WashU weekly Neuroscience publications: December 17, 2023

The role of purpose in the stress process: A homeostatic account
(2024) Journal of Research in Personality, 108, art. no. 104444, . 

Burrow, A.L.^a , Hill, P.L.^b , Stanley, M.^c , Sumner, R.^a

^a Cornell University, Department of Psychology, United States
^b Washington University in St. Louis, Department of Psychological and Brain Sciences, United States
^c Harvard University, Human Development and Psychology, United States

Abstract
The accumulation of evidence that having a sense of purpose contributes to greater health and well-being has vastly outpaced investigations into why this is so. Here, we offer a novel functional account for the demonstrated benefits of purpose by characterizing it as a resource that maintains psychological homeostasis. We posit that a sense of purpose recenters conscious attention toward prospective and overarching aims, thereby limiting the magnitude of disruption to well-being caused by the proximal stimuli. By attenuating reactivity to proximal events both stressful and uplifting, a sense of purpose facilitates greater stability in health and functioning over time. We leverage this mechanistic account with specific examples found across areas of psychological science and outline questions to guide future research. © 2023 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Dopamine Modulates Effective Connectivity in Frontal Cortex
(2024) Journal of Cognitive Neuroscience, 36 (1), pp. 155-166. 

Vogelsang, D.A.^a b , Furman, D.J.^a , Nee, D.E.^c , Pappas, I.^a d , White, R.L., 3rd^e , Kayser, A.S.^a f , D’Esposito, M.^a f

^a University of California
^b Leiden University
^c Florida State University
^d University of Southern California
^e Washington University School of Medicine, Saint Louis, MO
^f VA Northern California Health Care System

Abstract
There is increasing evidence that the left lateral frontal cortex is hierarchically organized such that higher-order regions have an asymmetric top-down influence over lower order regions. However, questions remain about the underlying neuroarchitecture of this hierarchical control organization. Within the frontal cortex, dopamine plays an important role in cognitive control functions, and we hypothesized that dopamine may preferentially influence top-down connections within the lateral frontal hierarchy. Using a randomized, double-blind, within-subject design, we analyzed resting-state fMRI data of 66 healthy young participants who were scanned once each after administration of bromocriptine (a dopamine agonist with preferential affinity for D2 receptor), tolcapone (an inhibitor of catechol-O-methyltransferase), and placebo, to determine whether dopaminergic stimulation modulated effective functional connectivity between hierarchically organized frontal regions in the left hemisphere. We found that dopaminergic drugs modulated connections from the caudal middle frontal gyrus and the inferior frontal sulcus to both rostral and caudal frontal areas. In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other. © 2023 Massachusetts Institute of Technology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Deriving early single-rosette brain organoids from human pluripotent stem cells
(2023) Stem Cell Reports, 18 (12), pp. 2498-2514. 

Tidball, A.M.^a , Niu, W.^a , Ma, Q.^b , Takla, T.N.^a , Walker, J.C.^a , Margolis, J.L.^a , Mojica-Perez, S.P.^a , Sudyk, R.^a , Deng, L.^a , Moore, S.J.^a , Chopra, R.^c , Shakkottai, V.G.^d , Murphy, G.G.^e f , Yuan, Y.^g , Isom, L.L.^a e g , Li, J.Z.^b h , Parent, J.M.^a f i

^a Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States
^b Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States
^c Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
^e Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
^f Michigan Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, United States
^g Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
^h Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, United States
ⁱ VA Ann Arbor Healthcare System, Ann Arbor, MI, United States

Abstract
Brain organoid methods are complicated by multiple rosette structures and morphological variability. We have developed a human brain organoid technique that generates self-organizing, single-rosette cortical organoids (SOSR-COs) with reproducible size and structure at early timepoints. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D developmental transition from neural plate to neural tube. Most monolayer fragments form spheres with a single central lumen. Over time, the SOSR-COs develop appropriate progenitor and cortical laminar cell types as shown by immunocytochemistry and single-cell RNA sequencing. At early time points, this method demonstrates robust structural phenotypes after chemical teratogen exposure or when modeling a genetic neurodevelopmental disorder, and should prove useful for studies of human brain development and disease modeling. © 2023 The Authors

Author Keywords
cortical spheroid;  dorsal forebrain;  epilepsy;  induced pluripotent stem cells;  mosaicism;  neural tube defects;  neurodevelopment;  neurulation;  PCDH19;  valproic acid

Funding details
PCDH19
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR21HD106580, R21NS116250, R37NS076752, U54NS117170
University of MichiganU-MPCT/US2021/028610

Document Type: Article
Publication Stage: Final
Source: Scopus

Organ aging signatures in the plasma proteome track health and disease
(2023) Nature, 624 (7990), pp. 164-172.

Oh, H.S.-H.^a b c , Rutledge, J.^b c d , Nachun, D.^e , Pálovics, R.^b c f , Abiose, O.^c f , Moran-Losada, P.^b c f , Channappa, D.^b c f , Urey, D.Y.^b g , Kim, K.^b c f , Sung, Y.J.^h i , Wang, L.^h i , Timsina, J.^h i , Western, D.^h i j , Liu, M.^h i , Kohlfeld, P.^h i , Budde, J.^h i , Wilson, E.N.^c f , Guen, Y.^f k , Maurer, T.M.^e , Haney, M.^b c f , Yang, A.C.^l m n , He, Z.^f , Greicius, M.D.^f , Andreasson, K.I.^c f o , Sathyan, S.^p , Weiss, E.F.^q , Milman, S.^p , Barzilai, N.^p , Cruchaga, C.^h i , Wagner, A.D.^c r , Mormino, E.^f , Lehallier, B.^f , Henderson, V.W.^c f s , Longo, F.M.^c f , Montgomery, S.B.^e t u , Wyss-Coray, T.^b c f

^a Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, United States
^b The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
^c Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
^d Graduate Program in Genetics, Stanford University, Stanford, CA, United States
^e Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
^f Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
^g Department of Bioengineering, Stanford University School of Engineering, Stanford, CA, United States
^h Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
ⁱ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^j Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^k Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
^l Departments of Neurology and Anatomy, University of California San Francisco, San Francisco, CA, United States
^m Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, United States
ⁿ Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, United States
^o Chan Zuckerberg Biohub, San Francisco, CA, United States
^p Departments of Medicine and Genetics, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, United States
^q Department of Neurology, Montefiore Medical Center, New York, NY, United States
^r Department of Psychology, Stanford University, Stanford, CA, United States
^s Department of Epidemiology and Population Health, Stanford University, Stanford, CA, United States
^t Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
^u Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, United States

Abstract
Animal studies show aging varies between individuals as well as between organs within an individual1–4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects. © 2023, The Author(s).

Funding details
T32AG047126
National Science FoundationNSF
National Institutes of HealthNIHP01AG003991, R01AG044546, RF1AG053303, RF1AG058501, RF1AG074007, U01AG058922
National Institute on AgingNIAAG044829, AG057909, AG061155, AG066206, P30AG066515, P50AG047366
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAZEN-22-848604
Milky Way Research FoundationMWRF
Nan Fung Life SciencesNFLS

Document Type: Article
Publication Stage: Final
Source: Scopus

Teaching NeuroImage: Severe Amyloid-Related Imaging Abnormalities after Anti-β-Amyloid Monoclonal Antibody Treatment
(2023) Neurology, 101 (23), pp. 1079-1080. 

Bonomi, S.^a , Samara, A.^a , Balestra, N.^a , Padalia, A.^a , Benzinger, T.L.^b c , Kang, P.^a

^a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
A 74-year-old woman with mild Alzheimer disease joined a clinical trial of anti-amyloid-β therapy. Three weeks after receiving remternetug, a N3pH-Aβ monoclonal antibody, a scheduled brain MRI showed new periventricular and subcortical FLAIR hyperintensities (Figure, A) suggestive of mild amyloid-related imaging abnormalities (ARIA).1,2 Two weeks later, she was hospitalized for rapid cognitive and functional decline. Her admission examination was notable for severe disorientation, inattention, and global aphasia. Repeat MRI showed diffuse and confluent FLAIR hyperintensities consistent with progression to severe ARIA-edema/effusion (ARIA-E), but no hemosiderosis/microhemorrhages (ARIA-H) (Figure, B). She was treated with steroids and continued to have a gradual improvement in her cognition and language. A follow-up MRI 6 weeks later showed a marked reduction in FLAIR hyperintensities (Figure, C). In clinical trials, ARIA-E has often been observed to improve within 3-4 months.2 Early suspicion of ARIAs is essential for identifying and managing this adverse effect of anti-amyloid-β therapy. © American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Agreement between Published Reference Resources for Neurofilament Light Chain Levels in People with Multiple Sclerosis
(2023) Neurology, 101 (23), pp. E2448-E2453. 

Sotirchos, E.S.^a , Hu, C.^a , Smith, M.D.^a , Lord, H.-N.^a , Duval, A.L.^a , Arrambide, G.^b , Montalban, X.^b , Akgun, K.^c , Ziemssen, T.^c , Naismith, R.T.^d , Hersh, C.M.^e , Hyland, M.^f , Krupp, L.B.^g , Nicholas, J.A.^h , Bermel, R.A.ⁱ , Mowry, E.M.^a , Calabresi, P.A.^a , Fitzgerald, K.C.^a

^a Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Neurology-Neuroimmunology, Centre d’Esclerosi Multiple de Catalunya (Cemcat), Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Spain
^c Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl-Gustav Carus, TU Dresden, Germany
^d Department of Neurology, Washington University in St. LouisMO, United States
^e Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States
^f Department of Neurology, University of Rochester Medical CenterNY, United States
^g Department of Neurology, New York University, New York City, United States
^h OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, United States
ⁱ Mellen Center, Neurological Institute, Cleveland ClinicOH, United States

Abstract
ObjectivesTo examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS).MethodsSix published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources.ResultsNfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89.DiscussionInterpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes. © American Academy of Neurology.

Funding details
National Institutes of HealthNIHK01MH121582, K23NS117883, U01NS111678
National Multiple Sclerosis SocietyNMSSRG-1904-33800, RG-1904-33834
Biogen

Document Type: Article
Publication Stage: Final
Source: Scopus

Socioeconomic status and healthcare utilization disparities among children with epilepsy in the United States: Results from a nationally representative sample
(2023) Scientific Reports, 13 (1), art. no. 21776, . 

Muthiah, N.^a , Rothenberger, S.^b , Abel, T.J.^c

^a Department of Neurological Surgery, Washington University in Saint Louis School of Medicine, Saint Louis, United States
^b Department of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States
^c Department of Neurological Surgery, UPMC Children’s Hospital of Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224, United States

Abstract
Epilepsy affects 1% of the US population. Healthcare disparities are well-studied among adults with epilepsy but less so among children. We examined whether children with epilepsy (1) have lower income than or (2) utilize the emergency department (ED) differently from children without epilepsy, and (3) if income moderates ED utilization. Data from the 2016–2019 National Survey of Children’s Health were used to identify children with active “epilepsy or seizure disorder”. Children with versus without epilepsy were compared. Income and ED visits were modeled with logistic and Poisson regressions. This analysis included 131,326 children; 835 were diagnosed with epilepsy. Estimated population prevalence of epilepsy was 0.6%. Children from higher-income-households were less likely to have epilepsy (aOR: 0.7). Children with epilepsy were more likely to visit EDs (aOR = 10.2), see healthcare professionals (aOR: 2.7), and receive care from specialists (aOR: 10.3). Income moderated the relationship between having epilepsy and ED visits. 7.7% of children with epilepsy did not receive needed healthcare. Some barriers were acquiring appointments (aOR: 3.9) and transportation (aOR: 4.7). In conclusion, children with epilepsy were more likely than children without epilepsy to live in lower-income-households, visit EDs, see healthcare professionals, and not receive needed healthcare. Barrier-specific policy interventions may improve medical access for children with epilepsy. © 2023, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Docking for EP4R antagonists active against inflammatory pain
(2023) Nature Communications, 14 (1), art. no. 8067, . 

Gahbauer, S.^a , DeLeon, C.^b , Braz, J.M.^c , Craik, V.^c , Kang, H.J.^b j , Wan, X.^a , Huang, X.-P.^b , Billesbølle, C.B.^a , Liu, Y.^b , Che, T.^b k , Deshpande, I.^a , Jewell, M.^c , Fink, E.A.^a , Kondratov, I.S.^d e , Moroz, Y.S.^f g , Irwin, J.J.^a , Basbaum, A.I.^c , Roth, B.L.^b h i , Shoichet, B.K.^a

^a Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, United States
^b Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States
^c Department of Anatomy, University of California San Francisco, San Francisco, CA 94158, United States
^d Enamine Ltd., Kyiv, Ukraine
^e V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
^f Chemspace LLC, Kyiv, Ukraine
^g National Taras Shevchenko University of Kyiv, Kyiv, Ukraine
^h National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, United States
ⁱ Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, NC 27514, United States
^j Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
^k Center of Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHR01GM133836, R35GM122481, US R35 NS097306
Defense Advanced Research Projects AgencyDARPAHR0011-19-2-0020
American Institute of BisexualityAIB
Facial Pain Research Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor
(2023) Nature Communications, 14 (1), art. no. 8064, . 

Muratspahić, E.^a b , Deibler, K.^b n , Han, J.^c , Tomašević, N.^a , Jadhav, K.B.^d , Olivé-Marti, A.-L.^e , Hochrainer, N.^e , Hellinger, R.^a , Koehbach, J.^f o , Fay, J.F.^g , Rahman, M.H.^h , Hegazy, L.^h , Craven, T.W.^b , Varga, B.R.^c i , Bhardwaj, G.^b , Appourchaux, K.^c i , Majumdar, S.^c i , Muttenthaler, M.^d j , Hosseinzadeh, P.^k , Craik, D.J.^f , Spetea, M.^e , Che, T.^c i , Baker, D.^b l m , Gruber, C.W.^a

^a Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, 1090, Austria
^b Institute for Protein Design, University of Washington, Seattle, WA 98195, United States
^c Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO 63110, United States
^d Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, 1090, Austria
^e Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, Innsbruck, 6020, Austria
^f Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia
^g Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD 21201, United States
^h Department of Pharmaceutical and Administrative Sciences, Saint Louis College of Pharmacy, University of Health Sciences & Pharmacy in St. Louis, St. Louis, MO 63110, United States
ⁱ Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
^k Department of Bioengineering, Knight Campus, University of Oregon, Eugene, OR 97403, United States
^l Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
^m Howard Hughes Medical Institute, University of Washington, Seattle, Washington, WA 98195, United States
ⁿ Novo Nordisk Research Center Seattle, Novo Nordisk A/S, 530 Fairview Ave N #5000, Seattle, WA 97403, United States
^o School of Biomedical Sciences, Faculty for Medicine, The University of Queensland, Brisbane, QLD 4072, Australia

Abstract
Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA–KOR–Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions. © 2023, The Author(s).

Funding details
P2387582
University of North CarolinaUNCHEK293T
Engineering Research CentersERCFA 705007
Australian Research CouncilARCCE200100012
National Health and Medical Research CouncilNHMRC2009564
Austrian Science FundFWF
Medizinische Universität WienI4697, P32109, ZK-81B
Bundesministerium für Bildung, Wissenschaft und ForschungBMBWFICM-2019-13441

Document Type: Article
Publication Stage: Final
Source: Scopus

A common single nucleotide variant in the cytokine receptor-like factor-3 (CRLF3) gene causes neuronal deficits in human and mouse cells
(2023) Human Molecular Genetics, 32 (24), pp. 3342-3352. 

Wilson, A.F.^a , Barakat, R.^a , Mu, R.^a , Karush, L.L.^a , Gao, Y.^a , Hartigan, K.A.^a , Chen, J.-K.^a , Shu, H.^b , Turner, T.N.^c d , Maloney, S.E.^b d , Mennerick, S.J.^b , Gutmann, D.H.^a , Anastasaki, C.^a

^a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, Box 8232, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^d Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, Box 8504, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Single nucleotide variants in the general population are common genomic alterations, where the majority are presumed to be silent polymorphisms without known clinical significance. Using human induced pluripotent stem cell (hiPSC) cerebral organoid modeling of the 1.4 megabase Neurofibromatosis type 1 (NF1) deletion syndrome, we previously discovered that the cytokine receptor-like factor-3 (CRLF3) gene, which is co-deleted with the NF1 gene, functions as a major regulator of neuronal maturation. Moreover, children with NF1 and the CRLF3L389P variant have greater autism burden, suggesting that this gene might be important for neurologic function. To explore the functional consequences of this variant, we generated CRLF3L389P-mutant hiPSC lines and Crlf3L389P-mutant genetically engineered mice. While this variant does not impair protein expression, brain structure, or mouse behavior, CRLF3L389P-mutant human cerebral organoids and mouse brains exhibit impaired neuronal maturation and dendrite formation. In addition, Crlf3L389P-mutant mouse neurons have reduced dendrite lengths and branching, without any axonal deficits. Moreover, Crlf3L389P-mutant mouse hippocampal neurons have decreased firing rates and synaptic current amplitudes relative to wild type controls. Taken together, these findings establish the CRLF3L389P variant as functionally deleterious and suggest that it may be a neurodevelopmental disease modifier. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Author Keywords
cerebral organoids;  CRLF3;  dendrites;  neurodevelopment;  neuron deficits;  single nucleotide variant

Document Type: Article
Publication Stage: Final
Source: Scopus

Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors
(2023) New England Journal of Medicine, 389 (22), pp. 2029-2038. Cited 2 times.

Dhar, R.^a , Marklin, G.F.^c d , Klinkenberg, W.D.^c d , Wang, J.^b , Goss, C.W.^b , Lele, A.V.^e f , Kensinger, C.D.^g h , Lange, P.A.ⁱ , Lebovitz, D.J.^j

^a The Department of Neurology, Section of Neurocritical Care, St. Louis, United States
^b The Center for Biostatistics and Data Science, St. Louis, United States
^c Washington University School of Medicine, St. Louis, United States
^d Mid-America Transplant, St. Louis, United States
^e The Department of Anesthesiology and Pain Medicine, University of Washington, Harborview Medical Center, Seattle, WA, United States
^f LifeCenter Northwest, Bellevue, WA, United States
^g LifeLink of Georgia, Norcross, GA, United States
^h Piedmont Transplant Institute, Atlanta, GA, United States
ⁱ Donor Alliance, Denver, United States
^j Akron Children’s Hospital, Akron, OH, United States

Abstract
BACKGROUND Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation. METHODS In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 µg per hour for a minimum of 12 hours) or saline placebo. The primary outcome was transplantation of the donor heart; graft survival at 30 days after transplantation was a prespecified recipient safety outcome. Secondary outcomes included weaning from vasopressor therapy, donor ejection fraction, and number of organs transplanted per donor. RESULTS Of the 852 brain-dead donors who underwent randomization, 838 were included in the primary analysis: 419 in the levothyroxine group and 419 in the saline group. Hearts were transplanted from 230 donors (54.9%) in the levothyroxine group and 223 (53.2%) in the saline group (adjusted risk ratio, 1.01; 95% confidence interval [CI], 0.97 to 1.07; P = 0.57). Graft survival at 30 days occurred in 224 hearts (97.4%) transplanted from donors assigned to receive levothyroxine and 213 hearts (95.5%) transplanted from donors assigned to receive saline (difference, 1.9 percentage points; 95% CI, -2.3 to 6.0; P<0.001 for noninferiority at a margin of 6 percentage points). There were no substantial between-group differences in weaning from vasopressor therapy, ejection fraction on echocardiography, or organs transplanted per donor, but more cases of severe hypertension and tachycardia occurred in the levothyroxine group than in the saline group. CONCLUSIONS In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion. (Funded by Mid-America Transplant and others; ClinicalTrials .gov number, NCT04415658.). © 2023 Massachusetts Medical Society.

Funding details
National Institutes of HealthNIH
National Cancer InstituteNCIP30 CA091842
National Center for Advancing Translational SciencesNCATS
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTS
Alvin J. Siteman Cancer Center

Document Type: Article
Publication Stage: Final
Source: Scopus

Cortical origin of theta error signals
(2023) Cerebral Cortex, 33 (23), pp. 11300-11319. 

Herrera, B.^a , Sajad, A.^b , Errington, S.P.^b c , Schall, J.D.^d , Riera, J.J.^a

^a Department of Biomedical Engineering, Florida International University, Miami, FL 33174, United States
^b Department of Psychology, Vanderbilt Vision Research Center, Center for Integrative & Cognitive Neuroscience, Vanderbilt University, Nashville, TN 37203, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Centre for Vision Research, Vision: Science to Applications Program, Departments of Biology and Psychology, York University, Toronto, ON M3J 1P3, Canada

Abstract
A multi-scale approach elucidated the origin of the error-related-negativity (ERN), with its associated theta-rhythm, and the post-error-positivity (Pe) in macaque supplementary eye field (SEF). Using biophysical modeling, synaptic inputs to a subpopulation of layer-3 (L3) and layer-5 (L5) pyramidal cells (PCs) were optimized to reproduce error-related spiking modulation and inter-spike intervals. The intrinsic dynamics of dendrites in L5 but not L3 error PCs generate theta rhythmicity with random phases. Saccades synchronized the phases of the theta-rhythm, which was magnified on errors. Contributions from error PCs to the laminar current source density (CSD) observed in SEF were negligible and could not explain the observed association between error-related spiking modulation in L3 PCs and scalp-EEG. CSD from recorded laminar field potentials in SEF was comprised of multipolar components, with monopoles indicating strong electro-diffusion, dendritic/axonal electrotonic current leakage outside SEF, or violations of the model assumptions. Our results also demonstrate the involvement of secondary cortical regions, in addition to SEF, particularly for the later Pe component. The dipolar component from the observed CSD paralleled the ERN dynamics, while the quadrupolar component paralleled the Pe. These results provide the most advanced explanation to date of the cellular mechanisms generating the ERN. © The Author(s) 2023. Published by Oxford University Press. All rights reserved.

Author Keywords
biophysical models;  CSD;  ERN;  multiscale analysis;  theta rhythm

Funding details
National Institute of Mental HealthNIMHF31MH129101, R01MH55806
National Eye InstituteNEIP30EY008126, R01EY019882
Canadian Institutes of Health ResearchIRSC
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN-2022-04592

Document Type: Article
Publication Stage: Final
Source: Scopus

Psychosocial factors and well-being among adults with Charcot-Marie-Tooth disease: A cross-sectional study
(2023) Rehabilitation Psychology, 68 (4), pp. 431-442. 

Rule, P.D., Hill, P.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis

Abstract
PURPOSE/OBJECTIVE: The goal of the current study is to examine the relationships between psychosocial factors and well-being among adults with Charcot-Marie-Tooth (CMT) disease, a progressive neuromuscular disorder. Specifically, we aimed to examine associations between psychosocial factors and sense of purpose as well as the moderating role of sense of purpose on associations between psychosocial factors and two other measures of well-being (life satisfaction and health-related quality of life). RESEARCH METHOD/DESIGN: In 2021, we recruited 263 U.S. adults with CMT (Mage = 60.15 years, 58.56% female, 92.40% White) to take part in a cross-sectional study. Participants were asked to complete an online survey assessing components of well-being as well as various psychosocial factors. RESULTS: Moderate-to-strong associations were found between most psychosocial factors assessed and sense of purpose in individuals with CMT. In addition, sense of purpose moderated the relationship between multiple psychosocial factors and other measures of well-being. CONCLUSIONS/IMPLICATIONS: Psychosocial factors may be important to consider when examining well-being among individuals with CMT. Furthermore, sense of purpose may be a beneficial tool for promoting well-being in this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

Nerve Transfer After Cervical Spinal Cord Injury: Who Has a “Time Sensitive” Injury Based on Electrodiagnostic Findings?
(2023) Archives of Physical Medicine and Rehabilitation, . 

Berger, M.J.^a b , Dengler, J.^c d , Westman, A.^e , Curt, A.^f , Schubert, M.^f , Abel, R.^g , Weidner, N.^h , Röhrich, F.ⁱ , Fox, I.K.^e

^a International Collaboration on Repair Discoveries (ICORD), Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
^b Division of Physical Medicine & Rehabilitation, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
^c Division of Plastic Surgery, Tory Trauma Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
^d Division of Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
^e Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^f Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
^g Hohe Warte Bayreuth, Bayreuth, Germany
^h Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
ⁱ BG Klinikum Bergmannstrost, Zentrum für Rückenmarkverletzte und Klinik für Orthopädie, Halle, Germany

Abstract
Objective: To use the ulnar compound muscle action potential (CMAP) to abductor digiti minimi (ADM) to identify the proportion of individuals with cervical spinal cord injury (SCI) who have lower motor neuron (LMN) abnormalities involving the C8-T1 spinal nerve roots, within 3-6 months, and thus may influence the response to nerve transfer surgery. Design: Retrospective analysis of prospectively collected data. Data were analyzed from European Multicenter Study About SCI database. Setting: Multi-center, academic hospitals. Participants: We included 79 subjects (age=41.4±17.7, range:16-75; 59 men; N=79), who were classified as cervical level injuries 2 weeks after injury and who had manual muscle strength examinations that would warrant consideration for nerve transfer (C5≥4, C8<3). Interventions: None. Main Outcome Measures: The ulnar nerve CMAP amplitude to ADM was used as a proxy measure for C8-T1 spinal segment health. CMAP amplitude was stratified into very abnormal (<1.0 mV), sub-normal (1.0-5.9 mV), and normal (>6.0 mV). Analysis took place at 3 (n=148 limbs) and 6 months (n=145 limbs). Results: At 3- and 6-month post-injury, 33.1% and 28.3% of limbs had very abnormal CMAP amplitudes, respectively, while in 54.1% and 51.7%, CMAPs were sub-normal. Median change in amplitude from 3 to 6 months was 0.0 mV for very abnormal and 1.0 mV for subnormal groups. A 3-month ulnar CMAP <1 mV had a positive predictive value of 0.73 (95% CI 0.69-0.76) and 0.78 (95% CI 0.75-0.80) for C8 and T1 muscle strength of 0 vs 1 or 2. Conclusion: A high proportion of individuals have ulnar CMAPs below the lower limit of normal 3- and 6-month post cervical SCI and may also have intercurrent LMN injury. Failure to identify individuals with LMN denervation could result in a lost opportunity to improve hand function through timely nerve transfer surgeries. © 2023 American Congress of Rehabilitation Medicine

Author Keywords
Compound muscle action potential;  Nerve conduction study;  Nerve transfer;  Rehabilitation;  Spinal cord injury;  Ulnar nerve

Funding details
Congressionally Directed Medical Research ProgramsCDMRP

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

Behavioral Mechanisms That Mediate Mental and Physical Health Improvements in People With Chronic Pain Who Receive a Digital Health Intervention: Prospective Cohort Pilot Study
(2023) JMIR Formative Research, 7 (1), art. no. e51422, . 

Cheng, A.L.^a , Agarwal, M.^b , Armbrecht, M.A.^a , Abraham, J.^c , Calfee, R.P.^d , Goss, C.W.^b

^a Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States
^b Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^c Department of Anesthesiology, Institute for Informatics, Washington University School of Medicine, St Louis, MO, United States
^d Division of Hand and Wrist, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Preliminary evidence suggests that digital mental health intervention (Wysa for Chronic Pain) can improve mental and physical health in people with chronic musculoskeletal pain and coexisting symptoms of depression or anxiety. However, the behavioral mechanisms through which this intervention acts are not fully understood. Objective: The purpose of this study was to identify behavioral mechanisms that may mediate changes in mental and physical health associated with use of Wysa for Chronic Pain during orthopedic management of chronic musculoskeletal pain. We hypothesized that improved behavioral activation, pain acceptance, and sleep quality mediate improvements in self-reported mental and physical health. Methods: In this prospective cohort, pilot mediation analysis, adults with chronic (≥3 months) neck or back pain received the Wysa for Chronic Pain digital intervention, which uses a conversational agent and text-based access to human counselors to deliver cognitive behavioral therapy and related therapeutic content. Patient-reported outcomes and proposed mediators were collected at baseline and 1 month. The exposure of interest was participants’ engagement (ie, total interactions) with the digital intervention. Proposed mediators were assessed using the Behavioral Activation for Depression Scale–Short Form, Chronic Pain Acceptance Questionnaire, and Athens Insomnia Scale. Outcomes included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Pain Interference, and Physical Function scores. A mediation analysis was conducted using the Baron and Kenny method, adjusting for age, sex, and baseline mediators and outcome values. P<.20 was considered significant for this pilot study. Results: Among 30 patients (mean age 59, SD 14, years; 21 [70%] female), the mediation effect of behavioral activation on the relationship between increased intervention engagement and improved anxiety symptoms met predefined statistical significance thresholds (indirect effect –0.4, 80% CI –0.7 to –0.1; P=.13, 45% of the total effect). The direction of mediation effect was generally consistent with our hypothesis for all other proposed mediator or outcome relationships, as well. © 2023 The Author(s).

Author Keywords
anxiety;  behavioral activation;  behavioral mechanism;  chronic musculoskeletal pain;  chronic pain;  depression;  digital health intervention;  digital mental health intervention;  mediation analysis;  mobile phone;  pain acceptance;  pain interference;  physical function;  sleep quality

Funding details
National Institutes of HealthNIHK23AR074520, P30CA091842, P50MH122351, UL1TR002345
Doris Duke Charitable FoundationDDCF

Document Type: Article
Publication Stage: Final
Source: Scopus

Abuse of tapentadol compared to other atypical opioids among individuals entering treatment for opioid use disorders
(2023) Journal of Opioid Management, 19 (5), pp. 445-453. 

Severtson, S.G.^a , Gurrola, M.C.^a , Parrino, M.W.^b , Ellis, M.S.^c , Cicero, T.J.^c , Iwanicki, J.L.^a , Dart, R.C.^a d

^a Rocky Mountain Poison & Drug Safety, Denver Health and Hospital Authority, Denver, CO, United States
^b American Association for the Treatment of Opioid Dependence (AATOD), New York, NY, United States
^c Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Emergency Medicine, School of Medicine, University of Colorado, Aurora, CO, United States

Abstract
Objective: Tapentadol is an atypical opioid analgesic thought to have dual mechanisms of action: μ-receptor agonism and inhibition of norepinephrine reuptake. Unlike other atypical opioids, tapentadol is a schedule II-controlled substance. We compared the prevalence of abuse (use to get high) of tapentadol to other atypical opioids used to treat pain (buprenorphine and tramadol). Design: An observational, serial cross-sectional study. Setting: Individuals enrolling in treatment programs for opioid use disorder in 2019. Each completed a self-administered, paper questionnaire assessing prescription drug abuse and illegal drug use within 1 week of enrollment. Main outcome measures: Indication of past month abuse of tapentadol or comparator drugs on a self-administered questionnaire. Results: There were 6,987 respondents. Unadjusted and utilization-adjusted logistic regression models were used to compare odds of endorsement of tapentadol to tramadol and buprenorphine products indicated for the management of pain. Unadjusted abuse prevalence was 0.20 percent for total tapentadol (0.03 percent for NUCYNTA® and 0.06 percent for NUCYNTA ER). Relative to total tapentadol, the odds of abuse of buprenorphine for pain was 2.9 times greater (95 percent CI: 1.6 to 5.3, p &lt; 0.001), and for tramadol, 43.1 times greater (95 percent CI: 25.3 to 73.3, p &lt; 0.001). Adjusting for prescriptions dispensed, differences in odds of abuse were not statistically significant (odds ratio (OR) = 1.6, 95 percent CI: 0.9 to 3.0, p = 0.108 for buprenorphine for pain and OR = 0.7, 95 percent CI: 0.4 to 1.2, p = 0.209 for tramadol). Conclusions: Tapentadol use to get high is less frequent than other atypical opioids. Findings suggest tapentadol is rarely the primary drug abused by an individual. © 2023 Journal of Opioid Management, All Rights Reserved.

Author Keywords
abuse;  atypical opioids;  opioids;  tapentadol

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurocognitive function and health-related quality of life in adolescents and young adults with CHD with pulmonary valve dysfunction
(2023) Cardiology in the Young, . 

Zampi, J.D.^a , Heinrich, K.P.^b , Bergersen, L.^c , Goldstein, B.H.^d , Batlivala, S.P.^e , Fuller, S.^f , Glatz, A.C.^g , O’Byrne, M.L.^h , Marino, B.ⁱ , Afton, K.^a , Lowery, R.^a , Yu, S.^a , Goldberg, C.S.^a

^a Department of Pediatrics, University of Michigan Congenital Heart Center, Ann Arbor, MI, United States
^b Department of Psychology, University of Michigan, Ann Arbor, MI, United States
^c Division of Pediatric Cardiology, Boston Children’s Hospital, Boston, MA, United States
^d UPMC Children’s Hospital of Pittsburgh, Department of Pediatrics, Heart Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^e Cincinnati Children’s Hospital Heart Institute, Cincinnati, OH, United States
^f Division of Cardiac Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g Division of Pediatric Cardiology, St. Louis Children’s and Washington University Heart Center, St. Louis, MO, United States
^h Division of Pediatric Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁱ Department of Pediatrics, Division of Pediatric Cardiology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States

Abstract
Background: Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood. Methods: In this prospective longitudinal multi-institutional study, patients 13-30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies. Results: Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19-31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients. Conclusion: In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes. © The Author(s), 2023. Published by Cambridge University Press.

Author Keywords
CHD;  executive function;  neurocognitive function;  quality of life

Funding details
University of MichiganU-M

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

Dual-systems models of the genetic architecture of impulsive personality traits: Neurogenetic evidence of distinct but related factors
(2023) Psychological Medicine, . 

Miller, A.P.^a , Gizer, I.R.^b

^a Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychological Sciences, University of Missouri, Columbia, MO, United States

Abstract
Background Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. Results GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. Conclusions Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology. © The Author(s), 2023. Published by Cambridge University Press.

Author Keywords
dual-systems models;  endophenotype;  genetic factors;  impulsive personality traits;  neurogenetic;  neuroimaging

Funding details
National Science FoundationNSFCNS-1429294
National Institutes of HealthNIH
Wellcome TrustWTWT091310
Association for Project ManagementAPMF31AA027957, T32DA015035

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

Alzheimer disease biomarkers are associated with decline in subjective memory, attention, and spatial navigation ability in clinically normal adults
(2023) Journal of the International Neuropsychological Society, . 

Levine, T.F.^a , Dessenberger, S.J.^a , Allison, S.L.^b , Head, D.^a c d

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^b Neurosciences Institute, Intermountain Medical Center, Murray, UT, United States
^c Charles F. and Joanna Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
^d Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Objective: Subtle changes in memory, attention, and spatial navigation abilities have been associated with preclinical Alzheimer disease (AD). The current study examined whether baseline AD biomarkers are associated with self- and informant-reported decline in memory, attention, and spatial navigation. Method: Clinically normal (Clinical Dementia Rating Scale (CDR®) = 0) adults aged 56-93 (N = 320) and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog) annually for an average of 4 years. Biomarker data was collected within (±) 2 years of baseline (i.e., cerebrospinal fluid (CSF) p-tau181/Aβ42 ratio and hippocampal volume). Clinical progression was defined as CDR &gt; 0 at time of final available ECog. Results: Self- and informant-reported memory, attention, and spatial navigation significantly declined over time (ps &lt;.001). Baseline AD biomarkers were significantly associated with self- and informant-reported decline in cognitive ability (ps &lt;.030), with the exception of p-tau181/Aβ42 ratio and self-reported attention (p =.364). Clinical progression did not significantly moderate the relationship between AD biomarkers and decline in self- or informant-reported cognitive ability (ps &gt;.062). Post-hoc analyses indicated that biomarker burden was also associated with self- and informant-reported decline in total ECog (ps &lt;.002), and again clinical progression did not significantly moderate these relationships (ps &gt;.299). Conclusions: AD biomarkers at baseline may indicate risk of decline in self- and informant-reported change in memory, attention, and spatial navigation ability. As such, subjectively reported decline in these domains may have clinical utility in tracking the subtle cognitive changes associated with the earliest stages of AD. © The Author(s), 2023. Published by Cambridge University Press on behalf of International Neuropsychological Society.

Author Keywords
attention;  biomarkers;  Everyday Cognition Scale;  memory;  Preclinical Alzheimer disease;  spatial navigation

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDODW81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s Disease Neuroimaging InitiativeADNI

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

Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1–TFEB pathway to Huntington’s disease neurodegeneration
(2023) Nature Aging, . 

Lee, S.W.^a g , Oh, Y.M.^a g , Victor, M.B.^b , Yang, Y.^a , Chen, S.^a , Strunilin, I.^a , Dahiya, S.^c , Dolle, R.E.^d , Pak, S.C.^e , Silverman, G.A.^e , Perlmutter, D.H.^e , Yoo, A.S.^a f

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^f Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Biomedical Sciences, Mercer University School of Medicine, Columbus, GA, United States

Abstract
Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington’s disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington’s disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB’s nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1–calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington’s disease. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institute on AgingNIAR01AG078964, RF1AG056296
National Institute of Neurological Disorders and StrokeNINDSR01NS107488
Hereditary Disease FoundationHDF
CHDI FoundationCHDI
Cure Alzheimer’s FundCAF

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

CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review
(2023) Clinical Genetics, . 

Al-Kateb, H.^a , Au, P.Y.B.^b , Berland, S.^c , Cogne, B.^d , Demurger, F.^e , Fluss, J.^f , Isidor, B.^d , Frank, L.M.^g , Varvagiannis, K.^f , Koolen, D.A.^h , McDonald, M.ⁱ , Montgomery, S.ⁱ , Moortgat, S.^j , Deprez, M.^j , Karadurmus, D.^j , Paulsen, J.^c , Reis, A.^k , Rieger, M.^k , Vasileiou, G.^k , Willing, M.^l , Shinawi, M.^l

^a Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^b University of Calgary, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada
^c Department of medical genetics, Haukeland University Hospital, Bergen, Norway
^d Centre Hospitalier Universitaire de Nantes, Service de G’en’etique M’edicale, Nantes, France
^e Service de Génétique, Vannes, France
^f Genetic Medicine division, Diagnostic Department, Hôpitaux Universitaires de Genève, Genève (CH), Switzerland
^g Division of Neurology, Children’s Hospital of The King’s Daughters, Norfolk, VA, United States
^h Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
ⁱ Duke University Medical Center, Durham, NC, United States
^j Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
^k Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
^l Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals. © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Author Keywords
behavioral;  CAMTA1;  CECBA;  developmental delay;  gait;  hypotonia;  neurodevelopmental disorder;  reduced penetrance;  variants

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

Evaluation of gliovascular functions of AQP4 readthrough isoforms
(2023) Frontiers in Cellular Neuroscience, 17, art. no. 1272391, . 

Mueller, S.M.^a b , McFarland White, K.^a b , Fass, S.B.^a b , Chen, S.^a b c , Shi, Z.^d , Ge, X.^c e , Engelbach, J.A.^c e , Gaines, S.H.^c , Bice, A.R.^c , Vasek, M.J.^a b , Garbow, J.R.^c e , Culver, J.P.^{c f g h i} , Martinez-Lozada, Z.^j , Cohen-Salmon, M.^k , Dougherty, J.D.^a b e , Sapkota, D.^d l

^a Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, United States
^e Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Physics, Washington University in St. Louis, Saint Louis, MO, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
^h Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
ⁱ Imaging Science PhD Program, Washington University in St. Louis, Saint Louis, MO, United States
^j Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^k Center for Interdisciplinary Research in Biology (CIRB), The National Centre for Scientific Research (CNRS), Collège de France, France
^l Department of Neuroscience, University of Texas at Dallas, Richardson, TX, United States

Abstract
Aquaporin-4 (AQP4) is a water channel protein that links the astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, which preferentially localizes around the BBB through interaction with the scaffolding protein α-syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel AQP4 mouse line (AllX) to increase relative levels of the readthrough variant above the ~15% of AQP4 in the brain of wild-type (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and α-syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to WT and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. An increased dose of AQP4x enhanced perivascular localization of α-syntrophin and AQP4, while total protein expression of the two was unchanged. However, at 100% readthrough, AQP4x localization and the formation of higher order complexes were disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for an increased proportion of endothelial cells with budding vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels. Copyright © 2023 Mueller, McFarland White, Fass, Chen, Shi, Ge, Engelbach, Gaines, Bice, Vasek, Garbow, Culver, Martinez-Lozada, Cohen-Salmon, Dougherty and Sapkota.

Author Keywords
AQP4;  AQP4x;  astrocyte;  blood-brain barrier;  glymphatic;  readthrough

Funding details
National Institutes of HealthNIHR00AG061231, R01MH116999, R01NS102272
Children’s Hospital of PhiladelphiaCHOP
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
Intellectual and Developmental Disabilities Research CenterIDDRCP50HD103525
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus

Prevalence and Incidence of Parkinson’s Disease in Latin America: A Meta-Analysis
(2023) Movement Disorders, . 

Kim, D.J.^a b , Isidro-Pérez, A.L.^c d , Doering, M.^e , Llibre-Rodriguez, J.J.^f , Acosta, I.^c d , Rodriguez Salgado, A.M.^g , Pinilla-Monsalve, G.D.^h , Tanner, C.ⁱ , Llibre-Guerra, J.J.^j , Prina, M.^a b

^a Health Service and Population Research Department, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
^b Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
^c Laboratory of the Dementias, National Institute of Neurology and Neurosurgery, Mexico City, Mexico
^d National Autonomous University of Mexico, Mexico City, Mexico
^e Bernard Becker Medical Library, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^f Dementia Research Unit, Medical University of Havana, Havana, Cuba
^g Global Brain Health Institute, University of San Francisco California, San Francisco, CA, United States
^h Centre de Recherche, Institut Universitaire de Gériatrie de Montréal, Université de Montréal, Montreal, QC, Canada
ⁱ Department of Neurology, Weill Institute for Neurosciences, University of California-San Francisco, San Francisco, CA, United States
^j Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Background: Parkinson’s disease (PD) is a rapidly growing neurodegenerative disorder, but up-to-date epidemiological data are lacking in Latin America. We sought to estimate the prevalence and incidence of PD and parkinsonism in Latin America. Methods: We searched Medline, Embase, Scopus, Web of Science, Scientific Electronic Library Online, and Literatura Latino-Americana e do Caribe em Ciências da Saúde or the Latin American and Caribbean Health Science Literature databases for epidemiological studies reporting the prevalence or incidence of PD or parkinsonism in Latin America from their inception to 2022. Quality of studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Data were pooled via random-effects meta-analysis and analyzed by data source (cohort studies or administrative databases), sex, and age group. Significant differences between groups were determined by meta-regression. Results: Eighteen studies from 13 Latin American countries were included in the review. Meta-analyses of 17 studies (nearly 4 million participants) found a prevalence of 472 (95% CI, 271–820) per 100,000 and three studies an incidence of 31 (95% CI, 23–40) per 100,000 person-years for PD; and seven studies found a prevalence of 4300 (95% CI, 1863–9613) per 100,000 for parkinsonism. The prevalence of PD differed by data source (cohort studies, 733 [95% CI, 427–1255] vs. administrative databases. 114 [95% CI, 63–209] per 100,000, P < 0.01), age group (P < 0.01), but not sex (P = 0.73). PD prevalence in ≥60 years also differed significantly by data source (cohort studies. 1229 [95% CI, 741–2032] vs. administrative databases, 593 [95% CI, 480–733] per 100,000, P < 0.01). Similar patterns were observed for parkinsonism. Conclusions: The overall prevalence and incidence of PD in Latin America were estimated. PD prevalence differed significantly by the data source and age, but not sex. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Author Keywords
Hispanics;  incidence;  Latin America;  Parkinson’s disease;  prevalence

Funding details
K01AG073526
Michael J. Fox Foundation for Parkinson’s ResearchMJFFMJFF‐020770

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

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals
(2023) Nature Medicine, . 

Zhou, H.^a b c , Kember, R.L.^d e , Deak, J.D.^a b , Xu, H.^e , Toikumo, S.^d e , Yuan, K.^f g , Lind, P.A.^h i j , Farajzadeh, L.^k l m , Wang, L.^a b , Hatoum, A.S.ⁿ , Johnson, J.^o p , Lee, H.^q , Mallard, T.T.^f q r , Xu, J.^a , Johnston, K.J.A.^a , Johnson, E.C.^s , Nielsen, T.T.^k l m , Galimberti, M.^a b , Dao, C.^a b , Levey, D.F.^a b , Overstreet, C.^a b , Byrne, E.M.^t , Gillespie, N.A.^u , Gordon, S.^v , Hickie, I.B.^w , Whitfield, J.B.^v , Xu, K.^a b , Zhao, H.^x y , Huckins, L.M.^a , Davis, L.K.^z aa ab , Sanchez-Roige, S.^aa ac , Madden, P.A.F.^s , Heath, A.C.^s , Medland, S.E.^h j ad , Martin, N.G.^v , Ge, T.^f q ae , Smoller, J.W.^f r ae , Hougaard, D.M.^l af , Børglum, A.D.^k l m , Demontis, D.^k l m ag , Krystal, J.H.^{a b ah ai aj ak} , Gaziano, J.M.^al am an , Edenberg, H.J.^ao ap , Agrawal, A.^s , Zhao, H.^y z , Justice, A.C.^b aq ar , Stein, M.B.^ac as at , Kranzler, H.R.^d e , Gelernter, J.^a b y ah

^a Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^b Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
^c Section of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, United States
^d Crescenz Veterans Affairs Medical Center, Philadelphia, PA, United States
^e Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^f Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
^g Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
^h Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
ⁱ School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
^j Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
^k Department of Biomedicine – Human Genetics, Aarhus University, Aarhus, Denmark
^l The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
^m Center for Genomics and Personalized Medicine, Aarhus, Denmark
ⁿ Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, MO, United States
^o Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^p Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^q Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^r Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^s Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^t Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia
^u Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^v Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^w Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia
^x Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States
^y Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^z Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
^aa Department of Medicine, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, United States
^ab Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
^ac Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
^ad School of Psychology, University of Queensland, Brisbane, QLD, Australia
^ae Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^af Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
^ag The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^ah Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^ai National Center for PTSD, US Department of Veterans Affairs, West Haven, CT, United States
^aj Department of Psychology, Yale University, New Haven, CT, United States
^ak Psychiatry and Behavioral Health Services, Yale–New Haven Hospital, New Haven, CT, United States
^al Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, United States
^am Department of Medicine, Divisions of Aging and Preventative Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^an Department of Medicine, Harvard Medical School, Boston, MA, United States
^ao Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^ap Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^aq Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
^ar Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, United States
^as Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, United States
^at Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, United States

Abstract
Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer. © 2023, The Author(s).

Funding details
241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498, AA07535, AA07728, AA11998, AA13320, AA13321, AA14041, AA17688, APP10499110, APP1138514, APP1172917, DA012854, DA019951, K99R00, R00DA023549
01BX003341, 01BX004820, 01CX001849
K01 AA030083
575B, MVP004, MVP025
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01 MH124839
National Institute on Drug AbuseNIDAK01 DA051759
National Institute on Alcohol Abuse and AlcoholismNIAAAK01 AA028292, P50 AA12870
National Cancer InstituteNCIR01 AA026364, R21 CA252916, T32 AA028259, U54 AA027989
Brain and Behavior Research FoundationBBRF
Tobacco-Related Disease Research ProgramTRDRPT29KT0526, T32IR5226
Biogen
National Center for Advancing Translational SciencesNCATSUL1TR001878
Enzon Pharmaceuticals
Icahn School of Medicine at Mount SinaiISMMSS10OD018522, S10OD026880
Aarhus UniversitetAU
Perelman School of Medicine, University of Pennsylvania
National Alliance for Research on Schizophrenia and DepressionNARSAD27835
Horizon 2020 Framework ProgrammeH20201R01MH124851-01, 1U01MH109514-01, 965381, R102-A9118, R155-2014-1724, R248-2017-2003
American Society of Clinical PsychopharmacologyASCP
Australian Research CouncilARCA7960034, A79801419, A79906588, DP0212016, DP0343921, DP0770096, R01DA054869
National Health and Medical Research CouncilNHMRC1086683, APP 1172990
Lundbeck FoundationR344-2020-1060
Novo Nordisk FondenNNFNNF20OC0065561

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

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial
(2023) Developmental Neuroscience, . 

Wisnowski, J.L.^a b , Monsell, S.E.^c , Bluml, S.^a , Goodman, A.M.^d , Li, Y.^e , Comstock, B.A.^c , Heagerty, P.J.^c , Juul, S.E.^f , Wu, Y.W.^d g , McKinstry, R.C.^h , Mathur, A.M.ⁱ

^a Radiology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
^b Pediatrics, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
^c Biostatistics, University of Washington, Seattle, WA, United States
^d Neurology, University of California, San Francisco, CA, United States
^e Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States
^f Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
^g Pediatrics, University of California, San Francisco, CA, United States
^h Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
ⁱ Pediatrics, Saint Louis University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks’ gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5-5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population. © 2023 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution 4.0 International License (CC BY). Usage, derivative works and distribution are permitted provided that proper credit is given to the author and the original publisher.

Author Keywords
Erythropoietin;  Lactate;  MRI;  Neonatal;  Neuroprotection

Funding details
National Institutes of HealthNIHU01NS092553, U01NS092764
National Institute of Neurological Disorders and StrokeNINDS
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDK23HD099309

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

Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy
(2023) Ophthalmology Retina, . 

Wang, W.X., Shah, A.V., Bruck, B., Van Stavern, G., Rao, P.K., Apte, R.S.

John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States

Abstract
Objective: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. Design: Cross sectional descriptive study from December 2021 to December 2022. Participants: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. Methods: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). Main Outcome Measures: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (μm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. Results: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 μm (range, 217–488 μm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18–1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9–6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. Conclusions: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. © 2023 American Academy of Ophthalmology

Author Keywords
FA;  Multimodal characterization;  OCT;  OCT-A;  Retinal vasculopathy with cerebral leukoencephalopathy

Funding details
Research to Prevent BlindnessRPB
Roche

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

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma
(2023) Neuro-Oncology Advances, 5 (1), art. no. vdad116, . 

Batchelor, T.T.^a , Won, M.^b , Chakravarti, A.^c , Hadjipanayis, C.G.^d , Shi, W.^e , Ashby, L.S.^f , Stieber, V.W.^g , Robins, H.I.^h , Gray, H.J.ⁱ , Voloschin, A.^j , Fiveash, J.B.^k , Robinson, C.G.^l , Chamarthy, U.^m , Kwok, Y.ⁿ , Cescon, T.P.^o , Sharma, A.K.^p , Chaudhary, R.^q , Polley, M.-Y.^b r , Mehta, M.P.^a s

^a Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
^b Department of Statistics, NRG Oncology Statistics and Data Management Center, Philadelphia, PA, United States
^c Department of Radiation Oncology, Wexner Medical Center, Ohio State University, Comprehensive Cancer Center, Columbus, OH, United States
^d Department of Neuro-Oncology Neurosurgery, University of Pittsburgh Medical Center, Pittsburg, PA, United States
^e Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, United States
^f Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^g Department of Radiation Oncology, Novant Health Forsyth Medical Center, Winston-Salem, NC, United States
^h Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
ⁱ Department of Obstetrics and Gynecology, University of Washington Medical Center, Seattle, WA, United States
^j Department of Neuro-Oncology, Orlando Health Cancer Institute, Orlando, FL, United States
^k Department of Radiation Oncology, University of Alabama, Birmingham Medical Center, Birmingham, AL, United States
^l Department of Radiation Oncology, Washington University, St. Louis, MO, United States
^m Department of Medical Oncology/Hematology, Sparrow HH Cancer Center, Lansing, MI, United States
ⁿ Department of Radiation Oncology, University of Maryland Medical Systems, Baltimore, MD, United States
^o Department of Hematology, Reading Hospital, Reading, PA, United States
^p Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, United States
^q Department of Hematology Oncology, University of Cincinnati, Cincinnati, OH, United States
^r Department of Statistics, University of Chicago, Chicago, IL, United States
^s Department of Radiation Oncology, Miami Cancer Institute, Miami, FL, United States

Abstract
Background. A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods. Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results. One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions. This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms. © The Author(s) 2023.

Funding details
National Cancer InstituteNCIU10CA180822, U10CA180868
AstraZeneca

Document Type: Article
Publication Stage: Final
Source: Scopus