology: Challenges and Opportunities in Diagnosis and Delivery
(2021) Pediatric Neurology, 125, pp. 53-57.

Shellhaas, R.A.^a , deVeber, G.^b , Bonkowsky, J.L.^c , Augustine, E.F.^d , Bassuk, A.G.^e , Calame, D.G.^f , Carrasco, M.^g , Dlamini, N.^h , Felling, R.J.ⁱ , Glass, H.C.^j ^k ^l , Grinspan, Z.M.^m , Guerriero, R.M.ⁿ , Hewitt, A.^o , Jeste, S.^p , Knowles, J.K.^q , Lyons-Warren, A.M.^r , Maricich, S.M.^s , Musolino, P.L.^t , Raju, G.P.^u , Rho, J.M.^v , Rotenberg, A.^w , Sherr, E.^x , Soul, J.S.^y , Ziobro, J.^z , Child Neurology Society Research Committee^aa

^a Department of Pediatrics, University of Michigan (Michigan Medicine), Ann Arbor, MI, United States
^b Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
^c Department of Pediatrics, University of Utah School of Medicine, Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT, United States
^d Department of Neurodevelopmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
^e Department of Pediatrics, University of Iowa, Iowa City, IA, United States
^f Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
^g Department of Neurology, University of Wisconsin, Madison, WI, United States
^h Department of Paediatrics and Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada
ⁱ Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, United States
^k Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, United States
^l Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, United States
^m Departments of Population Health Sciences and Pediatrics, Weill Cornell Medicine, New York, NY, United States
ⁿ Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^o Department of Neurology, University of Rochester, Rochester, NY, United States
^p Departments of Psychiatry, Neurology and Pediatrics at the UCLA David Geffen School of Medicine, Los Angeles, CA, United States
^q Child Neurology and Epilepsy, Stanford University School of Medicine, Stanford, CA, United States
^r Instructor, Division of Child Neurology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^s Chief Medical Officer, Allievex Corporation, Marblehead, MA, United States
^t Department of Neurology and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^u Departments of Neurology and Pediatrics, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^v Rady Children’s Hospital, San Diego, La Jolla, CA, United States
^w Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^x Departments of Neurology and Pediatrtics, Institute of Human Genetics, Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, United States
^y Associate Professor, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^z Department of Pediatrics (Pediatric Neurology), Michigan Medicine, University of Michigan, Ann Arbor, MI, United States

Abstract
Background: Gene-targeted therapies are becoming a reality for infants and children with diseases of the nervous system. Rapid scientific advances have led to disease-modifying or even curative treatments. However, delays and gaps in diagnosis, inequitable delivery, and the need for long-term surveillance pose unresolved challenges. Objective and Methods: The goal of the Child Neurology Society Research Committee was to evaluate and provide guidance on the obstacles, opportunities, and uncertainties in gene-targeted therapies for pediatric neurological disease. The Child Neurology Society Research Committee engaged in collaborative, iterative literature review and committee deliberations to prepare this consensus statement. Results: We identified important challenges for gene-targeted therapies that require resource investments, infrastructure development, and strategic planning. Barriers include inequities in diagnosis and delivery of therapies, high costs, and a need for long-term surveillance of efficacy and safety, including systematic tracking of unanticipated effects. Key uncertainties regarding technical aspects and usage of gene-targeted therapies should be addressed, and characterization of new natural histories of diseases will be needed. Counterbalanced with these obstacles and uncertainties is the tremendous potential being demonstrated in treatments and clinical trials of gene-targeted therapies. Conclusions: Given that gene-targeted therapies for neurological diseases are in their earliest phase, the pediatric neurology community can play a vital role in their guidance and implementation. This role includes facilitating development of infrastructure and guidelines; ensuring efficient, equitable, and ethical implementation of treatments; and advocating for affordable and broad access for all children. © 2021 Elsevier Inc.

Author Keywords
Antisense oligonucleotide; Child neurology; Diagnosis; Disparities; Ethics; Gene therapy; Health economics; Rare disease

Document Type: Article
Publication Stage: Final
Source: Scopus

“In vitro characterization of (3H)VAT in cells, animal and human brain tissues for vesicular acetylcholine transporter” (2021) European Journal of Pharmacology

In vitro characterization of [3H]VAT in cells, animal and human brain tissues for vesicular acetylcholine transporter
(2021) European Journal of Pharmacology, 911, art. no. 174556, .

Liang, Q.^a , Joshi, S.^a , Liu, H.^a , Yu, Y.^a , Zhao, H.^a , Benzinger, T.L.S.^a ^b , Perlmutter, J.S.^a ^b ^c , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neurology, Program in Occupational Therapy, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Vesicular acetylcholine transporter plays a crucial role in the cholinergic system, and its alterations is implicated in several neurodegenerative disorders. We recently developed a PET imaging tracer [18F]VAT to target VAChT in vivo with high affinity and selectivity. Here we report in vitro characterization of [3H]VAT, a tritiated counterpart of [18F]VAT. Using human VAChT-rich cell membrane extracts, a saturated binding curve was obtained for [3H]VAT with Kd = 6.5 nM and Bmax = 22.89 pmol/mg protein. In the [3H]VAT competition-binding assay with a panel of CNS ligands, binding inhibition of [3H]VAT was observed using VAChT ligands, the Ki values ranged from 5.41 to 33.3 nM. No inhibition was detected using a panel of other CNS ligands. In vitro [3H]VAT autoradiography of rat brain sections showed strong signals in the striatum, moderate to high signals in vermis, thalamus, cortex, and hippocampus, and weak signals in cerebellum. Strong [3H]VAT ARG signals were also observed from striatal sections of normal nonhuman primates and human brains. Competitive ARG study with human striatal sections demonstrated strong ARG signals of [3H]VAT in caudate and putamen were blocked significantly by either VAChT ligand TZ659 or (−)-vesamicol, but not by the σ1 receptor ligand Yun-122. ARG study also indicated that signal in the striatal sections from PSP human brains was lower than normal human brains. These data provide solid evidence supporting [18F]VAT as a suitable PET radiotracer for quantitative assessment of VAChT levels in vivo. © 2021 Elsevier B.V.

Author Keywords
Autoradiography; Binding assay; Progressive supranuclear palsy; Radioligand; Striatum; Vesicular acetylcholine transporter

Document Type: Article
Publication Stage: Final
Source: Scopus

“Identifying the neurophysiological effects of memory-enhancing amygdala stimulation using interpretable machine learning” (2021) Brain Stimulation

Identifying the neurophysiological effects of memory-enhancing amygdala stimulation using interpretable machine learning
(2021) Brain Stimulation, 14 (6), pp. 1511-1519.

Sendi, M.S.E.^a ^b , Inman, C.S.^c , Bijanki, K.R.^d , Blanpain, L.^e , Park, J.K.^g , Hamann, S.^f , Gross, R.E.^a ^g ^h , Willie, J.T.ⁱ , Mahmoudi, B.^a ^j

^a Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, 313 Ferst Dr NW, Atlanta, GA 30332, United States
^b Department of Electrical and Computer Engineering at Georgia Institute of Technology, 777 Atlantic Dr, Atlanta, GA 30313, United States
^c Department of Psychology at University of Utah, 380 1530 E, Salt Lake City, UT 84112, United States
^d Department of Neurosurgery at Baylor College of Medicine, 7200 Cambridge St 9th Floor, Houston, TX 77030, United States
^e Neuroscience Graduate Program at Emory University, 1462 Clifton Rd. Suite 314, Atlanta, GA 30322, United States
^f Department of Psychology at Emory University, 36 Eagle Row, Atlanta, GA 3032, United States
^g Department of Neurosurgery at Emory University, 100 Woodruff Circle, Atlanta, GA 30322, United States
^h Department of Neurology at Emory University, 12 Executive Park Dr NE, Atlanta, GA 30322, United States
ⁱ Department of Neurology at Washington University School of Medicine in Saint Louis, 660 S. Euclid Avenue Campus Box 8057 St, Louis, MO 63110, United States
^j Department of Biomedical Informatics at Emory University, 100 Woodruff Circle, Atlanta, GA 30322, United States

Abstract
Background: Direct electrical stimulation of the amygdala can enhance declarative memory for specific events. An unanswered question is what underlying neurophysiological changes are induced by amygdala stimulation. Objective: To leverage interpretable machine learning to identify the neurophysiological processes underlying amygdala-mediated memory, and to develop more efficient neuromodulation technologies. Method: Patients with treatment-resistant epilepsy and depth electrodes placed in the hippocampus and amygdala performed a recognition memory task for neutral images of objects. During the encoding phase, 160 images were shown to patients. Half of the images were followed by brief low-amplitude amygdala stimulation. For local field potentials (LFPs) recorded from key medial temporal lobe structures, feature vectors were calculated by taking the average spectral power in canonical frequency bands, before and after stimulation, to train a logistic regression classification model with elastic net regularization to differentiate brain states. Results: Classifying the neural states at the time of encoding based on images subsequently remembered versus not-remembered showed that theta and slow-gamma power in the hippocampus were the most important features predicting subsequent memory performance. Classifying the post-image neural states at the time of encoding based on stimulated versus unstimulated trials showed that amygdala stimulation led to increased gamma power in the hippocampus. Conclusion: Amygdala stimulation induced pro-memory states in the hippocampus to enhance subsequent memory performance. Interpretable machine learning provides an effective tool for investigating the neurophysiological effects of brain stimulation. © 2021 The Authors

Author Keywords
Amygdala stimulation; Feature learning; Hippocampus; Interpretable machine learning; Local field potential; Memory; Neurophysiological biomarkers

Document Type: Article
Publication Stage: Final
Source: Scopus

“Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss” (2021) American Journal of Human Genetics

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
(2021) American Journal of Human Genetics, 108 (10), pp. 2006-2016.

Richard, E.M.^a , Bakhtiari, S.^b ^c , Marsh, A.P.L.^b ^c , Kaiyrzhanov, R.^d , Wagner, M.^e ^f , Shetty, S.^b ^c , Pagnozzi, A.^g , Nordlie, S.M.^b ^c , Guida, B.S.^b ^c , Cornejo, P.^h ⁱ ^j , Magee, H.^b ^c , Liu, J.^b ^c , Norton, B.Y.^b ^c , Webster, R.I.^k , Worgan, L.^l , Hakonarson, H.^m , Li, J.ⁿ , Guo, Y.^o ^p , Jain, M.^q , Blesson, A.^r , Rodan, L.H.^s ^t , Abbott, M.-A.^u , Comi, A.^v ^w , Cohen, J.S.^v ^w , Alhaddad, B.^e , Meitinger, T.^e , Lenz, D.^x , Ziegler, A.^y , Kotzaeridou, U.^y , Brunet, T.^e , Chassevent, A.^v , Smith-Hicks, C.^v ^w , Ekstein, J.^z , Weiden, T.^aa , Hahn, A.^ab , Zharkinbekova, N.^ac , Turnpenny, P.^ad , Tucci, A.^ae , Yelton, M.^af , Horvath, R.^ag , Gungor, S.^ah , Hiz, S.^ai ^aj , Oktay, Y.^ai ^ak , Lochmuller, H.^al , Zollino, M.^am ^an , Morleo, M.^ao , Marangi, G.^am ^an , Nigro, V.^ao ^ap , Torella, A.^ao ^ap , Pinelli, M.^ao , Amenta, S.^am ^an , Husain, R.A.^aq , Grossmann, B.^ar , Rapp, M.^as , Steen, C.^at , Marquardt, I.^au , Grimmel, M.^ar , Grasshoff, U.^ar , Korenke, G.C.^au , Owczarek-Lipska, M.^av ^aw , Neidhardt, J.^av ^ax , Radio, F.C.^ay , Mancini, C.^ay , Claps Sepulveda, D.J.^ay , McWalter, K.^az , Begtrup, A.^az , Crunk, A.^az , Guillen Sacoto, M.J.^az , Person, R.^az , Schnur, R.E.^az , Mancardi, M.M.^ba , Kreuder, F.^bb , Striano, P.^bc ^bd , Zara, F.^bd ^be , Chung, W.K.^bf , Marks, W.A.^bg ^bh , van Eyk, C.L.^bi ^bj , Webber, D.L.^bi ^bj , Corbett, M.A.^bi ^bj , Harper, K.^bi ^bj , Berry, J.G.^bi ^bj , MacLennan, A.H.^bi ^bj , Gecz, J.^bi ^bj ^bk , Tartaglia, M.^ay , Salpietro, V.^bc ^bd , Christodoulou, J.^bl ^bm , Kaslin, J.^bb , Padilla-Lopez, S.^b ^c , Bilguvar, K.^bn ^bo , Munchau, A.^as , Ahmed, Z.M.^a ^bp , Hufnagel, R.B.^bq , Fahey, M.C.^br , Maroofian, R.^d , Houlden, H.^d , Sticht, H.^bs , Mane, S.M.^bn ^bo , Rad, A.^bt , Vona, B.^bt , Jin, S.C.^bu , Haack, T.B.^ar ^bv , Makowski, C.^bw , Hirsch, Y.^z , Riazuddin, S.^a ^bp , Kruer, M.C.^b ^c

^a Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
^b Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
^c Departments of Child Health, Neurology, Cellular, and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine – Phoenix, Phoenix, AZ 85004, United States
^d Department of Neuromuscular Disorders, Institute of Neurology, University College London, Queen Square, London, UK WC1N 3BG, United Kingdom
^e Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, 81675, Germany
^f Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, 85764, Germany
^g CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, QLD 4029, Australia
^h Pediatric Neuroradiology Division, Pediatric Radiology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
ⁱ University of Arizona College of Medicine, Phoenix, AZ 85004, United States
^j Mayo Clinic, Scottsdale, AZ 85259, United States
^k Neurology Department, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia
^l Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
^m Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁿ Department of Computer Science, City University of Hong Kong, Kowloon, 999077, Hong Kong
^o Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^p Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19146, United States
^q Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, United States
^r Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD 21211, United States
^s Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
^t Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, United States
^u University of Massachusetts Medical School – Baystate, Baystate Children’s Hospital, Springfield, MA 01107, United States
^v Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, United States
^w Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^x Centre of Child and Adolescent Medicine, Department of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, 69120, Germany
^y Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
^z Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, New York, NY 11211, United States
^aa Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases9054020, Israel
^ab Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, 35392, Germany
^ac Department of Neurology, South Kazakhstan Medical Academy, Shymkent, 160001, Kazakhstan
^ad Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK EX1 2ED, United Kingdom
^ae Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, School of Medicine and Dentistry Queen Mary University of London, London, UK EC1M 6BQ, United Kingdom
^af Penn State Health Children’s Hospital, Hershey, PA 17033, United States
^ag Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Cambridge, UK CB2 0PY, United Kingdom
^ah Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, 44280, Turkey
^ai Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, 35340, Turkey
^aj Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35340, Turkey
^ak Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35220, Turkey
^al Children’s Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
^am Università Cattolica Sacro Cuore, Facoltà di Medicina e Chirurgia, Dipartimento Scienze della Vita e Sanità Pubblica, Roma, 00168, Italy
^an Fondazione Policlinico A. Gemelli IRCCS, Sezione di Medicina Genomica, Roma, 00168, Italy
^ao Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, 80078, Italy
^ap Department of Precision Medicine, University of Campania “Luigi Vanvitelli,”, Naples, 80138, Italy
^aq Department of Neuropediatrics, Jena University Hospital, Jena, 07747, Germany
^ar Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tuebingen, 72076, Germany
^as Institute of Systems Motor Science, University of Lübeck, Lübeck, 23538, Germany
^at Department of Paediatric and Adolescent Medicine, St Joseph Hospital, Berlin, 12101, Germany
^au University Children’s Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, Oldenburg, 26133, Germany
^av Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
^aw Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI-School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
^ax Research Center Neurosensory Science, University of Oldenburg, Oldenburg, 26129, Germany
^ay Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
^az GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States
^ba Unit of Child Neuropsichiatry, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Giannina Gaslini, Genoa, 16147, Italy
^bb Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3168, Australia
^bc Pediatric Neurology and Muscular Diseases Unit, IRRCS Istituto Giannina Gaslini, Genoa, 16148, Italy
^bd Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 16142, Italy
^be Unit of Medical Genetics, IRRCS Istituto Giannina Gaslini, Genoa, 16147, Italy
^bf Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, United States
^bg Department of Neurology, Cook Children’s Medical Center, Fort Worth, TX 76104, United States
^bh Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
^bi Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5006, Australia
^bj Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia
^bk South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
^bl Brain and Mitochondrial Research Group, Murdoch Children’s Research Institute, Melbourne Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
^bm Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia
^bn Yale Center for Genome Analysis, Yale University, New Haven, CT 06520, United States
^bo Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, United States
^bp Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
^bq Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, United States
^br Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
^bs Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^bt Department of Otolaryngology – Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, 72076, Germany
^bu Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^bv Centre for Rare Diseases, University of Tübingen, Tuebingen, 72074, Germany
^bw Department of Paediatrics, Adolescent Medicine and Neonatology, Munich Clinic, Schwabing Hospital and Technical University of Munich, School of Medicine, Munich, 80804, Germany

Abstract
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype. © 2021

Author Keywords
AAA+ superfamily; ATPase; cerebral palsy; epilepsy; intellectual disability; movement disorder; neurodevelopmental disorder; sensorineural hearing loss; SPATA5L1

Document Type: Article
Publication Stage: Final
Source: Scopus

“Comparison of hippocampal subfield segmentation agreement between 2 automated protocols across the adult life span” (2021) American Journal of Neuroradiology

Comparison of hippocampal subfield segmentation agreement between 2 automated protocols across the adult life span
(2021) American Journal of Neuroradiology, 42 (10), pp. 1783-1789.

Samara, A.^a , Raji, C.A.^b ^c , Li, Z.^a ^d , Hershey, T.^a ^b ^c

^a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Psychological and Brain Sciences, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND AND PURPOSE: The hippocampus is a frequent focus of quantitative neuroimaging research, and structural hippocampal alterations are related to multiple neurocognitive disorders. An increasing number of neuroimaging studies are focusing on hippocampal subfield regional involvement in these disorders using various automated segmentation approaches. Direct comparisons among these approaches are limited. The purpose of this study was to compare the agreement between two automated hippocampal segmentation algorithms in an adult population. MATERIALS AND METHODS: We compared the results of 2 automated segmentation algorithms for hippocampal subfields (FreeSurfer v6.0 and volBrain) within a single imaging data set from adults (n ¼ 176, 89 women) across a wide age range (20-79 years). Brain MR imaging was acquired on a single 3T scanner as part of the IXI Brain Development Dataset and included T1- and T2-weighted MR images. We also examined subfield volumetric differences related to age and sex and the impact of different intracranial volume and total hippocampal volume normalization methods. RESULTS: Estimated intracranial volume and total hippocampal volume of both protocols were strongly correlated (r ¼ 0.93 and 0.9, respectively; both P,.001). Hippocampal subfield volumes were correlated (ranging from r ¼ 0.42 for the subiculum to r ¼ 0.78 for the cornu ammonis [CA]1, all P,.001). However, absolute volumes were significantly different between protocols. volBrain produced larger CA1 and CA4-dentate gyrus and smaller CA2-CA3 and subiculum volumes compared with FreeSurfer v6.0. Regional age- and sex-related differences in subfield volumes were qualitatively and quantitatively different depending on segmentation protocol and intracranial volume/total hippocampal volume normalization method. CONCLUSIONS: The hippocampal subfield volume relationship to demographic factors and disease states should undergo nuanced interpretation, especially when considering different segmentation protocols. © 2021 American Society of Neuroradiology. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Fatigue in Children With Unilateral and Bilateral Hearing Loss” (2021) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and) European Academy of Otology and Neurotology

Fatigue in Children With Unilateral and Bilateral Hearing Loss
(2021) Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society (and) European Academy of Otology and Neurotology, 42 (9), pp. e1301-e1307.

Sindhar, S.^a , Friesen, T.L.^b , Carpenter, D.^c , Kesser, B.^c , Lieu, J.E.C.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Otolaryngology, Department of Surgery, University of California San Diego, San Diego, CA, Mexico
^c Department of Otolaryngology-Head and Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA, United States

Abstract
OBJECTIVE: To determine whether children with unilateral hearing loss (UHL) experience similar levels fatigue as children with bilateral hearing loss (BHL) or normal-hearing (NH). DESIGN: Cross-sectional study. SETTING: Two tertiary care otolaryngology practices. PARTICIPANTS: Children, 5 to 18 years old, with UHL or BHL and their parents. MAIN OUTCOME MEASURES: PedsQL Multidimensional Fatigue Scale (MFS) survey. RESULTS: Overall response rate was 90/384 (23%). Mean age of child participants was 10.7 years old (standard deviations [SD] 3.1); 38 (42%) were men and 52 (58%) were women. Sixty-nine (77%) children had UHL, 21 (23%) had BHL. Children with BHL (mean 65, SD 21) and UHL (mean 75, SD 17) reported greater levels of fatigue than children with NH (BHL difference -15, 95% confidence interval [CI] -25 to -5; UHL difference -6, 95% CI -13-1.2). Parent-proxy reports for children with BHL (mean 67, SD 20) and UHL (mean 76, SD 20) reported more fatigue than NH (BHL difference -22, 95% CI -33 to -12; UHL difference -14; 95% CI -20 to -8). Sub-section scores for general, sleep, and cognitive fatigue were higher for children with BHL and UHL than NH. CONCLUSION AND RELEVANCE: Children with UHL and BHL reported significantly more fatigue than children with NH, and children with BHL reported more fatigue than UHL. These findings underscore the need to increase auditory rehabilitation and educational resources for children with UHL and support the use of the PedsQL MFS questionnaire as a measure to follow disability experienced by children with HL as they undergo hearing rehabilitation. Copyright © 2021, Otology & Neurotology, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia” (2021) Science Translational Medicine

APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
(2021) Science Translational Medicine, 13 (613), art. no. eabc9375, .

Liu, C.-C.^a , Murray, M.E.^a , Li, X.^a , Zhao, N.^a , Wang, N.^a , Heckman, M.G.^b , Shue, F.^a , Martens, Y.^a , Li, Y.^a , Raulin, A.-C.^a , Rosenberg, C.L.^a , Doss, S.V.^a , Zhao, J.^a , Wren, M.C.^a , Jia, L.^a , Ren, Y.^b , Ikezu, T.C.^a , Lu, W.^a , Fu, Y.^a , Caulfield, T.^a , Trottier, Z.A.^a , Knight, J.^a , Chen, Y.^a , Linares, C.^a , Wang, X.^b , Kurti, A.^a , Asmann, Y.W.^b , Wszolek, Z.K.^c , Smith, G.E.^d , Vemuri, P.^e , Kantarci, K.^e , Knopman, D.S.^f , Lowe, V.J.^e , Jack, C.R., Jr.^e , Parisi, J.E.^f ^g , Ferman, T.J.^h , Boeve, B.F.^f , Graff-Radford, N.R.^c , Petersen, R.C.^f , Younkin, S.G.^a , Fryer, J.D.ⁱ , Wang, H.^j , Han, X.^j ^k , Frieden, C.^l , Dickson, D.W.^a , Ross, O.A.^a ^m , Bu, G.^a

^a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
^b Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, United States
^c Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, United States
^d Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, United States
^e Department of Radiology, Mayo Clinic, Rochester, MN 55905, United States
^f Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
^g Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States
^h Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, United States
ⁱ Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, United States
^j Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, United States
^k Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States
^l Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110, United States
^m Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, United States

Abstract
Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB. Copyright © 2021 The Authors, some rights reserved;

Document Type: Article
Publication Stage: Final
Source: Scopus

“Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells” (2021) Frontiers in Synaptic Neuroscience

Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells
(2021) Frontiers in Synaptic Neuroscience, 13, art. no. 740368, .

Boero, L.E.^a ^b ^d , Payne, S.^c , Gómez-Casati, M.E.^b , Rutherford, M.A.^c , Goutman, J.D.^a

^a Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres” (INGEBI), Buenos Aires, Argentina
^b Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
^c Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^d Luis E. Boero, Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, United States

Abstract
Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔCm showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3KO mice showed a noise-induced reduction in ΔCm and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis. © Copyright © 2021 Boero, Payne, Gómez-Casati, Rutherford and Goutman.

Author Keywords
exocytosis; hair cells; noise exposure; synapse loss; Vglut3KO

Document Type: Article
Publication Stage: Final
Source: Scopus

“Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair” (2021) eLife

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair
(2021) eLife, 10, art. no. e68457, .

Avraham, O.^a , Feng, R.^a , Ewan, E.E.^a , Rustenhoven, J.^b ^c , Zhao, G.^a ^b , Cavalli, V.^a ^d ^e

^a Department of Neuroscience, Washington University School of Medicine, Saint Louis, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
^c Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St Louis, United States
^d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, United States

Abstract
Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease. © 2021, eLife Sciences Publications Ltd. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease” (2021) Neurology

Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease
(2021) Neurology, 97 (9), pp. e902-e912.

Wang, Y., Fellah, S., Fields, M.E., Guilliams, K.P., Binkley, M.M., Eldeniz, C., Shimony, J.S., Reis, M., Vo, K.D., Chen, Y., Lee, J.-M., An, H., Ford, A.L.

From the Department of Neurology (Y.W., S.F., M.M.B., J.-M.L., H.A., A.L.F.), Division of Pediatric Hematology/Oncology (M.E.F.), Division of Pediatric Neurology (K.P.G.), and Mallinckrodt Institute of Radiology (C.E., J.S.S., M.R., K.D.V., Y.C., J.-M.L., H.A., A.L.F.), Washington University School of Medicine, St. Louis, MO

Abstract
OBJECTIVE: To determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD). METHODS: Control participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location. RESULTS: Of 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g, p < 0.001), increased OEF (0.35 vs 0.25, p < 0.001), increased MD (0.76 vs 0.72 × 10-3 mm2s-1, p = 0.005), and decreased FA (0.40 vs 0.42, p = 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19, p = 0.035), but not CBF (β = 0.00, p = 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort. CONCLUSION: Elevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Note
Publication Stage: Final
Source: Scopus

“Association of Disease Severity and Socioeconomic Status in Black and White Americans With Multiple Sclerosis” (2021) Neurology

Association of Disease Severity and Socioeconomic Status in Black and White Americans With Multiple Sclerosis
(2021) Neurology, 97 (9), pp. e881-e889.

Gray-Roncal, K.^a , Fitzgerald, K.C.^b , Ryerson, L.Z.^b , Charvet, L.^b , Cassard, S.D.^b , Naismith, R.^b , Ontaneda, D.^b , Mahajan, K.^b , Castro-Borrero, W.^b , Mowry, E.M.^b

^a From the Johns Hopkins University (K.G.-R., K.F., S.D.C., E.M.), Baltimore, MD; NYU Langone Health (L.Z.R., L.C.), New York; Washington University in St. Louis (R.N.), MO; Cleveland Clinic (D.O., K.M.), OH; and Biogen (W.C.-B.), Cambridge, MA. kgrayroncal@jhu.edu
^b From the Johns Hopkins University (K.G.-R., K.F., S.D.C., E.M.), Baltimore, MD; NYU Langone Health (L.Z.R., L.C.), New York; Washington University in St. Louis (R.N.), MO; Cleveland Clinic (D.O., K.M.), OH; and Biogen (W.C.-B.), Cambridge, MA

Abstract
OBJECTIVE: To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BAs) and White Americans (WAs) and to evaluate the role of socioeconomic status. METHODS: We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics, including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit zip codes. RESULTS: Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or to be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs mild disability, 95% confidence interval [CI] 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, 95% CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96), and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BAs. CONCLUSION: We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors; developing optimal treatment strategies among BAs with MS is warranted. © 2021 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Genetic and Depressive Traits Moderate the Reward-Enhancing Effects of Acute Nicotine in Young Light Smokers” (2021) Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco

Genetic and Depressive Traits Moderate the Reward-Enhancing Effects of Acute Nicotine in Young Light Smokers
(2021) Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco, 23 (10), pp. 1779-1786.

Whitton, A.E.^a ^b , Rabinovich, N.E.^c , Lindt, J.D.^c , Pergadia, M.L.^d , Pizzagalli, D.A.^a , Gilbert, D.G.^c

^a McLean Hospital & Harvard Medical School, MA, Boston, United States
^b Black Dog Institute, University of New South Wales, NSW, Sydney, Australia
^c Department of Psychology, Southern Illinois University, Carbondale, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

Abstract
INTRODUCTION: Rates of light smoking have increased in recent years and are associated with adverse health outcomes. Reducing light smoking is a challenge because it is unclear why some but not others, progress to heavier smoking. Nicotine has profound effects on brain reward systems and individual differences in nicotine’s reward-enhancing effects may drive variability in smoking trajectories. Therefore, we examined whether a genetic risk factor and personality traits known to moderate reward processing, also moderate the reward-enhancing effects of nicotine. METHODS: Light smokers (n = 116) performed a Probabilistic Reward Task to assess reward responsiveness after receiving nicotine or placebo (order counterbalanced). Individuals were classified as nicotine dependence ‘risk’ allele carriers (rs16969968 A-allele carriers) or non-carriers (non-A-allele carriers), and self-reported negative affective traits were also measured. RESULTS: Across the sample, reward responsiveness was greater following nicotine compared to placebo (p = 0.045). For Caucasian A-allele carriers but not non-A-allele carriers, nicotine enhanced reward responsiveness compared to placebo for those who received placebo first (p = 0.010). Furthermore, for A-allele carriers but not non-A-allele carriers who received nicotine first, the enhanced reward responsiveness in the nicotine condition carried over to the placebo condition (p < 0.001). Depressive traits also moderated the reward-enhancing effects of nicotine (p = 0.010) and were associated with blunted reward responsiveness following placebo but enhanced reward responsiveness following nicotine. CONCLUSION: These findings suggest that individual differences in a genetic risk factor and depressive traits alter nicotine’s effect on reward responsiveness in light smokers and may be important factors underpinning variability in smoking trajectories in this growing population. IMPLICATIONS: Individuals carrying genetic risk factors associated with nicotine dependence(rs16969968 A-allele carriers) and those with higher levels of depressive personality traits, showmore pronounced increases in reward learning following acute nicotine exposure. These findingssuggest that genetic and personality factors may drive individual differences in smoking trajectoriesin young light smokers by altering the degree to which nicotine enhances reward processing. CLINICAL TRIAL REGISTRATION: NCT02129387 (pre-registered hypothesis: www.clinicaltrials.gov). © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

“IL-33 signaling in sensory neurons promotes dry skin itch” (2021) Journal of Allergy and Clinical Immunology

IL-33 signaling in sensory neurons promotes dry skin itch
(2021) Journal of Allergy and Clinical Immunology, .

Trier, A.M.^a ^b , Mack, M.R.^a ^b , Fredman, A.^a ^b , Tamari, M.^a ^b , Ver Heul, A.M.^a ^c , Zhao, Y.^a ^d , Guo, C.J.^a ^d , Avraham, O.^e , Ford, Z.K.^j , Oetjen, L.K.^a ^b , Feng, J.^a ^d , Dehner, C.^b , Coble, D.^f , Badic, A.^a ^b , Joshita, S.^k , Kubo, M.^l ^m , Gereau, R.W., IV^d ^e ^g , Alexander-Brett, J.^h , Cavalli, V.^e , Davidson, S.^j , Hu, H.^a ^d , Liu, Q.^a ^d , Kim, B.S.^a ^b ^d ⁱ

^a Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St Louis, Mo, United States
^b Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^c Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^d Department of Anesthesiology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^e Department of Neuroscience, Washington University School of Medicine, St Louis, Mo, United States
^f Division of Biostatistics, Washington University School of Medicine, St Louis, Mo, United States
^g Washington University Pain Center, Washington University School of Medicine, St Louis, Mo, United States
^h Division of Pulmonary and Critical Care, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
ⁱ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Mo, United States
^j Department of Anesthesiology and Neuroscience Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^k Division of Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Nagano, Japan
^l Laboratory of Cytokine Regulation, Center for Integrative Medical Science (IMS), RIKEN Yokohama Institute, Yokohama, Japan
^m Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, Japan

Abstract
Background: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron–restricted activity of IL-33 is necessary for chronic itch remains poorly understood. Objectives: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. Methods: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. Results: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. Conclusions: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch. © 2021 The Authors

Author Keywords
Atopic dermatitis; chronic pruritus of unknown origin; dry skin; IL-33; itch; neuroimmunology; pruriceptor; pruritogen

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

“Glucocorticoid Production, Activity Levels, And Personality Traits Of Fennec Foxes (Vulpes zerda) Managed For Different Roles In Zoos” (2021) Journal of Applied Animal Welfare Science

Glucocorticoid Production, Activity Levels, And Personality Traits Of Fennec Foxes (Vulpes zerda) Managed For Different Roles In Zoos
(2021) Journal of Applied Animal Welfare Science, .

Kozlowski, C.P.^a , Bauman, K.L.^a , Franklin, A.D.^b , Sahrmann, J.M.^c , Gartner, M.^d , Baskir, E.^a , Hanna, S.^e , LaMattina, K.^f , Seyfried, A.^g , Powell, D.M.^a

^a Department of Reproductive and Behavioral Sciences, Saint Louis Zoo, Saint Louis, MO, United States
^b Association of Zoos and Aquarium Reproductive Management Center, Saint Louis Zoo, Saint Louis, Mo, United States
^c Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, Mo, United States
^d Collections Department, Zoo Atlanta, Atlanta, GA, United States
^e Exotic Endeavors, Santa Rosa Valley, CA, United States
^f Animal Encounters, Bronx Zoo, Bronx, NY, United States
^g Children’s Zoo, Saint Louis Zoo, Saint Louis, MO, United States

Abstract
Fecal glucocorticoid metabolite (FGM) concentrations, activity, and personality were assessed for 35 fennec foxes (Vulpes zerda) to determine whether animals managed as ambassadors differed from exhibit or off-exhibit animals. A FGM assay, pedometer, and personality assessment tool were validated. Then, fecal samples and movement data were collected during winter and summer periods. Handling was recorded, and the personality of each fox was evaluated. Generalized linear mixed models assessed the relationships between FGM concentrations, activity, personality, handling, sex, season, rearing type, and role. FGM concentrations did not differ in relation to role or handling. Foxes were most active at night; the time of peak activity did not vary with role or handling. Foxes were more active in winter; males were more active than females, and ambassador foxes were more active than off-exhibit animals. Hand-reared foxes were more sociable, and, at one institution, ambassador foxes were more sociable than foxes in other roles. These results suggest that management for ambassador programs is not associated with changes in glucocorticoid production or circadian patterns but may increase activity and be associated with greater sociability. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Ambassador animals; circadian rhythm; cortisol metabolites; pedometer; temperament

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

“An endogenous opioid circuit determines state-dependent reward consumption” (2021) Nature

An endogenous opioid circuit determines state-dependent reward consumption
(2021) Nature, .

Castro, D.C.^a ^b ^c ^d , Oswell, C.S.^a ^d , Zhang, E.T.^d ^e , Pedersen, C.E.^d ^e , Piantadosi, S.C.^a ^d , Rossi, M.A.^a ^d , Hunker, A.C.^d , Guglin, A.^b ^c , Morón, J.A.^b ^c , Zweifel, L.S.^d , Stuber, G.D.^a ^d ^f , Bruchas, M.R.^a ^b ^c ^d ^e ^f

^a Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
^b Departments of Anesthesiology, Neuroscience and Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^c Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
^d Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA, United States
^e Department of Bioengineering, University of Washington, Seattle, WA, United States
^f Department of Pharmacology, University of Washington, Seattle, WA, United States

Abstract
µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose1–3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR–Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

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

“Accuracy of an Algorithm in Predicting Upper Limb Functional Capacity in a United States Population” (2021) Archives of Physical Medicine and Rehabilitation

Accuracy of an Algorithm in Predicting Upper Limb Functional Capacity in a United States Population
(2021) Archives of Physical Medicine and Rehabilitation, .

Barth, J.^a , Waddell, K.J.^a , Bland, M.D.^a ^b ^c , Lang, C.E.^a ^b ^c

^a Program in Physical Therapy, Washington University in St. Louis, St. Louis, MO, United States
^b Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^c Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: To determine the accuracy of an algorithm, using clinical measures only, on a sample of persons with first-ever stroke in the United States (US). It was hypothesized that algorithm accuracy would fall in a range of 70%-80%. Design: Secondary analysis of prospective, observational, longitudinal cohort; 2 assessments were done: (1) within 48 hours to 1 week poststroke and (2) at 12 weeks poststroke. Setting: Recruited from a large acute care hospital and followed over the first 6 months after stroke. Participants: Adults with first-ever stroke (N=49) with paresis of the upper limb (UL) at ≤48 hours who could follow 2-step commands and were expected to return to independent living at 6 months. Intervention: Not applicable. Main Outcome Measures: The overall accuracy of the algorithm with clinical measures was quantified by comparing predicted (expected) and actual (observed) categories using a correct classification rate. Results: The overall accuracy (61%) and weighted κ (62%) were significant. Sensitivity was high for the Excellent (95%) and Poor (81%) algorithm categories. Specificity was high for the Good (82%), Limited (98%), and Poor (95%) categories. Positive predictive value (PPV) was high for Poor (82%) and negative predictive value (NPV) was high for all categories. No differences in participant characteristics were found between those with accurate or inaccurate predictions. Conclusions: The results of the present study found that use of an algorithm with clinical measures only is better than chance alone (chance=25% for each of the 4 categories) at predicting a category of UL capacity at 3 months post troke. The moderate to high values of sensitivity, specificity, PPV, and NPV demonstrates some clinical utility of the algorithm within health care settings in the US. © 2021 The American Congress of Rehabilitation Medicine

Author Keywords
Multivariate analysis; Occupational therapy; Physical therapy; Rehabilitation; Stroke; Upper extremity

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

“Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP” (2021) Autophagy

Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP
(2021) Autophagy, .

Wani, A.^a ^b , Weihl, C.C.^a

^a Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of mechanisms causing fronto-temporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) by VCP disease mutations remains unclear. Our recent work identified VCP activity as a mediator of FTLD-TARDBP. Specifically, brain atrophy, behavioral changes, neuronal loss, gliosis, and TARDBP pathology were observed in vcp conditional knockout (cKO) mice. We also found that autophago-lysosomal dysfunction, TARDBP inclusions, and ubiquitin-proteasome impairment precede neuronal loss. We further studied conditional expression of the disease-associated mutation VCPR155C in vcp-null mice. We observed features similar to those of VCP inactivation, suggesting that VCP mutation is hypomorphic. Furthermore, proteomic, and transcriptomic signatures in vcp cKO mice resemble those of GRN/Progranulin carriers. Therefore, VCP is essential for neuronal survival by several mechanisms and could be a therapeutic target aimed at restoring protein homeostasis in patients with FTLD-TARDBP. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Autophagy; FTLD-TDP-43; neurodegeneration; progranulin; valosin-containing protein

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

“Smaller Hippocampal Volume Among Black and Latinx Youth Living in High-Stigma Contexts” (2021) Journal of the American Academy of Child and Adolescent Psychiatry

Smaller Hippocampal Volume Among Black and Latinx Youth Living in High-Stigma Contexts
(2021) Journal of the American Academy of Child and Adolescent Psychiatry, .

Hatzenbuehler, M.L.^a , Weissman, D.G.^a , McKetta, S.^b , Lattanner, M.R.^a , Ford, J.V.^b , Barch, D.M.^c , McLaughlin, K.A.^a

^a Harvard University, Cambridge, MA, United States
^b Mailman School of Public Health, Columbia University, New York, United States
^c Washington University in St. Louis, MO, United States

Abstract
Objective: To determine whether structural and individual forms of stigma are associated with neurodevelopment in children. Method: Stigma related to gender, race, and Latinx ethnicity was measured at the structural level using objective state-level indicators of social policies and prejudicial attitudes and at the individual level using self-reports of perceived discrimination. Respective associations of stigma with hippocampal volume and amygdala reactivity to threat were examined using data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 11,534, mean age 9.9 years), the first multisite neuroimaging study that provided substantial variability in sociopolitical contexts and that included individual-level measures of stigma among youth. Results: In a preregistered analysis, Black (B = −58.26, p = .023) and Latinx (B = −40.10, p = .044) youths in higher (vs lower) structural stigma contexts were found to have smaller hippocampal volume, controlling for total intracranial volume, demographics, and family socioeconomic status. This association was also observed at a trend-level among girls (p = .082). The magnitude of the difference in hippocampal volume between high and low structural stigma states was equivalent to the predicted impact of a $20,000 difference in annual family income in this sample. As hypothesized, structural stigma was not associated with hippocampal volume in nonstigmatized youths, providing evidence of specificity. Perceived discrimination was unrelated to hippocampal volume in stigmatized groups. No associations between perceived discrimination or structural stigma and amygdala reactivity to threat were observed. Conclusion: This study provides novel evidence that an objective measure of structural stigma may be more strongly related to hippocampal volume than subjective perceptions of stigma, suggesting that contextual approaches to stigma could yield new insights into neurodevelopment among marginalized youth. © 2021 American Academy of Child and Adolescent Psychiatry

Author Keywords
hippocampal volume; neurodevelopment; population neuroscience; stigma

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

“Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States” (2021) Multiple Sclerosis Journal

Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States
(2021) Multiple Sclerosis Journal, .

Solomon, A.J.^a , Kaisey, M.^b , Krieger, S.C.^c , Chahin, S.^d , Naismith, R.T.^d , Weinstein, S.M.^e , Shinohara, R.T.^e , Weinshenker, B.G.^f

^a Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT, United States
^b Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^c Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Neurology, Mayo Clinic, Rochester, MN, United States

Abstract
Background: Few studies have addressed the results of educational efforts concerning proper use of McDonald criteria (MC) revisions outside multiple sclerosis (MS) subspecialty centers. Neurology residents and MS subspecialist neurologists demonstrated knowledge gaps for core elements of the MC in a recent prior study. Objective: To assess comprehension and application of MC core elements by non-MS specialist neurologists in the United States who routinely diagnose MS. Methods: Through a cross-sectional study design, a previously developed survey instrument was distributed online. Results: A total of 222 neurologists completed the study survey. Syndromes atypical for MS were frequently incorrectly considered “typical” MS presentations. Fourteen percent correctly identified definitions of both “periventricular” and “juxtacortical” lesions and 2% correctly applied these terms to 9/9 images. Twenty-four percent correctly identified all four central nervous system (CNS) regions for satisfaction of magnetic resonance imaging (MRI) dissemination in space. In two presented cases, 61% and 71% correctly identified dissemination in time (DIT) was not fulfilled, and 85% and 86% subsequently accepted nonspecific historical symptoms without objective evidence for DIT fulfillment. Conclusion: The high rate of knowledge deficiencies and application errors of core elements of the MC demonstrated by participants in this study raise pressing questions concerning adequacy of dissemination and educational efforts upon publication of revisions to MC. © The Author(s), 2021.

Author Keywords
Demyelinating disease (CNS); diagnosis; diagnostic criteria; education; multiple sclerosis

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