WashU weekly Neuroscience publications: September 17, 2023

Spinal Cord Injury and Assays for Regeneration
(2024) Methods in Molecular Biology (Clifton, N.J.), 2707, pp. 215-222. 

Burris, B.^a , Mokalled, M.H.^b

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

Abstract
Due to their renowned regenerative capacity, adult zebrafish are a premier vertebrate model to interrogate mechanisms of innate spinal cord regeneration. Following complete transection to their spinal cord, zebrafish extend glial and axonal bridges across severed tissue, regenerate neurons proximal to the lesion, and regain swim capacity within 8 weeks of injury. Here, we describe methods to perform complete spinal cord transections and to assess functional and cellular recovery during regeneration. For spinal cord injury, a complete transection is performed 4 mm caudal to the brainstem. Swim endurance is quantified as a central readout of functional spinal cord repair. For swim endurance, zebrafish are subjected to a constantly increasing water current velocity until exhaustion, and time at exhaustion is reported. To assess cellular regeneration, histological examination is performed to analyze the extents of glial and axonal bridging across the lesion. © 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Axon tracing;  Axonal bridging quantification;  Glial bridging quantification;  Spinal cord histology;  Spinal cord injury;  Swim endurance assay

Document Type: Article
Publication Stage: Final
Source: Scopus

Painted playgrounds for preschoolers’ physical activity and fundamental motor skill improvement: a randomized controlled pilot trial of effectiveness
(2023) BMC Pediatrics, 23 (1), art. no. 455, . 

Webster, E.K.^a , Kepper, M.M.^b , Saha, S.^c , Beyl, R.A.^c , Kracht, C.L.^c , Romain, J.S.^c d , Staiano, A.E.^c

^a Department of Kinesiology, Recreation, and Sport Studies, University of Tennessee, 1914 Andy Holt Ave, Knoxville, TN 37996, United States
^b Washington University of St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
^c Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, United States
^d Virginia Commonwealth University Health, Sanger Hall 1101 E. Marshall, Richmond, VA 23298, United States

Abstract
Background: Preschool children are not meeting recommended levels of physical activity (PA) nor are they proficient in fundamental motor skills (FMS), which are the foundation for PA. As such, interventions are needed to increase PA and FMS in young children. This trial examined the effects of an environmental (“painted playgrounds”) and capacity-building (written toolkit) intervention on child FMS, PA, and sedentary behavior at early childhood education (ECE) centers and examined feasibility. Methods: In a randomized controlled trial, four ECE centers were randomly assigned to an intervention group or wait-list control. For intervention centers, stencils were spray painted adjacent to playgrounds and teachers were provided material for using stencils for FMS practice. Follow-up assessments were conducted six to eight weeks after baseline. Time spent in PA and sedentary behavior was assessed via accelerometry and FMS were evaluated using the Test of Gross Motor Development (TGMD-3) at baseline and follow-up. A repeated measures linear model was performed to test the effects of the painted playgrounds on the primary outcomes of interest. Feasibility was measured by stencil engagement via direct observation and satisfaction surveys. Results: A total of 51 preschoolers completed baseline assessments (4.3±0.6 years; 43.1% male). There were no significant changes in PA or sedentary behavior (all confidence intervals contain 0) between control and intervention groups. Intervention children significantly improved ball skill, locomotor, and overall TGMD-3 percentile scores at follow-up (all (all confidence intervals contain 0), which was not observed in control group. However, there was no significant change in FMS between the control and intervention groups (confidence intervals contain 0). For stencil use, boys and girls interacted with different stencils during their free play. Directors and teachers reported children incorporated academic concepts and initiated games, and teachers prompted more PA opportunities on the playground. Conclusions: This intervention did not show statistically significant changes in children’s PA, FMS, or sedentary behavior compared to a control group; however, small FMS improvements for the intervention group were found from baseline to follow-up. Further work should examine intervention fidelity as well as inexpensive supplies, teacher training, or other strategies to increase preschool children’s PA and improve FMS at ECE centers. © 2023, BioMed Central Ltd., part of Springer Nature.

Author Keywords
Children;  Early childhood;  Exercise;  Playground;  Preschool

Funding details
National Institutes of HealthNIHK99HD107158, P30 DK072476, T32DK064584, U54 GM104940
University of TennesseeUT

Document Type: Article
Publication Stage: Final
Source: Scopus

Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions
(2023) Nature Communications, 14 (1), art. no. 5527, . 

Farag, M.^a , Borcherds, W.M.^b , Bremer, A.^b , Mittag, T.^b , Pappu, R.V.^a

^a Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States

Abstract
Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular condensates often encompass numerous distinct proteins with PLCDs. Here, we combine simulations and experiments to study mixtures of PLCDs from two RNA-binding proteins, hnRNPA1 and FUS. Using simulations and experiments, we find that 1:1 mixtures of A1-LCD and FUS-LCD undergo phase separation more readily than either of the PLCDs on their own due to complementary electrostatic interactions. Tie line analysis reveals that stoichiometric ratios of different components and their sequence-encoded interactions contribute jointly to the driving forces for condensate formation. Simulations also show that the spatial organization of PLCDs within condensates is governed by relative strengths of homotypic versus heterotypic interactions. We uncover rules for how interaction strengths and sequence lengths modulate conformational preferences of molecules at interfaces of condensates formed by mixtures of proteins. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIHR01NS121114
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241

Document Type: Article
Publication Stage: Final
Source: Scopus

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder
(2023) Genetics in Medicine, 25 (11), art. no. 100938, . 

Accogli, A.^a b , Lin, S.-J.^c , Severino, M.^d , Kim, S.-H.^e f , Huang, K.^c , Rocca, C.^g , Landsverk, M.^h i , Zaki, M.S.^j , Al-Maawali, A.^k l , Srinivasan, V.M.^m , Al-Thihli, K.^k l , Schaefer, G.B.ⁿ , Davis, M.ⁿ , Tonduti, D.^o p , Doneda, C.^q , Marten, L.M.^r , Mühlhausen, C.^r , Gomez, M.^s , Lamantea, E.^t , Mena, R.^u v , Nizon, M.^w x , Procaccio, V.^y z , Begtrup, A.^aa , Telegrafi, A.^aa , Cui, H.^aa , Schulz, H.L.^ab , Mohr, J.^ab , Biskup, S.^ab ac , Loos, M.A.^ad , Aráoz, H.V.^ae , Salpietro, V.^g af , Keppen, L.D.^h i , Chitre, M.^ag , Petree, C.^c , Raymond, L.^ag , Vogt, J.^ah , Sawyer, L.B.^ai , Basinger, A.A.^ai , Pedersen, S.V.^aj , Pearson, T.S.^ak , Grange, D.K.^al am , Lingappa, L.^an , McDunnah, P.^ao , Horvath, R.^ap , Cognè, B.^w x , Isidor, B.^w , Hahn, A.^aq , Gripp, K.W.^ao , Jafarnejad, S.M.^ar , Østergaard, E.^aj as , Prada, C.E.^at au av , Ghezzi, D.^t aw , Gowda, V.K.^m , Taylor, R.W.^ax ay , Sonenberg, N.^e f , Houlden, H.^g , Sissler, M.^az , Varshney, G.K.^c , Maroofian, R.^g

^a Division of Medical Genetics, Department of Specialized Medicine, Montreal Children’s Hospital, McGill University Health Centre (MUHC), Montreal, Canada
^b Department of Human Genetics, McGill University, Montreal, QC, Canada
^c Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
^d Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^e Goodman Cancer Institute, McGill University, Montreal, Canada
^f Department of Biochemistry, McGill University, Montreal, Canada
^g Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
^h University of South Dakota Sanford School of Medicine Sioux FallsSD
ⁱ Sanford Research, Pediatrics and Rare Diseases Group, Sioux Falls, SD, United States
^j Human Genetics and Genome Research Institute, Clinical Genetics Department, National Research Centre, Cairo, Egypt
^k Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
^l Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman
^m Indira Gandhi Institute of Child Health, Bangalore, India
ⁿ Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^o Unit of Pediatric Neurology, COALA (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, Milan, Italy
^p Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
^q Pediatric Radiology and Neuroradiology Department, Children’s Hospital Vittore Buzzi, Milan, Italy
^r Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Germany
^s Centro de Obsetricia y Ginecologia & Centro Medico Moderno, Santo Domingo, Dominican Republic
^t Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
^u Division of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^v Centro de Obsetricia y Ginecologia, Santo Domingo, Dominican Republic
^w Service de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France
^x Nantes Université, CNRS, INSERM, l’Institut du Thorax, Nantes, France
^y University of Angers, MitoLab Team, Unité MitoVasc, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France
^z Department of Genetics, CHU Angers, Angers, France
^aa GeneDx, Gaithersburg, MD, United States
^ab Human Genetic center Tübingen, Baden-Württemberg, Germany
^ac CeGaT GmbH, Germany
^ad Department of Neurology, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina
^ae Genomics Laboratory, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina
^af Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
^ag Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
^ah West Midlands Regional Genetics Service, Birmingham Women and Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom
^ai Children’s Hospital of the King’s Daughters, Norfolk, Virginia, VA, United States
^aj Department of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
^ak Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^al Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^am Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, MO, United States
^an Rainbow Children Hospital, Hyderabad, India
^ao Division of Medical Genetics, Nemours/A I duPont Hospital for Children, Wilmington, DE
^ap Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
^aq Department of Child Neurology, University Hospital, Gießen, Germany
^ar Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
^as Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
^at Division of Genetics, Genomics, and Metabolism, Ann & Robert Lurie Children’s Hospital of Chicago, Chicago
^au Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago
^av Fundacion Cardiovascular de Colombia, Floridablanca, Colombia
^aw Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
^ax Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
^ay NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle University, Newcastle upon Tyne, United Kingdom
^az ARNA – UMR5320 CNRS – U1212 INSERM, Université de Bordeaux, IECB, Pessac, France

Abstract
Purpose: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. Methods: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. Results: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. Conclusion: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity. © 2023 The Authors

Author Keywords
Cerebellar atrophy;  Mitochondrial dysfunction;  Mitochondrial threonyl-tRNA-synthetase;  mTORC1 signaling;  TARS2

Funding details
National Institutes of HealthNIH
Presbyterian Health FoundationPHF4411-09-09-0
Oklahoma Medical Research FoundationOMRF
Wellcome TrustWT109915/Z/15/Z, MR/V009346/1
NIHR Maudsley Biomedical Research CentreNIHR BRCBRC-1215-20014
National Institute for Health and Care ResearchNIHR
Ministero della Salute203105/Z/16/Z, G0800674, RF-2016-02361241
Fondazione Pierfranco e Luisa Mariani
Medical Research Council CanadaMRCMR/S005021/1
Lily Foundation825575

Document Type: Article
Publication Stage: Final
Source: Scopus

Elucidating individual differences in chronic pain and whole person health with allostatic load biomarkers
(2023) Brain, Behavior, and Immunity – Health, 33, art. no. 100682, . 

Mickle, A.M.^a , Tanner, J.J.^b , Olowofela, B.^c , Wu, S.^a , Garvan, C.^c , Lai, S.^d , Addison, A.^e , Przkora, R.^c , Edberg, J.C.^f , Staud, R.^g , Redden, D.^h , Goodin, B.R.^e i , Price, C.C.^b , Fillingim, R.B.^j , Sibille, K.T.^a c

^a Department of Physical Medicine & Rehabilitation, University of Florida, 101 Newell Dr, Gainesville, FL 32603, United States
^b Department of Clinical and Health Psychology, University of Florida, 1225 Center Dr, Gainesville, FL 32603, United States
^c Department of Anesthesiology, Division of Pain Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, United States
^d Department of Radiation Oncology & CTSI Human Imaging Core, University of Florida, 2004 Mowry Rd, Gainesville, FL 32610, United States
^e Department of Psychology, University of Alabama at Birmingham, Campbell Hall 415, 1300 University Blvd, Birmingham, AL 35223, United States
^f Department of Medicine, Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, 1825 University Blvd, Birmingham, AL 35294, United States
^g Department of Medicine, University of Florida, PO Box 100277, Gainesville, FL, United States
^h Department of Biostatistics, The University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, United States
ⁱ Department of Anesthesiology, Washington University, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^j Department of Community of Dentistry, University of Florida, 1329 SW 16th St, Room 5180, Gainesville, FL 32610, United States

Abstract
Chronic pain is a stressor that affects whole person functioning. Persistent and prolonged activation of the body’s stress systems without adequate recovery can result in measurable physiological and neurobiological dysregulation recognized as allostatic load. We and others have shown chronic pain is associated with measures of allostatic load including clinical biomarker composites, telomere length, and brain structures. Less is known regarding how different measures of allostatic load align. The purpose of the study was to evaluate relationships among two measures of allostatic load: a clinical composite and pain-related brain structures, pain, function, and socioenvironmental measures. Participants were non-Hispanic black and non-Hispanic white community-dwelling adults between 45 and 85 years old with knee pain. Data were from a brain MRI, questionnaires specific to pain, physical and psychosocial function, and a blood draw. Individuals with all measures for the clinical composite were included in the analysis (n = 175). Indicating higher allostatic load, higher levels of the clinical composite were associated with thinner insula cortices with trends for thinner inferior temporal lobes and dorsolateral prefrontal cortices (DLPFC). Higher allostatic load as measured by the clinical composite was associated with greater knee osteoarthritis pathology, pain disability, and lower physical function. Lower allostatic load as indicated by thicker insula cortices was associated with higher income and education, and greater physical functioning. Thicker insula and DLPFC were associated with a lower chronic pain stage. Multiple linear regression models with pain and socioenvironmental measures as the predictors were significant for the clinical composite, insular, and inferior temporal lobes. We replicate our previously reported bilateral temporal lobe group difference pattern and show that individuals with high chronic pain stage and greater socioenvironmental risk have a higher allostatic load as measured by the clinical composite compared to those individuals with high chronic pain stage and greater socioenvironmental buffers. Although brain structure differences are shown in individuals with chronic pain, brain MRIs are not yet clinically applicable. Our findings suggest that a clinical composite measure of allostatic load may help identify individuals with chronic pain who have biological vulnerabilities which increase the risk for poor health outcomes. © 2023 The Authors

Author Keywords
Allostatic load;  Brain structure;  Chronic pain;  Knee pain;  Socioenvironmental factors;  Stress

Funding details
UL1TR000064, UL1TR001417, UL1TR001427
National Science FoundationNSFDMR-1644779
National Institutes of HealthNIH
National Institute on AgingNIAR01AG054370, R37AG033906
Diabetes Research CenterDRCP30DK079626
Center for Clinical and Translational Science, University of Alabama at BirminghamCCTSU54TR002731
State of Florida

Document Type: Article
Publication Stage: Final
Source: Scopus

An LC-ESI-MS/MS method for determination of ondansetron in low-volume plasma and cerebrospinal fluid: Method development, validation, and clinical application
(2023) Journal of Pharmaceutical and Biomedical Analysis, 235, art. no. 115625, . 

Siemiątkowska, A.^a b , Frey, K.^c , Gurba, K.N.^c , Crock, L.W.^c , Haroutounian, S.^c , Kagan, L.^a

^a Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, United States
^b Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 3 Rokietnicka Street, Poznań, 60-806, Poland
^c Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Ondansetron is used in clinical settings as an antiemetic drug. Although the animal studies showed its potential effectiveness also in treating neuropathic pain, the results from humans are inconclusive. The lack of efficacy of ondansetron in a subset of patients might be due to the overexpression of P-glycoprotein, which could result in low concentrations of ondansetron in the central nervous system (CNS). A surrogate of the CNS exposure might be drug concentration in the cerebrospinal fluid (CSF), especially in humans, as assessing the drug disposition directly in the patient’s brain would be challenging. The study aimed to develop a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine concentrations of ondansetron in human K3EDTA plasma and CSF. Ondansetron was extracted from biological matrices by liquid-liquid extraction. The quantification was performed on a Sciex QTRAP 6500+ mass spectrometer with labeled ondansetron as an internal standard. The calibration range was 0.25–350 ng/mL in plasma and 0.025–100 ng/mL in CSF; for both matrices, 25 µL of samples was required for the assays. The method was validated according to the FDA and EMA guidelines and showed acceptable results. A pilot study confirmed its suitability for clinical samples: after 4–16 mg of intravenous ondansetron, the determined concentrations in plasma were 1.22–235.90 ng/mL, while in CSF – 0.018–11.93 ng/mL. In conclusion, the developed method fulfilled all validation requirements and can be applied to pharmacokinetic studies assessing the CNS ondansetron exposure in humans. The method’s advantages, such as a low volume of matrix and a wide calibration range, support its use in a study in which rich sampling and various drug doses are expected. © 2023 Elsevier B.V.

Author Keywords
5-HT3 receptor antagonist;  Assay validation;  Blank matrices;  Carry-over;  Methods comparison;  P-glycoprotein

Funding details
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis
(2023) eBioMedicine, 96, art. no. 104789, . 

Touil, H.^a , Li, R.^a , Zuroff, L.^a , Moore, C.S.^b , Healy, L.^c , Cignarella, F.^d , Piccio, L.^e , Ludwin, S.^f , Prat, A.^g , Gommerman, J.^h , Bennett, F.C.ⁱ , Jacobs, D.^a , Benjamins, J.A.^j , Lisak, R.P.^j , Antel, J.P.^c , Bar-Or, A.^a

^a Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
^c Neuroimmunology Unit, Montréal Neurological Institute, McGill University, Canada
^d Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO, United States
^e Charles Perkins Centre and School of Medical Sciences, The University of Sydney, Camperdown, NSW, Australia
^f Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
^g Université de Montréal Centre de Recherche du CHUM (CRCHUM) and Department of Neuroscience, Université de Montréal, 900 Saint Denis Street, Montréal, QC H2X 0A9, Canada
^h Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
ⁱ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^j Departments of Neurology and Biochemistry, Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, United States

Abstract
Background: B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors to progressive disease. This subpial demyelination is notable for a ‘surface-in’ gradient of neuronal loss and microglial activation, potentially reflecting the effects of soluble factors secreted into the CSF. We previously demonstrated that MS B-cell secreted products are toxic to oligodendrocytes and neurons. The potential for B-cell–myeloid cell interactions to propagate progressive MS is of considerable interest. Methods: Secreted products of MS-implicated pro-inflammatory effector B cells or IL-10-expressing B cells with regulatory potential were applied to human brain-derived microglia or monocyte-derived macrophages, with subsequent assessment of myeloid phenotype and function through measurement of their expression of pro-inflammatory, anti-inflammatory and homeostatic/quiescent molecules, and phagocytosis (using flow cytometry, ELISA and fluorescently-labeled myelin). Effects of secreted products of differentially activated microglia on B-cell survival and activation were further studied. Findings: Secreted products of MS-implicated pro-inflammatory B cells (but not IL-10 expressing B cells) substantially induce pro-inflammatory cytokine (IL-12, IL-6, TNFα) expression by both human microglia and macrophage (in a GM-CSF dependent manner), while down-regulating their expression of IL-10 and of quiescence-associated molecules, and suppressing their myelin phagocytosis. In contrast, secreted products of IL-10 expressing B cells upregulate both human microglia and macrophage expression of quiescence-associated molecules and enhance their myelin phagocytosis. Secreted factors from pro-inflammatory microglia enhance B-cell activation. Interpretation: Potential cross-talk between disease-relevant human B-cell subsets and both resident CNS microglia and infiltrating macrophages may propagate CNS-compartmentalized inflammation and injury associated with MS disease progression. These interaction represents an attractive therapeutic target for agents such as Bruton’s tyrosine kinase inhibitors (BTKi) that modulate responses of both B cells and myeloid cells. Funding: Stated in Acknowledgments section of manuscript. © 2023 The Author(s)

Author Keywords
CNS-compartmentalized inflammation;  Human B cells;  Human macrophage;  Human microglia;  Multiple sclerosis

Funding details
National Institutes of HealthNIHAG058501, R21NS118227

Document Type: Article
Publication Stage: Final
Source: Scopus

Differential impacts of road diets on driving behavior among older adults with and without preclinical Alzheimer’s pathology
(2023) Transportation Research Part F: Traffic Psychology and Behaviour, 98, pp. 18-28. 

Wisch, J.K.^a , Kianfar, J.^b , Carr, D.B.^a c , Dickerson, A.D.^d , Vivoda, J.^e , Harmon, A.^c , Trani, J.F.^f , Johnson, A.M.^g , Doherty, J.M.^a , Murphy, S.A.^a , Domash, H.^a , Ashraf, S.^a , Aschenbrenner, A.J.^a , Schindler, S.E.^a h , Benzinger, T.L.S.^h i , Morris, J.C.^a h , Ances, B.M.^a h , Babulal, G.M.^a j k

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Department of Civil Engineering, St. Louis University, St. Louis, MO 63110, United States
^c Department of Medicine, Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Occupational Therapy, East Carolina University, Greenville, NC 27858, United States
^e Department of Sociology and Gerontology, Miami University, Oxford, OH 45056, United States
^f Brown School of Social Work, Washington University in St. Louis, St. Louis, MO 63110, United States
^g Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO 63110, United States
^h Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
ⁱ Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^j Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^k Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa

Abstract
The driving populace of the United States is aging. The prevalence of Alzheimer disease (AD) will increase in the coming decades. Road diets (that is, the reallocation of one or more lanes of car traffic to other uses) have been proposed as a modification to increase pedestrian safety, particularly for older adults. In contrast, we considered the impacts of road diets on aging drivers, and on those with early pathological accumulation of AD. We observed naturalistic driving data for 60 cognitively normal older drivers (Age Range = 62–87 years, Median = 75 years) driving across three road segments located in the St. Louis metropolitan area, Missouri, United States. We used neuroimaging and lumbar puncture derived biomarker data to determine which of the drivers had preclinical AD. Since previous AD studies identified a variety of changes in driving behavior among older drivers with preclinical AD, we examined driving speed before and after lane repurposing. We found that drivers with preclinical AD drove at lower speeds compared to those without preclinical AD prior to road diet implementation. After lanes were repurposed, there was no statistical difference in the speed between older drivers with and without preclinical AD. We evaluated cognitive performance and found that attentional control had a mediating effect on driver speed, suggesting that an individual’s ability to focus on a specific task and filter out distractions was associated with faster driving. Driving speed after lane repurposing is not mediated by attentional control, suggesting that road diets are impervious to individual driver capacity. We conclude that lane repurposing has potential as an important mobility infrastructure solution that could enhance older driver safety and facilitate aging in place. © 2023 Elsevier Ltd

Author Keywords
Aging;  Alzheimer disease;  Biomarkers;  Naturalistic driving;  Older adults;  Policy;  Road diets

Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG0066444, R01AG067428, R01AG068183, R01AG074302, R01NR012657, R01NR012907, R01NR014449, U19 AG024904, U19 AG032438
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTSUL1 TR000448
Hope Center for Neurological Disorders

Document Type: Article
Publication Stage: Final
Source: Scopus

Tangent functional connectomes uncover more unique phenotypic traits
(2023) iScience, 26 (9), art. no. 107624, . 

Abbas, K.^a b , Liu, M.^a b , Wang, M.^a b , Duong-Tran, D.^c d , Tipnis, U.^e , Amico, E.^f g , Kaplan, A.D.^e , Dzemidzic, M.^h , Kareken, D.^h , Ances, B.M.ⁱ , Harezlak, J.^j , Goñi, J.^a b k

^a Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, United States
^b School of Industrial Engineering, Purdue University, West Lafayette, IN, United States
^c Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Mathematics, United States Naval Academy, Annapolis, MD, United States
^e Lawrence Livermore National Laboratory, Livermore, CA, United States
^f Institute of Bioengineering, Center for Neuroprosthetics, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
^g Department of Radiology and Medical Informatics, University of Geneva (UNIGE), Geneva, Switzerland
^h Department of Neurology, Indiana University School of Medicine, Indiana Alcohol Research Center, Indianapolis, IN, United States
ⁱ Department of Neurology, Washington University in Saint Louis, School of Medicine, St Louis, MO, United States
^j Department of Epidemiology and Biostatistics, Indiana University, Bloomington, IN, United States
^k Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States

Abstract
Functional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when using tangent-FCs across the “fingerprint gradient” (here including test-retest, monozygotic and dizygotic twins). Highest identification rates were achieved when minimally (0.01) regularizing FCs while performing tangent space projection using Riemann reference matrix and using correlation distance to compare the resulting tangent-FCs. Such configuration was validated in a second dataset (resting-state). © 2023 The Author(s)

Author Keywords
Biological sciences;  Phenotyping

Funding details
National Institutes of HealthNIHCTSI CTR EPAR2169, R01 AA029607, R21 AA029614
McDonnell Center for Systems Neuroscience
Indiana Alcohol Research CenterIARCP60AA07611
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNFPZ00P2_185716, R01 DA054009, R01 MH118031, R01 NR0112657, R01 NR012907, R01 NR014449, R01 NR015738

Document Type: Article
Publication Stage: Final
Source: Scopus

Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin
(2023) Cancer Cell, 41 (9), pp. 1567-1585.e7. 

Liang, W.-W.^a b , Lu, R.J.-H.^a b , Jayasinghe, R.G.^a b , Foltz, S.M.^a b , Porta-Pardo, E.^c d , Geffen, Y.^e f , Wendl, M.C.^b g h , Lazcano, R.ⁱ , Kolodziejczak, I.^j k , Song, Y.^a b , Govindan, A.^a b , Demicco, E.G.^l , Li, X.^a b , Li, Y.^a b , Sethuraman, S.^a b , Payne, S.H.^m , Fenyö, D.^n o , Rodriguez, H.^p , Wiznerowicz, M.^j q r , Shen, H.^s , Mani, D.R.^e , Rodland, K.D.^t u , Lazar, A.J.ⁱ , Robles, A.I.^p , Ding, L.^a b v , Aguet, F.^w , Akiyama, Y.^w , An, E.^w , Anand, S.^w , Anurag, M.^w , Babur, O.^w , Bavarva, J.^w , Birger, C.^w , Birrer, M.^w , Calinawan, A.^w , Cantley, L.C.^w , Cao, S.^w , Carr, S.^w , Ceccarelli, M.^w , Chan, D.^w , Chinnaiyan, A.^w , Cho, H.^w , Chowdhury, S.^w , Cieslik, M.^w , Clauser, K.^w , Colaprico, A.^w , Zhou, D.C.^w , da Veiga Leprevost, F.^w , Day, C.^w , Dhanasekaran, M.^w , Domagalski, M.^w , Dou, Y.^w , Druker, B.^w , Edwards, N.^w , Ellis, M.^w , Selvan, M.E.^w , Francis, A.^w , Getz, G.^w , Gillette, M.A.^w , Robles, T.G.^w , Gosline, S.^w , Gümüş, Z.^w , Heiman, D.^w , Hiltke, T.^w , Hong, R.^w , Hostetter, G.^w , Hu, Y.^w , Huang, C.^w , Huntsman, E.^w , Iavarone, A.^w , Jaehnig, E.^w , Jewel, S.^w , Ji, J.^w , Jiang, W.^w , Lee Johnson, J.^w , Katsnelson, L.^w , Ketchum, K.^w , Krug, K.^w , Kumar-Sinha, C.^w , Lei, J.^w , Liao, Y.^w , Lindgren, C.^w , Liu, T.^w , Liu, W.^w , Ma, W.^w , Rodrigues, F.M.^w , McKerrow, W.^w , Mesri, M.^w , Nesvizhskii, A.I.^w , Newton, C.^w , Oldroyd, R.^w , Omenn, G.^w , Paulovich, A.^w , Petralia, F.^w , Pugliese, P.^w , Reva, B.^w , Ruggles, K.^w , Rykunov, D.^w , Satpathy, S.^w , Savage, S.^w , Schadt, E.^w , Schnaubelt, M.^w , Schraink, T.^w , Shi, Z.^w , Smith, D.^w , Song, X.^w , Stathias, V.^w , Storrs, E.^w , Tan, J.^w , Terekhanova, N.^w , Thangudu, R.^w , Thiagarajan, M.^w , Tignor, N.^w , Wang, J.^w , Wang, L.-B.^w , Wang, P.^w , Wang, Y.C.^w , Wen, B.^w , Wu, Y.^w , Yao, L.^w , Yaron, T.M.^w , Yi, X.^w , Zhang, B.^w , Zhang, H.^w , Zhang, Q.^w , Zhang, X.^w , Zhang, Z.^w , Chan, D.W.^w , Dhanasekaran, S.M.^w , Schürer, S.^w , Smith, R.D.^w , Wyczalkowski, M.A.^w , Clinical Proteomic Tumor Analysis Consortium^x

^a Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, United States
^b McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, United States
^c Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916, Spain
^d Barcelona Supercomputing Center (BSC), Barcelona, 08034, Spain
^e Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, United States
^f Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, United States
^g Department of Genetics, Washington University in St. Louis, St. Louis, MO 63130, United States
^h Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63130, United States
ⁱ Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
^j International Institute for Molecular Oncology, Poznań, 60-203, Poland
^k Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, 02-091, Poland
^l Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
^m Department of Biology, Brigham Young University, Provo, UT 84602, United States
ⁿ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, United States
^o Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, United States
^p Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD 20850, United States
^q Heliodor Swiecicki Clinical Hospital in Poznań, Ul. Przybyszewskiego 49, Poznań, 60-355, Poland
^r Poznań University of Medical Sciences, Poznań, 61-701, Poland
^s Van Andel Research Institute, Grand Rapids, MI 49503, United States
^t Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, United States
^u Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97221, United States
^v Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor’s epigenetic landscape and the role of its cell-of-origin. © 2023 The Author(s)

Funding details
National Institutes of HealthNIHGR0012005, HHSN26100064, HHSN261201500003I, U01CA214114, U01CA214116, U01CA214125, U24CA210954, U24CA210955, U24CA210967, U24CA210972, U24CA210979, U24CA210985, U24CA210986, U24CA210993
U.S. Department of Health and Human ServicesHHS
National Cancer InstituteNCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Transdiagnostic Predictors of Everyday Functioning: Examining the Relationships of Depression and Reinforcement Learning
(2023) Schizophrenia Bulletin, 49 (5), pp. 1281-1293. 

Dalloul, N.^a , Moran, E.K.^b , Gold, J.M.^c , Carter, C.S.^d , MacDonald, A.W.^e , Ragland, J.D.^d , Silverstein, S.M.^f , Luck, S.J.^g , Barch, D.M.^a b h

^a Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Maryland Psychiatric Research Center, Baltimore, MD, United States
^d Department of Psychiatry, University of California, Davis, CA, United States
^e Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^f Department of Psychiatry, University of Rochester, Rochester, NY, United States
^g Department of Psychology, University of California, Davis, CA, United States
^h Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND AND HYPOTHESIS: Impairments in function (ie, the ability to independently accomplish daily tasks) have been established in psychotic disorders. Identifying factors that contribute to these deficits is essential to developing effective interventions. The current study had several goals: examine potential differential relationships across domains of neurocognition, assess whether reinforcement learning is related to function, identify if predictors of function are transdiagnostic, determine whether depression and positive symptoms contribute to function, and to explore whether the modality of assessment impacts observed relationships. STUDY DESIGN: Data from 274 participants were examined with schizophrenia/schizoaffective disorder (SZ; n = 195) and bipolar disorder (BD; n = 79). To reduce dimensionality, a PCA was completed on neurocognitive tasks which resulted in 3 components. These components and clinical interview data were used to investigate predictors of functional domains across measures of function (self- and informant-report SLOF and UPSA). RESULTS: Two components, working memory/processing speed/episodic memory (βs = 0.18-0.42), and negative/positive reinforcement learning (β = -0.04), predicted different functional domains. Predictors of function were largely transdiagnostic with two exceptions: reinforcement learning had a positive association with self-reported interpersonal relationships for SZ and a negative association for BD (β = 0.34), and the negative association between positive symptoms and self-reported social acceptability was stronger for BD than for SZ (β = 0.93). Depression robustly predicted self-reported but not informant-reported function, and anhedonia predicted all domains of informant-reported function. CONCLUSIONS: These findings imply that reinforcement learning may differentially relate to function across disorders, traditional domains of neurocognition can be effective transdiagnostic targets for interventions, and positive symptoms and depression play a critical role in self-perceived functional impairments. © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
bipolar disorder;  neurocognition;  psychosis;  schizophrenia

Document Type: Article
Publication Stage: Final
Source: Scopus

Acceptability of Cognitive Behavioral Therapy for Tinnitus: A Study With Veterans and Nonveterans
(2023) American Journal of Audiology, 32 (3), pp. 593-603. 

Rodriguez, C.R.^a b , Piccirillo, J.F.^c , Rodebaugh, T.L.^d

^a Department of Psychiatry, University of Michigan, Ann Arbor, United States
^b Addiction Center, University of Michigan, Ann Arbor, United States
^c Clinical Outcomes Research Office, Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. LouisMO, United States
^d Department of Psychological & Brain Sciences, Washington University in St. LouisMO, United States

Abstract
PURPOSE: Cognitive behavioral therapy (CBT) is a gold standard yet underutilized treatment for tinnitus, and tinnitus is especially highly prevalent among veterans. The aims of this study were twofold: to determine (a) if CBT for tinnitus is underutilized because participants find it less acceptable than other behavioral treatments for tinnitus and (b) if veterans and nonveterans rate behavioral treatments for tinnitus differently. METHOD: This cross-sectional study was conducted online with a sample of 277 adults in the United States who self-reported at least some level of bothersome tinnitus in the past week. The sample for this study consisted of 129 veterans and 148 nonveterans. Participants read descriptions of CBT, tinnitus retraining therapy (TRT), and mindfulness-based stress reduction (MBSR). For each treatment, presented to them in random order, they provided credibility, expectancy, and acceptability ratings. RESULTS: Among 277 participants, 147 (53.07%) reporting gender were women, 216 (77.98%) reporting race/ethnicity were White, and 129 (46.57%) were veterans of any branch of the U.S. Armed Forces. Veteran ratings of credibility, expectancy, and acceptability were significantly lower than nonveteran ratings across treatments. There were differences in credibility, expectancy, and acceptability ratings across treatments, and post hoc testing revealed that TRT was consistently rated higher than CBT or MBSR. CONCLUSIONS: Despite strong research support, CBT was rated as less acceptable than a different, less widely empirically supported treatment. Veterans’ ratings of acceptability were lower than those of nonveterans across all treatments.

Document Type: Article
Publication Stage: Final
Source: Scopus

Development and Replication of Objective Measurements of Social Visual Engagement to Aid in Early Diagnosis and Assessment of Autism
(2023) JAMA Network Open, 6 (9), p. e2330145. 

Jones, W.^a b c , Klaiman, C.^a b , Richardson, S.^a b , Lambha, M.^a b , Reid, M.^a , Hamner, T.^a , Beacham, C.^a , Lewis, P.^a , Paredes, J.^a b , Edwards, L.^a b , Marrus, N.^d e , Constantino, J.N.^e f g , Shultz, S.^a b , Klin, A.^a b c

^a Marcus Autism Center, Children’s Healthcare of Atlanta, Atlanta, Georgia
^b Division of Autism and Related Disabilities, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
^c Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia
^d Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, United States
^e Intellectual and Developmental Disabilities Research Center, Washington University in St Louis School of Medicine, St Louis, MO, United States
^f Now with Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia
^g Now with Division of Behavioral and Mental Health, Children’s Healthcare of Atlanta, Atlanta, Georgia

Abstract
Importance: Autism spectrum disorder is a common and early-emerging neurodevelopmental condition. While 80% of parents report having had concerns for their child’s development before age 2 years, many children are not diagnosed until ages 4 to 5 years or later. Objective: To develop an objective performance-based tool to aid in early diagnosis and assessment of autism in children younger than 3 years. Design, Setting, and Participants: In 2 prospective, consecutively enrolled, broad-spectrum, double-blind studies, we developed an objective eye-tracking-based index test for children aged 16 to 30 months, compared its performance with best-practice reference standard diagnosis of autism (discovery study), and then replicated findings in an independent sample (replication study). Discovery and replication studies were conducted in specialty centers for autism diagnosis and treatment. Reference standard diagnoses were made using best-practice standardized protocols by specialists blind to eye-tracking results. Eye-tracking tests were administered by staff blind to clinical results. Children were enrolled from April 27, 2013, until September 26, 2017. Data were analyzed from March 28, 2018, to January 3, 2019. Main Outcomes and Measures: Prespecified primary end points were the sensitivity and specificity of the eye-tracking-based index test compared with the reference standard. Prespecified secondary end points measured convergent validity between eye-tracking-based indices and reference standard assessments of social disability, verbal ability, and nonverbal ability. Results: Data were collected from 1089 children: 719 children (mean [SD] age, 22.4 [3.6] months) in the discovery study, and 370 children (mean [SD] age, 25.4 [6.0] months) in the replication study. In discovery, 224 (31.2%) were female and 495 (68.8%) male; in replication, 120 (32.4%) were female and 250 (67.6%) male. Based on reference standard expert clinical diagnosis, there were 386 participants (53.7%) with nonautism diagnoses and 333 (46.3%) with autism diagnoses in discovery, and 184 participants (49.7%) with nonautism diagnoses and 186 (50.3%) with autism diagnoses in replication. In the discovery study, the area under the receiver operating characteristic curve was 0.90 (95% CI, 0.88-0.92), sensitivity was 81.9% (95% CI, 77.3%-85.7%), and specificity was 89.9% (95% CI, 86.4%-92.5%). In the replication study, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.86-0.93), sensitivity was 80.6% (95% CI, 74.1%-85.7%), and specificity was 82.3% (95% CI, 76.1%-87.2%). Eye-tracking test results correlated with expert clinical assessments of children’s individual levels of ability, explaining 68.6% (95% CI, 58.3%-78.6%), 63.4% (95% CI, 47.9%-79.2%), and 49.0% (95% CI, 33.8%-65.4%) of variance in reference standard assessments of social disability, verbal ability, and nonverbal cognitive ability, respectively. Conclusions and Relevance: In two diagnostic studies of children younger than 3 years, objective eye-tracking-based measurements of social visual engagement quantified diagnostic status as well as individual levels of social disability, verbal ability, and nonverbal ability in autism. These findings suggest that objective measurements of social visual engagement can be used to aid in autism diagnosis and assessment.

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults
(2023) JAMA Neurology, 80 (9), pp. 929-939. 

Walters, S.^a b , Contreras, A.G.^a b , Eissman, J.M.^a b , Mukherjee, S.^c , Lee, M.L.^c , Choi, S.-E.^c , Scollard, P.^c , Trittschuh, E.H.^d e , Mez, J.B.^f , Bush, W.S.^g , Kunkle, B.W.^h , Naj, A.C.^i j , Peterson, A.^a , Gifford, K.A.^a , Cuccaro, M.L.^h , Cruchaga, C.^k l , Pericak-Vance, M.A.^h , Farrer, L.A.^f m n , Wang, L.-S.^j , Haines, J.L.^g , Jefferson, A.L.^a , Kukull, W.A.^o , Keene, C.D.^p , Saykin, A.J.^q r , Thompson, P.M.^s , Martin, E.R.^h , Bennett, D.A.^t , Barnes, L.L.^t , Schneider, J.A.^t , Crane, P.K.^c , Hohman, T.J.^a b , Dumitrescu, L.^a b , Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Genetics Consortium, and Alzheimer’s Disease Sequencing Project^u

^a Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, United States
^b Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
^c Department of Medicine, University of Washington, Seattle, United States
^d Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, United States
^e Geriatric Research Education and Clinical Center (GRECC), VA Puget Sound Health Care System, Seattle, WA, United States
^f Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
^g Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
^h John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, Puerto Rico
ⁱ Department of Biostatistics, Epidemiology, Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
^j Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
^k Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^l NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, United States
^m Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
ⁿ Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
^o Department of Epidemiology, School of Public Health, University of Washington, Seattle, United States
^p Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
^q Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, United States
^r Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States
^s Keck School of Medicine, University of Southern California, Los Angeles, Mexico
^t Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

Abstract
Importance: Sex differences are established in associations between apolipoprotein E (APOE) ε4 and cognitive impairment in Alzheimer disease (AD). However, it is unclear whether sex-specific cognitive consequences of APOE are consistent across races and extend to the APOE ε2 allele. Objective: To investigate whether sex and race modify APOE ε4 and ε2 associations with cognition. Design, Setting, and Participants: This genetic association study included longitudinal cognitive data from 4 AD and cognitive aging cohorts. Participants were older than 60 years and self-identified as non-Hispanic White or non-Hispanic Black (hereafter, White and Black). Data were previously collected across multiple US locations from 1994 to 2018. Secondary analyses began December 2021 and ended September 2022. Main Outcomes and Measures: Harmonized composite scores for memory, executive function, and language were generated using psychometric approaches. Linear regression assessed interactions between APOE ε4 or APOE ε2 and sex on baseline cognitive scores, while linear mixed-effect models assessed interactions on cognitive trajectories. The intersectional effect of race was modeled using an APOE × sex × race interaction term, assessing whether APOE × sex interactions differed by race. Models were adjusted for age at baseline and corrected for multiple comparisons. Results: Of 32 427 participants who met inclusion criteria, there were 19 007 females (59%), 4453 Black individuals (14%), and 27 974 White individuals (86%); the mean (SD) age at baseline was 74 years (7.9). At baseline, 6048 individuals (19%) had AD, 4398 (14%) were APOE ε2 carriers, and 12 538 (38%) were APOE ε4 carriers. Participants missing APOE status were excluded (n = 9266). For APOE ε4, a robust sex interaction was observed on baseline memory (β = -0.071, SE = 0.014; P = 9.6 × 10-7), whereby the APOE ε4 negative effect was stronger in females compared with males and did not significantly differ among races. Contrastingly, despite the large sample size, no APOE ε2 × sex interactions on cognition were observed among all participants. When testing for intersectional effects of sex, APOE ε2, and race, an interaction was revealed on baseline executive function among individuals who were cognitively unimpaired (β = -0.165, SE = 0.066; P = .01), whereby the APOE ε2 protective effect was female-specific among White individuals but male-specific among Black individuals. Conclusions and Relevance: In this study, while race did not modify sex differences in APOE ε4, the APOE ε2 protective effect could vary by race and sex. Although female sex enhanced ε4-associated risk, there was no comparable sex difference in ε2, suggesting biological pathways underlying ε4-associated risk are distinct from ε2 and likely intersect with age-related changes in sex biology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations between childhood irritability and neural reactivity to maternal feedback in adolescence
(2023) Biological Psychology, 182, art. no. 108645, . 

Mohamed Ali, O.^a , Vandermeer, M.R.J.^a b , Liu, P.^a c , Joanisse, M.F.^a , Barch, D.M.^d , Hayden, E.P.^a

^a Department of Psychology, Brain and Mind Institute, University of Western Ontario, London, ON N6A 5B7, Canada
^b St. Joseph’s Healthcare Hamilton, Hamilton, ON L8N 4A6, Canada
^c Department of Psychology, North Dakota State University, Fargo, ND 58102, United States
^d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Early irritability, a transdiagnostic vulnerability for psychopathology, is associated with alterations in neural reactivity to emotional stimuli and reward; however, associations between childhood irritability and neural markers of risk may be mitigated by the quality of caregiving youth receive. We examined longitudinal relationships between irritability in childhood and young adolescents’ neural activity of regions typically associated with emotion regulation and reward processing during processing of maternal feedback and tested whether these associations were moderated by youth’s perceptions of the parent-child relationship quality. Eighty-one adolescents (Mage = 11.1 years) listened to maternal critical and praising feedback while undergoing functional magnetic resonance imaging. Age 3 irritability, assessed observationally, was negatively associated with age 11 neural reactivity to maternal criticism in a cluster in the right dorsolateral prefrontal cortex (dlPFC), particularly for youths who reported more positive maternal parenting. Given the role of the dlPFC activation in the effortful processing of emotional stimuli, decreased activation may reflect disengagement from negatively valenced interpersonal feedback in the context of a positive caregiving environment, thereby mitigating psychopathology risk associated with irritability. © 2023 Elsevier B.V.

Author Keywords
Adolescence;  FMRI;  Irritability;  Maternal feedback;  Parenting

Funding details
Children’s Health Research InstituteCHRI
Canadian Institutes of Health ResearchIRSCMOP 86458
Social Sciences and Humanities Research Council of CanadaSSHRC

Document Type: Article
Publication Stage: Final
Source: Scopus

Self-Identified Stage in Recovery and Substance-Use Behaviors among Pregnant and Postpartum Women and People with Opioid Use Disorder
(2023) Healthcare (Switzerland), 11 (17), art. no. 2392, . 

Szlyk, H.S.^a , Constantino-Pettit, A.^a b , Li, X.^a , Kasson, E.^a , Maranets, E.^a , Worku, Y.^a , Montayne, M.^a , Banks, D.E.^c , Kelly, J.C.^d , Cavazos-Rehg, P.A.^a

^a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Brown School, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
^c Department of Psychological Sciences, University of Missouri–St. Louis, One University Blvd., 325 Stadler Hall, St. Louis, MO 63121, United States
^d Department of Obstetrics & Gynecology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Abstract
Opioid use among pregnant and postpartum women and people (PPWP) has significant health repercussions. This study explores how substance-use behaviors may vary by stage in recovery among PPWP with opioid use disorder (OUD). We recruited 29 PPWP with OUD. “High-risk” participants self-identified as “not being engaged in treatment” or “new or early in their recovery” (n = 11); “low-risk” participants self-identified as being “well-established” or “in long-term recovery” (n = 18). Participants were queried regarding sociodemographic, mental health, and drug-misuse factors; urine drug screens were collected at baseline. Univariate group comparisons between high-risk and low-risk PPWP were conducted. High-risk PPWP were more likely to self-identify as non-Hispanic African American and more likely to report current opioid use, other illicit drugs, and tobacco. High-risk PPWP had higher opioid cravings versus low-risk PPWP. High-risk PPWP were more likely to screen positive on urine tests for non-opioid drugs and on concurrent use of both non-opioid drugs and opioids versus low-risk participants. PPWP earlier in recovery are at higher-risk for opioid and other illicit drug misuse but are willing to disclose aspects of their recent use. PPWP early in recovery are an ideal population for interventions that can help facilitate recovery during the perinatal period and beyond. © 2023 by the authors.

Author Keywords
maternal healthcare;  opioid use disorder;  postpartum;  pregnancy;  stage in recovery

Funding details
T37 MD014128
National Institutes of HealthNIHK02 DA043657, R34DA050453
National Institute on Drug AbuseNIDAK12 DA041449
Substance Abuse and Mental Health Services AdministrationSAMHSA1H79TIO80271
National Center for Advancing Translational SciencesNCATSKL2 TR002346

Document Type: Article
Publication Stage: Final
Source: Scopus

Risk of autism spectrum disorder and association of its symptoms with psychiatric and substance use disorders in non-clinical student sample in Kenya: Cross-sectional study
(2023) BJPsych Open, 9 (5), art. no. e160, . 

Mutiso, V.N.^a , Ndetei, D.M.^b e , Muia, E.N.^c , Masake, M.^c , Alietsi, R.K.^a , Onsinyo, L.^a , Musyimi, C.^a , Mamah, D.^d

^a Africa Mental Health Research and Training Foundation, Nairobi, Kenya
^b Africa Mental Health Research and Training Foundation, Department of Psychiatry, University of Nairobi, Nairobi, Kenya
^c Department of Public and Community Health, Machakos University, Machakos, Kenya
^d Department of Psychiatry, Washington University Medical School, St Louis, MO, United States
^e World Psychiatric Association Collaborating Centre for Research and Training, Nairobi, Kenya

Abstract
Background The prevalence and patterns of autism spectrum disorder (ASD) symptoms/traits and the associations of ASD with psychiatric and substance use disorders has not been documented in non-clinical students in Sub-Saharan Africa, and Kenya in particular. Aims To document the risk level of ASD and its traits in a Kenyan student population (high school, college and university) using the Autism-Spectrum Quotient (AQ); and to determine the associations between ASD and other psychiatric and substance use disorders. Method This was a cross-sectional study among students (n = 9626). We used instruments with sufficient psychometric properties and good discriminative validity to collect data. A cut-off score of ≥32 on the AQ was used to identify those at high risk of ASD. We conducted the following statistical tests: (a) basic descriptive statistics; (b) chi-squared tests and Fisher’s exact tests to analyse associations between categorical variables and ASD; (c) independent t-tests to examine two-group comparisons with ASD; (d) one-way analysis of variance to make comparisons between categorical variables with three or more groups and ASD; (e) statistically significant (P < 0.05) variables fitted into an ordinal logistic regression model to identify determinants of ASD; (f) Pearson’s correlation and reliability analysis. Results Of the total sample, 54 (0.56%) were at high risk of ASD. Sociodemographic differences were found in the mean scores for the various traits, and statistically significant (P < 0.05) associations we found between ASD and various psychiatric and substance use disorders. Conclusions Risk of ASD, gender characteristics and associations with psychiatric and substance use disorders are similar in this Kenyan sample to those found in Western settings in non-clinical populations. © The Author(s), 2023. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists.

Author Keywords
ASD;  Kenyan students;  patterns;  psychiatric and substance use disorders;  risk

Document Type: Article
Publication Stage: Final
Source: Scopus

Comprehensive Social Trait Judgments From Faces in Autism Spectrum Disorder
(2023) Psychological Science, . 

Cao, R.^a b , Zhang, N.^b , Yu, H.^c , Webster, P.J.^d , Paul, L.K.^e , Li, X.^b , Lin, C.^f , Wang, S.^a b

^a Department of Radiology, Washington University in St. Louis, United States
^b Lane Department of Computer Science and Electrical Engineering, West Virginia University, United States
^c Department of Psychological & Brain Sciences, University of California, Santa Barbara, United States
^d Department of Chemical and Biomedical Engineering, West Virginia University, United States
^e Division of the Humanities and Social Sciences, California Institute of Technology, United States
^f Department of Psychology, University of California, San Diego, United States

Abstract
Processing social information from faces is difficult for individuals with autism spectrum disorder (ASD). However, it remains unclear whether individuals with ASD make high-level social trait judgments from faces in the same way as neurotypical individuals. Here, we comprehensively addressed this question using naturalistic face images and representatively sampled traits. Despite similar underlying dimensional structures across traits, online adult participants with self-reported ASD showed different judgments and reduced specificity within each trait compared with neurotypical individuals. Deep neural networks revealed that these group differences were driven by specific types of faces and differential utilization of features within a face. Our results were replicated in well-characterized in-lab participants and partially generalized to more controlled face images (a preregistered study). By investigating social trait judgments in a broader population, including individuals with neurodevelopmental variations, we found important theoretical implications for the fundamental dimensions, variations, and potential behavioral consequences of social cognition. © The Author(s) 2023.

Author Keywords
autism spectrum disorder;  face perception;  facial feature;  open data;  open materials;  preregistered;  social trait judgment

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

Cognitive deficits and altered functional brain network organization in pediatric brain tumor patients
(2023) Brain Imaging and Behavior, . 

Seitzman, B.A.^a , Anandarajah, H.^b , Dworetsky, A.^c , McMichael, A.^d , Coalson, R.S.^c d , Agamah, A.M.^a , Jiang, C.^e , Gu, H.^f , Barbour, D.L.^e g , Schlaggar, B.L.^d h i j , Limbrick, D.D.^k , Rubin, J.B.^b g , Shimony, J.S.^c , Perkins, S.M.^a

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, St. Louis Children’s Hospital, 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 Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^h Kennedy Krieger Institute, Baltimore, MD, United States
ⁱ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^k Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. The exact mechanisms of cognitive injury are poorly understood, and validated predictors of long-term cognitive outcome are lacking. Resting state functional magnetic resonance imaging allows for the study of the spontaneous fluctuations in bulk neural activity, providing insight into brain organization and function. Here, we evaluated cognitive performance and functional network architecture in pediatric brain tumor patients. Forty-nine patients (7–18 years old) with a primary brain tumor diagnosis underwent resting state imaging during regularly scheduled clinical visits. All patients were tested with a battery of cognitive assessments. Extant data from 139 typically developing children were used as controls. We found that obtaining high-quality imaging data during routine clinical scanning was feasible. Functional network organization was significantly altered in patients, with the largest disruptions observed in patients who received propofol sedation. Awake patients demonstrated significant decreases in association network segregation compared to controls. Interestingly, there was no difference in the segregation of sensorimotor networks. With a median follow-up of 3.1 years, patients demonstrated cognitive deficits in multiple domains of executive function. Finally, there was a weak correlation between decreased default mode network segregation and poor picture vocabulary score. Future work with longer follow-up, longitudinal analyses, and a larger cohort will provide further insight into this potential predictor. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Brain networks;  Cognition;  Pediatric brain tumor

Funding details
National Institutes of HealthNIHU54 HD087011
University of WashingtonUW
Children’s Discovery InstituteCDI
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

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

Toggling between food-seeking and self-preservation behaviors via hypothalamic response networks
(2023) Neuron, . 

de Araujo Salgado, I.^a , Li, C.^a , Burnett, C.J.^a , Rodriguez Gonzalez, S.^a , Becker, J.J.^a , Horvath, A.^a , Earnest, T.^b , Kravitz, A.V.^b , Krashes, M.J.^a c

^a Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
^b Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, United States
^c National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD 21224, United States

Abstract
Motivated behaviors are often studied in isolation to assess labeled lines of neural connections underlying innate actions. However, in nature, multiple systems compete for expression of goal-directed behaviors via complex neural networks. Here, we examined flexible survival decisions in animals tasked with food seeking under predation threat. We found that predator exposure rapidly induced physiological, neuronal, and behavioral adaptations in mice highlighted by reduced food seeking and consumption contingent on current threat level. Diminishing conflict via internal state or external environment perturbations shifted feeding strategies. Predator introduction and/or selective manipulation of danger-responsive cholecystokinin (Cck) cells of the dorsal premammilary nucleus (PMd) suppressed hunger-sensitive Agouti-related peptide (AgRP) neurons, providing a mechanism for threat-evoked hypophagia. Increased caloric need enhanced food seeking under duress through AgRP pathways to the bed nucleus of the stria terminalis (BNST) and/or lateral hypothalamus (LH). Our results suggest oscillating interactions between systems underlying self-preservation and food seeking to promote optimal behavior. © 2023

Author Keywords
calcium imaging;  cell-specific perturbation;  chemogenetics;  choice;  conflict behavior;  feeding;  foraging;  in vivo neural activity recordings;  optogenetics;  self-preservation

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBI
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK075087-06, DK075088
Diabetes Research Center, University of WashingtonDRC, UW
Nutrition Obesity Research Center, University of North CarolinaNORC
Noor Ophthalmology Research CenterNORC

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

Clinical utility of self- and informant-reported memory, attention, and spatial navigation in detecting biomarkers associated with Alzheimer disease in clinically normal adults
(2023) Journal of the International Neuropsychological Society, . 

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

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^b Neurosciences Institute at 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: Preclinical Alzheimer disease (AD) has been associated with subtle changes in memory, attention, and spatial navigation abilities. The current study examined whether self- and informant-reported domain-specific cognitive changes are sensitive to AD-associated biomarkers. Method: Clinically normal adults aged 56-93 and their informants completed the memory, divided attention, and visuospatial abilities (which assesses spatial navigation) subsections of the Everyday Cognition Scale (ECog). Reliability and validity of these subsections were examined using Cronbach’s alpha and confirmatory factor analysis. Logistic regression was used to examine the ability of ECog subsections to predict AD-related biomarkers (cerebrospinal fluid (CSF) ptau181/Aβ42 ratio (N = 371) or hippocampal volume (N = 313)). Hierarchical logistic regression was used to examine whether the self-reported subsections continued to predict biomarkers when controlling for depressive symptomatology if available (N = 197). Additionally, logistic regression was used to examine the ability of neuropsychological composites assessing the same or similar cognitive domains as the subsections (memory, executive function, and visuospatial abilities) to predict biomarkers to allow for comparison of the predictive ability of subjective and objective measures. Results: All subsections demonstrated appropriate reliability and validity. Self-reported memory (with outliers removed) was the only significant predictor of AD biomarker positivity (i.e., CSF ptau181/Aβ42 ratio; p =.018) but was not significant when examined in the subsample with depressive symptomatology available (p =.517). Self-reported memory (with outliers removed) was a significant predictor of CSF ptau181/Aβ42 ratio biomarker positivity when the objective memory composite was included in the model. Conclusions: ECog subsections were not robust predictors of AD biomarker positivity. Copyright © INS. Published by Cambridge University Press, 2023.

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

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy
(2023) Annals of Neurology, . 

Kao, H.-Y.^a , Yao, Y.^b , Yang, T.^a , Ziobro, J.^c , Zylinski, M.^b , Mir, M.Y.^b , Hu, S.^a , Cao, R.^d , Borna, N.N.^a , Banerjee, R.^a , Parent, J.M.^a e f , Wang, S.^d , Leventhal, D.K.^a e g h , Li, P.^b f i j , Wang, Y.^a e f

^a Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^b Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States
^c Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^e VA Ann Arbor Healthcare System, Ann Arbor, MI, United States
^f Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
^g Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
^h Parkinson Disease Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI, United States
ⁱ Department of Biologic and Material Sciences, University of Michigan, Ann Arbor, MI, United States
^j Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States

Abstract
Objectives: DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions. Methods: Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice. Results: Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. Interpretation: Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023. © 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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

Adult Age Differences in Event Memory Updating: The Roles of Prior-Event Retrieval and Prediction
(2023) Psychology and Aging, . 

Stawarczyk, D.^a b , Wahlheim, C.N.^c , Zacks, J.M.^a

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
^b Department of Psychology, Psychology and Neuroscience of Cognition Research Unit, University of Liège, Belgium
^c Department of Psychology, University of North Carolina at Greensboro, United States

Abstract
Remembering past events can lead to predictions of what is to come and to experiencing prediction errors when things change. Previous research has shown enhanced memory updating for ongoing events that are inconsistent with predictions based on past experiences. According to the Event Memory Retrieval and Comparison (EMRC) Theory, such memory updating depends on the encoding of configural representations that bind retrieved features of the previous event, changed features, and the relationship between the two. We investigated potential age-related differences in these mechanisms by showing older and younger adults two movies of everyday activities. Activities in the second movie either repeated from the first movie or included changed endings. During the second movie, before activities ended, participants were instructed to predict the upcoming action based on the first movie. One week later, participants were instructed to recall activity endings from the second movie. For younger adults, having predicted endings consistent with the first movie before seeing changed endings was subsequently associated with better recall of these changed endings and recollection that activities had changed. Conversely, for older adults, making such predictions prior to changes was associated with intruding details from the first movie endings and was less strongly associated with change recollection. Consistent with EMRC, these findings suggest that retrieval of relevant experiences when events change can trigger prediction errors that prompt associative encoding of existing memories and current perceptions. These mechanisms were less efficient in older adults, which may account for their poorer event memory updating than younger adults. © 2023 American Psychological Association

Author Keywords
action observation;  change detection;  event cognition;  integrative encoding;  memory updating

Funding details
National Institutes of HealthNIHR21AG05231401
Marie Curie
European CommissionEC798109

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

Identifying individuals with non-Alzheimer’s disease co-pathologies: A precision medicine approach to clinical trials in sporadic Alzheimer’s disease
(2023) Alzheimer’s and Dementia, . 

Tosun, D.^a , Yardibi, O.^b , Benzinger, T.L.S.^c , Kukull, W.A.^d , Masters, C.L.^e , Perrin, R.J.^f g , Weiner, M.W.^a , Simen, A.^b , Schwarz, A.J.^b

^a Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
^b Takeda Pharmaceutical Company Ltd, Cambridge, MA, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Epidemiology, National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, United States
^e The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
^f Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
INTRODUCTION: Biomarkers remain mostly unavailable for non-Alzheimer’s disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA). METHODS: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214). RESULTS: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aβ+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aβ and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%. DISCUSSION: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  CAA;  Lewy body;  TDP-43

Funding details
National Institutes of HealthNIHAG047366, P01 AG003991, P30 AG013854, P30 AG028383, P50 AG005133, P50 AG005681, R01AG058676, U01 AG016976, U01AG068057, U19AG024904, U24AG074855
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Biogen
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
Takeda Pharmaceuticals U.S.A.TPUSA
BioClinica

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

Personality traits moderate associations between word recall and subjective memory
(2023) Aging, Neuropsychology, and Cognition, . 

Hill, P.L.^a , Pfund, G.N.^a b , Cruitt, P.J.^c , Spears, I.^a , Norton, S.A.^a , Bogdan, R.^a , Oltmanns, T.F.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Medical Social Sciences, Northwestern University, Evanston, IL, United States
^c Minneapolis VA Health Care System, Minneapolis, MN, United States

Abstract
Cognitive gerontology research requires consideration of performance as well as perceptions of performance. While subjective memory is positively associated with memory performance, these correlations typically are modest in magnitude, leading to the need to consider whether certain people may show weaker or stronger linkages between performance and perceptions. The current study leveraged personality (NEO Big Five), memory performance (i.e., word recall), and perceptions of memory ability (i.e., metamemory in adulthood and memory decline) data from the St. Louis Personality and Aging Network (SPAN) study (n = 774, mean age: 71.52 years). Extraversion and conscientiousness held the most consistent associations with the cognitive variables of interest, as both traits were positively associated with metamemory and word recall, but negatively associated with subjective decline. Moreover, extraversion moderated associations between word recall and both memory capacity and complaints, insofar that objective-subjective associations were weaker for those adults higher in extraversion. These findings highlight the need to understand how personality influences the sources of information employed for subjective cognitive beliefs. © 2023 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
memory decline;  moderation;  Personality;  subjective memory;  word recall

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

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning
(2023) Journal of Neuro-Oncology, . 

Luckett, P.H.^a , Olufawo, M.^a , Lamichhane, B.^a b , Park, K.Y.^a c , Dierker, D.^d , Verastegui, G.T.^a , Yang, P.^a , Kim, A.H.^a e , Chheda, M.G.^e f , Snyder, A.Z.^d g , Shimony, J.S.^d e , Leuthardt, E.C.^{a e h i j k l}

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center for Health Sciences, Oklahoma State University, Tulsa, OK 74136, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^e Brain Tumor Center at Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO 63130, United States
ⁱ Department of Mechanical Engineering and Materials Science, Washington University in Saint Louis, St. Louis, MO 63130, United States
^j Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO 63110, United States
^k Brain Laser Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^l National Center for Adaptive Neurotechnologies, Albany, United States

Abstract
Purpose: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care. Methods: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models. Results: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks. Conclusion: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain’s structural and functional organization, which is predictive of survival. © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Author Keywords
Cortical thickness;  Deep learning;  Functional MRI;  Glioblastoma;  Survival

Funding details
National Cancer InstituteNCIR01CA203861
National Institute of Neurological Disorders and StrokeNINDSU24NS109103
National Institute of Biomedical Imaging and BioengineeringNIBIBP41EB018783, R01EB026439
University of WashingtonUW

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