WashU weekly Neuroscience publications | Office of Neuroscience Research

"Cardiac glycosides target barrier inflammation of the vasculature, meninges and choroid plexus" (2021) Communications Biology

Cardiac glycosides target barrier inflammation of the vasculature, meninges and choroid plexus
(2021) Communications Biology, 4 (1), art. no. 260, .

Jansson, D.^a ^b ^c , Dieriks, V.B.^b ^d , Rustenhoven, J.^e ^f , Smyth, L.C.D.^g ^h , Scotter, E.^a ^b , Aalderink, M.^a ^b , Feng, S.^a ^b , Johnson, R.^a ^b , Schweder, P.ⁱ , Mee, E.ⁱ , Heppner, P.^j , Turner, C.^k , Curtis, M.^b ^d , Faull, R.^b ^d , Dragunow, M.^a ^b

^a Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
^b Centre for Brain Research, The University of Auckland, Auckland, New Zealand
^c Department of Psychiatry and Behavioural Science, University of Washington, Seattle, WA, United States
^d Department of Anatomy and Medical Imaging, The University of Auckland, Auckland, New Zealand
^e Center for Brain Immunology and Glia (BIG), Washington University, St. Louis, MO, United States
^f Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St. Louis, MO, United States
^g Department of Pathology, University of Otago, Christchurch, New Zealand
^h Centre for Free Radical Research, University of Otago, Christchurch, New Zealand
ⁱ Department of Neurosurgery, Auckland City Hospital, Auckland, New Zealand
^j Starship Hospital, Auckland, New Zealand
^k Department of Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand

Abstract
Neuroinflammation is a key component of virtually all neurodegenerative diseases, preceding neuronal loss and associating directly with cognitive impairment. Neuroinflammatory signals can originate and be amplified at barrier tissues such as brain vasculature, surrounding meninges and the choroid plexus. We designed a high content screening system to target inflammation in human brain-derived cells of the blood–brain barrier (pericytes and endothelial cells) to identify inflammatory modifiers. Screening an FDA-approved drug library we identify digoxin and lanatoside C, members of the cardiac glycoside family, as inflammatory-modulating drugs that work in blood–brain barrier cells. An ex vivo assay of leptomeningeal and choroid plexus explants confirm that these drugs maintain their function in 3D cultures of brain border tissues. These results suggest that cardiac glycosides may be useful in targeting inflammation at border regions of the brain and offer new options for drug discovery approaches for neuroinflammatory driven degeneration. © 2021, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

"Diffusion histology imaging differentiates distinct pediatric brain tumor histology" (2021) Scientific Reports

Diffusion histology imaging differentiates distinct pediatric brain tumor histology
(2021) Scientific Reports, 11 (1), art. no. 4749, .

Ye, Z.^a , Srinivasa, K.^b , Meyer, A.^c , Sun, P.^a , Lin, J.^a ^f , Viox, J.D.^a ^g , Song, C.^d , Wu, A.T.^d , Song, S.-K.^a ^d , Dahiya, S.^b , Rubin, J.B.^c ^e

^a Department of Radiology, Washington University School of Medicine, Room 3221, 4525 Scott Ave., St. Louis, MO 63110, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^c Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Keck School of Medicine, University of Southern California, Los Angeles, CA 9003389, United States
^g School of Medicine, University of Missouri – Kansas City, Kansas City, MO 64110, United States

Abstract
High-grade pediatric brain tumors exhibit the highest cancer mortality rates in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumors clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in their clinical management. We employed a novel Diffusion Histology Imaging (DHI) approach employing diffusion basis spectrum imaging (DBSI) derived metrics as the input classifiers for deep neural network analysis. DHI aims to detect, differentiate, and quantify heterogeneous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 85.8%. Receiver operating analysis (ROC) analysis suggested DHI’s great capability in distinguishing individual tumor histology with AUC values (95% CI) of 0.984 (0.982–0.986), 0.960 (0.956–0.963), 0.991 (0.990–0.993), 0.950 (0.944–0.956), 0.977 (0.973–0.981) and 0.976 (0.972–0.979) for normal WM, densely cellular tumor, less densely cellular tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If these results could be further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR01-NS047592
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP

Document Type: Article
Publication Stage: Final
Source: Scopus

"Three types of individual variation in brain networks revealed by single-subject functional connectivity analyses" (2021) Current Opinion in Behavioral Sciences

Three types of individual variation in brain networks revealed by single-subject functional connectivity analyses
(2021) Current Opinion in Behavioral Sciences, 40, pp. 79-86.

Gordon, E.M.^a , Nelson, S.M.^b ^c ^d

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX 76711, United States
^c Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75235, United States
^d Department of Psychology and Neuroscience, Baylor University, Waco, TX 76789, United States

Abstract
The human brain is organized into large-scale networks that can be noninvasively identified using functional connectivity (FC) functional magnetic resonance imaging. FC varies across individuals, and there is significant interest in associating individual variation in FC with external behavioral measures. However, only recently has FC variation been characterized by studying brain networks within individual humans. We review these recent efforts, and we argue that individual variation in FC networks comes in three distinct forms: 1) variability in connectional strength, in which brain regions in the same location have variable FC strength across subjects; 2) variability in spatial localization, in which regions exhibit the same connections across subjects, but are expanded/contracted or spatially displaced in specific subjects; and 3) topological variability, in which networks have variable sets of constituent nodes. Unfortunately, each of these three types of variation confounds attempts to measure the others, which significantly impacts research studying brain networks. © 2021 Elsevier Ltd

Funding details
1IK2CX001680

Document Type: Review
Publication Stage: Final
Source: Scopus

"Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25" (2021) Neurobiology of Aging

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25
(2021) Neurobiology of Aging, 102, pp. 64-72.

Butt, O.H.^a , Long, J.M.^a ^d ^e , Henson, R.L.^a ^d , Herries, E.^a ^d , Sutphen, C.L.^a ^d , Fagan, A.M.^a ^d ^e , Cruchaga, C.^c ^d ^e , Ladenson, J.H.^f , Holtzman, D.M.^a ^d ^e , Morris, J.C.^a ^d ^e ^f , Ances, B.M.^a ^b ^d ^e , Schindler, S.E.^a ^d , for the Alzheimer’s Disease Neuroimaging Initiative^g

^a Department of Neurology, Washington University, Saint Louis, MO, United States
^b Department of Radiology, Washington University, Saint Louis, MO, United States
^c Department of Psychiatry, Washington University, Saint Louis, MO, United States
^d Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
^f Department of Pathology and Immunology, Washington University, Saint Louis, MO, United States

Abstract
Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status. © 2021 Elsevier Inc.

Author Keywords
APOE; Biomarker; CSF; Neurogranin; SNAP-25; Synapse

Funding details
Johnson and JohnsonJ&J
National Institute on AgingNIAK23AG053426, R03AG050921, P01 AG026276
Janssen Research and DevelopmentJRD
National Institutes of HealthNIHU01 AG024904
Fujirebio US
University of Southern CaliforniaUSC
U.S. Department of DefenseDODW81XWH-12-2-0012
GE Healthcare
H. Lundbeck A/S
Hope Center for Neurological Disorders
Genentech
National Institute of Biomedical Imaging and BioengineeringNIBIB
Northern California Institute for Research and EducationNCIRE
Alzheimer’s Disease Neuroimaging InitiativeADNI
Merck
IXICO

Document Type: Article
Publication Stage: Final
Source: Scopus

"Long runs of homozygosity are associated with Alzheimer’s disease" (2021) Translational Psychiatry

Long runs of homozygosity are associated with Alzheimer’s disease
(2021) Translational Psychiatry, 11 (1), art. no. 142, .

Moreno-Grau, S.^a ^b , Fernández, M.V.^c ^d , de Rojas, I.^a ^b , Garcia-González, P.^a , Hernández, I.^a , Farias, F.^c ^d , Budde, J.P.^c ^d , Quintela, I.^e , Madrid, L.^f , González-Pérez, A.^f , Montrreal, L.^a , Alarcón-Martín, E.^a , Alegret, M.^a , Maroñas, O.^e , Pineda, J.A.^g , Macías, J.^g , Abdelnour, C.^a ^b , Aguilera, N.^a , Alarcón-Martín, E.^a , Alegret, M.^a ^b , Benaque, A.^a , Boada, M.^a ^b , Buendía, M.^a , Cañabate, P.^a ^b , Carracedo, A.^e ^z , Corbatón, A.^aa , de Rojas, I.^a , Diego, S.^a , Espinosa, A.^a ^b , Gailhajenet, A.^a , García González, P.^a , Gil, S.^a , Guitart, M.^a , González Pérez, A.^f , Hernández, I.^a ^b , Ibarria, M.^a , Lafuente, A.^a , Macías, J.^g , Maroñas, O.^d , Martín, E.^a , Martínez, M.T.^aa , Marquié, M.^a , Mauleón, A.^a , Monté-Rubio, G.^a , Montrreal, L.^a , Moreno-Grau, S.^a ^b , Moreno, M.^a , Orellana, A.^a , Ortega, G.^a ^b , Pancho, A.^a , Pelejà, E.^a , Pérez-Cordon, A.^a , Pineda, J.A.^h , Preckler, S.^a , Quintela, I.^e , Real, L.M.^g ^r , Rodríguez-Gómez, O.^a ^b , Rosende-Roca, M.^a , Ruiz, A.^a ^b , Ruiz, S.^a ^b , Sáez, M.E.^f , Sanabria, A.^a ^b , Santos-Santos, M.A.^a , Serrano-Ríos, M.^aa ^ab , Sotolongo-Grau, O.^a , Tárraga, L.^a ^b , Valero, S.^a ^b , Vargas, L.^a , Adarmes-Gómez, A.D.^b ^t , Alarcón-Martín, E.^a , Álvarez, I.^l , Álvarez, V.ⁿ ^o , Amer-Ferrer, G.^ac , Antequera, M.^y , Antúnez, C.^y , Baquero, M.^ad , Bernal, M.^s , Blesa, R.^b ^h , Boada, M.^a ^b , Buiza-Rueda, D.^b ^t , Bullido, M.J.^b ⁱ ⁿ , Burguera, J.A.^ad , Calero, M.^b ^u ^v , Carrillo, F.^b ^t , Carrión-Claro, M.^b ^t , Casajeros, M.J.^k , Clarimón, J.^b ^h , Cruz-Gamero, J.M.^r , de Pancorbo, M.M.^ae , de Rojas, I.^a ^b , del Ser, T.^j , Diez-Fairen, M.^l , Fortea, J.^b ^h , Franco, E.^s , Frank-García, A.^b ^j ^af , García-Alberca, J.M.^q , García Madrona, S.^v , Garcia-Ribas, G.^k , Gómez-Garre, P.^b ^t , Hernández, I.^a ^b , Hevilla, S.^q , Jesús, S.^b ^t , Labrador Espinosa, M.A.^b ^t , Lage, C.^b ^m , Legaz, A.^as , Lleó, A.^b ^h , López de Munáin, A.^ag , López-García, S.^b ^m , Macías, D.^b ^t , Manzanares, S.^y ^ah , Marín, M.^s , Marín-Muñoz, J.^y , Marín, T.^q , Marquié, M.^a ^b , Martín-Montes, A.^b ⁱ ^af , Martínez, B.^y , Martínez, C.^o ^ai , Martínez, V.^y , Martínez-Lage Álvarez, P.^aj , Medina, M.^b ^u , Mendioroz Iriarte, M.^ak , Menéndez-González, M.^o ^al , Mir, P.^b ^t , Molinuevo, J.L.^am , Montrreal, L.^a , Moreno-Grau, S.^a ^b , Orellana, A.^a , Pastor, A.B.^u , Pastor, P.^l , Pérez-Tur, J.^b ^an ^ao , Periñán-Tocino, T.^b ^t , Piñol-Ripoll, G.^b ^p , Rábano, A.^b ^u ^w , Real de Asúa, D.^ap , Rodrigo, S.^s , Rodríguez-Rodríguez, E.^b ^m , Royo, J.L.^r , Ruiz, A.^a ^b , Sanchez del Valle Díaz, R.^aq , Sánchez-Juan, P.^b ^m , Sastre, I.^b ^s , Sotolongo-Grau, O.^a , Tárraga, L.^a ^b , Valero, S.^a ^b , Vicente, M.P.^y , Vivancos, L.^y , Marquié, M.^a ^b , Valero, S.^a ^b , Benaque, A.^a , Clarimón, J.^b ^h , Bullido, M.J.^b ⁱ ^j , García-Ribas, G.^k , Pástor, P.^l , Sánchez-Juan, P.^b ^m , Álvarez, V.ⁿ ^o , Piñol-Ripoll, G.^b ^p , García-Alberca, J.M.^q , Royo, J.L.^r , Franco-Macías, E.^s , Mir, P.^b ^t , Calero, M.^b ^u ^v , Medina, M.^b ^u , Rábano, A.^b ^u ^w , Ávila, J.^b ^x , Antúnez, C.^y , Real, L.M.^g ^r , Orellana, A.^a , Carracedo, Á.^e ^z , Sáez, M.E.^f , Tárraga, L.^a ^b , Boada, M.^a ^b , Cruchaga, C.^c ^d , Ruiz, A.^a ^b , The GR@ACE study group^ar , DEGESCO consortium^ar , for the Alzheimer’s Disease Neuroimaging Initiative^as

^a Research Center and Memory clinic Fundació ACE. Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
^b CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, Carlos III Institute of Health, Madrid, Spain
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^e Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
^f CAEBI. Centro Andaluz de Estudios Bioinformáticos, Sevilla, Spain
^g Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain
^h Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
ⁱ Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Madrid, Spain
^j Instituto de Investigación Sanitaria “Hospital la Paz” (IdIPaz), Madrid, Spain
^k Hospital Universitario Ramón y Cajal, Madrid, Spain
^l Fundació per la Recerca Biomèdica i Social Mútua Terrassa, and Memory Disorders Unit, Department of Neurology, Hospital Universitari Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain
^m Neurology Service “Marqués de Valdecilla” University Hospital (University of Cantabria and IDIVAL), Santander, Spain
ⁿ Laboratorio de Genética Hospital Universitario Central de Asturias, Oviedo, Spain
^o Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
^p Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Institut de Recerca Biomédica de Lleida (IRBLLeida), Lleida, Spain
^q Alzheimer Research Center & Memory Clinic, Andalusian Institute for Neuroscience, Málaga, Spain
^r Dep. of Surgery, Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain
^s Unidad de Demencias, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
^t Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
^u CIEN Foundation, Queen Sofia Foundation Alzheimer Center, Madrid, Spain
^v Instituto de Salud Carlos III (ISCIII), Madrid, Spain
^w BT-CIEN, Madrid, Spain
^x Department of Molecular Neuropathology, Centro de Biología Molecular “Severo Ochoa” (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid, Spain
^y Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Madrid, Spain
^z Fundación Pública Galega de Medicina Xenómica- CIBERER-IDIS, Santiago de Compostela, Spain
^aa Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Madrid, Spain
^ab Hospital Clínico San Carlos, Madrid, Spain
^ac Department of Neurology, Hospital Universitario Son Espases, Palma, Spain
^ad Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain
^ae BIOMICs, País Vasco; Centro de Investigación Lascaray. Universidad del País Vasco UPV/EHU, Vitori-Gasteiz, Spain
^af Neurology Service, Hospital Universitario La Paz (UAM), Madrid, Spain
^ag Hospital Donostia de San Sebastián, San Sebastián, Spain
^ah Fundación para la Formación e Investigación Sanitarias de la Región de Murcia, Murcia, Spain
^ai Servicio de Neurología-Hospital de Cabueñes-Gijón, Gijón, Spain
^aj Centro de Investigación y Terapias Avanzadas. Fundación CITA-alzheimer, San Sebastián, Spain
^ak Navarrabiomed, Pamplona, Spain
^al Servicio de Neurología -Hospital Universitario Central de Asturias, Oviedo, Spain
^am Barcelona βeta Brain Research Center – Fundació Pasqual Maragall, Barcelona, Spain
^an Unitat de Genètica Molecular. Institut de Biomedicina de València-CSIC, Valencia, Spain
^ao Unidad Mixta de Neurologia Genètica. Instituto de Investigación Sanitaria La Fe, Valencia, Spain
^ap Hospital Universitario La Princesa, Madrid, Spain
^aq Hospital Clínic Barcelona, Barcelona, Spain

Abstract
Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHP01AG003991, R01AG044546, R01AG057777, R01AG058501, RF1AG053303, U01AG058922
Alzheimer’s AssociationAAAARG-16-441560, BAND-14-338165, BFG-15-362540, NIRG-11-200110

Document Type: Article
Publication Stage: Final
Source: Scopus

"Objective and Clinically Feasible Analysis of Diffusion MRI Data can Help Predict Dystonia After Neonatal Brain Injury" (2021) Pediatric Neurology

Objective and Clinically Feasible Analysis of Diffusion MRI Data can Help Predict Dystonia After Neonatal Brain Injury
(2021) Pediatric Neurology, 118, pp. 6-11.

Chintalapati, K.^a , Miao, H.^a , Mathur, A.^b , Neil, J.^a , Aravamuthan, B.R.^a

^a Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
^b Division of Neonatology, Department of Pediatrics, St. Louis University and Cardinal Glennon Children’s Hospital, St. Louis, MO, United States

Abstract
Background: Dystonia in cerebral palsy is debilitating but underdiagnosed precluding targeted treatment that is most effective if instituted early. Deep gray matter injury is associated with dystonic cerebral palsy but is difficult to quantify. Objective and clinically feasible identification of injury preceding dystonia could help determine the children at the highest risk for developing dystonia and thus facilitate early dystonia detection. Methods: We examined brain magnetic resonance images from four- to five-day-old neonates after therapeutic hypothermia for hypoxic-ischemic encephalopathy at a tertiary care center. Apparent diffusion coefficient values in the striatum and thalamus were determined using a web-based viewer integrated with the electronic medical record (IBM iConnect Access). The notes of specialists in neonatal neurology, pediatric movement disorders, and pediatric cerebral palsy (physicians most familiar with motor phenotyping after neonatal brain injury) were screened for all subjects through age of five years for motor phenotype documentation. Results: Striatal and thalamic apparent diffusion coefficient values significantly predicted dystonia with receiver operator characteristic areas under the curve of 0.862 (P = 0.0004) and 0.838 (P = 0.001), respectively (n = 50 subjects). Striatal apparent diffusion coefficient values less than 1.014 × 10−3 mm2/s provided 100% specificity and 70% sensitivity for dystonia. Thalamic apparent diffusion coefficient values less than 0.973 × 10−3 mm2/s provided 100% specificity and 80% sensitivity for dystonia. Conclusions: Lower striatal and thalamic apparent diffusion coefficient values predicted dystonia in four- to five-day-old neonates who underwent therapeutic hypothermia for hypoxic ischemic encephalopathy. Objective and clinically feasible neonatal brain imaging assessment could help increase vigilance for dystonia in cerebral palsy. © 2020 Elsevier Inc.

Author Keywords
Apparent diffusion coefficient; Cerebral palsy; Dystonia; Hypoxic-ischemic encephalopathy; Magnetic resonance imaging

Funding details
National Institute of Neurological Disorders and StrokeNINDS5K12NS098482-02

Document Type: Article
Publication Stage: Final
Source: Scopus

"Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium" (2021) Journal of Molecular Biology

Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
(2021) Journal of Molecular Biology, 433 (8), art. no. 166878, .

Nahass, G.R.^a ^b ^c ^f , Sun, Y.^b , Xu, Y.^d , Batchelor, M.^b , Reilly, M.^b , Benilova, I.^b , Kedia, N.^c , Spehar, K.^c , Sobott, F.^d , Sessions, R.B.^e , Caughey, B.^f , Radford, S.E.^d , Jat, P.S.^b , Collinge, J.^b , Bieschke, J.^b ^c

^a Colorado College, Colorado Springs, CO, United States
^b Medical Research Council Prion Unit / UCL Institute of Prion Diseases, University College London, London, United Kingdom
^c Washington University in St. Louis, St Louis, MO, United States
^d Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
^e Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, United Kingdom
^f Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, United States

Abstract
Alpha-synuclein (α-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinson’s disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (Aβ) and α-syn as well as remodel mature fibrils and reduce cytotoxicity. Here we test the effects of Brazilin on both seeded and unseeded α-syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of α-syn by a unique mechanism that alters conformational equilibria in two separate points of the assembly mechanism: Brazilin preserves the natively unfolded state of α-syn by specifically binding to the compact conformation of the α-syn monomer. Brazilin also eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and reduces toxicity of pre-formed assemblies in primary neurons by inducing the formation of large fibril clusters. Molecular docking of Brazilin shows the molecule to interact both with unfolded α-syn monomers and with the cross-β sheet structure of α-syn fibrils. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s disease. © 2021

Author Keywords
Amyloid; Molecular Modelling; Neurdegeneration; Parkinson’s disease; Polyphenol

Funding details
National Institutes of HealthNIH1R21NS101588-01A1
National Institute of Allergy and Infectious DiseasesNIAID
National Institute of Neurological Disorders and StrokeNINDS
Wellcome TrustWT204963
Medical Research CouncilMRC
Biotechnology and Biological Sciences Research CouncilBBSRCBB/E012558/1

Document Type: Article
Publication Stage: Final
Source: Scopus

"Harnessing mobile technology to reduce mental health disorders in college populations: A randomized controlled trial study protocol" (2021) Contemporary Clinical Trials

Harnessing mobile technology to reduce mental health disorders in college populations: A randomized controlled trial study protocol
(2021) Contemporary Clinical Trials, 103, art. no. 106320, .

Fitzsimmons-Craft, E.E.^a , Taylor, C.B.^b ^c , Newman, M.G.^d , Zainal, N.H.^d , Rojas-Ashe, E.E.^c , Lipson, S.K.^e , Firebaugh, M.-L.^a , Ceglarek, P.^f , Topooco, N.^c ^g , Jacobson, N.C.^h , Graham, A.K.ⁱ , Kim, H.M.^j , Eisenberg, D.^k , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, Mailstop 8134-29-2100, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^c Center for m<sup>2</sup>Health, Palo Alto University, Palo Alto, CA, United States
^d Department of Psychology, Penn State University, University Park, PA, United States
^e Department of Health Law Policy and Management, Boston University School of Public Health, Boston, MA, United States
^f Department of Health Management and Policy, University of Michigan School of Public Health, Ann Arbor, MI, United States
^g Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden
^h Departments of Biomedical Data Science and Psychiatry, Center for Technology and Behavioral Health, Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
ⁱ Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^j Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
^k Department of Health Policy and Management, Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA, United States

Abstract
About a third of college students struggle with anxiety, depression, or an eating disorder, and only 20–40% of college students with mental disorders receive treatment. Inadequacies in mental health care delivery result in prolonged illness, disease progression, poorer prognosis, and greater likelihood of relapse, highlighting the need for a new approach to detect mental health problems and engage college students in services. We have developed a transdiagnostic, low-cost mobile mental health targeted prevention and intervention platform that uses population-level screening to engage college students in tailored services that address common mental health problems. We will test the impact of this mobile mental health platform for service delivery in a large-scale trial across 20+ colleges. Students who screen positive or at high-risk for clinical anxiety, depression, or an eating disorder and who are not currently engaged in mental health services (N = 7884) will be randomly assigned to: 1) intervention via the mobile mental health platform; or 2) referral to usual care (i.e., campus health or counseling center). We will test whether the mobile mental health platform, compared to referral, is associated with improved uptake, reduced clinical cases, disorder-specific symptoms, and improved quality of life and functioning. We will also test mediators, predictors, and moderators of improved mental health outcomes, as well as stakeholder-relevant outcomes, including cost-effectiveness and academic performance. This population-level approach to service engagement has the potential to improve mental health outcomes for the millions of students enrolled in U.S. colleges and universities. © 2021

Author Keywords
Anxiety; College mental health; Depression; Eating disorders; mHealth; Prevention; Screening; Treatment

Funding details
National Institute of Mental HealthNIMHK08 MH120341, R01 MH115128
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKK01 DK116925

Document Type: Article
Publication Stage: Final
Source: Scopus

"Localized EMT reprograms glial progenitors to promote spinal cord repair" (2021) Developmental Cell

Localized EMT reprograms glial progenitors to promote spinal cord repair
(2021) Developmental Cell, 56 (5), pp. 613-626.e7.

Klatt Shaw, D.^a , Saraswathy, V.M.^a , Zhou, L.^a , McAdow, A.R.^a , Burris, B.^a , Butka, E.^a , Morris, S.A.^a , Dietmann, S.^a , Mokalled, M.H.^a ^b

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

Abstract
Anti-regenerative scarring obstructs spinal cord repair in mammals and presents a major hurdle for regenerative medicine. In contrast, adult zebrafish possess specialized glial cells that spontaneously repair spinal cord injuries by forming a pro-regenerative bridge across the severed tissue. To identify the mechanisms that regulate differential regenerative capacity between mammals and zebrafish, we first defined the molecular identity of zebrafish bridging glia and then performed cross-species comparisons with mammalian glia. Our transcriptomics show that pro-regenerative zebrafish glia activate an epithelial-to-mesenchymal transition (EMT) gene program and that EMT gene expression is a major factor distinguishing mammalian and zebrafish glia. Functionally, we found that localized niches of glial progenitors undergo EMT after spinal cord injury in zebrafish and, using large-scale CRISPR-Cas9 mutagenesis, we identified the gene regulatory network that activates EMT and drives functional regeneration. Thus, non-regenerative mammalian glia lack an essential EMT-driving gene regulatory network that reprograms pro-regenerative zebrafish glia after injury. Shaw et al. defined the molecular identity of regenerative zebrafish glia and performed cross-species comparisons with mammalian glia. They found that EMT localizes to zebrafish glial progenitors and distinguishes mammalian and zebrafish glia. They uncovered evidence that an EMT transcriptional module reprograms glial progenitors and promotes spinal cord repair in zebrafish. © 2021 Elsevier Inc.

Author Keywords
astrocytes; bridging; CRISPR/Cas9 mutagenesis; EMT; glia; regeneration; spinal cord injury; zebrafish

Funding details
National Institutes of HealthNIHR01 HL081674
University of MissouriMU
University of WashingtonUW
Center of Regenerative Medicine, Washington University in St. LouisCRM, WUSTLT32 EB028092

Document Type: Article
Publication Stage: Final
Source: Scopus

"Enteric helminth coinfection enhances host susceptibility to neurotropic flaviviruses via a tuft cell-IL-4 receptor signaling axis" (2021) Cell

Enteric helminth coinfection enhances host susceptibility to neurotropic flaviviruses via a tuft cell-IL-4 receptor signaling axis
(2021) Cell, 184 (5), pp. 1214-1231.e16. Cited 1 time.

Desai, P.^a , Janova, H.^b , White, J.P.^a , Reynoso, G.V.^c , Hickman, H.D.^c , Baldridge, M.T.^a ^d , Urban, J.F., Jr.^e , Stappenbeck, T.S.^f , Thackray, L.B.^a , Diamond, M.S.^a ^b ^d ^g

^a Department of Medicine, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
^c Viral Immunity and Pathogenesis Unit, Laboratory of Clinical Microbiology and Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20892, United States
^d Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, St. LouisMO 63110, United States
^e US Department of Agriculture, Agricultural Research Services, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, and Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD 20705-2350, United States
^f Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, United States
^g The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States

Abstract
Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on systemic microbes remain less established. Here, we observe increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV). This enhanced susceptibility is associated with altered gut morphology and transit, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These outcomes were due to type 2 immune skewing, because coinfection in Stat6−/− mice rescues mortality, treatment of helminth-free WNV-infected mice with interleukin (IL)-4 mirrors coinfection, and IL-4 receptor signaling in intestinal epithelial cells mediates the susceptibility phenotypes. Moreover, tuft cell-deficient mice show improved outcomes with coinfection, whereas treatment of helminth-free mice with tuft cell-derived cytokine IL-25 or ligand succinate worsens WNV disease. Thus, helminth activation of tuft cell-IL-4-receptor circuits in the gut exacerbates infection and disease of a neurotropic flavivirus. Desai et al. show that the tuft cell/IL-4Rα circuit in the intestine can have detrimental consequences in the context of helminth and viral coinfection. Flavivirus infection of enteric neurons, in the setting of a type 2 immune response due to helminths, IL-25, or IL-4 signaling, impairs intestinal integrity and compromises host CD8+ T cell responses and survival. © 2021 Elsevier Inc.

Author Keywords
CD8+ T cells; flavivirus; helminth; IL-4; microbiome; succinate; tuft cells; type 2 immunity; viral pathogenesis

Funding details
8042-31000-107-00D
National Institutes of HealthNIHR01 AI101400, R01 DK122790, R01 HD091218, R01AI145296
Division of Intramural Research, National Institute of Allergy and Infectious DiseasesDIR, NIAID

Document Type: Article
Publication Stage: Final
Source: Scopus

"Diagnostic Error of Neuro-ophthalmologic Conditions: State of the Science" (2021) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society

Diagnostic Error of Neuro-ophthalmologic Conditions: State of the Science
(2021) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 41 (1), pp. 98-113.

Stunkel, L., Newman-Toker, D.E., Newman, N.J., Biousse, V.

Departments of Ophthalmology and Visual Sciences (LS) and Neurology (LS), Washington University in St. Louis School of Medicine, St. Louis, Missouri; Department of Neurology (DEN-T), The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Ophthalmology (NJN, VB), Neurology (NJN, VB), and Neurological Surgery (NJN), Emory University School of Medicine, Atlanta, Georgia

Abstract
BACKGROUND: Diagnostic error is prevalent and costly, occurring in up to 15% of US medical encounters and affecting up to 5% of the US population. One-third of malpractice payments are related to diagnostic error. A complex and specialized diagnostic process makes neuro-ophthalmologic conditions particularly vulnerable to diagnostic error. EVIDENCE ACQUISITION: English-language literature on diagnostic errors in neuro-ophthalmology and neurology was identified through electronic search of PubMed and Google Scholar and hand search. RESULTS: Studies investigating diagnostic error of neuro-ophthalmologic conditions have revealed misdiagnosis rates as high as 60%-70% before evaluation by a neuro-ophthalmology specialist, resulting in unnecessary tests and treatments. Correct performance and interpretation of the physical examination, appropriate ordering and interpretation of neuroimaging tests, and generation of a differential diagnosis were identified as pitfalls in the diagnostic process. Most studies did not directly assess patient harms or financial costs of diagnostic error. CONCLUSIONS: As an emerging field, diagnostic error in neuro-ophthalmology offers rich opportunities for further research and improvement of quality of care. Copyright © 2020 by North American Neuro-Ophthalmology Society.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Effects of anticholinergic medication use on brain integrity in persons living with HIV and persons without HIV" (2021) AIDS (London, England)

Effects of anticholinergic medication use on brain integrity in persons living with HIV and persons without HIV
(2021) AIDS (London, England), 35 (3), pp. 381-391.

Cooley, S.A.^a , Paul, R.H.^b , Strain, J.F.^a , Boerwinkle, A.^a , Kilgore, C.^a , Ances, B.M.^a ^c ^d

^a Department of Neurology, Washington University in Saint Louis
^b Department of Psychology, University of MissouriSaint Louis, Seychelles
^c Department of Radiology
^d Hope Center for Neurological Disorders, Washington University in Saint Louis, Saint Louis, Missouri, USA

Abstract
OBJECTIVE: This study examined relationships between anticholinergic medication burden and brain integrity in people living with HIV (PLWH) and people without HIV (HIV-). METHODS: Neuropsychological performance z-scores (learning, retention, executive function, motor/psychomotor speed, language domains, and global cognition), and neuroimaging measures (brain volumetrics and white matter fractional anisotropy) were analyzed in PLWH (n = 209) and HIV- (n = 95) grouped according to the Anticholinergic Cognitive Burden (ACB) scale (0 = no burden, 1-3 = low burden, >3 = high burden). Neuropsychological performance and neuroimaging outcomes were compared between HIV- and PLWH with high anticholinergic burden. Within a cohort of PLWH (n = 90), longitudinal change in ACB score over ∼2 years was correlated to the rate of change per month of study interval in neuropsychological performance and neuroimaging measures. RESULTS: A higher number of anticholinergic medications and ACB was observed in PLWH compared with HIV- (P < 0.05). A higher ACB was associated with worse motor/psychomotor performance, smaller occipital lobe, putamen, subcortical gray matter and total gray matter volumes in HIV-; and poorer executive function, retention and global cognition, smaller brain volumes (frontal, parietal and temporal lobes, hippocampus, amygdala, cortex, subcortical gray matter and total gray matter), and reduced fractional anisotropy (posterior corpus callosum, perforant pathway) in PLWH. PLWH with high anticholinergic burden performed worse on tests of learning and executive function compared with HIV- with high anticholinergic burden. Longitudinally, PLWH who reduced their ACB over time had better neuropsychological performance and neuroimaging measures. CONCLUSION: Anticholinergic medications were associated with worse neuropsychological performance and reduced structural brain integrity, and these effects were more widespread in PLWH. Use of anticholinergic medications should be carefully monitored in older adults with deprescription considered whenever possible. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding" (2021) Science Advances

Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding
(2021) Science Advances, 7 (9), art. no. eabd3666, .

Luskin, A.T.^a ^b ^c ^d ^e ^f , Bhatti, D.L.^a ^b ^k , Mulvey, B.^c ^g , Pedersen, C.E.^a ^b ^d ^e ^h ⁱ , Girven, K.S.^d ^e ^j , Oden-Brunson, H.^a ^b , Kimbell, K.^a ^b , Blackburn, T.^d , Sawyer, A.^d , Gereau, R.W., IV^a ^b ^g , Dougherty, J.D.^g ^h , Bruchas, M.R.^a ^b ^c ^d ^e ^f ^g ⁱ

^a Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Washington University Pain Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
^c Division of Biology and Biomedical Sciences, Washington University, School of Medicine, St. Louis, MO 63110, United States
^d Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195, United States
^e Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA 98195, United States
^f Graduate Program in Neuroscience, University of Washington, Seattle, WA 98195, United States
^g Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
^h Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
ⁱ Department of Bioengineering, University of Washington, Seattle, WA 98105, United States
^j Department of Pharmacology, University of Washington, Seattle, WA 98195, United States
^k Program in Neuroscience, Harvard Medical School, Boston, MA 02115, United States

Abstract
An animal’s evolutionary success depends on the ability to seek and consume foods while avoiding environmental threats. However, how evolutionarily conserved threat detection circuits modulate feeding is unknown. In mammals, feeding and threat assessment are strongly influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits feeding. Here, we report that the PBN receives dense inputs from two discrete neuronal populations in the bed nucleus of the stria terminalis (BNST), an extended amygdala structure that encodes affective information. Using a series of complementary approaches, we identify opposing BNST-PBN circuits that modulate neuropeptide-expressing PBN neurons to control feeding and affective states. These previously unrecognized neural circuits thus serve as potential nodes of neural circuitry critical for the integration of threat information with the intrinsic drive to feed. Copyright © 2021 The Authors, some rights reserved.

Funding details
National Institute of Mental HealthNIMHR01-MH112355, F31-MH122033
National Institute on Drug AbuseNIDAR01-DA033396, P30-DA048736, F31-DA051124
National Institute of Mental HealthNIMHF30-MH116654, U01-MH109133, UL1-RR024992
National Center for Research ResourcesNCRR
National Institute of General Medical SciencesNIGMST32-GM008151
National Institute of Neurological Disorders and StrokeNINDSR01-NS106953, R56-NS048602

Document Type: Article
Publication Stage: Final
Source: Scopus

"Microglia control small vessel calcification via TREM2" (2021) Science Advances

Microglia control small vessel calcification via TREM2
(2021) Science Advances, 7 (9), art. no. eabc4898, .

Zarb, Y.^a ^b ⁱ , Sridhar, S.^a ^b , Nassiri, S.^c , Utz, S.G.^d , Schaffenrath, J.^a ^b , Maheshwari, U.^a ^b , Rushing, E.J.^e , Peter Nilsson, K.R.^f , Delorenzi, M.^c ^g , Colonna, M.^h , Greter, M.^d , Keller, A.^a ^b

^a Department of Neurosurgery, Clinical Neurocentre, Zurich University Hospital, Zurich University, Zürich, Switzerland
^b Neuroscience Center Zurich, University of Zurich, ETH Zurich, Zurich, Switzerland
^c Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland
^d Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
^e Institute of Neuropathology, Zurich University Hospital, Zurich, Switzerland
^f Department of Chemistry, Linköping University, Linköping, Sweden
^g Department of Oncology, University Lausanne, Lausanne, Switzerland
^h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Institute of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-University Munich, Munich, Germany

Abstract
Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, Pdgfbret/ret, to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Funding details
Horizon 2020819229
FK-16-034
Stiftung Synapsis – Alzheimer Forschung Schweiz AFS
Fondation Leducq14CVD02
European Research CouncilERC
Krebsliga SchweizKLS-3848-02-2016
2019-PI02
Universität ZürichUZH
Schweizerische Herzstiftung
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF31003A_159514, BSGI0_155832, 310030_188952, PP00P3_170626

Document Type: Article
Publication Stage: Final
Source: Scopus

"Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study" (2021) Frontiers in Endocrinology

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study
(2021) Frontiers in Endocrinology, 11, art. no. 549928, .

Herting, M.M.^a ^b , Uban, K.A.^c ^d , Gonzalez, M.R.^e ^f , Baker, F.C.^g , Kan, E.C.^b ^f , Thompson, W.K.^h , Granger, D.A.^d ⁱ ^j , Albaugh, M.D.^a , Anokhin, A.P.^l , Bagot, K.S.^m , Banich, M.T.ⁿ , Barch, D.M.^o , Baskin-Sommers, A.^p , Breslin, F.J.^q , Casey, B.J.^p , Chaarani, B.^k , Chang, L.^r , Clark, D.B.^s , Cloak, C.C.^r , Constable, R.T.^t , Cottler, L.B.^u , Dagher, R.K.^v , Dapretto, M.^w , Dick, A.S.^x , Dosenbach, N.^y , Dowling, G.J.^z , Dumas, J.A.^k , Edwards, S.^aa , Ernst, T.^r , Fair, D.A.^ab , Feldstein-Ewing, S.W.^ac , Freedman, E.G.^ad , Fuemmeler, B.F.^ae , Garavan, H.^k , Gee, D.G.^p , Giedd, J.N.^af , Glaser, P.E.A.^l , Goldstone, A.^g , Gray, K.M.^ag , Hawes, S.W.^x , Heath, A.C.^l , Heitzeg, M.M.^ah , Hewitt, J.K.ⁿ , Heyser, C.J.^ai , Hoffman, E.A.^z , Huber, R.S.^aj , Huestis, M.A.^ak , Hyde, L.W.^al , Infante, M.A.^e , Ivanova, M.Y.^a , Jacobus, J.^af , Jernigan, T.L.^am , Karcher, N.R.^l , Laird, A.R.^an , LeBlanc, K.H.^z , Lisdahl, K.^ao , Luciana, M.^ap , Luna, B.^s , Maes, H.H.^aq , Marshall, A.T.^b ^ar , Mason, M.J.^as , McGlade, E.C.^aj , Morris, A.S.^q ^at , Nagel, B.J.^au , Neigh, G.N.^av , Palmer, C.E.^ai , Paulus, M.P.^q , Potter, A.S.^k , Puttler, L.I.^ah , Rajapakse, N.^v , Rapuano, K.^p , Reeves, G.^aa , Renshaw, P.F.^aw , Schirda, C.^ax , Sher, K.J.^ay , Sheth, C.^aw , Shilling, P.D.^e , Squeglia, L.M.^ag , Sutherland, M.T.^x , Tapert, S.F.^b , Tomko, R.L.^ag , Yurgelun-Todd, D.^aw , Wade, N.E.^e , Weiss, S.R.B.^z , Zucker, R.A.^ah , Sowell, E.R.^f

^a Preventive Medicine, University of Southern California, Los Angeles, CA, United States
^b Department of Pediatrics, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
^c Public Health, University of California, Irvine, Irvine, CA, United States
^d Institute for Interdisciplinary Salivary Bioscience Research, University of California, Irvine, Irvine, CA, United States
^e Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States
^f Research on Children, Youth, and Families, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
^g Center for Health Sciences, SRI International, Menlo Park, CA, United States
^h Division of Biostatistics, University of California, San Diego, La Jolla, CA, United States
ⁱ Social Ecology, University of California, Irvine, Irvine, CA, United States
^j Bloomberg School of Public Health, Johns Hopkins University, Baltimore, CA, United States
^k Department of Psychiatry, University of Vermont, Burlington, VT, United States
^l Department of Psychiatry, Washington University, St. Louis, MO, United States
^m Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁿ Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
^o Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^p Department of Psychology, University of Yale, New Haven, CT, United States
^q Laureate Institute for Brain Research, Tulsa, OK, United States
^r Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States
^s Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^t Radiology and Biomedical Imaging, University of Yale, New Haven, CT, United States
^u Department of Epidemiology, University of Florida, Gainesville, FL, United States
^v Division of Scientific Programs, National Institute on Minority Health and Health Disparities, BethesdaMD, United States
^w Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, United States
^x Department of Psychology, Florida International University, Miami, FL, United States
^y Department of Neurology, Washington University, St. Louis, MO, United States
^z Division of Extramural Research, National Institute on Drug Abuse, Bethesda, MD, United States
^aa Department of Psychiatry, University of Maryland, Baltimore, MD, United States
^ab Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
^ac Department of Psychology, University of Rhode Island, Kingston, RI, United States
^ad Department of Neuroscience, University of Rochester, Rochester, NY, United States
^ae Health Behavior and Policy, Virginia Commonwealth University, Richmon, VA, United States
^af Department of Psychiatry, University of San Diego, La JollaCA, United States
^ag Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
^ah Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
^ai Center for Human Development, University of California, San Diego, La Jolla, CA, United States
^aj Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
^ak Medical Cannabis Science Program, Thomas Jefferson University, Philadelphia, PA, United States
^al Department of Psychology, University of Michigan, Ann Arbor, MI, United States
^am Department of Cognitive Science, University of San Diego, La JollaCA, United States
^an Department of Physics, Florida International University, Miami, FL, United States
^ao Department of Psychology, University of Wisconsin, Milwaukee, WI, United States
^ap Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^aq Human Molecular Genetics, Virginia Commonwealth University, Richmond, VT, United States
^ar Department of Pediatrics, University of Southern California, Los Angeles, CA, United States
^as Center for Behavioral Health Research, University of Tennessee, Knoxville, TN, United States
^at Human Development and Family Science, Oklahoma State University, Tulsa, OK, United States
^au Department of Psychiatry, Oregon Health Science University, Portland, OR, United States
^av Anatomy Neurobiology, Virginia Commonwealth University, Richmond, VT, United States
^aw Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
^ax Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
^ay Department of Psychology, University of Missouri, Columbia, MO, United States

Abstract
Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9–10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study—a multi-site sample of 9–10 year-olds (n = 11,875)—and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child’s weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9–10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes. © Copyright © 2021 Herting, Uban, Gonzalez, Baker, Kan, Thompson, Granger, Albaugh, Anokhin, Bagot, Banich, Barch, Baskin-Sommers, Breslin, Casey, Chaarani, Chang, Clark, Cloak, Constable, Cottler, Dagher, Dapretto, Dick, Dosenbach, Dowling, Dumas, Edwards, Ernst, Fair, Feldstein-Ewing, Freedman, Fuemmeler, Garavan, Gee, Giedd, Glaser, Goldstone, Gray, Hawes, Heath, Heitzeg, Hewitt, Heyser, Hoffman, Huber, Huestis, Hyde, Infante, Ivanova, Jacobus, Jernigan, Karcher, Laird, LeBlanc, Lisdahl, Luciana, Luna, Maes, Marshall, Mason, McGlade, Morris, Nagel, Neigh, Palmer, Paulus, Potter, Puttler, Rajapakse, Rapuano, Reeves, Renshaw, Schirda, Sher, Sheth, Shilling, Squeglia, Sutherland, Tapert, Tomko, Yurgelun-Todd, Wade, Weiss, Zucker and Sowell.

Author Keywords
adolescent brain cognitive development; dehydroepiandrosterone; estradiol; pubertal development scale; puberty; salivary hormones; testosterone

Document Type: Article
Publication Stage: Final
Source: Scopus

"Henry R. Viets, MD, and the History of Myasthenia Gravis" (2021) Neurology

Henry R. Viets, MD, and the History of Myasthenia Gravis
(2021) Neurology, 96 (7), pp. 322-326.

Feibel, R.M.

From the Department of Ophthalmology and Visual Sciences, and the Center for History Of Medicine, Washington University School of Medicine, St. Louis, MO

Abstract
Henry R. Viets (1890-1969) was both a noted neurologist and medical historian. While at Harvard Medical School, from which he graduated in 1916, he attracted the attention of Harvey Cushing who directed Viets into these disciplines. Cushing arranged for Viets to take a fellowship in Oxford in the year after his graduation. With Cushing’s recommendation, he lived with Sir William and Lady Osler and did research with the famous neurologist Sir Charles Sherrington. Viets was in London in 1935 when he heard about the remarkable success of Mary Walker in treating myasthenia gravis, first with physostigmine and then with neostigmine (Prostigmin). Securing an ampoule of this drug, he took it to the Massachusetts General Hospital where he was an attending neurologist and in March 1935 injected it into a myasthenic patient with great success. He established the first Myasthenia Gravis clinic in the world and was a pioneer in the treatment of this once obscure disease; he evaluated hundreds of patients and published many articles on myasthenia. He continued this association for more than 30 years. Under the tutelage of Cushing and Osler, Viets became a medical historian and bibliophile, publishing hundreds of articles and several books on many different subjects in the history of medicine. He was a president of the American Association for the History of Medicine and curator of the Boston Medical Library that eventually joined with the Harvard Medical School Library. Viets served on the Editorial Board of the New England Journal of Medicine for 40 years. © 2020 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity" (2021) Neurosurgery

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity
(2021) Neurosurgery, 88 (3), pp. 698-706.

Morales, D.M.^a , Smyser, C.D.^b ^c ^d , Han, R.H.^a , Kenley, J.K.^b , Shimony, J.S.^c , Smyser, T.A.^e , Strahle, J.M.^a ^d , Inder, T.E.^f , Limbrick, D.D.^a ^d

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Pediatric Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA

Abstract
BACKGROUND: Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. OBJECTIVE: To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. METHODS: A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. RESULTS: APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. CONCLUSION: Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae. Copyright © 2020 by the Congress of Neurological Surgeons.

Author Keywords
Biomarker; Cerebrospinal fluid; Diffusion MRI, Intraventricular hemorrhage; Diffusion tensor imaging; MRI; Periventricular white matter; Posthemorrhagic hydrocephalus; Preterm

Document Type: Article
Publication Stage: Final
Source: Scopus

"Clinical Accuracy, Technical Precision, and Workflow of the First in Human Use of an Augmented-Reality Head-Mounted Display Stereotactic Navigation System for Spine Surgery" (2021) Operative Neurosurgery (Hagerstown, Md.)

Clinical Accuracy, Technical Precision, and Workflow of the First in Human Use of an Augmented-Reality Head-Mounted Display Stereotactic Navigation System for Spine Surgery
(2021) Operative Neurosurgery (Hagerstown, Md.), 20 (3), pp. 300-309.

Molina, C.A.^a ^b , Sciubba, D.M.^b , Greenberg, J.K.^a , Khan, M.^c , Witham, T.^b

^a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
BACKGROUND: Augmented reality mediated spine surgery is a novel technology for spine navigation. Benchmark cadaveric data have demonstrated high accuracy and precision leading to recent regulatory approval. Absence of respiratory motion in cadaveric studies may positively bias precision and accuracy results and analogous investigations are prudent in live clinical scenarios. OBJECTIVE: To report a technical note, accuracy, precision analysis of the first in-human deployment of this technology. METHODS: A 78-yr-old female underwent an L4-S1 decompression, pedicle screw, and rod fixation for degenerative spine disease. Six pedicle screws were inserted via AR-HMD (xvision; Augmedics, Chicago, Illinois) navigation. Intraoperative computed tomography was used for navigation registration as well as implant accuracy and precision assessment. Clinical accuracy was graded per the Gertzbein-Robbins (GS) scale by an independent neuroradiologist. Technical precision was analyzed by comparing 3-dimensional (3D) (x, y, z) virtual implant vs real implant position coordinates and reported as linear (mm) and angular (°) deviation. Present data were compared to benchmark cadaveric data. RESULTS: Clinical accuracy (per the GS grading scale) was 100%. Technical precision analysis yielded a mean linear deviation of 2.07 mm (95% CI: 1.62-2.52 mm) and angular deviation of 2.41° (95% CI: 1.57-3.25°). In comparison to prior cadaveric data (99.1%, 2.03 ± 0.99 mm, 1.41 ± 0.61°; GS accuracy 3D linear and angular deviation, respectively), the present results were not significantly different (P > .05). CONCLUSION: The first in human deployment of the single Food and Drug Administration approved AR-HMD stereotactic spine navigation platform demonstrated clinical accuracy and technical precision of inserted hardware comparable to previously acquired cadaveric studies. © Congress of Neurological Surgeons 2020.

Author Keywords
Augmented reality; Computer-assisted spine surgery; Mixed reality; Spine navigation

Document Type: Article
Publication Stage: Final
Source: Scopus

"Non-invasive quantification of inflammation, axonal and myelin injury in multiple sclerosis" (2021) Brain: A Journal of Neurology

Non-invasive quantification of inflammation, axonal and myelin injury in multiple sclerosis
(2021) Brain: A Journal of Neurology, 144 (1), pp. 213-223.

Schiavi, S.^a ^b ^c , Petracca, M.^a , Sun, P.^d , Fleysher, L.^e , Cocozza, S.^a ^f , El Mendili, M.M.^a , Signori, A.^g , Babb, J.S.^h , Podranski, K.^a , Song, S.-K.^d ⁱ ^j ^k , Inglese, M.^a ^b ^c

^a Department of Neurology, Icahn School of Medicine at Mount Sinai, NY, NY, United States
^b Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Italy
^c Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
^d Radiology, Washington University School of Medicine, St. Louis, MO, USA
^e Department of Radiology, Icahn School of Medicine at Mount Sinai, NY, NY, United States
^f Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy
^g Department of Health Sciences, University of Genoa, Genoa, Italy
^h Department of Radiology, Center for Biomedical Imaging, New York University, Langone Medical CenterNY, United States
ⁱ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
^j Biomedical Engineering, Washington University, St. Louis, MO, USA
^k Biomedical MR Laboratory, Washington University School of Medicine, St. Louis, MO, USA

Abstract
The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to <0.001) and between lesions’ centre and rim (P < 0.001) for all the metrics. When comparing the three subject groups in terms of metrics derived from corpus callosum normal appearing white matter and T2-hyperintense lesions, a significant difference was found between healthy controls and relapsing-remitting patients for all metrics except restricted fraction and fractional anisotropy; between healthy controls and progressive patients for all metrics except restricted fraction and between relapsing-remitting and progressive multiple sclerosis patients for all metrics except fibres and restricted fractions (P ranging from 0.05 to <0.001 for all). Significant associations were found between corpus callosum normal-appearing white matter fibres fraction/non-restricted fraction and the Symbol Digit Modality Test (respectively, r = 0.35, P = 0.043; r = -0.35, P = 0.046), and between black holes radial diffusivity and Expanded Disability Status Score (r = 0.59, P = 0.002). We showed the feasibility of diffusion basis spectrum imaging metrics at 7 T, confirmed the role of the derived metrics in the characterization of lesions and normal appearing white matter tissue in different stages of the disease and demonstrated their clinical relevance. Thus, suggesting that diffusion basis spectrum imaging is a promising tool to investigate multiple sclerosis pathophysiology, monitor disease progression and treatment response. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
axonal injury; diffusion basis spectrum imaging; inflammation; multiple sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

"Hippocampus Guides Adaptive Learning during Dynamic Social Interactions" (2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Hippocampus Guides Adaptive Learning during Dynamic Social Interactions
(2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 41 (6), pp. 1340-1348.

FeldmanHall, O.^a ^b , Montez, D.F.^c , Phelps, E.A.^d , Davachi, L.^e , Murty, V.P.^f

^a Department of Cognitive, Linguistic & Psychological Sciences, Brown University, Providence, RI 02912, United States
^b Carney Institute of Brain Science, Brown University, Providence, RI 02912, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Psychology, Harvard University, Cambridge, MA 02138
^e Department of Psychology, Columbia UniversityNY 10027
^f Department of Psychology, Temple University, Philadelphia, PA 19122, United States

Abstract
How do we evaluate whether someone will make a good friend or collaborative peer? A hallmark of human cognition is the ability to make adaptive decisions based on information garnered from limited prior experiences. Using an interactive social task measuring adaptive choice (deciding who to reengage or avoid) in male and female participants, we find the hippocampus supports value-based social choices following single-shot learning. These adaptive choices elicited a suppression signal in the hippocampus, revealing sensitivity for the subjective perception of a person and how well they treat you during choice. The extent to which the hippocampus was suppressed was associated with flexibly interacting with prior generous individuals and avoiding selfish individuals. Further, we found that hippocampal signals during decision-making were related to subsequent memory for a person and the offer they made before. Consistent with the hippocampus leveraging previously executed choices to solidify a reliable neural signature for future adaptive behavior, we also observed a later hippocampal enhancement. These findings highlight the hippocampus playing a multifaceted role in socially adaptive learning.SIGNIFICANCE STATEMENT Adaptively navigating social interactions requires an integration of prior experiences with information gleaned from the current environment. While most research has focused on striatal-based feedback learning, open questions remain regarding the role of hippocampal-based episodic memory systems. Here, we show that during social decisions based on prior experience, hippocampal suppression signals were sensitive to adaptive choice, while hippocampal enhancements was related to subsequent memory for the original social interaction. These findings highlight the hippocampus playing a multifaceted role in socially adaptive learning. Copyright © 2021 the authors.

Author Keywords
choice; decision-making; Dictator Task; hippocampus; social learning; value

Document Type: Article
Publication Stage: Final
Source: Scopus

"Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals" (2021) Neurology

Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals
(2021) Neurology, 96 (5), pp. e662-e670. Cited 1 time.

van der Kall, L.M., Truong, T., Burnham, S.C., Doré, V., Mulligan, R.S., Bozinovski, S., Lamb, F., Bourgeat, P., Fripp, J., Schultz, S., Lim, Y.Y., Laws, S.M., Ames, D., Fowler, C., Rainey-Smith, S.R., Martins, R.N., Salvado, O., Robertson, J., Maruff, P., Masters, C.L., Villemagne, V.L., Rowe, C.C.

From Austin Health (L.M.v.d.K., T.T., V.D., R.S.M., S.B., F.L., S.S., V.L.V., C.C.R.); CSIRO (S.C.B., V.D.), Melbourne; CSIRO (P.B., J.F., O.S.), Brisbane; The Florey Institute of Neuroscience and Mental Health (Y.Y.L., C.F., J.R., P.M., C.L.M.), Melbourne; University of Melbourne (T.T., D.A., C.L.M., V.L.V., C.C.R.); Edith Cowan University (S.M.L., S.R.R.-S., R.N.M.), Perth, Australia; and Washington University (S.S.), St. Louis, MO

Abstract
OBJECTIVE: To determine the effect of β-amyloid (Aβ) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. METHODS: All CN from the Australian Imaging Biomarkers and Lifestyle study with Aβ PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aβ positive; follow-up 5.3 ± 1.7 years). Aβ level was divided using the standardized 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. RESULTS: Aβ levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aβ, the hazard ratio for progression for moderate Aβ was 3.2 (95% confidence interval [CI] 1.3-7.6; p < 0.05), for high was 7.0 (95% CI 3.7-13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p = 0.05), while the high and very high declined substantially (high -0.08 SD/year, p < 0.001; very high -0.35 SD/year, p < 0.001). CONCLUSION: The risk of MCI or dementia over 5 years in older CN is related to Aβ level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site" (2021) eLife

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site
(2021) eLife, 10, art. no. e56519, pp. 1-58.

Uprety, R.^a , Che, T.^b ^c ^d , Zaidi, S.A.^e , Grinnell, S.G.^f , Varga, B.R.^c ^d , Faouzi, A.^c ^d , Slocum, S.T.^b , Allaoa, A.^a , Varadi, A.^a , Nelson, M.^f , Bernhard, S.M.^c , Kulko, E.^f , Rouzic, V.L.^a , Eans, S.O.^g , Simons, C.A.^g , Hunkele, A.^a , Subrath, J.^a , Pan, Y.X.^a ^h , Javitch, J.A.^f , McLaughlin, J.P.^g , Roth, B.L.^b , Pasternak, G.W.^a , Katritch, V.^e , Majumdar, S.^a ^c ^d

^a Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, United States
^b Department of Pharmacology, University of North Carolina, Chapel Hill, United States
^c Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, United States
^d Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, United States
^e Department of Quantitative and Computational Biology, Department of Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, United States
^f Division of Molecular Therapeutics, New York State Psychiatric Institute and Departments of Psychiatry, Pharmacology, Columbia University Vagelos College of Physicians & Surgeons, New York, United States
^g Department of Pharmacodynamics, University of Florida, Gainesville, United States
^h Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ, United States

Abstract
Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism. © Uprety et al.

Funding details
National Institutes of HealthNIHAA026949, DA045884, DA046487, W81XWH-17-1-0256
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDADA006241, DA007242, DA042888, DA046714, MH54137, P01DA035764, R33DA038858, T32 MH018870
National Cancer InstituteNCIP30 CA008748
Hope for Depression Research FoundationHDRFR37DA045657, RO1MH112205
University of FloridaUF
University of WashingtonUW

Document Type: Article
Publication Stage: Final
Source: Scopus

"Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy" (2021) Pediatrics

Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy
(2021) Pediatrics, 147 (2), art. no. e2020022962, .

Peeples, E.S.^a , Rao, R.^b , Dizon, M.L.V.^c , Johnson, Y.R.^d ^e , Joe, P.^f , Flibotte, J.^g , Hossain, T.^h , Smith, D.ⁱ , Hamrick, S.^j , DiGeronimo, R.^k , Natarajan, G.^l , Lee, K.-S.^m , Yanowitz, T.D.ⁿ , Mietzsch, U.^k , Wu, T.-W.^o , Maitre, N.L.^p , Pallotto, E.K.^q , Speziale, M.^r , Mathur, A.M.^s , Zaniletti, I.^t , Massaro, A.^u , Piazza, A.^v , Sysyn, G.^w , Coghill, C.^x , Talati, A.^y , Hansen, A.^z , Hossain, T.^z , Murthy, K.^aa , Falciglia, G.^aa , Haberman, B.^ab , Reber, K.^ac , Savani, R.^ad , Grover, T.^ae , Natarajan, G.^af , Chi, A.^ag , Johnson, Y.^ag , Suresh, G.^ah , Engle, W.^ai , Pallotto, E.^aj , Lyle, R.^ak , Rogers, B.^ak , Chapman, R.^al , Limjoco, J.^am , Joe, P.^an , Evans, J.^ao , Padula, M.^ao , Munson, D.^ao , Touch, S.^ap , Brozanski, B.^aq , Rao, R.^ar , Mathur, A.^ar , McKay, V.^as , Speziale, M.^at , Moyer, L.^at , Short, B.^au , Sullivan, K.^av , Ling, C.Y.^aw , Uhing, M.^ax , Datta, A.^ax , Birge, N.^ay , Wadhawan, R.^az , Jacobsen-Misbe, E.^ba , DiGeronimo, R.^ba , Lee, K.-S.^bb , Mikhael, M.^bc , Children’s Hospitals Neonatal Consortium Hypoxic-Ischemic Encephalopathy Focus Group^bd

^a Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, United States
^b Department of Pediatrics, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^c Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, IL, United States
^d Department of Pediatrics, Cook Children’s Medical Center, Fort Worth, TX, United States
^e Department of Pediatrics, Texas Christian University, University of North Texas Health Science Center, Fort Worth, TX, United States
^f Department of Pediatrics, University of California, San Francisco Benioff Children’s Hospital, Oakland, CA, United States
^g Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^h Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
ⁱ Department of Pediatrics, University of Colorado Denver, Denver, CO, United States
^j Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, United States
^k Department of Pediatrics, University of Washington, Seattle, WA, United States
^l Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, United States
^m Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
ⁿ Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^o Department of Pediatrics, Keck School of Medicine, University of Southern California and Children’s Hospital Los Angeles, Los Angeles, CA, United States
^p Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
^q Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, United States
^r Department of Pediatrics, Rady Children’s Hospital-San Diego, University of California, San Diego, San Diego, CA, United States
^s Department of Pediatrics, Saint Louis University, St Louis, MO, United States
^t Department of Pediatrics, Children’s Hospital Association, Lenexa, KS, United States
^u Department of Pediatrics, Children’s National Health System, Washington, DC, United States
^v Children’s Healthcare of Atlanta, Atlanta, GA, United States
^w Children’s Healthcare of Atlanta at Scottish Rite, Atlanta, GA, United States
^x Children’s of Alabama, Birmingham, AL, United States
^y Le Bonheur Children’s Hospital, Memphis, TN, United States
^z Boston Children’s Hospital, Boston, MA, United States
^aa Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^ab Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^ac Nationwide Children’s Hospital, Columbus, OH, United States
^ad Children’s Medical Center Dallas, Dallas, TX, United States
^ae Children’s Hospital Colorado, Aurora, CO, United States
^af Children’s Hospital of Michigan, Detroit, MI, United States
^ag Cook Children’s Health Care System, Fort Worth, TX, United States
^ah Texas Children’s Hospital, Houston, TX, United States
^ai Riley Children’s Hospital, Indianapolis, IN, United States
^aj Children’s Mercy Hospitals and Clinics, Kansas City, MO, United States
^ak Arkansas Children’s Hospital, Little Rock, AR, United States
^al Children’s Hospital Los Angeles, Los Angeles, CA, United States
^am American Family Children’s Hospital, Madison, WI, United States
^an University of California, San Francisco Benioff Children’s Hospital, Oakland, CA, United States
^ao Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ap St Christopher’s Hospital for Children, Philadelphia, PA, United States
^aq University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
^ar St Louis Children’s Hospital, St Louis, MO, United States
^as Johns Hopkins All Children’s Hospital, St Petersburg, FL, United States
^at Rady Children’s Hospital-San Diego, San Diego, CA, United States
^au Children’s National Medical Center, Washington, DC, United States
^av Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, United States
^aw Primary Children’s Medical Center, Salt Lake City, UT, United States
^ax Children’s Wisconsin, Milwaukee, WI, United States
^ay Children’s Hospital and Medical Center, Omaha, NE, United States
^az Florida Hospital for Children, Orlando, FL, United States
^ba Seattle Children’s Hospital, Seattle, WA, United States
^bb Hospital for Sick Children, Toronto, Canada
^bc Children’s Hospital of Orange County, Los Angeles, CA, United States

Abstract
OBJECTIVES: To develop predictive models for death or neurodevelopmental impairment (NDI) after neonatal hypoxic-ischemic encephalopathy (HIE) from data readily available at the time of NICU admission (“early”) or discharge (“cumulative”). METHODS: In this retrospective cohort analysis, we used data from the Children’s Hospitals Neonatal Consortium Database (2010-2016). Infants born at $35 weeks’ gestation and treated with therapeutic hypothermia for HIE at 11 participating sites were included; infants without Bayley Scales of Infant Development scores documented after 11 months of age were excluded. The primary outcome was death or NDI. Multivariable models were generated with 80% of the cohort; validation was performed in the remaining 20%. RESULTS: The primary outcome occurred in 242 of 486 infants; 180 died and 62 infants surviving to followup had NDI. HIE severity, epinephrine administration in the delivery room, and respiratory support and fraction of inspired oxygen of 0.21 at admission were significant in the early model. Severity of EEG findings was combined with HIE severity for the cumulative model, and additional significant variables included the use of steroids for blood pressure management and significant brain injury on MRI. Discovery models revealed areas under the curve of 0.852 for the early model and of 0.861 for the cumulative model, and both models performed well in the validation cohort (goodness-of-fit x2: P =.24 and.06, respectively). CONCLUSIONS: Establishing reliable predictive models will enable clinicians to more accurately evaluate HIE severity and may allow for more targeted early therapies for those at highest risk of death or NDI. Copyright © 2021 by the American Academy of Pediatrics

Document Type: Article
Publication Stage: Final
Source: Scopus

"Measuring the subjective cost of listening effort using a discounting task" (2021) Journal of Speech, Language, and Hearing Research

Measuring the subjective cost of listening effort using a discounting task
(2021) Journal of Speech, Language, and Hearing Research, 64 (2), pp. 337-347. Cited 1 time.

McLaughlin, D.J.^a , Braver, T.S.^a , Peelle, J.E.^b

^a Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^b Department of Otolaryngology, Washington University, St. Louis, MO, United States

Abstract
Purpose: Objective measures of listening effort have been gaining prominence, as they provide metrics to quantify the difficulty of understanding speech under a variety of circumstances. A key challenge has been to develop paradigms that enable the complementary measurement of subjective listening effort in a quantitatively precise manner. In this study, we introduce a novel decision-making paradigm to examine age-related and individual differences in subjective effort during listening. Method: Older and younger adults were presented with spoken sentences mixed with speech-shaped noise at multiple signal-to-noise ratios (SNRs). On each trial, subjects were offered the choice between completing an easier listening trial (presented at +20 dB SNR) for a smaller monetary reward and completing a harder listening trial (presented at either +4, 0, −4, −8, or −12 dB SNR) for a greater monetary reward. By varying the amount of the reward offered for the easier option, the subjective value of performing effortful listening trials at each SNR could be assessed. Results: Older adults discounted the value of effortful listening to a greater degree than young adults, opting to accept less money in order to avoid more difficult SNRs. Additionally, older adults with poorer hearing and smaller working memory capacities were more likely to choose easier trials; however, in younger adults, no relationship with hearing or working memory was found. Self-reported measures of economic status did not affect these relationships. Conclusions: These findings suggest that subjective listening effort depends on factors including, but not necessarily limited to, hearing and working memory. Additionally, this study demonstrates that economic decision-making paradigms can be a useful approach for assessing subjective listening effort and may prove beneficial in future research. © 2021 The Authors.

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIH
Washington University in St. LouisWUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

"Test-Retest Reliability of Audiometric Assessment in Individuals with Mild Dementia" (2021) JAMA Otolaryngology – Head and Neck Surgery

Test-Retest Reliability of Audiometric Assessment in Individuals with Mild Dementia
(2021) JAMA Otolaryngology – Head and Neck Surgery, .

McClannahan, K.S.^a , Chiu, Y.-F.^b , Sommers, M.S.^a , Peelle, J.E.^c

^a Department of Psychological and Brain Sciences, Washington University in St Louis, One Brookings Dr, Campus Box 1125, St Louis, MO 63130, United States
^b Department of Communication Sciences and Disorders, St Louis University, St Louis, MO, United States
^c Department of Otolaryngology, Washington University in St Louis, St Louis, MO, United States

Abstract
Importance: Accurate assessment of hearing is critically important regardless of a person’s cognitive ability. The degree to which hearing can be reliably measured in adults with mild dementia has not been determined. Objective: To obtain quantitative measures of reliability to evaluate the degree to which audiologic testing can be accurately conducted in older adults with mild dementia. Design, Setting, and Participants: This repeated-measures cross-sectional study consisted of a comprehensive audiologic assessment on 2 occasions separated by 1 to 2 weeks performed in the department of otolaryngology at the Washington University School of Medicine from December 3, 2018, to March 4, 2020. Participants were 15 older adults with a verified diagnosis of mild dementia and 32 older adults without a verified diagnosis of mild dementia who were recruited from the Knight Alzheimer Disease Research Center at Washington University in St Louis. Main Outcomes and Measures: Test-retest reliability was assessed for tympanometry, acoustic reflex thresholds, otoacoustic emissions, hearing sensitivity, speech reception threshold, speech perception in noise, and hearing handicap, using standard clinical audiology measures. Results: A total of 47 older adults (26 women; mean [SD] age, 74.8 [6.0] years [range, 53-87 years]), including 32 with normal cognitive function and 15 with very mild or mild dementia, completed the study protocol. For participants with mild dementia, high test-retest reliability (Spearman ρ > 0.80) was found for most measures typically included in a comprehensive audiometric evaluation. For acoustic reflex thresholds, agreement was moderate to high, averaging approximately 83% across frequencies for both groups. Scores for the screening Hearing Handicap Inventory for the Elderly at time 1 and time 2 were highly correlated for the group with normal cognitive function (r = 0.84 [95% CI, 0.70-0.93]) and for the group with mild dementia (r = 0.96 [95% CI, 0.88-0.99]). For hearing thresholds, all rank-order correlations were above 0.80 with 95% CIs at or below 15% in width, with the exception of a moderate correlation of bone conduction thresholds at 500 Hz for the group with normal cognitive function (r = 0.69 [95% CI, 0.50-0.84]) and slightly wider 95% CIs for low-frequency bone conduction thresholds for both groups. For speech reception thresholds, correlations were high for groups with normal cognitive function (r = 0.91 [95% CI, 0.84-0.95]) and mild dementia (r = 0.83 [95% CI, 0.63-0.94]). Conclusions and Relevance: Test-retest reliability for hearing measures obtained from participants with mild dementia was comparable to that obtained from cognitively normal participants. These findings suggest that mild cognitive impairment does not preclude accurate audiologic assessment.. © 2021 CSIRO. All rights reserved.

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

"Motivating and Discouraging Factors for Bipolar Patient Participation in Genomic Research" (2021) Public Health Genomics

Motivating and Discouraging Factors for Bipolar Patient Participation in Genomic Research
(2021) Public Health Genomics, .

Vallender, E.J.^a , Ladner, M.E.^a , Akinhanmi, M.O.^b , Caples, F.V.^c , Frye, M.A.^d , Balls-Berry, J.E.^d ^e

^a Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, United States
^b Satcher Health Leadership Institute, Morehouse School of Medicine, Atlanta, GA, United States
^c Department of Behavioral and Environmental Health, Jackson State University, Jackson, MS, United States
^d Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States

Abstract
Aims: The goal of this project was to better understand the motivating and discouraging factors toward genetic research and biobank programs in patients with bipolar disorder, particularly across gender and racial identities. Methods: A survey (n = 63) of adults diagnosed with bipolar disorder was conducted at the general psychiatric inpatient unit and outpatient clinic at the University of Mississippi Medical Center. Participants were asked to rate on a Likert scale their attitudes toward medical research generally, mental health research specifically, and willingness to participate in a bipolar DNA biobank. Last, they were asked to endorse motivating factors or concerns for their attitude toward participation. Results: Neither attitudes toward research nor willingness to participate in a bipolar biobank differed across gender, age, or education level, but Black/African American participants were statistically significantly less likely to endorse a willingness to participate in a biobank compared to White participants. As observed in previous work, Black/African American participants were significantly more likely to endorse concerns regarding violations of trust, privacy, or autonomy. However, while there were no significant differences in discouraging factors among individuals who indicated an opposition to participating in a biobank compared to those who indicated support, there was a significant decrease in support of motivating factors, including increasing knowledge, personal benefit, and duty to community, for those not interested in participating. Conclusions: Black/African American participants with bipolar disorder were more likely to express concerns about DNA and biobank research. But while race was a contributing factor to support or opposition to biobanking for bipolar disorder research, more salient was insufficient positive motivation. These results highlight the need to emphasize contemporary safeguards on DNA research and biobanking as an ethical duty and to identify the need for community-based educational interventions to promote a greater understanding of the positive benefits to motivate increased research participation. © 2021 The Author(s) Published by S. Karger AG, Basel.

Author Keywords
Biobank; Community-based participatory research; Ethnic/racial minorities; Psychiatric genetics

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

"Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome" (2021) JAMA Neurology

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome
(2021) JAMA Neurology, pp. E1-E12.

Larovere, K.L.^a , Riggs, B.J.^b , Poussaint, T.Y.^c , Young, C.C.^d , Newhams, M.M.^d , Maamari, M.^e , Walker, T.C.^f , Singh, A.R.^g , Dapul, H.^h , Hobbs, C.V.ⁱ , McLaughlin, G.E.^j , Son, M.B.F.^k , Maddux, A.B.^l , Clouser, K.N.^m , Rowan, C.M.ⁿ , McGuire, J.K.^o , Fitzgerald, J.C.^p , Gertz, S.J.^q , Shein, S.L.^r , Munoz, A.C.^s , Thomas, N.J.^t , Irby, K.^u , Levy, E.R.^v , Staat, M.A.^w , Tenforde, M.W.^x ^y , Feldstein, L.R.^x ^y , Halasa, N.B.^z , Giuliano, J.S., Jr^aa , Hall, M.W.^ab , Kong, M.^ac , Carroll, C.L.^ad , Schuster, J.E.^ae , Doymaz, S.^af , Loftis, L.L.^ag , Tarquinio, K.M.^ah , Babbitt, C.J.^ai , Nofziger, R.A.^aj , Kleinman, L.C.^ak , Keenaghan, M.A.^al , Cvijanovich, N.Z.^am , Spinella, P.C.^an , Hume, J.R.^ao , Wellnitz, K.^ap , Mack, E.H.^aq , Michelson, K.N.^ar , Flori, H.R.^as , Patel, M.M.^x ^y , Randolph, A.G.^d ^at

^a Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^b Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
^c Department of Radiology, Boston Children’s Hospital, Boston, MA, United States
^d Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, United States
^e Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern, Children’s Health Medical Center Dallas, United States
^f Department of Pediatrics, University of North Carolina, Chapel Hill Children’s Hospital, Chapel Hill, United States
^g Pediatric Critical Care Division, Maria Fareri Children’s Hospital, Westchester Medical Center, New York Medical College, Valhalla, United States
^h Division of Pediatric Critical Care Medicine, Department of Pediatrics, New York University Grossman, School of Medicine, New York, United States
ⁱ Division of Infectious Diseases, Department of Pediatrics, Department of Microbiology, University of Mississippi Medical Center, Jackson, United States
^j Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, FL, United States
^k Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
^l Section of Critical Care Medicine, Department of Pediatrics, University of Colorado, School of Medicine, Children’s Hospital Colorado, Aurora, United States
^m Department of Pediatrics, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ, United States
ⁿ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University, School of Medicine, Riley Hospital for Children, Indianapolis, United States
^o Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington, Seattle, United States
^p Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
^q Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, NJ, United States
^r Division of Pediatric Critical Care Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
^s Pediatric Critical Care Division, Department of Pediatrics, University of Texas, Health Science Center at Houston, Houston, United States
^t Department of Pediatrics, Penn State Hershey Children’s Hospital, Pennsylvania State University, College of Medicine, Hershey, United States
^u Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, United States
^v Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United States
^w Department of Pediatrics, University of Cincinnati, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^x COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, GA, United States
^y Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, United States
^z Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
^aa Division of Critical Care, Yale University, School of Medicine, New Haven, CT, United States
^ab Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
^ac Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama, Birmingham, United States
^ad Division of Critical Care, Connecticut Children’s, Hartford, CT, United States
^ae Division of Pediatric Infectious Diseases, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO, United States
^af Division of Pediatric Critical Care, Department of Pediatrics, State University of New York Downstate, Health Sciences University, Brooklyn, United States
^ag Section of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Houston, United States
^ah Division of Critical Care Medicine, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA, United States
^ai Miller Children’s and Women’s Hospital of Long Beach, Long Beach, CA, United States
^aj Division of Critical Care Medicine, Akron Children’s Hospital, Akron, OH, United States
^ak Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
^al Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital, Brooklyn, NY, United States
^am Division of Critical Care Medicine, University of California, San Francisco, Benioff Children’s Hospital, Oakland, United States
^an Division of Critical Care, Department of Pediatrics, Washington University, School of Medicine in St Louis, St Louis, MO, United States
^ao Division of Pediatric Critical Care, University of Minnesota, Masonic Children’s Hospital, Minneapolis, United States
^ap Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver, College of Medicine, Iowa City, IA, United States
^aq Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston, United States
^ar Division of Critical Care Medicine, Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^as Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mott Children’s Hospital, University of Michigan, Ann Arbor, United States
^at Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA, United States

Abstract
Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures: Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.. © 2021 Cambridge University Press. All rights reserved.

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

"Preschool Age Predictors of Adolescent Borderline Personality Symptoms" (2021) Journal of the American Academy of Child and Adolescent Psychiatry

Preschool Age Predictors of Adolescent Borderline Personality Symptoms
(2021) Journal of the American Academy of Child and Adolescent Psychiatry, .

Geselowitz, B., Whalen, D.J., Tillman, R., Barch, D.M., Luby, J.L., Vogel, A.

Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Developmental models of borderline personality disorder (BPD) have highlighted the interplay of psychological variables (ie, impulsivity and emotional reactivity) with social risk factors, including invalidating parenting and childhood trauma. Prospective longitudinal studies have demonstrated the association of BPD with social, familial, and psychological antecedents. However, to date, few of these studies have studied the interaction of multiple risk domains and their potential manifestations in the preschool period. Method: Participants were 170 children enrolled in a prospective longitudinal study of early childhood depression. Participants completed a baseline assessment between ages 3 and 6 years. Psychopathology, suicidality, and self-harm were assessed using a semistructured age-appropriate psychiatric interview before age 8 and self-report after age 8. BPD symptoms were assessed between ages 14 and 19 by self-report. Adverse childhood experiences (ACEs) and peer relationships were reported by parents. Maternal support was assessed using an observational measure between ages 3 and 6. Results: Preschool ACEs accounted for 14.9% of adolescent BPD symptom variance in a regression analysis. Controlling for gender and preschool ACEs, preschool and school-age externalizing symptoms, preschool internalizing symptoms, and low maternal support were significant predictors of BPD symptoms in multivariate analyses. Preschool and school-age suicidality composite scores significantly predicted BPD symptoms. Conclusion: These findings suggest that preschool factors may be early predictors of BPD symptoms. Findings demonstrate that preschoolers with internalizing and externalizing psychopathology, high ACEs, and early suicidality are at greater risk of developing BPD symptoms. However, further research is needed to guide key factors for targeted early intervention. © 2020 American Academy of Child and Adolescent Psychiatry

Author Keywords
adverse childhood experiences; early childhood; maternal support; preschool onset disorders; suicidality

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01 MH084840-08, 1 U01 MH109589-01, R01 MH117436, 1 R21 HD095490-02, 1 U01 DA041120-01, 1 R01 MH117436-01, 1 R56 MH121877, 1 R24 MH108315-01, 1 R01 MH113883-02, R37 MH066031-11, 2 P50 MH096889-06A1, R21 HD095490-01, 5 R01 MH110488-02, R01 HD083614-01A1, 5 U54 HD087011-05, 1 R01 MH122389-01
National Institutes of HealthNIHR01 MH064769-06A1, K23MH22325028202-01, L30 MH108015, T32 MH100019-06, 5T35HL7815-24
Children’s Discovery InstituteCDI
National Institute of Mental HealthNIMHR01 MH117436-01, R01 MH113883-01
McDonnell Center for Systems Neuroscience

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

"Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome" (2021) Annals of Clinical and Translational Neurology

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome
(2021) Annals of Clinical and Translational Neurology, .

Dzinovic, I.^a , Škorvánek, M.^b ^c , Pavelekova, P.^b ^c , Zhao, C.^a , Keren, B.^d , Whalen, S.^e , Bakhtiari, S.^f ^g , Chih Jin, S.^h , Kruer, M.C.^f ^g , Jech, R.ⁱ , Winkelmann, J.^a ^j ^k ^l , Zech, M.^a ^j

^a Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
^b Department of Neurology, P.J. Safarik University, Kosice, Slovakia
^c Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia
^d Department of Genetics, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris, France
^e UF de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France
^f Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^g Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
^h Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Neurology, Charles University, 1st Faculty of Medicine, General University Hospital, Prague, Czech Republic
^j Institute of Human Genetics, Technical University of Munich, Munich, Germany
^k Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany
^l Munich Cluster for Systems Neurology, SyNergy, Munich, Germany

Abstract
The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction. © 2021 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

"Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior" (2021) Genetics in Medicine

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior
(2021) Genetics in Medicine, .

Harris, H.K.^a ^b , Nakayama, T.^c ^d , Lai, J.^c ^e , Zhao, B.^c ^d , Argyrou, N.^c ^d , Gubbels, C.S.^c ^d , Soucy, A.^c ^d , Genetti, C.A.^c ^d , Suslovitch, V.^c ^d , Rodan, L.H.^c ^d ^f , Tiller, G.E.^g , Lesca, G.^h , Gripp, K.W.ⁱ , Asadollahi, R.^j , Hamosh, A.^k , Applegate, C.D.^k , Turnpenny, P.D.^l , Simon, M.E.H.^m , Volker-Touw, C.M.L.^m , Gassen, K.L.I.^m , Binsbergen, E.^m , Pfundt, R.ⁿ , Gardeitchik, T.ⁿ , Vries, B.B.A.ⁿ , Immken, L.D.L.^o , Buchanan, C.^o , Willing, M.^p , Toler, T.L.^p , Fassi, E.^p , Baker, L.ⁱ , Vansenne, F.^q , Wang, X.^r , Ambrus, J.L., Jr.^s , Fannemel, M.^t , Posey, J.E.^u , Agolini, E.^v , Novelli, A.^v , Rauch, A.^j , Boonsawat, P.^j , Fagerberg, C.R.^w , Larsen, M.J.^w , Kibaek, M.^w , Labalme, A.^h , Poisson, A.^h , Payne, K.K.^x , Walsh, L.E.^x ^y , Aldinger, K.A.^z , Balciuniene, J.^aa , Skraban, C.^aa , Gray, C.^aa , Murrell, J.^aa , Bupp, C.P.^ab , Pascolini, G.^ac , Grammatico, P.^ac , Broly, M.^ad , Küry, S.^ad , Nizon, M.^ad , Rasool, I.G.^ae ^af , Zahoor, M.Y.^ae , Kraus, C.^af , Reis, A.^af , Iqbal, M.^ag , Uguen, K.^ah ^ai , Audebert-Bellanger, S.^ah , Ferec, C.^ah ^ai , Redon, S.^ah ^ai , Baker, J.^aj , Wu, Y.^ak , Zampino, G.^al , Syrbe, S.^am , Brosse, I.^am , Jamra, R.A.^an , Dobyns, W.B.^ao , Cohen, L.L.^ap , Blomhoff, A.^t , Mignot, C.^aq ^ar , Keren, B.^aq , Courtin, T.^aq , Agrawal, P.B.^c ^d , Beggs, A.H.^c ^d , Yu, T.W.^c ^d ^e

^a Division of Developmental Medicine, Department of Medicine, Boston Children’s Hospital, Boston, MA, United States
^b Department of Pediatrics, Baylor College of Medicine and Meyer Center for Developmental Pediatrics, Texas Children’s Hospital, Houston, TX, United States
^c Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
^d The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, United States
^e Program in Neuroscience, Harvard University, Boston, MA, United States
^f Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^g Department of Genetics, Kaiser Permanente, Los Angeles, CA, United States
^h Department of Medical Genetics, Lyon University Hospital, Bron, France
ⁱ Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, United States
^j Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
^k Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, United States
^l Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
^m Department of Genetics, University Medical Centre Utrecht, Utrecht, Netherlands
ⁿ Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
^o Dell Children’s Medical Group, Department of Clinical and Metabolic Genetics, Austin, TX, United States
^p Division of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^q Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
^r Ciphergene, Beijing, China
^s Division of Allergy, Immunology, and Rheumatology, SUNY at Buffalo School of Medicine, Buffalo, NY, United States
^t Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^u Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^v Laboratory of Medical Genetics, Bambino Gesu Children’s Hospital, Rome, Italy
^w Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
^x Department of Neurology, Indiana University Health Neuroscience Center, Indianapolis, IN, United States
^y Department of Medical and Molecular Genetics, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
^z Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, United States
^aa Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ab Spectrum Health Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
^ac Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Roma, Italy
^ad CHU Nantes, Service de Génétique Médicale, Nantes, France; L’institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
^ae Institute of Biochemistry & Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan
^af Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
^ag Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Punjab, Pakistan
^ah Department of Medical Genetics, Brest University Hospital, Brest, France
^ai Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France
^aj Department of Genomic Medicine, Children’s Minnesota, Minneapolis, MN, United States
^ak Shanxi Children’s Hospital, Taiyuan, China
^al Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Universita Cattolica del Sacro Cuore, Rome, Italy
^am Division of Pediatric Epileptology, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
^an Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^ao Departments of Pediatrics and Genetics, University of Minnesota, Minneapolis, MN, United States
^ap Division of Medical Genetics, Weill Cornell Medical College, New York, NY, United States
^aq APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
^ar Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France

Abstract
Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

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

"Convolutional Neural Networks for Pediatric Refractory Epilepsy Classification Using Resting-State Functional Magnetic Resonance Imaging" (2021) World Neurosurgery

Convolutional Neural Networks for Pediatric Refractory Epilepsy Classification Using Resting-State Functional Magnetic Resonance Imaging
(2021) World Neurosurgery, .

Nguyen, R.D.^a , Kennady, E.H.^a , Smyth, M.D.^e , Zhu, L.^d , Pao, L.P.^a , Swisher, S.K.^a , Rosas, A.^a , Mitra, A.^f , Patel, R.P.^b , Lankford, J.^c , Von Allmen, G.^c , Watkins, M.W.^c , Funke, M.E.^c , Shah, M.N.^a

^a Department of Pediatric Surgery and Neurosurgery, McGovern Medical School at UTHealth, Houston, TX, United States
^b Department of Diagnostic and Interventional Imaging, McGovern Medical School at UTHealth, Houston, TX, United States
^c Department of Pediatric Neurology, McGovern Medical School at UTHealth, Houston, TX, United States
^d Biostatistics and Epidemiology Research Design Core, Institute for Clinical and Translational Sciences, McGovern Medical School at UTHealth, Houston, TX, United States
^e Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^f Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: This study aims to evaluate the performance of convolutional neural networks (CNNs) trained with resting-state functional magnetic resonance imaging (rfMRI) latency data in the classification of patients with pediatric epilepsy from healthy controls. Methods: Preoperative rfMRI and anatomic magnetic resonance imaging scans were obtained from 63 pediatric patients with refractory epilepsy and 259 pediatric healthy controls. Latency maps of the temporal difference between rfMRI and the global mean signal were calculated using voxel-wise cross-covariance. Healthy control and epilepsy latency z score maps were pseudorandomized and partitioned into training data (60%), validation data (20%), and test data (20%). Healthy control individuals and patients with epilepsy were labeled as negative and positive, respectively. CNN models were then trained with the designated training data. Model hyperparameters were evaluated with a grid-search method. The model with the highest sensitivity was evaluated using unseen test data. Accuracy, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve were used to evaluate the ability of the model to classify epilepsy in the test data set. Results: The model with the highest validation sensitivity correctly classified 74% of unseen test patients with 85% sensitivity, 71% specificity, F1 score of 0.56, and an area under the receiver operating characteristic curve of 0.86. Conclusions: Using rfMRI latency data, we trained a CNN model to classify patients with pediatric epilepsy from healthy controls with good performance. CNN could serve as an adjunct in the diagnosis of pediatric epilepsy. Identification of pediatric epilepsy earlier in the disease course could decrease time to referral to specialized epilepsy centers and thus improve prognosis in this population. © 2021 Elsevier Inc.

Author Keywords
Convolutional neural networks; Machine learning; Pediatric epilepsy; Pediatric refractory epilepsy; Resting-state functional MRI; Temporal latency

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

"Redox-Responsive Hyaluronic Acid-Based Nanogels for the Topical Delivery of the Visual Chromophore to Retinal Photoreceptors" (2021) ACS Omega

Redox-Responsive Hyaluronic Acid-Based Nanogels for the Topical Delivery of the Visual Chromophore to Retinal Photoreceptors
(2021) ACS Omega, .

Laradji, A.M.^a ^b , Kolesnikov, A.V.^a , Karakoçak, B.B.^a ^b , Kefalov, V.J.^a , Ravi, N.^a ^b ^c

^a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Department of Veterans Affairs, St. Louis Medical Center, St. Louis, MO 63106, United States
^c Department of Energy, Environmental, and Chemical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Delivering therapeutics to the posterior segment of the eye is challenging due to various anatomical and physical barriers. While significant improvements have been realized by introducing direct injections to diseased sites, these approaches come with potential side effects that can range from simple inflammation to severe retinal damage. The topical instillation of drugs remains a safer and preferred alternative for patients’ compliance. Here, we report the synthesis of penetratin-complexed, redox-responsive hyaluronic acid-based nanogels for the triggered release and delivery of therapeutics to the posterior part of the eye via topical application. The synthesized nanogels were shown to release their load only when exposed to a reducing environment, similar to the cytoplasm. As a model drug, visual chromophore analog, 9-cis-retinal, was loaded into nanogels and efficiently delivered to the mouse retina’s photoreceptors when applied topically. Electroretinogram measurements showed a partial recovery of photoreceptor function in all treated eyes versus untreated controls. To the best of our knowledge, this report constitutes the first attempt to use a topically applied triggered-release drug delivery system to target the pigmented layer of the retina, in addition to the first attempt to deliver the visual chromophore topically. © 2021 The Authors. Published by American Chemical Society.

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

"Adults with Cerebral Palsy Require Ongoing Neurologic Care: A Systematic Review" (2021) Annals of Neurology

Adults with Cerebral Palsy Require Ongoing Neurologic Care: A Systematic Review
(2021) Annals of Neurology, .

Smith, S.E.^a , Gannotti, M.^b , Hurvitz, E.A.^c , Jensen, F.E.^d , Krach, L.E.^e , Kruer, M.C.^f ^g , Msall, M.E.^h , Noritz, G.ⁱ , Rajan, D.S.^j , Aravamuthan, B.R.^k

^a Washington University School of Medicine, St Louis, MO, United States
^b Shriners Hospitals for Children, Cerebral Palsy Network, University of Hartford, West Hartford, CT, United States
^c Department of Physical Medicine and Rehabilitation, Michigan Medicine/University of Michigan, Ann Arbor, MI, United States
^d Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Gillette Children’s Specialty Healthcare, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, United States
^f Cerebral Palsy & Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^g Departments of Child Health, Neurology, and Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine–Phoenix Children’s Hospital, Tucson, AZ, United States
^h University of Chicago Kennedy Research Center on Neurodevelopmental Disabilities, Chicago, IL, United States
ⁱ Department of Pediatrics, Nationwide Children’s Hospital and the Ohio State University, Columbus, OH, United States
^j Department of Pediatrics, Division of Child Neurology, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States
^k Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Cerebral palsy (CP) neurologic care and research efforts typically focus on children. However, most people with CP are adults. Adults with CP are at increased risk of new neurologic conditions, such as stroke and myelopathy, that require ongoing neurologic surveillance to distinguish them from baseline motor impairments. Neurologic factors could also contribute to the motor function decline, chronic pain, and chronic fatigue that are commonly experienced by adults with CP. Based on a systematic literature review, we suggest (1) guidelines for neurologic surveillance and neurologist referral and (2) clinical research questions regarding the evolving neurologic risks for adults with CP. ANN NEUROL 2021. © 2021 American Neurological Association

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

"Investigating the Impact of Cognitive Training for Individuals With Bothersome Tinnitus: A Randomized Controlled Trial" (2021) Otolaryngology – Head and Neck Surgery (United States)

Investigating the Impact of Cognitive Training for Individuals With Bothersome Tinnitus: A Randomized Controlled Trial
(2021) Otolaryngology – Head and Neck Surgery (United States), .

Xing, M., Kallogjeri, D., Piccirillo, J.F.

Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objective: To evaluate the effectiveness of cognitive training in improving tinnitus bother and to identify predictors of patient response. Study Design: Prospective open-label randomized controlled trial. Setting: Online. Methods: Participants were adults with subjective idiopathic nonpulsatile tinnitus causing significant tinnitus-related distress. The intervention group trained by using auditory-intensive exercises for 20 minutes per day, 5 days per week, for 8 weeks. The active control group trained on the same schedule with non–auditory intensive games. Surveys were completed at baseline, 8 weeks, and 12 weeks. Results: A total of 64 participants completed the study. The median age was 63 years (range, 25-69) in the intervention group and 61 years (34-68) in the control group. Mixed model analysis revealed that within-subject change in Tinnitus Functional Index in the intervention group was not different than the control group, with marginal mean differences (95% CI): 0.24 (–11.20 to 10.7) and 2.17 (–8.50 to 12.83) at 8 weeks and 2.33 (–8.6 to 13.3) and 3.36 (–7.91 to 14.6) at 12 weeks, respectively. When the 2 study groups were compared, the control group had higher Tinnitus Functional Index scores than the intervention group by 10.5 points at baseline (95% CI, –0.92 to 29.89), 8.1 at 8 weeks (95% CI, –3.27 to 19.42), and 9.4 at 12 weeks (95% CI, –2.45 to 21.34). Conclusion: Auditory-intensive cognitive training was not associated with changes in self-reported tinnitus bother. Given the potential for neuroplasticity to affect tinnitus, we believe that future studies on cognitive training for tinnitus remain relevant. © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2021.

Author Keywords
auditory intensive; cognitive training; neuroplasticity; tinnitus

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

"Autoimmune encephalitis: Proposed recommendations for symptomatic and long-term management" (2021) Journal of Neurology, Neurosurgery and Psychiatry

Autoimmune encephalitis: Proposed recommendations for symptomatic and long-term management
(2021) Journal of Neurology, Neurosurgery and Psychiatry, .

Abboud, H.^a ^b , Probasco, J.^c , Irani, S.R.^d , Ances, B.^e , Benavides, D.R.^f , Bradshaw, M.^g ^h , Christo, P.P.ⁱ , Dale, R.C.^j , Fernandez-Fournier, M.^k , Flanagan, E.P.^l , Gadoth, A.^m , George, P.ⁿ , Grebenciucova, E.^o , Jammoul, A.ⁿ , Lee, S.-T.^p , Li, Y.ⁿ , Matiello, M.^q ^r , Morse, A.M.^s , Rae-Grant, A.ⁿ , Rojas, G.^t ^u , Rossman, I.^v , Schmitt, S.^w , Venkatesan, A.^c , Vernino, S.^x , Pittock, S.J.^l , Titulaer, M.^y

^a Neurology, Case Western Reserve University, Cleveland, OH 44106, United States
^b Multiple Sclerosis and Neuroimmunology Program, University Hospitals of Cleveland, Cleveland, OH, United States
^c Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
^d Oxford Autoimmune Neurology Group, John Radcliffe Hospital, Oxford, United Kingdom
^e Neurology, Washington University in St Louis, St Louis, MO, United States
^f Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
^g Neurology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
^h Neurology, Billings Clinic, Billings, MT, United States
ⁱ Neurology, Minas Gerais Federal University, Risoleta Tolentino Neves Hospital, Belo Horizonte, Brazil
^j Neuroimmunology Group, University of Sydney, Faculty of Medicine and Health, Sydney, NSW, Australia
^k Neurology, La Paz University Hospital, Madrid, Spain
^l Neurology, Mayo Clinic, Rochester, MN, United States
^m Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
ⁿ Neurology, Cleveland Clinic, Cleveland, OH, United States
^o Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^p Neurology, Seoul National University, College of Medicine, Seoul, South Korea
^q Neurology, Massachusetts General Hospital, Boston, MA, United States
^r Neurology, Harvard Medical School, Boston, MA, United States
^s Pediatric Neurology, Geisinger Commonwealth School of Medicine, Scranton, PA, United States
^t Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina
^u Favaloro Foundation, Buenos Aires, Argentina
^v Neuro-developmental Science Center, Akron Children’s Hospital, Akron, OH, United States
^w Neurology, MUSC, Charleston, SC, United States
^x Neurology, UT Southwestern, Dallas, TX, United States
^y Neurology, Erasmus Medical Center, Zuid-Holland Rotterdam, Netherlands

Abstract
The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Author Keywords
autoimmune encephalitis; neuroimmunology; paraneoplastic syndrome

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

"Correction to: Preschool-Onset Major Depressive Disorder is Characterized by Electrocortical Deficits in Processing Pleasant Emotional Pictures (Research on Child and Adolescent Psychopathology, (2020), 48, 1, (91-108), 10.1007/s10802-019-00585-8)" (2021) Research on Child and Adolescent Psychopathology

Correction to: Preschool-Onset Major Depressive Disorder is Characterized by Electrocortical Deficits in Processing Pleasant Emotional Pictures (Research on Child and Adolescent Psychopathology, (2020), 48, 1, (91-108), 10.1007/s10802-019-00585-8)
(2021) Research on Child and Adolescent Psychopathology, .

Whalen, D.J.^a , Gilbert, K.E.^a , Kelly, D.^a , Hajcak, G.^b , Kappenman, E.S.^c , Luby, J.L.^a , Barch, D.M.^a ^d ^e ^f

^a Department of Psychiatry, Washington University School of Medicine in St. Louis, 4444 Forest Park, Suite 2100, St. Louis, MO 63108, United States
^b Department of Psychology, Florida State University, Tallahassee, FL, United States
^c Department of Psychology, San Diego State University, San Diego, CA, United States
^d The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The original version of this article unfortunately contained a mistake. The authors discovered an error in the processing of the ERP data included in originally published manuscript. All of the data has been reprocessed using average referencing. The primary findings in our original paper highlighted diagnostic group differences in ERPs from the 400–600 ms range but no group differences from 600–1000 ms. We now report significant differences from 600–1000 ms and also a trend for significant group differences from 400–600 ms. One correlation between ERP responses to neutral pictures during the 400–600 ms window and BAS drives scores is no longer statistically significant, however this does not alter the conclusions made in the paper. The original article has been corrected. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

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

"Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression" (2021) Alzheimer's and Dementia

Alzheimer’s disease alters oligodendrocytic glycolytic and ketolytic gene expression
(2021) Alzheimer’s and Dementia, .

Saito, E.R.^a , Miller, J.B.^b , Harari, O.^c , Cruchaga, C.^c ^d ^e ^f , Mihindukulasuriya, K.A.^g , Kauwe, J.S.K.^b , Bikman, B.T.^a

^a Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, United States
^b Department of Biology, Brigham Young University, Provo, UT, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^f NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
^g The Edison Family Center for Genome Sciences and Systems Biology, Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Sporadic Alzheimer’s disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. Methods: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer’s Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease; astrocytes; glycolysis; ketolysis; metabolic RNA-seq profiles; microglia; neurons; oligodendrocytes

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

"Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management" (2021) Journal of Neurology, Neurosurgery and Psychiatry

Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management
(2021) Journal of Neurology, Neurosurgery and Psychiatry, .

Abboud, H.^a ^b , Probasco, J.C.^c , Irani, S.^d , Ances, B.^e , Benavides, D.R.^f , Bradshaw, M.^g ^h , Christo, P.P.ⁱ , Dale, R.C.^j , Fernandez-Fournier, M.^k , Flanagan, E.P.^l , Gadoth, A.^m , George, P.ⁿ , Grebenciucova, E.^o , Jammoul, A.ⁿ , Lee, S.-T.^p , Li, Y.ⁿ , Matiello, M.^q ^r , Morse, A.M.^s , Rae-Grant, A.ⁿ , Rojas, G.^t ^u , Rossman, I.^v , Schmitt, S.^w , Venkatesan, A.^c , Vernino, S.^x , Pittock, S.J.^l , Titulaer, M.J.^y

^a Neurology, Case Western Reserve University, Cleveland, OHO, United States
^b Multiple Sclerosis and Neuroimmunology Program, University Hospitals of Cleveland, Cleveland, OHO, United States
^c Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
^d Oxford Autoimmune Neurology Group, John Radcliffe Hospital, Oxford, United Kingdom
^e Neurology, Washington University in St Louis, St Louis, MO, United States
^f Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
^g Neurology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
^h Billings Clinic, Billings, MT, United States
ⁱ Neurology, Minas Gerais Federal University, Risoleta Tolentino Neves Hospital, Belo Horizonte, MG, Brazil
^j Neuroimmunology Group, University of Sydney, Faculty of Medicine and Health, Sydney, NSW, Australia
^k Neurology, La Paz University Hospital, General Hospital, Department of Neurology, Madrid, Spain
^l Neurology, Mayo Clinic, Rochester, MN, United States
^m Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
ⁿ Neurology, Cleveland Clinic, Cleveland, OH, United States
^o Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^p Neurology, Seoul National University, College of Medicine, Seoul, South Korea
^q Neurology, Massachusetts General Hospital, Boston, MA, United States
^r Neurology, Harvard Medical School, Boston, MA, United States
^s Pediatric Neurology, Geisinger Commonwealth School of Medicine, Scranton, PA, United States
^t Neurology, Sanatorio de la Trinidad Mitre, Buenos Aires, Argentina
^u Neurology, Favaloro Foundation, Buenos Aires, Argentina
^v Neuro-developmental Science Center, Akron Children’s Hospital, Akron, OH, United States
^w Neurology, MUSC, Charleston, SC, United States
^x Neurology, UT Southwestern, Dallas, TX, United States
^y Neurology, Erasmus Medical Center, Zuid-Holland Rotterdam, Netherlands

Abstract
The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
autoimmune encephalitis; neuroimmunology; paraneoplastic syndrome

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

"The effect of delayed judgments of learning on retention" (2021) Metacognition and Learning

The effect of delayed judgments of learning on retention
(2021) Metacognition and Learning, .

Tekin, E., Roediger, H.L., III

Department of Psychological and Brain Sciences, Washington University in St. Louis, St Louis, MO 63130-4899, United States

Abstract
Evidence is mixed concerning whether delayed judgments of learning (JOLs) enhance learning and if so, whether their benefit is similar to retrieval practice. One potential explanation for the mixed findings is the truncated search hypothesis, which states that not all delayed JOLs lead to a full-blown covert retrieval attempt. In three paired-associate learning experiments, we examined the effect of delayed JOLs on later recall by comparing them to conditions of restudy, overt retrieval, and various other delayed JOL conditions. In Experiment 1, after an initial study phase, subjects either restudied word pairs, practiced overt retrieval, or made cue-only or cue-target delayed JOLs. In Experiments 2a and 2b, where conditions were manipulated within-subjects, subjects either restudied word pairs, practiced overt retrieval, made cue-only delayed JOLs, made cue-only delayed JOLs followed by a yes/no retrieval question or, in another condition, by an overt retrieval prompt. The final cued recall tests were delayed by two days. In Experiment 1, recall after cue-only delayed JOLs did not reliably differ from recall after overt retrieval or restudy. In Experiments 2a and 2b, delayed JOLs consistently produced poorer recall relative to overt retrieval. Furthermore, reaction times for delayed JOLs were shorter relative to delayed JOLs paired with overt retrieval prompts. We conclude that only some delayed JOLs elicit covert retrieval attempts, a pattern supporting the truncated search hypothesis. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Author Keywords
Covert retrieval; Delayed judgments of learning; Reactivity; Truncated search

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

"Reported autism diagnosis is associated with psychotic-like symptoms in the Adolescent Brain Cognitive Development cohort" (2021) European Child and Adolescent Psychiatry

Reported autism diagnosis is associated with psychotic-like symptoms in the Adolescent Brain Cognitive Development cohort
(2021) European Child and Adolescent Psychiatry, .

Jutla, A.^a , Donohue, M.R.^b , Veenstra-VanderWeele, J.^a , Foss-Feig, J.H.^c

^a Department of Psychiatry, Columbia University, New York, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States

Abstract
Although the schizophrenia (SCZ) rate is increased in autism spectrum disorder (ASD), it is difficult to identify which ASD youth will develop psychosis. We explored the relationship between ASD and emerging psychotic-like experiences (PLS) in a sample of 9127 youth aged 9–11 from the Adolescent Brain Cognitive Development (ABCD) cohort. We predicted that parent-reported ASD would be associated with PLS severity, and that ASD youth with PLS (ASD+/PLS+) would differ from ASD youth without PLS (ASD+/PLS−) and youth with PLS but not ASD (ASD−/PLS+) in cognitive function. We fit regression models that included parent-reported ASD, family history of psychosis, lifetime trauma, executive function, processing speed, working memory, age, sex, race, ethnicity, and income-to-needs ratio as predictors of Prodromal Questionnaire-Brief Child (PQ-BC) distress score, a continuous index of PLS severity. We assessed cognitive differences using regression models with ASD/PLS status and relevant covariates as predictors of NIH Toolbox measures. ASD increased raw PQ-BC distress scores by 2.47 points (95% CI 1.33–3.61), an effect at least as large as Black race (1.27 points, 95% CI 0.75–1.78), family history of psychosis (1.05 points, 95% CI 0.56–1.54), and Latinx ethnicity (0.99 points, 95% CI 0.53–1.45. We did not identify differences in cognition for ASD+/PLS+ youth relative to other groups. Our finding of association between ASD and PLS in youth is consistent with previous literature and adds new information in suggesting that ASD may be a strong risk factor for PLS even compared to established SCZ risk factors. © 2021, Springer-Verlag GmbH, DE part of Springer Nature.

Author Keywords
Autism spectrum disorder; Early diagnosis; Neurodevelopmental disorders; Psychotic-like symptoms; Schizophrenia

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041028, U01DA041174, U01DA041156, U01DA041048, U24DA041147, U24DA041123, U01DA041106, U01DA041148, U01DA041134, U01DA041117, U01DA041089, U01DA041120
National Institutes of HealthNIH2T32MH01643441

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

"Neuromodulation by the immune system: a focus on cytokines" (2021) Nature Reviews Immunology

Neuromodulation by the immune system: a focus on cytokines
(2021) Nature Reviews Immunology, .

Salvador, A.F.^a ^b , de Lima, K.A.^a , Kipnis, J.^a

^a Center for Brain Immunology and Glia (BIG), Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^b Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, United States

Abstract
Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism’s ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens. © 2021, Springer Nature Limited.

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

"Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis" (2021) Multiple Sclerosis Journal

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis
(2021) Multiple Sclerosis Journal, .

Fox, R.J.^a , Raska, P.^b , Barro, C.^c , Karafa, M.^b , Konig, V.^b , Bermel, R.A.^a , Chase, M.^d , Coffey, C.S.^e , Goodman, A.D.^f , Klawiter, E.C.^d , Naismith, R.T.^g , Kuhle, J.^c

^a Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
^b Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States
^c Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
^d Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^e University of Iowa, Iowa City, IA, United States
^f Department of Neurology, University of Rochester, Rochester, NY, United States
^g Department of Neurology, Washington University, St Louis, MO, United States

Abstract
Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS. Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS. Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable. Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum (p = 0.76) or CSF (p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed. Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL. © The Author(s), 2021.

Author Keywords
biomarker; Multiple sclerosis; neurofilament

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

"Transpupillary two-photon in vivo imaging of the mouse retina" (2021) Journal of Visualized Experiments

Transpupillary two-photon in vivo imaging of the mouse retina
(2021) Journal of Visualized Experiments, 2021 (168), art. no. e61970, pp. 1-23.

Wang, Z.^a ^b , McCracken, S.^a ^b , Williams, P.R.^a ^c ^d

^a John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, United States
^b Washington University School of Medicine, United States
^c Department of Neuroscience, Washington University School of Medicine, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, United States

Abstract
The retina transforms light signals from the environment into electrical signals that are propagated to the brain. Diseases of the retina are prevalent and cause visual impairment and blindness. Understanding how such diseases progress is critical to formulating new treatments. In vivo microscopy in animal models of disease is a powerful tool for understanding neurodegeneration and has led to important progress towards treatments of conditions ranging from Alzheimer’s disease to stroke. Given that the retina is the only central nervous system structure inherently accessible by optical approaches, it naturally lends itself towards in vivo imaging. However, the native optics of the lens and cornea present some challenges for effective imaging access. This protocol outlines methods for in vivo two-photon imaging of cellular cohorts and structures in the mouse retina at cellular resolution, applicable for both acuteand chronic-duration imaging experiments. It presents examples of retinal ganglion cell (RGC), amacrine cell, microglial, and vascular imaging using a suite of labeling techniques including adeno-associated virus (AAV) vectors, transgenic mice, and inorganic dyes. Importantly, these techniques extend to all cell types of the retina, and suggested methods for accessing other cellular populations of interest are described. Also detailed are example strategies for manual image postprocessing for display and quantification. These techniques are directly applicable to studies of retinal function in health and disease. © 2021 JoVE Creative Commons Attribution.

Funding details
BrightFocus FoundationBFF
T32 EY013360
Research to Prevent BlindnessRPB

Document Type: Article
Publication Stage: Final
Source: Scopus

"Neuroimaging the Neuropathogenesis of HIV" (2021) Current HIV/AIDS Reports

Neuroimaging the Neuropathogenesis of HIV
(2021) Current HIV/AIDS Reports, .

Boerwinkle, A.H., Meeker, K.L., Luckett, P., Ances, B.M.

Department of Neurology, Washington University in St. Louis, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Purpose of Review: This review highlights neuroimaging studies of HIV conducted over the last 2 years and discusses how relevant findings further our knowledge of the neuropathology of HIV. Three major avenues of neuroimaging research are covered with a particular emphasis on inflammation, aging, and substance use in persons living with HIV (PLWH). Recent Findings: Neuroimaging has been a critical tool for understanding the neuropathological underpinnings observed in HIV. Recent studies comparing levels of neuroinflammation in PLWH and HIV-negative controls show inconsistent results but report an association between elevated neuroinflammation and poorer cognition in PLWH. Other recent neuroimaging studies suggest that older PLWH are at increased risk for brain and cognitive compromise compared to their younger counterparts. Finally, recent findings also suggest that the effects of HIV may be exacerbated by alcohol and drug abuse. Summary: These neuroimaging studies provide insight into the structural, functional, and molecular changes occurring in the brain due to HIV. HIV triggers a strong neuroimmune response and may lead to a cascade of events including increased chronic inflammation and cognitive decline. These outcomes are further exacerbated by age and age-related comorbidities, as well as lifestyle factors such as drug use/abuse. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Author Keywords
Aging; HIV; Inflammation; Neuroimaging; Substance use

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