WashU weekly Neuroscience publications: August 11, 2024

Benefits and challenges of geographic information systems (GIS) for data-driven outreach in black communities experiencing overdose disparities: results of a stakeholder focus group
(2024) BMC Public Health, 24 (1), art. no. 2103, . 

Banks, D.E.^a b , Paschke, M.^c , Ghonasgi, R.^b , Thompson, V.L.S.^d

^a Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b Department of Psychological Sciences, University of Missouri, St. Louis, MO, United States
^c Missouri Institute of Mental Health, University of Missouri, St. Louis, MO, United States
^d Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Black individuals in the U.S. face increasing racial disparities in drug overdose related to social determinants of health, including place-based features. Mobile outreach efforts work to mitigate social determinants by servicing geographic areas with low drug treatment and overdose prevention access but are often limited by convenience-based targets. Geographic information systems (GIS) are often used to characterize and visualize the overdose crisis and could be translated to community to guide mobile outreach services. The current study examines the initial acceptability and appropriateness of GIS to facilitate data-driven outreach for reducing overdose inequities facing Black individuals. Methods: We convened a focus group of stakeholders (N = 8) in leadership roles at organizations conducting mobile outreach in predominantly Black neighborhoods of St. Louis, MO. Organizations represented provided adult mental health and substance use treatment or harm reduction services. Participants were prompted to discuss current outreach strategies and provided feedback on preliminary GIS-derived maps displaying regional overdose epidemiology. A reflexive approach to thematic analysis was used to extract themes. Results: Four themes were identified that contextualize the acceptability and utility of an overdose visualization tool to mobile service providers in Black communities. They were: 1) importance of considering broader community context; 2) potential for awareness, engagement, and community collaboration; 3) ensuring data relevance to the affected community; and 4) data manipulation and validity concerns. Conclusions: There are several perceived benefits of using GIS to map overdose among mobile providers serving Black communities that are overburdened by the overdose crisis but under resourced. Perceived potential benefits included informing location-based targets for services as well as improving awareness of the overdose crisis and facilitating collaboration, advocacy, and resource allocation. However, as GIS-enabled visualization of drug overdose grows in science, public health, and community settings, stakeholders must consider concerns undermining community trust and benefits, particularly for Black communities facing historical inequities and ongoing disparities. © The Author(s) 2024.

Author Keywords
Data visualization;  Drug overdose;  Geographic information systems;  Mobile outreach;  Racial disparities

Funding details
National Center for Advancing Translational SciencesNCATSKL2TR002346
National Center for Advancing Translational SciencesNCATS
National Institute on Drug AbuseNIDAK08 DA058080
National Institute on Drug AbuseNIDA

Document Type: Article
Publication Stage: Final
Source: Scopus

The Human Connectome Project of adolescent anxiety and depression dataset
(2024) Scientific Data, 11 (1), art. no. 837, . 

Hubbard, N.A.^a b , Bauer, C.C.C.^c d , Siless, V.^e f , Auerbach, R.P.^g , Elam, J.S.^h , Frosch, I.R.^d , Henin, A.^e i , Hofmann, S.G.^j , Hodge, M.R.^k , Jones, R.^f , Lenzini, P.^k , Lo, N.^d , Park, A.T.^d , Pizzagalli, D.A.^e l , Vaz-DeSouza, F.ⁱ , Gabrieli, J.D.E.^d , Whitfield-Gabrieli, S.^c d , Yendiki, A.^e f , Ghosh, S.S.^d e

^a Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, United States
^b Center for Brain, Biology, and Behavior, University of Nebraska-Lincoln, Lincoln, NE, United States
^c Department of Psychology, Northeastern University, Boston, MA, United States
^d Department of Brain and Cognitive Sciences and McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, United States
^e Harvard Medical School, Boston, MA, United States
^f Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
^g Department of Psychiatry, Columbia University, New York, NY, United States
^h Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
ⁱ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^j Department of Psychology, Philipps University of Marburg, Germany
^k Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^l Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, United States

Abstract
This article describes primary data and resources available from the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, a novel arm of the Human Connectome Project (HCP). Data were collected from 215 adolescents (14–17 years old), 152 of whom had current diagnoses of anxiety and/or depressive disorders at study intake. Data include cross-sectional structural (T1- and T2-weighted), functional (resting state and three tasks), and diffusion-weighted magnetic resonance images. Both unprocessed and HCP minimally-preprocessed imaging data are available within the data release packages. Adolescent and parent clinical interview data, as well as cognitive and neuropsychological data are also included within these packages. Release packages additionally provide data collected from self-report measures assessing key features of adolescent psychopathology, including: anxious and depressive symptom dimensions, behavioral inhibition/activation, exposure to stressful life events, and risk behaviors. Finally, the release packages include 6- and 12-month longitudinal data acquired from clinical measures. Data are publicly accessible through the National Institute of Mental Health Data Archive (ID: #2505). © The Author(s) 2024.

Funding details
Hessisches Ministerium für Wissenschaft und Kunst
James S. McDonnell FoundationJSMF
Alexander von Humboldt-StiftungAvH
P41EB019936, R01MH135488, R01EB021265, R01AT007257, P20GM130461-6206, R01EB020740, U01EB026996, R01MH099021, R01MH101521, R01MH119771, R37MH068376
National Institute of Mental HealthNIMHU01MH108168, F32MH114525
National Institute of Mental HealthNIMH
1S10RR023043, 1S10RR023401, 1S10RR019307
Brain and Behavior Research FoundationBBRF27970
Brain and Behavior Research FoundationBBRF

Document Type: Data Paper
Publication Stage: Final
Source: Scopus

Impact of social vulnerability index on severity of obstructive sleep apnea: Insights from drug-induced sleep endoscopy
(2024) American Journal of Otolaryngology – Head and Neck Medicine and Surgery, 45 (6), art. no. 104450, . 

Franklin, A.^a , Gallo, N.^a , Gillespie, M.B.^a , Nieri, C.^b

^a Department of Otolaryngology – Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, TN, United States
^b Department of Otolaryngology – Head and Neck Surgery, Washington University, St. Louis, MO, United States

Abstract
Objectives: To examine the association between neighborhood-level social vulnerability on the severity of obstructive sleep apnea (OSA) in patients undergoing drug-induced sleep endoscopy (DISE). Study design: Single center retrospective cohort study. Methods: We conducted a retrospective chart review of patients >18 years of age that underwent DISE from July 2016 to July 2022. Patient addresses were geocoded with geographic information systems, and spatial overlays were used to assign census-tract level social vulnerability index (SVI) scores in the four sub-themes: Socioeconomic (theme 1), Household Composition/Disability (theme 2), Minority Status/Language (theme 3), and Housing/Transportation (theme 4). Results: The study included 165 patients (61.2 years ± 11.6; 31.0 BMI ± 6.1, 102 male, 63 female). Mild OSA was present in13 patients; 55 patients had moderate OSA; and 97 patients had severe OSA. A higher SVI value in minority status and language, and a higher BMI both predicted an increased Apnea Hypopnea Index (AHI) (p = 0.042, and <0.001, respectively) in the multivariate model; whereas, race, age, gender, or the other three SVI sub-theme values were not predictive. Conclusion: Adults residing in areas of greater social vulnerability – specifically a larger minority presence or English as a second language – and patients who are obese are more likely to have more severe OSA. There was no correlation, however, between obesity and residence in an area of high SVI. These results suggest that both neighborhood conditions and obesity are associated with OSA severity. This elevated risk has potential implications for diagnostic testing, clinic follow-ups, screening, and treatment plans for adults residing in disenfranchised neighborhoods. Level of evidence: IV. © 2024 Elsevier Inc.

Author Keywords
Drug-induced sleep endoscopy;  Health disparities;  Obstructive sleep apnea;  Social vulnerability index

Document Type: Article
Publication Stage: Final
Source: Scopus

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior
(2024) Human Genetics and Genomics Advances, 5 (4), art. no. 100333, . 

Liu, A.C.^a k , Shen, Y.^a , Serbinski, C.R.^b c , He, H.^a , Roman, D.^a , Endale, M.^a , Aschbacher-Smith, L.^b , King, K.A.^d , Granadillo, J.L.^d , López, I.^e , Krueger, D.A.^b , Dye, T.J.^b , Smith, D.F.^f g h i , Hogenesch, J.B.^b , Prada, C.E.^b c j

^a Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, United States
^b Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
^c Division of Genetics, Genomics & Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, United States
^d Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^e Pediatric Neurology Unit, Department of Neurology, Clínica Las Condes, Santiago, Chile
^f Divisions of Pediatric Otolaryngology and Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
^g The Sleep Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
^h The Center for Circadian Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
ⁱ Department of Otolaryngology Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States
^j Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, United States
^k Lead contact

Abstract
Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health. © 2024 The Author(s)

Funding details
National Institutes of HealthNIHR01 NS117457
National Institutes of HealthNIH
R01 NS054794
National Science FoundationNSFIOS 1656647
National Science FoundationNSF
2UL1TR001425-05A1

Document Type: Article
Publication Stage: Final
Source: Scopus

Rev-erbα regulate neurogenesis through suppression of Sox2 in neuronal cells to regenerate dopaminergic neurons and abates MPP+ induced neuroinflammation
(2024) Free Radical Biology and Medicine, 223, pp. 144-159. 

Gupta, S.^a c , Ahuja, N.^a d , Kumar, S.^a e , Arora, R.^a b , Kumawat, S.^a b , Kaushal, V.^a b , Gupta, P.^a b

^a Department of Molecular Biology, Council of Scientific and Industrial Research, Institute of Microbial Technology, Sector 39A, Chandigarh, 160036, India
^b Academy of Scientific & Innovative Research (AcSIR), Uttar Pradesh, Ghaziabad, 201002, India
^c Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
^d Laboratory of Molecular Neurodegeneration and Gene Therapy, University of Oxford, United Kingdom
^e Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Medical Center, Cincinnati, OH, United States

Abstract
Parkinson’s disease is a progressive neurodegenerative disease that affects the motor and non-motor circuits of the brain. Currently, there are no promising therapeutic measures for Parkinson’s disease, and most strategies designed to alleviate the Parkinson’s disease are palliative. The dearth of therapeutic interventions in Parkinson’s disease has driven attention in the search for targets that may augment dopamine secretion, promote differentiation towards dopaminergic neuronal lineage, or aid in neuroprotection from neuronal stress and inflammation, and prevent Parkinson’s disease associated motor impairment and behavioural chaos. The study first reports that Rev-erbα plays an important role in regulating the differentiation of undifferentiated neuronal cells towards dopaminergic neurons through abating Sox2 expression in human SH-SY5Y cells. Rev-erbα directly binds to the human Sox2 promoter region and represses their expression to promote differentiation towards dopaminergic neurons. We have reported a novel mechanism of Rev-erbα which effectively abrogates 1-methyl-4-phenylpyridinium induced cytotoxicity, inflammation, and oxidative stress, exerted a beneficial effect on transmembrane potential, and suppressed apoptosis in the neuronal in vitro model of Parkinson’s disease. Rev-erbα ligand SR9011 was observed to ease the disease severity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced mouse model of Parkinson’s disease. Rev-erbα alleviates the locomotor behavioural impairment, prevents cognitive decline and promotes motor coordination in mice. Administration of Rev-erbα ligand also helps in replenishing the dopaminergic neurons and abrogating the neurotoxin mediated toxicity in an in vitro and in vivo Parkinson’s disease model. We conclude that Rev-erbα emerges as a moonlighting nuclear receptor that could be targeted in the treatment and alleviation of Parkinson disease. © 2024 Elsevier Inc.

Author Keywords
Behaviour deficits;  Differentiation;  Gene regulation;  Neuroprotection

Funding details
CSIR – Institute of Microbial TechnologyIMTECH
Council of Scientific and Industrial Research, IndiaCSIROLP0704
Council of Scientific and Industrial Research, IndiaCSIR
Department of Biotechnology, Ministry of Science and Technology, IndiaDBTGAP0223, GAP0229
Department of Biotechnology, Ministry of Science and Technology, IndiaDBT

Document Type: Article
Publication Stage: Final
Source: Scopus

Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease
(2024) The American Journal of Occupational Therapy: Official publication of the American Occupational Therapy Association, 78 (5), . 

Kearson, L.^a , Dandar, C.^b , Hoyt, C.^c , Longoria, J.^d , Okhomina, V.^e , Raches, D.^f , Potter, B.^g , Kang, G.^h , Hankins, J.ⁱ , Takemoto, C.^j , Heitzer, A.^k

^a Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, is Neuropsychology Fellow, Memphis, TN, United States
^b Christina Dandar, MA, is Neuropsychology Intern, Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN
^c Catherine Hoyt, OTR/L, Neurology, Pediatrics, Department of Pediatrics and Medicine, School of Medicine, Washington University in St. Louis, is Assistant Professor of Occupational Therapy, St. Louis, MO, United States
^d Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, is Neuropsychologist, Memphis, TN, United States
^e Victoria Okhomina, MPH, MS, is Biostatistician, Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
^f Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, is Neuropsychologist, Memphis, TN, United States
^g Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, is Neuropsychologist, Memphis, TN, United States
^h Department of Biostatistics, St. Jude Children’s Research Hospital, is Biostatistician, Memphis, TN, United States
ⁱ Jane Hankins, MD, is Director of Global Hematology Program, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
^j Clifford Takemoto, MD, is Director of Clinical Hematology, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
^k Andrew Heitzer, PhD, is Neuropsychologist, Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN;

Abstract
IMPORTANCE: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN: Cross-sectional. SETTING: St. Jude Children’s Research Hospital. PARTICIPANTS: Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES: Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills. Copyright © 2024 by the American Occupational Therapy Association, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming
(2024) Science (New York, N.Y.), 385 (6708), p. adl2992. 

Sun, Z.^a b c , Kwon, J.-S.^a d , Ren, Y.^a e , Chen, S.^a b c , Walker, C.K.^a b c , Lu, X.^f , Cates, K.^a g , Karahan, H.^h i , Sviben, S.^j , Fitzpatrick, J.A.J.^j , Valdez, C.^k , Houlden, H.^l , Karch, C.M.^c f m , Bateman, R.J.^n o , Sato, C.^n o , Mennerick, S.J.^f , Diamond, M.I.^k , Kim, J.^h i , Tanzi, R.E.^p , Holtzman, D.M.^c m o , Yoo, A.S.^a b c

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Program in Developmental, Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, United States
^h Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States
ⁱ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
^j Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, United States
^k Center for Alzheimer’s and Neurodegenerative Diseases, Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390, United States
^l UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^m Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁿ Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO 63110, United States
^o Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^p Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States

Abstract
Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Aβ deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.

Document Type: Article
Publication Stage: Final
Source: Scopus

Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females
(2024) Pharmacogenomics Journal, 24 (4), art. no. 23, . 

Sprague, J.E.^a , Freiermuth, C.E.^b c , Lambert, J.^d , Braun, R.^b , Frey, J.A.^e , Bachmann, D.J.^e , Bischof, J.J.^e , Beaumont, L.^f , Lyons, M.S.^e , Pantalon, M.V.^g , Punches, B.E.^e h , Ancona, R.ⁱ , Kisor, D.F.^f

^a Bowling Green State University, The Ohio Attorney General’s Center for the Future of Forensic Science, Bowling Green, OH, United States
^b Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, United States
^c Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^d College of Nursing, University of Cincinnati, Cincinnati, OH, United States
^e Department of Emergency Medicine, The Ohio State University, Columbus, OH, United States
^f Department of Pharmaceutical Sciences and Pharmacogenomics, College of Pharmacy, Natural and Health Sciences, Manchester University, Fort Wayne, IN, United States
^g Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT, United States
^h College of Nursing, The Ohio State University, Columbus, OH, United States
ⁱ Washington University School of Medicine, St. Louis, MO, United States

Abstract
The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed. © The Author(s) 2024.

Funding details
Ohio Attorney General’s Office

Document Type: Article
Publication Stage: Final
Source: Scopus

Alzheimer Disease Pathology and Neurodegeneration in Midlife Obesity: A Pilot Study
(2024) Aging and Disease, 15 (4), pp. 1843-1854. Cited 4 times.

Dolatshahi, M.^a , Commean, P.K.^a , Rahmani, F.^a , Liu, J.^b , Lloyd, L.^a , Nguyen, C.^a , Hantler, N.^a , Ly, M.^a , Yu, G.^a , Ippolito, J.E.^a c , Sirlin, C.^d , Morris, J.C.^e f , Benzinger, T.L.S.^a f g , Raji, C.A.^a e f

^a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^b Washington University School of Medicine, Division of Public Health Sciences, Department of Surgery, St. Louis, MO, United States
^c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
^d Liver Imaging Group, Department of Radiology, University of California, La Jolla, San Diego, CA, United States
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
^g Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman’s partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology. Copyright: © 2023 Dolatshahi M. et al.

Author Keywords
Alzheimer disease;  beta-amyloid;  MRI;  obesity;  PET;  visceral adipose tissue

Funding details
Washington University in St. LouisWUSTL
National Institutes of HealthNIH1RF1AG072637-01
National Institutes of HealthNIH
P30AG066444
P01AG026276
P01AG003991

Document Type: Article
Publication Stage: Final
Source: Scopus

Meta-analysis identifies common gut microbiota associated with multiple sclerosis
(2024) Genome Medicine, 16 (1), p. 94. 

Lin, Q.^a b , Dorsett, Y.^b , Mirza, A.^c , Tremlett, H.^c , Piccio, L.^d e , Longbrake, E.E.^f , Choileain, S.N.^f , Hafler, D.A.^f , Cox, L.M.^g , Weiner, H.L.^g , Yamamura, T.^h , Chen, K.ⁱ , Wu, Y.^a , Zhou, Y.^b

^a Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, United States
^b Department of Medicine, University of Connecticut Health Center, Farmington, CT, United States
^c Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
^f Departments of Neurology and Immunobiology, Yale University School of Medicine, New Haven, CT 06511, United States
^g Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham & Women’s Hospital, Boston, MA 02115, United States
^h Department of Immunology, National Institute of NeuroscienceTokyo, Japan
ⁱ Department of Statistics, University of Connecticut, Storrs, CT, United States

Abstract
BACKGROUND: Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies. METHODS: To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings. RESULTS: The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS. CONCLUSIONS: Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies. © 2024. The Author(s).

Author Keywords
Faecalibacterium;  Prevotella;  Meta-analysis;  Microbiota;  Multiple sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognition Mediates the Association between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms
(2024) Journal of Alzheimer’s Disease, 100 (3), pp. 1055-1073. 

Frank, B.^a b c , Walsh, M.^b , Hurley, L.^a , Groh, J.^b , Blennow, K.^d e , Zetterberg, H.^{d e f g h i} , Tripodis, Y.^b j , Budson, A.E.^a b c , O’Connor, M.K.^b c k , Martin, B.^b l , Weller, J.^b c , McKee, A.^b c l m , Qiu, W.^b n o , Stein, T.D.^b c l m , Stern, R.A.^b c p q , Mez, J.^b c r , Henson, R.^s , Long, J.^s , Aschenbrenner, A.J.^s , Babulal, G.M.^s , Morris, J.C.^s , Schindler, S.^s , Alosco, M.L.^b c

^a U.S. Department of Veteran Affairs, VA Boston Healthcare System, Boston, MA, United States
^b Boston University Alzheimer’s Disease Research Center, CTE Center, Boston University Chobanian and Avedisian, School of Medicine, Boston, MA, United States
^c Department of Neurology, Boston University Chobanian, Avedisian School of Medicine, Boston, MA, United States
^d Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^e Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, The University of Gothenburg, Gothenburg, Sweden
^f Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^g UK Dementia Research Institute at UCL, London, United Kingdom
^h Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong
ⁱ Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^j Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^k VA Bedford Healthcare System, U.S. Department of Veteran Affairs, Bedford, MA, United States
^l Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA, United States
^m Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, United States
ⁿ Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
^o Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States
^p Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States
^q Department of Neurosurgery, Boston University School of Medicine, Boston, MA, United States
^r Framingham Heart Study, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, United States
^s Knight Alzheimer Disease Research Center (ADRC), Washington University, St. Louis, MO, United States

Abstract
Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer’s disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-Tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer’s Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOE ϵ4. Results: The sample was older adults (M=73.85, SD=6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n=688, 88.1%). Higher p-Tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-Tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-Tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia. © 2024-IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  amyloid;  biomarkers;  cerebrospinal fluid;  cognition;  neuropsychiatric symptoms;  p-Tau

Funding details
Alzheimer’s AssociationAA
Horizon 2020 Framework ProgrammeH2020
Cure Alzheimer’s FundCAF
U.S. Department of Veterans AffairsVAIK2 CX002065, P30 AG066444, P01AG003991, P01AG026276, I01BX005933
U.S. Department of Veterans AffairsVA
H2020 Marie Skłodowska-Curie ActionsMSCA860197
H2020 Marie Skłodowska-Curie ActionsMSCA
P30 AG066507, P30 AG062421, P20 AG068077, P20 AG068053, P20 AG068024, P30 AG072973, P30 AG072931, P30 AG072979, P30 AG066509, P30 AG066519, P30 AG062422, P30 AG062715, P30 AG066462, P30 AG062677, P30 AG066518, P30 AG066511, P30 AG072947, P30 AG072975, P30 AG072958, P30 AG066468, P30 AG072978, P30 AG079280, P30 AG066514, P30 AG072972, P30 AG066512, P30 AG072959, P30 AG062429, P30 AG066530, P30 AG072976, P30 AG066515, P30 AG066508, P30 AG072977, P30 AG066506, P20 AG068082, P30 AG066546, P30 AG072946
-715986
EU Joint Programme – Neurodegenerative Disease ResearchJPNDJPND2021-00694
EU Joint Programme – Neurodegenerative Disease ResearchJPND
Hjärnfonden#FO2020-0240
Hjärnfonden
1UL1TR001430
National Institutes of HealthNIHP30AG072978, 1R01AG068398-01
National Institutes of HealthNIH
JPND2019-466-236
-71320, 101053962
UK Dementia Research InstituteUK DRI2017-00915, UKDRI-1003, -201809-2016615
UK Dementia Research InstituteUK DRI
2020-00124
#FO2022-0270
Alzheimer’s Drug Discovery FoundationADDF201809-2016862
Alzheimer’s Drug Discovery FoundationADDF
BrightFocus FoundationBFFA2021142 S, -930627
BrightFocus FoundationBFF
U24 AG072122
Alzheimerfonden-0243, -742881
Alzheimerfonden
2022-01018, 2019-02397, 2023-00356
National Institute on AgingNIAR01AG068183, R01AG080469, R01AG067428, R01AG074302
National Institute on AgingNIA

Document Type: Article
Publication Stage: Final
Source: Scopus

Serotonergic amplification of odor-evoked neural responses maps onto flexible behavioral outcomes
(2024) eLife, 12, . 

Bessonova, Y., Raman, B.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States

Abstract
Behavioral responses to many odorants are not fixed but are flexible, varying based on organismal needs. How such variations arise and the role of various neuromodulators in achieving flexible neural-to-behavioral mapping is not fully understood. In this study, we examined how serotonin modulates the neural and behavioral responses to odorants in locusts (Schistocerca americana). Our results indicated that serotonin can increase or decrease appetitive behavior in an odor-specific manner. On the other hand, in the antennal lobe, serotonergic modulation enhanced odor-evoked response strength but left the temporal features or the combinatorial response profiles unperturbed. This result suggests that serotonin allows for sensitive and robust recognition of odorants. Nevertheless, the uniform neural response amplification appeared to be at odds with the observed stimulus-specific behavioral modulation. We show that a simple linear model with neural ensembles segregated based on behavioral relevance is sufficient to explain the serotonin-mediated flexible mapping between neural and behavioral responses. © 2023, Bessonova and Raman.

Author Keywords
appetitive behavior;  behavioral flexibility;  computational model;  neural robustness;  neuroscience;  olfaction;  serotonergic modulation

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic Associations With an Amyotrophic Lateral Sclerosis Reversal Phenotype
(2024) Neurology, 103 (4), art. no. e209696, . 

Crayle, J.I.^a b , Rampersaud, E.^c , Myers, J.R.^c , Wuu, J.^d , Taylor, J.P.^e , Wu, G.^c , Benatar, M.^d , Bedlack, R.S.^a

^a The Department of Neurology, Duke University School of Medicine, Durham, NC, United States
^b Department of Neurology, Washington University, Saint Louis, MO, United States
^c Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Department of Neurology, University of Miami Miller School of MedicineFL, United States
^e Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
Background and Objectives The term “ALS Reversal”describes patients who initially meet diagnostic criteria for amyotrophic lateral sclerosis (ALS) or had clinical features most consistent with progressive muscular atrophy (PMA) but subsequently demonstrated substantial and sustained clinical improvement. The objective of this genome-wide association study (GWAS) was to identify correlates of this unusual clinical phenotype. Methods Participants were recruited from a previously created database of individuals with the ALS Reversal phenotype. Whole-genome sequencing (WGS) data were compared with ethnicity-matched patients with typically progressive ALS enrolled through the CReATe Consortium’s Phenotype-Genotype-Biomarker (PGB) study. These results were replicated using an independent ethnically matched WGS data set from Target ALS. Significant results were further explored with available databases of genetic regulatory markers and expression quantitative trait loci (eQTL) analysis. Results WGS from 22 participants with documented ALS Reversals was compared with the PGB primary cohort (n = 103) and the Target ALS validation cohort (n = 140). Two genetic loci met predefined criteria for statistical significance (two-sided permutation p ≤ 0.01) and remained plausible after fine-mapping. The lead single nucleotide variant (SNV) from the first locus was rs4242007 (primary cohort GWAS OR = 12.0, 95% CI 4.1 to 34.6), which is in an IGFBP7 intron and is in near-perfect linkage disequilibrium with a SNV in the IGFBP7 promoter region. Both SNVs are associated with decreased frontal cortex IGFBP7 expression in eQTL data sets. Notably, 3 Reversals, but none of the typically progressive individuals (n = 243), were homozygous for rs4242007. The importance of the second locus, located near GRIP1, is uncertain given the absence of an associated effect on nearby gene transcription. Discussion We found a significant association between the Reversal phenotype and an IGFBP7 noncoding SNV that is associated with IGFBP7 expression. This is biologically relevant as IGFBP7 is a reported inhibitor of the insulin growth factor-1 (IGF-1) receptor that activates the possibly neuroprotective IGF-1 signaling pathway. This finding is limited by small sample size but suggests that there may be merit in further exploration of IGF-1 pathway signaling as a therapeutic mechanism for ALS. © 2024 American Academy of Neurology.

Funding details
Rare Diseases Clinical Research NetworkRDCRN
Duke UniversityDU
Tow Foundation
17-LGCA-331, 16-TACL-242
U54NS092091
National Cancer InstituteNCIP30 CA021765
National Cancer InstituteNCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Gemykibivirus detection in acute encephalitis patients from Nepal
(2024) mSphere, 9 (7), p. e0021924. 

Tuladhar, E.T.^a , Shrestha, S.^a , Vernon, S.^b , Droit, L.^b , Mihindukulasuriya, K.A.^b , Tamang, M.^a , Karki, L.^a , Elong Ngono, A.^c , Jha, B.^d , Awal, B.K.^d , Chalise, B.S.^e , Jha, R.^d , Shresta, S.^c , Wang, D.^b , Manandhar, K.D.^a

^a Tribhuvan University Central Department of Biotechnology, Kathmandu, Nepal
^b Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c La Jolla Institute for Immunology, San Diego, CA, United States
^d National Public Health Laboratory, Kathmandu, Nepal
^e Sukraraj Tropical and Infectious Disease Hospital, Kathmandu, Nepal

Abstract
Acute encephalitis syndrome (AES) causes significant morbidity and mortality worldwide. In Nepal, Japanese encephalitis virus (JEV) accounts for ~5-20% of AES cases, but ~75% of AES cases are of unknown etiology. We identified a gemykibivirus in CSF collected in 2020 from an 8-year-old male patient with AES using metagenomic next-generation sequencing. Gemykibiviruses are single stranded, circular DNA viruses in the family Genomoviridae. The complete genome of 2,211 nucleotides was sequenced, which shared 98.69% nucleotide identity to its closest relative, Human associated gemykibivirus 2 isolate SAfia-449D. Two real-time PCR assays were designed, and screening of 337 cerebrospinal fluid (CSF) and 164 serum samples from AES patients in Nepal collected in 2020 and 2022 yielded 11 CSF and 1 serum sample that were positive in both PCR assays. Complete genomes of seven of the positives were sequenced. These results identify a potential candidate etiologic agent of encephalitis in Nepal. IMPORTANCE: Viral encephalitis is a devastating disease, but unfortunately, worldwide, the causative virus in many cases is unknown. Therefore, it is important to identify viruses that could be responsible for cases of human encephalitis. Here, using metagenomic sequencing of CSF, we identified a gemykibivirus in a male child from Nepal with acute encephalitis syndrome (AES). We subsequently detected gemykibivirus DNA in CSF or serum of 12 more encephalitis patients by real-time PCR. The virus genomes we identified are highly similar to gemykibiviruses previously detected in CSF of three encephalitis patients from Sri Lanka. These results raise the possibility that gemykibivirus could be an underrecognized human pathogen.

Author Keywords
acute encephalitis syndrome;  emerging infection;  gemykibivirus;  metagenomic analysis

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluation of the Use of Ketamine in Prehospital Seizure Management: A Retrospective Review of the ESO Database
(2024) Prehospital Emergency Care, . 

Finney, J.D.^a , Schuler, P.D.^b , Rudloff, J.R.^c , Agostin, N.^a , Lobanov, O.V.^d , Siegler, J.^e , Shah, M.I.^f , Guterman, E.L.^g , Chamberlain, J.M.^h , Ahmad, F.A.^a

^a Department of Pediatrics, Washington University in Saint Louis, Saint Louis, MO, United States
^b Department of Emergency Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
^c Department of Pediatrics, Institute for Informatics Data Science and Biostatistics, Washington University in Saint Louis, St. Louis, MO, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Emergency Medicine, Stanford University School of Medicine, Palo Alto, CA, United States
^g Philip R. Lee Institute for Health Policy Studies and Department of Neurology, University of California, San Francisco, CA, United States
^h Pediatrics and Emergency Medicine, George Washington University, Washington, DC, United States

Abstract
Objectives: Benzodiazepines are the primary antiseizure medication used by Emergency Medical Services (EMS) for seizures. Available literature in the United States and internationally shows 30% to 40% of seizures do not terminate with benzodiazepines called benzodiazepine refractory status epilepticus (BRSE). Ketamine is a potential treatment for BRSE due to its unique pharmacology. However, its application in the prehospital setting is mostly documented in case reports. Little is known about its use by EMS professionals for seizure management, whether as initial treatment or for BRSE, creating an opportunity to describe its current use and inform future research. Methods: We performed a retrospective review of 9-1-1 EMS encounters with a primary or secondary impression of seizure using the ESO Data Collaborative from 2018 to 2021. We isolated encounters during which ketamine was administered. We excluded medication administrations prior to EMS arrival and encounters without medication administration. Subgroup analysis was performed to control for airway procedure as an indication for ketamine administration. We also evaluated for co-administration with other antiseizure medications, dose and route of administration, and response to treatment. Results: We identified 99,576 encounters that met inclusion. There were 2,531/99,576 (2.54%) encounters with ketamine administration and 50.7% (1,283/2,531) received ketamine without an airway procedure. There were 616 cases (48%, 616/1,283) where ketamine was given without another antiseizure medication (ASM) and without any airway procedure. The remaining 667 (52%) cases received ketamine with at least one other ASM, most commonly midazolam (89%, 593/667). Adjusted for the growth in the ESO dataset, ketamine use by EMS professionals during encounters for seizures without an airway procedure increased from 0.90% (139/15,375) to 1.45% (416/28,651) an increase of 62% over the study period. Conclusions: In this retrospective review of the ESO Data Collaborative, ketamine administration for seizure encounters without an airway procedure increased over the study period, both as a single agent and with another ASM. Most ketamine administrations were for adult patients in the south and in urban areas. The frequency of BRSE, the need for effective treatment, and the growth in ketamine use warrant prospective prehospital research to evaluate the value of ketamine in prehospital seizure management. © 2024 National Association of EMS Physicians.

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

Generative whole-brain dynamics models from healthy subjects predict functional alterations in stroke at the level of individual patients
(2024) Brain Communications, 6 (4), art. no. fcae237, . 

Idesis, S.^a , Allegra, M.^b c , Vohryzek, J.^a d , Perl, Y.S.^a e f g , Metcalf, N.V.^h , Griffis, J.C.^h , Corbetta, M.^{b h i j k} , Shulman, G.L.^h j , Deco, G.^a l

^a Center for Brain and Cognition (CBC), Department of Information Technologies and Communications (DTIC), Pompeu Fabra University, Edifici Mercè Rodoreda, Catalonia, Barcelona, 08005, Spain
^b Padova Neuroscience Center (PNC), University of Padova, Padova, 35129, Italy
^c Department of Physics and Astronomy ‘G. Galilei’, University of Padova, Padova, 35131, Italy
^d Centre for Eudaimonia and Human Flourishing, Linacre College, University of Oxford, Oxford, OX3 9BX, United Kingdom
^e Universidad de San Andrés, Centro de Neurociencias Cognitivias, Buenos Aires, NC1006ACC, Argentina
^f National Scientific and Technical Research Council, C1425FQB, Buenos Aires, Argentina
^g Institut du Cerveau et de la Moelle épinière, ICM, Hôpital Pitié Salpêtrière, Paris, 75013, France
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Department of Neuroscience (DNS), University of Padova, Padova, 35128, Italy
^j Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^k VIMM, Venetian Institute of Molecular Medicine (VIMM), Biomedical Foundation, Padova, 35129, Italy
^l Institució Catalana de Recerca I Estudis Avançats (ICREA), Catalonia, Barcelona, 08010, Spain

Abstract
Computational whole-brain models describe the resting activity of each brain region based on a local model, inter-regional functional interactions, and a structural connectome that specifies the strength of inter-regional connections. Strokes damage the healthy structural connectome that forms the backbone of these models and produce large alterations in inter-regional functional interactions. These interactions are typically measured by correlating the time series of the activity between two brain regions in a process, called resting functional connectivity. We show that adding information about the structural disconnections produced by a patient’s lesion to a whole-brain model previously trained on structural and functional data from a large cohort of healthy subjects enables the prediction of the resting functional connectivity of the patient and fits the model directly to the patient’s data (Pearson correlation = 0.37; mean square error = 0.005). Furthermore, the model dynamics reproduce functional connectivity-based measures that are typically abnormal in stroke patients and measures that specifically isolate these abnormalities. Therefore, although whole-brain models typically involve a large number of free parameters, the results show that, even after fixing those parameters, the model reproduces results from a population very different than that on which the model was trained. In addition to validating the model, these results show that the model mechanistically captures the relationships between the anatomical structure and the functional activity of the human brain. © The Author(s) 2024.

Author Keywords
(f)MRI;  dynamics;  predictive;  stroke;  whole-brain models

Funding details
Fondazione Cassa di Risparmio di Padova e Rovigo
101071900
55403
PID2022-136216NB-I00, MICIU/AEI/10.13039/501100011033
CUP C94I20000420007
MART_ECCELLENZA18_01
Ministry of HealthMOHRF-2008 -12366899
Ministry of HealthMOH
RF-2019-12369300
ANR-17-HBPR-0001
869505, H2020-SC5-2019-2
Fundação Bial361/18
Fundação Bial

Document Type: Article
Publication Stage: Final
Source: Scopus

Cranioencephalic functional lymphoid units in glioblastoma
(2024) Nature Medicine, . 

Dobersalske, C.^a b c , Rauschenbach, L.^{a c d e f} , Hua, Y.^g , Berliner, C.^h , Steinbach, A.^a b c , Grüneboom, A.ⁱ , Kokkaliaris, K.D.^j k l , Heiland, D.H.^m n o , Berger, P.^a b c , Langer, S.^a b c , Tan, C.L.^p q r , Stenzel, M.ⁱ , Landolsi, S.^j k l , Weber, F.ⁱ , Darkwah Oppong, M.^e f , Werner, R.A.^s t u , Gull, H.^a c e f , Schröder, T.^v , Linsenmann, T.^w , Buck, A.K.^s , Gunzer, M.^i x , Stuschke, M.^a d y , Keyvani, K.^z , Forsting, M.^aa , Glas, M.^a d f ab , Kipnis, J.^ac ad , Steindler, D.A.^ae af , Reinhardt, H.C.^a d v ag , Green, E.W.^p q r , Platten, M.^{p q r ah ai aj} , Tasdogan, A.^a d ag ak , Herrmann, K.^a d h , Rambow, F.^a g ag , Cima, I.^a c , Sure, U.^a d e f , Scheffler, B.^{a b c d ag}

^a German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between DKFZ and University Hospital Essen, University Duisburg–Essen, Essen, Germany
^b German Cancer Research Center (DKFZ), Heidelberg, Germany
^c DKFZ Division Translational Neurooncology at the WTZ, University Medicine Essen, Essen, Germany
^d West German Cancer Center (WTZ), University Hospital Essen, Essen, Germany
^e Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
^f Center for Translational Neuroscience and Behavioral Science (C-TNBS), University of Duisburg–Essen, Essen, Germany
^g Department of Applied Computational Cancer Research, IKIM, University Hospital Essen, Essen, Germany
^h Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
ⁱ Leibniz-Institut für Analytische Wissenschaften—ISAS—e.V., Dortmund, Germany
^j Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany
^k DKTK, German Cancer Consortium, partner site Frankfurt/Mainz, Quantitative Spatial Cancer Biology Laboratory, University Hospital Frankfurt, Frankfurt am Main, Germany
^l Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany
^m DKTK, German Cancer Consortium, partner site Freiburg, Translational Neurosurgery, Microenvironment and Immunology Research Laboratory, University of Freiburg, Freiburg, Germany
ⁿ Department of Neurosurgery, University Clinic Erlangen, Erlangen, Germany
^o Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^p CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
^q DKTK, German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany
^r Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany
^s Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
^t University Hospital Frankfurt, Department of Nuclear Medicine, Clinic for Radiology and Nuclear Medicine, Frankfurt am Main, Germany
^u The Russell H. Morgan Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^v Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
^w Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany
^x Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg–Essen, Essen, Germany
^y Department of Radiation Oncology, University Hospital Essen, Essen, Germany
^z Institute of Neuropathology, University Hospital Essen, Essen, Germany
^aa Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
^ab Department of Neurology, Division of Neurooncology, University Hospital Essen, Essen, Germany
^ac Brain Immunology and Glia (BIG) Center, Washington University School of Medicine in St Louis, St Louis, MO, United States
^ad Department of Pathology and Immunology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^ae Steindler Consulting, Boston, MA, United States
^af The Eshelman Institute for Innovation, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^ag Center of Medical Biotechnology (ZMB), University Duisburg–Essen, Essen, Germany
^ah Immune Monitoring Unit, National Center for Tumor Diseases, Heidelberg, Germany
^ai Helmholtz Institute for Translational Oncology, Mainz, Germany
^aj German Cancer Research Center-Hector Cancer Institute at the Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
^ak Department of Dermatology, University Hospital Essen, Essen, Germany

Abstract
The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8+ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8+ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma. © The Author(s) 2024.

Funding details
Else Kröner-Fresenius-StiftungEKFS
Bundesministerium für Bildung und ForschungBMBF
Deutschen Konsortium für Translationale KrebsforschungDKTK
16LW0404
DFG HE 8145/6-1/5-1, SFB1430-A09, SFB1399-A01, RE 2246/13-1, 507803309, SFB1530-A01, 453989101
Nationales Centrum für Tumorerkrankungen HeidelbergNCT Heidelberg01KT2328
Nationales Centrum für Tumorerkrankungen HeidelbergNCT Heidelberg
INST 35/1503-1 FUGG
01ZX1303A, 70113041, 404521405, 394046768, 1117240
2017.148.2
405344257, SCHE656/2-2

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

Suicide in US Preteens Aged 8 to 12 Years, 2001 to 2022
(2024) JAMA Network Open, p. e2424664. 

Ruch, D.A.^a b , Horowitz, L.M.^c , Hughes, J.L.^d e , Sarkisian, K.^d , Luby, J.L.^f , Fontanella, C.A.^a e , Bridge, J.A.^a b e

^a Center for Suicide Prevention and Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, United States
^b Department of Pediatrics, The Ohio State University College of Medicine, Columbus, United States
^c Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
^d Big Lots Behavioral Health Services, Division of Child and Family Psychiatry, Nationwide Children’s Hospital, Columbus, OH, United States
^e Department of Psychiatry and Behavioral Health, The Ohio State University College of Medicine, Columbus, United States
^f Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States

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

A genetic and proteomic comparison of key AD biomarkers across tissues
(2024) Alzheimer’s and Dementia, . 

Marsh, T.W.^a b c , Western, D.^a b c , Timsina, J.^b c , Gorijala, P.^a b , Yang, C.^b c , Pastor, P.^d , Liu, M.^b c , Morris, J.C.^e f , Bateman, R.J.^f g , Schindler, S.E.^f , Sung, Y.J.^b c , Cruchaga, C.^{b c e h i} , Dominantly Inherited Alzheimer Network^j

^a Division of Biology & Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Neurogenomics and Informatics, Washington University in St. Louis, St. Louis, MO, United States
^d Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
^e Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^g Dominantly Inherited Alzheimer Network (DIAN), Washington University in St. Louis, St. Louis, MO, United States
^h Hope Center for Neurological Diseases, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Genetics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
INTRODUCTION: Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer’s disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD. METHOD: Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power. RESULTS: Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma. DISCUSSION: The present results indicate that CSF is more informative than plasma for genetic studies in AD. Highlights: The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration-related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer’s disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  biomarkers;  CSF;  genomics;  neurodegenerative disease;  plasma;  protein quantitative trait loci

Funding details
BioClinica
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Hope Center for Neurological Disorders, Washington University in St. Louis
Fleni
National Multiple Sclerosis SocietyNMSS
Fonds de Recherche du Québec – SantéFRQS
Chan Zuckerberg InitiativeCZI
Fondation Brain Canada
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Health~HollandLSH
Japan Agency for Medical Research and DevelopmentAMED
ZonMw
Canadian Institutes of Health ResearchCIHR
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
Korea Health Industry Development InstituteKHIDI
Ministerio de Ciencia e InnovaciónMCINPID2020‐115613RA‐I00
Comunidad de Madrid2018‐T2/BMD‐11885
U.S. Department of DefenseDODW81XWH2010849 A
BrightFocus FoundationBFFA2021033S, P01AG03991
European CommissionEC860197, 831434
Selfridges Group FoundationNR170065
Alzheimer’s AssociationAAZEN‐22‐848604, 73305095007
W81XWH‐12‐2‐0012
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
BiogenWE.03‐2018‐05
5U19AG032438, P30 AG066444, – SG‐20‐690363, P01AG003991, P01AG026276
U19AG032438
National Institutes of HealthNIHR01AG044546, P01AG003991, U01AG058922, RF1AG074007, RF1AG058501, P30 AG066515, R00AG062723, P01AG026276, P30AG066444, RF1AG053303

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

Future time perspective and depression, anxiety, and stress in adulthood
(2024) Anxiety, Stress and Coping, . 

Allemand, M.^a , Olaru, G.^b , Hill, P.L.^c

^a University Research Priority Program, Dynamics of Healthy Aging”, University of Zurich, Zurich, Switzerland
^b Department of Developmental Psychology, Tilburg University, Tilburg, Netherlands
^c Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, United States

Abstract
Background and objective: Research has shown that perceptions of future time as limited are associated with more depressive symptoms. However, there is limited research on which dimensions of future time perspective (FTP: opportunity, extension, constraint) are associated with depression, anxiety, and stress, and whether these findings vary across age. Design and methods: Data came from a cross-sectional study in a nonclinical U.S. sample (N = 793, 48.0% male; 48.7% female; age: M = 50 years, range: 19–85 years), and local structural equation modeling was used to examine the moderating role of age as a continuous variable rather than artificial age groups. Results: For all dimensions of FTP, the perception of the future as limited was moderately to strongly associated with higher depression, anxiety and stress levels. More importantly, the association between the perceived constraint dimension and depression, anxiety, and stress was twice as large at younger ages than at older ages. Conclusion: These findings indicate that perceived constraint is primarily a strong risk factor for or indicator of negative wellbeing in young adulthood, whereas perceived limited opportunity and extension are potential risk factors or indicators across the entire adulthood. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
adulthood;  depression and anxiety;  Future time perspective;  local structural equation modeling (LSEM);  stress

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

Effects of Chatbot Components to Facilitate Mental Health Services Use in Individuals With Eating Disorders Following Online Screening: An Optimization Randomized Controlled Trial
(2024) International Journal of Eating Disorders, . 

Fitzsimmons-Craft, E.^a , Rackoff, G.^b , Shah, J.^a , Strayhorn, J.^c , D’Adamo, L.^a d , DePietro, B.^a , Howe, C.^a , Firebaugh, M.-L.^a , Newman, M.^b , Collins, L.^c , Taylor, C.^e f , Wilfley, D.^a

^a Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Psychology, The Pennsylvania State University, University Park, PA, United States
^c Department of Social and Behavioral Sciences, School of Global Public Health, New York University, New York, NY, United States
^d Department of Psychological and Brain Sciences and Center for Weight, Eating, and Lifestyle Science, Drexel University, Philadelphia, PA, United States
^e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^f Center for m2Health, Palo Alto University, Palo Alto, CA, United States

Abstract
Objective: Few individuals with eating disorders (EDs) receive treatment. Innovations are needed to identify individuals with EDs and address care barriers. We developed a chatbot for promoting services uptake that could be paired with online screening. However, it is not yet known which components drive effects. This study estimated individual and combined contributions of four chatbot components on mental health services use (primary), chatbot helpfulness, and attitudes toward changing eating/shape/weight concerns (“change attitudes,” with higher scores indicating greater importance/readiness). Methods: Two hundred five individuals screening with an ED but not in treatment were randomized in an optimization randomized controlled trial to receive up to four chatbot components: psychoeducation, motivational interviewing, personalized service recommendations, and repeated administration (follow-up check-ins/reminders). Assessments were at baseline and 2, 6, and 14 weeks. Results: Participants who received repeated administration were more likely to report mental health services use, with no significant effects of other components on services use. Repeated administration slowed the decline in change attitudes participants experienced over time. Participants who received motivational interviewing found the chatbot more helpful, but this component was also associated with larger declines in change attitudes. Participants who received personalized recommendations found the chatbot more helpful, and receiving this component on its own was associated with the most favorable change attitude time trend. Psychoeducation showed no effects. Discussion: Results indicated important effects of components on outcomes; findings will be used to finalize decision making about the optimized intervention package. The chatbot shows high potential for addressing the treatment gap for EDs. © 2024 Wiley Periodicals LLC.

Author Keywords
chatbot;  conversational agent;  digital intervention;  eating disorder;  mental health treatment;  mHealth;  optimization;  screening

Funding details
National Institute of Mental HealthNIMHR01 MH115128‐04S1, K08 MH120341
National Heart, Lung, and Blood InstituteNHLBIT32 HL130357

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