WashU weekly Neuroscience publications: March 5, 2023

Predicting later categories of upper limb activity from earlier clinical assessments following stroke: an exploratory analysis
(2023) Journal of NeuroEngineering and Rehabilitation, 20 (1), art. no. 24, . 

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

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

Abstract
Background: Accelerometers allow for direct measurement of upper limb (UL) activity. Recently, multi-dimensional categories of UL performance have been formed to provide a more complete measure of UL use in daily life. Prediction of motor outcomes after stroke have tremendous clinical utility and a next step is to explore what factors might predict someone’s subsequent UL performance category. Purpose: To explore how different machine learning techniques can be used to understand how clinical measures and participant demographics captured early after stroke are associated with the subsequent UL performance categories. Methods: This study analyzed data from two time points from a previous cohort (n = 54). Data used was participant characteristics and clinical measures from early after stroke and a previously established category of UL performance at a later post stroke time point. Different machine learning techniques (a single decision tree, bagged trees, and random forests) were used to build predictive models with different input variables. Model performance was quantified with the explanatory power (in-sample accuracy), predictive power (out-of-bag estimate of error), and variable importance. Results: A total of seven models were built, including one single decision tree, three bagged trees, and three random forests. Measures of UL impairment and capacity were the most important predictors of the subsequent UL performance category, regardless of the machine learning algorithm used. Other non-motor clinical measures emerged as key predictors, while participant demographics predictors (with the exception of age) were generally less important across the models. Models built with the bagging algorithms outperformed the single decision tree for in-sample accuracy (26–30% better classification) but had only modest cross-validation accuracy (48–55% out of bag classification). Conclusions: UL clinical measures were the most important predictors of the subsequent UL performance category in this exploratory analysis regardless of the machine learning algorithm used. Interestingly, cognitive and affective measures emerged as important predictors when the number of input variables was expanded. These results reinforce that UL performance, in vivo, is not a simple product of body functions nor the capacity for movement, instead being a complex phenomenon dependent on many physiological and psychological factors. Utilizing machine learning, this exploratory analysis is a productive step toward the prediction of UL performance. Trial registration NA © 2023, The Author(s).

Author Keywords
Accelerometry;  Outcome assessments;  Rehabilitation;  Stroke;  Supervised machine learning;  Upper extremity

Funding details
National Institutes of HealthNIHR01HD068290, T32HD007434, TL1TR002344

Document Type: Article
Publication Stage: Final
Source: Scopus

Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment
(2023) NPJ Genomic Medicine, 8 (1), art. no. 4, . 

Morimoto, M.^a , Bhambhani, V.^b , Gazzaz, N.^c d e , Davids, M.^a , Sathiyaseelan, P.^f g , Macnamara, E.F.^a , Lange, J.^ad , Lehman, A.^c , Zerfas, P.M.^h , Murphy, J.L.^a , Acosta, M.T.^a , Wang, C.^a , Alderman, E.^c d , Adam, M.^l , Alvarez, R.L.^m , Alvey, J.ⁿ , Amendola, L.^l , Andrews, A.ⁿ , Ashley, E.A.^m , Azamian, M.S.^o , Bacino, C.A.^o , Bademci, G.^p , Balasubramanyam, A.^o , Baldridge, D.^q , Bale, J.ⁿ , Bamshad, M.^l , Barbouth, D.^p , Bayrak-Toydemir, P.^n r , Beck, A.^l , Beggs, A.H.^s , Behrens, E.^t , Bejerano, G.^m , Bellen, H.J.^o , Bennett, J.^l , Berg-Rood, B.^l , Bernstein, J.A.^m , Berry, G.T.^s , Bican, A.^u , Bivona, S.^p , Blue, E.^l , Bohnsack, J.ⁿ , Bonner, D.^m , Botto, L.ⁿ , Boyd, B.^l , Briere, L.C.^s , Brokamp, E.^u , Brown, G.^v , Burke, E.A.^a , Burrage, L.C.^o , Butte, M.J.^v , Byers, P.^l , Byrd, W.E.^w , Carey, J.ⁿ , Carrasquillo, O.^p , Cassini, T.^a , Chang, T.C.P.^p , Chanprasert, S.^l , Chao, H.-T.^o , Clark, G.D.^o , Coakley, T.R.^m , Cobban, L.A.^s , Cogan, J.D.^u , Coggins, M.^s , Cole, F.S.^q , Colley, H.A.^a , Cooper, C.M.^s , Cope, H.^x , Craigen, W.J.^o , Crouse, A.B.^w , Cunningham, M.^l , D’Souza, P.^a , Dai, H.^o , Dasari, S.^y , Davis, J.^a , Dayal, J.G.^a , Dell’Angelica, E.C.^v , Dipple, K.^l , Doherty, D.^l , Dorrani, N.^v , Doss, A.L.^a , Douine, E.D.^v , Duncan, L.^u , Earl, D.^l , Eckstein, D.J.^a , Emrick, L.T.^o , Eng, C.M.^o , Esteves, C.^z , Falk, M.^t , Fieg, E.L.^s , Fisher, P.G.^m , Fogel, B.L.^v , Forghani, I.^p , Glass, I.^l , Gochuico, B.^a , Goddard, P.C.^m , Godfrey, R.A.^a , Golden-Grant, K.^l , Grajewski, A.^p , Gutierrez, I.^v , Hadley, D.^a , Hahn, S.^l , Halley, M.C.^m , Hamid, R.^u , Hassey, K.^t , Hayes, N.^q , High, F.^s , Hing, A.^l , Hisama, F.M.^l , Holm, I.A.^s , Hom, J.^m , Horike-Pyne, M.^l , Huang, A.^v , Hutchison, S.^a , Introne, W.J.^a j k , Isasi, R.^p , Izumi, K.^t , Jamal, F.^o , Jarvik, G.P.^l , Jarvik, J.^l , Jayadev, S.^l , Jean-Marie, O.^a , Jobanputra, V.^aa , Karaviti, L.^o , Kennedy, J.^u , Ketkar, S.^o , Kiley, D.^q , Kilich, G.^t , Kobren, S.N.^z , Kohane, I.S.^z , Kohler, J.N.^m , Korrick, S.^s , Kozuira, M.^u , Krakow, D.^v , Krasnewich, D.M.^a , Kravets, E.^m , Lalani, S.R.^o , Lam, B.^p , Lam, C.^l , Lanpher, B.C.^y , Lanza, I.R.^y , LeBlanc, K.^z , Lee, B.H.^o , Levitt, R.^p , Lewis, R.A.^o , Liu, P.^o , Liu, X.Z.^p , Longo, N.ⁿ , Loo, S.K.^v , Loscalzo, J.^s , Maas, R.L.^s , MacRae, C.A.^s , Maduro, V.V.^a , Mahoney, R.^z , Mak, B.C.^v , Mamounas, L.A.^a , Manolio, T.A.^a , Mao, R.^n r , Maravilla, K.^l , Marom, R.^o , Marth, G.ⁿ , Martin, B.A.^m , Martin, M.G.^v , Martínez-Agosto, J.A.^v , Marwaha, S.^m , McCauley, J.^p , McConkie-Rosell, A.^x , McCray, A.T.^z , McGee, E.^v , Mefford, H.^l , Merritt, J.L.^l , Might, M.^w , Mirzaa, G.^l , Morava, E.^y , Moretti, P.ⁿ , Nakano-Okuno, M.^w , Nelson, S.F.^v , Newman, J.H.^u , Nicholas, S.K.^o , Nickerson, D.^l , Nieves-Rodriguez, S.^v , Novacic, D.^a , Oglesbee, D.^y , Orengo, J.P.^o , Pace, L.ⁿ , Pak, S.^q , Pallais, J.C.^s , Palmer, C.G.S.^v , Papp, J.C.^v , Parker, N.H.^v , Phillips, J.A., III^u , Posey, J.E.^o , Potocki, L.^o , Pusey Swerdzewski, B.N.^a , Quinlan, A.ⁿ , Rao, D.A.^s , Raper, A.^t ab , Raskind, W.^l , Renteria, G.^v , Reuter, C.M.^m , Rives, L.^u , Robertson, A.K.^u , Rodan, L.H.^s , Rosenfeld, J.A.^o , Rosenwasser, N.^l , Rossignol, F.^a , Ruzhnikov, M.^m , Sacco, R.^p , Sampson, J.B.^m , Saporta, M.^p , Schaechter, J.^p , Schedl, T.^q , Schoch, K.^x , Scott, D.A.^o , Scott, C.R.^l , Shashi, V.^x , Shin, J.^q , Silverman, E.K.^s , Sinsheimer, J.S.^v , Sisco, K.^q , Smith, E.C.^x , Smith, K.S.^m , Solem, E.^u , Solnica-Krezel, L.^q , Solomon, B.^a , Spillmann, R.C.^x , Stoler, J.M.^s , Sullivan, K.^t , Sullivan, J.A.^x , Sun, A.^l , Sutton, S.^m , Sweetser, D.A.^s , Sybert, V.^l , Tabor, H.K.^m , Tan, Q.K.-G.^x , Tan, A.L.M.^z , Tekin, M.^p , Telischi, F.^p , Thorson, W.^p , Toro, C.^a , Tran, A.A.^o , Ungar, R.A.^m , Urv, T.K.^a , Vanderver, A.^t , Velinder, M.ⁿ , Viskochil, D.ⁿ , Vogel, T.P.^o , Wahl, C.E.^a , Walker, M.^s , Wallace, S.^l , Walley, N.M.^x , Wambach, J.^q , Wan, J.^v , Wang, L.-K.^v , Wangler, M.F.^o , Ward, P.A.^o , Wegner, D.^q , Weisz Hubshman, M.^o , Wener, M.^l , Wenger, T.^l , Wesseling Perry, K.^v , Westerfield, M.^ac , Wheeler, M.T.^m , Whitlock, J.^w , Wolfe, L.A.^a , Worley, K.^o , Xiao, C.^a , Yamamoto, S.^o , Yang, J.^a , Zhang, Z.^t , Zuchner, S.^p , Reichert, S.^b , Thurm, A.ⁱ , Adams, D.R.^a j , Introne, W.J.^a j k , Gorski, S.M.^c f g , Boerkoel, C.F.^c d , Gahl, W.A.^a k , Tifft, C.J.^a j , Malicdan, M.C.V.^a k , Undiagnosed Diseases Network^ae

^a National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, United States
^b Department of Medical Genetics, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN 55404, United States
^c Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC V6H 3N1, Canada
^d Provincial Medical Genetics Program, British Columbia Women’s and Children’s Hospital, Vancouver, BC V6H 3N1, Canada
^e Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
^f Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 1L3, Canada
^g Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
^h Diagnostic and Research Services Branch, Office of Research Services, National Institutes of Health, Bethesda, MD 20892, United States
ⁱ Neurodevelopmental and Behavioral Phenotyping Service, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, United States
^j Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
^k Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
^l Pacific Northwest Undiagnosed Diseases Clinical Site at University of Washington and Seattle Children’s Hospital, Seattle, WA, United States
^m Center for Undiagnosed Diseases at Stanford, Stanford, CA, United States
ⁿ University of Utah, Salt Lake City, UT, United States
^o Baylor College of Medicine, Houston, TX, United States
^p University of Miami School of Medicine, Miami, FL, United States
^q Washington University in St. Louis, St. Louis, MO, United States
^r Associated Regional and University Pathologists Laboratories, Salt Lake City, UT 84108, United States
^s UDN Clinical Site at Harvard Medical School, Boston, MA, United States
^t Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^u Vanderbilt Center for Undiagnosed Diseases, Nashville, TN, United States
^v UCLA Undiagnosed Diseases Clinic, Los Angeles, CA, United States
^w University of Alabama at Birmingham, Birmingham, AL, United States
^x Duke University, Durham, NC, United States
^y Mayo Clinic, Rochester, MN, United States
^z Harvard Medical School, Boston, MA, United States
^aa Columbia University Irving Medical Center, New York, NY, United States
^ab University of Pennsylvania, Philadelphia, PA, United States
^ac University of Oregon, Eugene, OR, United States

Abstract
Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or “primed” by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder. © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Funding details
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRI
Office of the DirectorOD
Canadian Institutes of Health ResearchIRSCMOP-78882
University of Bristol
Monash UniversityMU
Monash Biomedicine Discovery Institute, Monash UniversityBDI

Document Type: Article
Publication Stage: Final
Source: Scopus

The sleep and wake electroencephalogram over the lifespan
(2023) Neurobiology of Aging, 124, pp. 60-70. 

Sun, H.^a , Ye, E.^b , Paixao, L.^c , Ganglberger, W.^b , Chu, C.J.^b , Zhang, C.^b , Rosand, J.^a , Mignot, E.^d , Cash, S.S.^b , Gozal, D.^e , Thomas, R.J.^f , Westover, M.B.^g

^a Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, MA, USA
^b Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^c Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
^d Center for Sleep Sciences and Medicine, Stanford University, Stanford, United States
^e Department of Child Health, University of Missouri, Columbia, MO, United States
^f Department of Medicine, Division of Pulmonary, Critical Care & Sleep, Beth Israel Deaconess Medical Center, Boston, MA, United States
^g Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, MA, USA. Electronic address: mwestove@bidmc.harvard.edu

Abstract
Both sleep and wake encephalograms (EEG) change over the lifespan. While prior studies have characterized age-related changes in the EEG, the datasets span a particular age group, or focused on sleep and wake macrostructure rather than the microstructure. Here, we present sex-stratified data from 3372 community-based or clinic-based otherwise neurologically and psychiatrically healthy participants ranging from 11 days to 80 years of age. We estimate age norms for key sleep and wake EEG parameters including absolute and relative powers in delta, theta, alpha, and sigma bands, as well as sleep spindle density, amplitude, duration, and frequency. To illustrate the potential use of the reference measures developed herein, we compare them to sleep EEG recordings from age-matched participants with Alzheimer’s disease, severe sleep apnea, depression, osteoarthritis, and osteoporosis. Although the partially clinical nature of the datasets may bias the findings towards less normal and hence may underestimate pathology in practice, age-based EEG reference values enable objective screening of deviations from healthy aging among individuals with a variety of disorders that affect brain health. Copyright © 2023 Elsevier Inc. All rights reserved.

Author Keywords
Age norm;  Aging;  Brain health;  Electroencephalogram;  Sleep

Document Type: Article
Publication Stage: Final
Source: Scopus

Targeted delivery of therapeutic agents to the mouse brain using a stereotactic-guided focused ultrasound device
(2023) STAR Protocols, 4 (1), art. no. 102132, . 

Hu, Z.^a , Yang, Y.^a , Ye, D.^a , Chen, S.^a , Gong, Y.^a , Chukwu, C.^a , Chen, H.^a b

^a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
^b Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States

Abstract
Existing protocols of focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) in preclinical research require expensive ultrasound equipment and complex operating procedures. We developed a low-cost, easy-to-use, and precise FUS device for small animal models in preclinical research. Here, we provide a detailed protocol for building the FUS transducer, attaching the transducer to a stereotactic frame for precise brain targeting, applying the integrated FUS device to perform FUS-BBBO in mice, and evaluating the FUS-BBBO outcome. For complete details on the use and execution of this protocol, please refer to Hu et al. (2022).1 © 2023 The Authors

Author Keywords
Biotechnology and bioengineering;  Cancer;  Health Sciences;  Neuroscience;  Physics

Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, UG3MH126861
Office of Naval ResearchONRN00014-19-1-2335

Document Type: Article
Publication Stage: Final
Source: Scopus

Principal component regression analysis of familial psychiatric histories and suicide risk factors among adults with opioid use disorder
(2023) Journal of Psychiatric Research, 159, pp. 6-13. 

Szlyk, H.S.^a , Li, X.^a , Filiatreau, L.M.^a , Bierut, L.J.^a , Banks, D.^b , Cavazos-Rehg, P.^a

^a Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave ,Campus Box 8314, St. Louis, MO 63130, United States
^b Department of Psychological Sciences, University of Missouri – St. Louis, One University BlvdMO, United States

Abstract
This study explores familial psychiatric risk factors that are closely linked to suicide risk among patients with opioid use disorder (OUD) as measured by the Family History Assessment Module (FHAM). Data was derived from adults diagnosed with OUD (N = 389). To analyze the covariance between the 11 items of the FHAM, principal component analysis was applied to infer principal components (PC) scores. Log-binominal regression was conducted to quantify the associations between PC scores and mental health symptoms (e.g., lifetime suicidal attempt, P30D suicidal ideation, depression, and anxiety). Analyses revealed that the first 3 three PCs could account for 56% of the total variance of the FHAM items within the data. Family history of substance misuse (PC1) was positively associated with lifetime suicide attempts and severe anxiety. Family history of serious mental illness (PC2) and of suicidal behavior (PC3) were not significantly associated with any outcomes. Our findings suggest current suicide risk is associated with an array of familial psychiatric issues among people with OUD. However, family history of suicide attempts and death by suicide has less bearing on current suicide risk in OUD patients whereas family history of substance use confers significant risk. Findings underscore suicide-related preventive interventions as necessary components of treatment plans among people with OUD, who commonly report family histories of substance misuse. Copyright © 2023 Elsevier Ltd. All rights reserved.

Author Keywords
Family medical histories;  Opioid use disorder;  Principal component analyses;  Suicidal ideation;  Suicide attempt

Document Type: Article
Publication Stage: Final
Source: Scopus

NRG Oncology/RTOG1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma
(2023) Journal of Clinical Oncology, 41 (6), pp. 1285-1295. Cited 3 times.

Tsien, C.I.^a , Pugh, S.L.^b , Dicker, A.P.^c , Raizer, J.J.^d , Matuszak, M.M.^e , Lallana, E.C.^f , Huang, J.^g , Algan, O.^h , Deb, N.ⁱ , Portelance, L.^j , Villano, J.L.^k , Hamm, J.T.^l , Oh, K.S.^m , Ali, A.N.ⁿ , Kim, M.M.^o , Lindhorst, S.M.^p , Mehta, M.P.^q

^a Johns Hopkins School of Medicine, Baltimore, MD, United States
^b NRG Oncology Statistics and Data Management Center, Philadelphia, PA, United States
^c Thomas Jefferson University, Philadelphia, PA, United States
^d Northwestern University, Chicago, IL, United States
^e University of Michigan, Ann Arbor, MI, United States
^f Kaiser Permanente Sacramento Medical Center, Sacramento, CA, United States
^g Washington University, School of Medicine, St Louis-Siteman Cancer Center, St. Louis, MO, United States
^h University of Oklahoma, Health Sciences Center, Oklahoma City, OK, United States
ⁱ St Luke’s University Hospital, Health Network Accruals Thomas Jefferson University Hospital, Bethlehem, PA, United States
^j University of Miami, Miller School of Medicine-Sylvester, Comprehensive Cancer Center, Miami, FL, United States
^k University of Kentucky, Markey Cancer Center, Lexington, KY, United States
^l Norton Hospital Pavilion, Medical Campus, Louisville, KY, United States
^m Dana-Farber/Harvard Cancer Center, Boston, MA, United States
ⁿ The Hope Center Accruals Emory University, Winship Cancer Institute, Dalton, GA, United States
^o University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI, United States
^p Medical University, South Carolina Minority Underserved NCORP, Charleston, SC, United States
^q Miami Cancer Institute, Miami, FL, United States

Abstract
PURPOSETo assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities.METHODSNRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression.RESULTSFrom December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P =.46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P =.05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P =.001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM.CONCLUSIONTo our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS. © American Society of Clinical Oncology.

Document Type: Article
Publication Stage: Final
Source: Scopus

fmr1 Mutation Alters the Early Development of Sensory Coding and Hunting and Social Behaviors in Larval Zebrafish
(2023) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 43 (7), pp. 1211-1224. 

Zhu, S.I.^a b , McCullough, M.H.^a , Pujic, Z.^a , Sibberas, J.^a , Sun, B.^a , Darveniza, T.^b , Bucknall, B.^a , Avitan, L.^a , Goodhill, G.J.^a b c

^a Queensland Brain Institute
^b Departments of Developmental Biology and Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
^c University of Queensland, School of Mathematics and Physics, Brisbane, QLD 4072, Australia

Abstract
Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in FMR1 Mutation of fmr1 in zebrafish causes anxiety-like behavior, hyperactivity, and hypersensitivity in auditory and visual processing. Here, we show that zebrafish fmr1-/- mutant larvae of either sex also display changes in hunting behavior, tectal coding, and social interaction. During hunting, they were less successful at catching prey and displayed altered behavioral sequences. In the tectum, representations of prey-like stimuli were more diffuse and had higher dimensionality. In a social behavioral assay, they spent more time observing a conspecific but responded more slowly to social cues. However, when given a choice of rearing environment fmr1-/- larvae preferred one with reduced visual stimulation, and rearing them in this environment reduced genotype-specific effects on tectal excitability. Together, these results shed new light on how fmr1-/- changes the early development of neural systems and behavior in a vertebrate.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are caused by changes in early neural development. Animal models of ASDs offer the opportunity to study these developmental processes in greater detail than in humans. Here, we found that a zebrafish mutant for a gene which in humans causes one type of ASD showed early alterations in hunting behavior, social behavior, and how visual stimuli are represented in the brain. However, we also found that mutant fish preferred reduced visual stimulation, and rearing them in this environment reduced alterations in neural activity patterns. These results suggest interesting new directions for using zebrafish as a model to study the development of brain and behavior in ASDs, and how the impact of ASDs could potentially be reduced. Copyright © 2023 the authors.

Author Keywords
behavior;  environmental enrichment;  neural assemblies;  optic tectum

Document Type: Article
Publication Stage: Final
Source: Scopus

On the Role of Theory and Modeling in Neuroscience
(2023) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 43 (7), pp. 1074-1088. 

Levenstein, D.^a , Alvarez, V.A.^b , Amarasingham, A.^c , Azab, H.^d , Chen, Z.S.^e , Gerkin, R.C.^f , Hasenstaub, A.^g , Iyer, R.^h , Jolivet, R.B.ⁱ , Marzen, S.^j , Monaco, J.D.^k , Prinz, A.A.^l , Quraishi, S.^m , Santamaria, F.^m , Shivkumar, S.ⁿ , Singh, M.F.^o , Traub, R.^p , Nadim, F.^a g , Rotstein, H.G.^a g , Redish, A.D.^q

^a Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
^b Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, Liberia
^c Departments of Mathematics and Biology, City College and the Graduate Center, City University of New YorkNY 10032, United States
^d Department of Neuroscience, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN 55455, United States
^e Department of Psychiatry, Neuroscience & Physiology, New York University School of MedicineNY 10016, United States
^f School of Life Sciences, Arizona State University, Tempe, AZ 85281, United States
^g Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94115, United States
^h Allen Institute for Brain Science, Seattle, WA 98109, United States
ⁱ Maastricht Centre for Systems Biology, Maastricht University, Maastricht, Netherlands
^j W. M. Keck Science Department, Pitzer, Scripps, Claremont McKenna Colleges, Claremont, CA 91711, United States
^k Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, Liberia
^l Department of Biology, Emory University, Atlanta, 30322, Georgia
^m Neuroscience, Developmental and Regnerative Biology Department, University of Texas at San Antonio, San Antonio, TX 78249, United States
ⁿ Brain and Cognitive Sciences, University of Rochester, Rochester, NY 14627, United States
^o Department of Psychological & Brain Sciences, Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO 63112, United States
^p IBM T.J. Watson Research Center, AI Foundations, Yorktown HeightsNY 10598, United States
^q Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, United States

Abstract
In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment. Copyright © 2023 the authors.

Document Type: Article
Publication Stage: Final
Source: Scopus

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling
(2023) Frontiers in Molecular Biosciences, 10, art. no. 1051494, . 

Minaya, M.A.^a , Mahali, S.^a , Iyer, A.K.^a , Eteleeb, A.M.^a , Martinez, R.^a , Huang, G.^a , Budde, J.^a , Temple, S.^b , Nana, A.L.^c , Seeley, W.W.^c , Spina, S.^c , Grinberg, L.T.^c d , Harari, O.^a e f , Karch, C.M.^a e f

^a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^b Neural Stem Cell Institute, Rensselaer, NY, United States
^c Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
^d Department of Pathology, University of Sao Paulo, Sao Paulo, Brazil
^e Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
^f NeuroGenomics and Informatics Center, Washington University in St Louis, St Louis, MO, United States

Abstract
Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. Methods: We analyzed genes differentially expressed in induced pluripotent stem cell–derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis. Copyright © 2023 Minaya, Mahali, Iyer, Eteleeb, Martinez, Huang, Budde, Temple, Nana, Seeley, Spina, Grinberg, Harari and Karch.

Author Keywords
calcium signaling;  frontotemporal dementia (FTD);  IPSC-derived neurons;  MAPT mutations (tau);  transcriptomics

Funding details
P01AG019724, P01AG026276, P01AG03991, P30AG062422, P30AG066444, U01AG057195, U19AG063911, UL1TR002345
National Institutes of HealthNIHK24 AG053435, OD021629, P30 AG066444, R01 AG056293, R01 AG057777, R01 AG062359, RF1 NS110890, U54 NS123985
Hope Center for Neurological Disorders
Rainwater Charitable FoundationRCF
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Health disparities in aging: Improving dementia care for Black women
(2023) Frontiers in Aging Neuroscience, 15, art. no. 1107372, . 

Findley, C.A.^a b , Cox, M.F.^c , Lipson, A.B.^a d , Bradley, R.^a , Hascup, K.N.^a b e , Yuede, C.^f , Hascup, E.R.^a b

^a Department of Neurology, Dale and Deborah Smith Center for Alzheimer’s Research and Treatment, Neuroscience Institute, Southern Illinois University School of Medicine, Springfield, IL, United States
^b Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Division of Neurosurgery, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, United States
^e Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States
^f Department of Psychiatry, Washington University, St. Louis, MO, United States

Abstract
In the United States, 80% of surveyed Black patients report experiencing barriers to healthcare for Alzheimer’s disease and related dementias (ADRD), delaying the time-sensitive treatment of a progressive neurodegenerative disease. According to the National Institute on Aging, Black study participants are 35% less likely to be given a diagnosis of ADRD than white participants, despite being twice as likely to suffer from ADRD than their white counterparts. Prior analysis of prevalence for sex, race, and ethnicity by the Centers for Disease Control indicated the highest incidence of ADRD in Black women. Older (≥65 years) Black women are at a disproportionately high risk for ADRD and yet these patients experience distinct inequities in obtaining clinical diagnosis and treatment for their condition. To that end, this perspective article will review a current understanding of biological and epidemiological factors that underlie the increased risk for ADRD in Black women. We will discuss the specific barriers Black women face in obtaining access to ADRD care, including healthcare prejudice, socioeconomic status, and other societal factors. This perspective also aims to evaluate the performance of intervention programs targeted toward this patient population and offer possible solutions to promote health equity. Copyright © 2023 Findley, Cox, Lipson, Bradley, Hascup, Yuede and Hascup.

Author Keywords
Alzheimer’s disease;  Alzheimer’s disease and related dementias;  discrimination;  healthcare equity;  outreach

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG057767, R01AG061937

Document Type: Article
Publication Stage: Final
Source: Scopus

The Mechanism of Enantioselective Neurosteroid Actions on GABAA Receptors
(2023) Biomolecules, 13 (2), art. no. 341, . 

Tateiwa, H.^a b , Chintala, S.M.^a , Chen, Z.^a c , Wang, L.^a d , Amtashar, F.^a , Bracamontes, J.^a , Germann, A.L.^a , Pierce, S.R.^a , Covey, D.F.^a c e f , Akk, G.^a c , Evers, A.S.^a c f

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kochi, 7838505, Japan
^c Taylor Institute for Innovative Psychiatric Research, St. Louis, MO 63110, United States
^d Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430074, China
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Developmental Biology (Pharmacology), Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABAA receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this difference in enantioselectivity. The oocyte electrophysiology studies showed that ent-ALLO potentiates GABA-elicited currents in α1β3 GABAA receptors with lower potency and efficacy than ALLO, PREG or ent-PREG. The small PAM effect of ent-ALLO was prevented by the α1(Q242L) mutation in the intersubunit neurosteroid binding site between the β3 and α1 subunits. Consistent with this result, neurosteroid analogue photolabeling with mass spectrometric readout, showed that ent-ALLO binds weakly to the β3-α1 intersubunit binding site in comparison to ALLO, PREG and ent-PREG. Rigid body docking predicted that ent-ALLO binds in the intersubunit site with a preferred orientation 180° different than ALLO, PREG or ent-PREG, potentially explaining its weak binding and effect. Photolabeling studies did not identify differences between ALLO and ent-ALLO binding to the α1 or β3 intrasubunit binding sites that also mediate neurosteroid modulation of GABAA receptors. The results demonstrate that differential binding of ent-ALLO and ent-PREG to the β3-α1 intersubunit site accounts for the difference in enantioselectivity between ALLO and PREG. © 2023 by the authors.

Author Keywords
enantiomers;  GABA-A receptors;  neurosteroids;  photolabeling

Funding details
NIGMS-R35 GM140947, NIMH-P50MH122379

Document Type: Article
Publication Stage: Final
Source: Scopus

Chikungunya Virus and Its Envelope Protein E2 Induce Hyperalgesia in Mice: Inhibition by Anti-E2 Monoclonal Antibodies and by Targeting TRPV1
(2023) Cells, 12 (4), art. no. 556, . 

Segato-Vendrameto, C.Z.^a , Zanluca, C.^b , Zucoloto, A.Z.^a , Zaninelli, T.H.^a , Bertozzi, M.M.^a , Saraiva-Santos, T.^a , Ferraz, C.R.^a , Staurengo-Ferrari, L.^a , Badaro-Garcia, S.^a , Manchope, M.F.^a , Dionisio, A.M.^a , Pinho-Ribeiro, F.A.^a c , Borghi, S.M.^a d , Mosimann, A.L.P.^b , Casagrande, R.^e , Bordignon, J.^b , Fattori, V.^a f , Santos, C.N.D.D.^b , Verri, W.A.^a

^a Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Londrina State University, PR, Londrina, 86057-970, Brazil
^b Laboratory of Molecular Virology, Carlos Chagas Institute/Fiocruz PR, PR, Curitiba, 81310-020, Brazil
^c Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Center for Research in Health Sciences, University of Northern Paraná, PR, Londrina, 86041-140, Brazil
^e Department of Pharmaceutical Sciences, University Hospital (Health Science Centre), Londrina State University, PR, Londrina, 86057-970, Brazil
^f Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, 1 Blackfan Circle, Karp Research Building 11.006C, Boston, MA 02115, United States

Abstract
Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain. © 2023 by the authors.

Author Keywords
Chikungunya virus;  E2 envelope protein;  joint pain;  monoclonal antibody;  TRPV1

Funding details
5301159
041/2017
Department of Science and Technology, Ministry of Science and Technology, Indiaडीएसटी
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCAPES001
Ministério da Ciência, Tecnologia e InovaçãoMCTI014/2017
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq307852/2019-9, 309633/2021-4, 405027/2021-4, 427946/2018-2
Secretário de Ciência, Tecnologia e Ensino Superior, Governo do Estado de ParanaSETI
Fundação Araucária
Ministério da Saúde

Document Type: Article
Publication Stage: Final
Source: Scopus

BrainWAVE: A Flexible Method for Noninvasive Stimulation of Brain Rhythms across Species
(2023) eNeuro, 10 (2), art. no. ENEURO.0257-22.2022, . 

Attokaren, M.K.^a , Jeong, N.^a b , Blanpain, L.^a b , Paulson, A.L.^a , Garza, K.M.^a b , Borron, B.^a , Walelign, M.^a , Willie, J.^c , Singer, A.C.^a b

^a Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, United States
^b Neuroscience Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, United States
^c Neurosurgery, Biomedical Engineering, Psychiatry, Neuroscience and Neurology, Washington University, St Louis, MO 63110, United States

Abstract
Rhythmic neural activity, which coordinates brain regions and neurons to achieve multiple brain functions, is impaired in many diseases. Despite the therapeutic potential of driving brain rhythms, methods to noninvasively target deep brain regions are limited. Accordingly, we recently introduced a noninvasive stimulation approach using flickering lights and sounds (“flicker”). Flicker drives rhythmic activity in deep and superficial brain regions. Gamma flicker spurs immune function, clears pathogens, and rescues memory performance in mice with amyloid pathology. Here, we present substantial improvements to this approach that is flexible, user-friendly, and generalizable across multiple experimental settings and species. We present novel opensource methods for flicker stimulation across rodents and humans. We demonstrate rapid, cross-species induction of rhythmic activity without behavioral confounds in multiple settings from electrophysiology to neuroimaging. This flicker approach provides an exceptional opportunity to discover the therapeutic effects of brain rhythms across scales and species. © 2023 Attokaren et al.

Author Keywords
brain oscillations;  brain stimulation;  entrainment;  flicker;  noninvasive deep brain modulation;  sensory stimulation

Funding details
5F31AG066410, R01 NS109226-S1, T32 NS007480-18
National Institutes of HealthNIH
David and Lucile Packard FoundationDLPF
National Institute on AgingNIARF1AG078736-01
National Institute of Neurological Disorders and StrokeNINDSR01 NS109226

Document Type: Article
Publication Stage: Final
Source: Scopus

TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma
(2023) Journal for Immunotherapy of Cancer, 11 (2), . 

Schaettler, M.O.^a , Desai, R.^a , Wang, A.Z.^a , Livingstone, A.J.^b , Kobayashi, D.K.^a , Coxon, A.T.^a , Bowman-Kirigin, J.A.^c , Liu, C.J.^d , Li, M.^e , Bender, D.E.^f , White, M.J.^g , Kranz, D.M.^h , Johanns, T.M.^b , Dunn, G.P.^e

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, United States
^e Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
^f Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^h Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL, United States

Abstract
BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3D81N neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response. RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
antigens;  brain neoplasms;  cell engineering;  immunotherapy;  T-lymphocytes

Document Type: Article
Publication Stage: Final
Source: Scopus

Lexical inferencing as a generation effect for foreign language vocabulary learning
(2023) Memory and Cognition, 51 (2), pp. 273-289. 

Dessenberger, S.^a , Wang, K.^a , Jordan, E.^a , Sommers, M.^b

^a Psychological and Brain Sciences, Washington University in St Louis, St. Louis, MO, United States
^b Washington University Psychology, St. Louis, MO, United States

Abstract
Prior research suggests that second language (L2) vocabulary learning often occurs through lexical inferencing (translations based on context), but there has been less emphasis on how lexical inferencing compares with other methods of L2 word learning. The present study compared lexical inferencing to simply studying word lists for L2 learning. A secondary goal was to determine whether any effect of inferencing is mediated by the generation effect of memory, a phenomenon wherein generated information (inferencing) is remembered better than obtained information (reading). Across four experiments, participants read English sentences with embedded Swahili words and were asked either to infer the word meaning using context or were provided with translations before reading the sentence (reading condition). In contrast to our initial hypotheses, the inference condition resulted in lower rates of retention compared with the reading condition. In addition, the data suggest a number of differences between lexical inferencing and the generation effect, that argue against the proposal that lexical inferencing operates as a type of generation effect © 2022, The Psychonomic Society, Inc.

Author Keywords
Associative learning;  Language acquisition;  Memory

Funding details
National Science FoundationNSFDGE-1745038

Document Type: Article
Publication Stage: Final
Source: Scopus

Acclimatization of force production during walking in persons with Parkinson’s disease
(2023) Journal of Biomechanics, 148, p. 111477. 

Pappas, M.C.^a , Baudendistel, S.T.^b , Schmitt, A.C.^c , Au, K.L.K.^d , Hass, C.J.^e

^a Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, United States
^b Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA; Program in Physical Therapy, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Electronic address: bsidney@wustl.edu
^c Department of Health, Human Performance, Recreation, University of Arkansas, Fayetteville, AR, United States
^d University of Kansas Medical Center, Kansas City, KS, United States
^e Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA

Abstract
Individuals with Parkinson’s disease walk slowly, with short strides resulting in decreased mobility. Treadmill walking assessments are utilized to understand gait impairment in persons with Parkinson’s disease and treadmill-based interventions to mobility have become increasingly popular. While walking on a treadmill, there is a reported initial acclimatization period where individuals adjust to the speed and dynamics of the moving belt before producing consistent walking patterns. It is unknown how much walking time is required for individuals with Parkinson’s disease to acclimate to the treadmill. We investigated how spatiotemporal parameters and ground reaction forces changed during treadmill acclimatization. Twenty individuals with idiopathic Parkinson’s (15 Males, 5 Females) walked for a five-minute treadmill session on an instrumented treadmill while motion capture data were collected. The measures of interest included ground reaction force measures (peak propulsive force, peak braking force, propulsive impulse, and braking impulse) and spatiotemporal measures (stride length, stride time, or double support time). Analyses demonstrated significantly increased propulsive impulse (p <.001) after the first minute, with no significant difference for the remaining minutes (p ≥ 0.395). There were no significant changes in the spatiotemporal measures (P =.065). These results quantify the stabilization of ground reaction force during the treadmill acclimatization period. Based on our findings, if steady-state gait is desired, we recommend participants walk for at least two minutes before data collection. Future clinical investigations should consider ground reaction force as sensitive parameters for evaluating gait in persons with Parkinson’s disease in treadmill-based assessments or interventional therapies. Copyright © 2023 Elsevier Ltd. All rights reserved.

Author Keywords
Gait;  Parkinson’s disease;  Treadmill;  Walking

Document Type: Article
Publication Stage: Final
Source: Scopus

Racial and ethnic differences in neuropsychiatric symptoms and progression to incident cognitive impairment among community-dwelling participants
(2023) Alzheimer’s and Dementia, . 

Babulal, G.M.^a b c d , Zhu, Y.^e f , Trani, J.-F.^b d f g

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^c Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^d Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
^e School of Social Work, Adelphi University, New York, United States
^f Brown School, Washington University in St. Louis, St. Louis, MO, United States
^g National Center for Arts and Crafts, Paris, France

Abstract
Introduction: Neuropsychiatric symptoms (NPS) are a risk factor for dementia; however, their prevalence and severity among ethnoracial groups are poorly understood. Methods: We used data from the National Alzheimer’s Coordinating Center (NACC) (n = 6958; ≥50 years old). Cognitively normal participants at baseline, without any NPS or dementia diagnosis, had at least one follow-up. Survival analyses assessed the hazard ratio for 12 NPS models and progression to cognitive impairment. Propensity score weighting (PSW) matched participants on age, sex, education, and race/ethnicity. Results: All 12 NPS were significantly associated with progression to cognitive impairment. In the PSW models, compared to whites, Black/African Americans were more likely to progress to cognitive impairment across all 12 NPS models, followed by Hispanic, and then Asian participants. Discussion: PSW minimized selection bias to provide robust risk estimates. There is a higher risk of progressing to cognitive impairment for ethnoracial groups with NPS. Tailored screening of NPS and cognitive impairment should incorporate patient and caregiver reports. © 2023 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  cognitive impairment;  ethnicity;  neuropsychiatric symptoms;  propensity score;  race

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG056466, R01AG067428, R01AG068183, R01AG074302

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

Psychometric Evaluation of the Perceived Research Burden Assessment (PeRBA) in Longitudinal Studies of Alzheimer Disease Using Rasch Analysis
(2023) Alzheimer Disease and Associated Disorders, 37 (1), pp. 28-34. 

Keleman, A.A.^a , Chang, C.-H.^a b c , Bollinger, R.M.^a , Lingler, J.H.^d , Gabel, M.^e , Stark, S.L.^a

^a Program in Occupational Therapy
^b Institute for Informatics
^c Department of Orthopaedic Surgery
^d School of Nursing, Department of Health and Community Systems University of Pittsburgh, Pittsburgh, PA, United States
^e Department of Political Science, Washington University in St. Louis, St. Louis, MO, United States

Abstract
INTRODUCTION: The Perceived Research Burden Assessment (PeRBA) was developed to measure participant perceptions of burden in research studies. This study aimed to examine the psychometric properties of this assessment using Rasch analysis in participants in the longitudinal studies of the Alzheimer disease (AD) and their family members. METHODS: PeRBA was administered to 443 participants in studies of AD and 212 family members across 4 Alzheimer Disease Research Centers. We used Rasch analysis to examine PeRBA’s psychometric properties, and data-model fit both at item and scale levels. RESULTS: PeRBA demonstrated good reliability and item and person fit for participants and family members. A few items did not fit the model for participants or family members. Areas of content redundancy were found in items assessing similar amounts of perceived research burden. Areas of content gaps were also found, with no items assessing certain levels of perceived research burden. CONCLUSION: Analysis results support the good overall psychometric properties of PeRBA among research participants in studies of AD and their family members. Recommendations have been provided to improve the assessment, including rewording items and adding items that could account for a broader range of perceived research burden. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive [Computational] Neuroscience Test Reliability and Clinical Applications for Serious Mental Illness (CNTRaCS) Consortium: Progress and Future Directions
(2023) Current Topics in Behavioral Neurosciences, 63, pp. 19-60. 

Barch, D.M.^a , Boudewyn, M.A.^b , Carter, C.C.^c , Erickson, M.^d , Frank, M.J.^e , Gold, J.M.^f , Luck, S.J.^c , MacDonald, A.W., 3rd^g , Ragland, J.D.^c , Ranganath, C.^c , Silverstein, S.M.^h , Yonelinas, A.^c

^a Department of Psychological &amp; Brain Sciences, Washington University in St. Louis, St. Louis, MO, USA
^b University of California, Santa Cruz, CA, USA
^c University of California, Davis, CA, United States
^d University of Chicago, Chicago, IL, United States
^e Brown University, Providence, RI, United States
^f Maryland Psychiatric Research Center, Baltimore, MD, United States
^g University of Minnesota, Minneapolis, MN, United States
^h University of Rochester, Rochester, NY, United States

Abstract
The development of treatments for impaired cognition in schizophrenia has been characterized as the most important challenge facing psychiatry at the beginning of the twenty-first century. The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) project was designed to build on the potential benefits of using tasks and tools from cognitive neuroscience to better understanding and treat cognitive impairments in psychosis. These benefits include: (1) the use of fine-grained tasks that measure discrete cognitive processes; (2) the ability to design tasks that distinguish between specific cognitive domain deficits and poor performance due to generalized deficits resulting from sedation, low motivation, poor test taking skills, etc.; and (3) the ability to link cognitive deficits to specific neural systems, using animal models, neuropsychology, and functional imaging. CNTRICS convened a series of meetings to identify paradigms from cognitive neuroscience that maximize these benefits and identified the steps need for translation into use in clinical populations. The Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRaCS) Consortium was developed to help carry out these steps. CNTRaCS consists of investigators at five different sites across the country with diverse expertise relevant to a wide range of the cognitive systems identified as critical as part of CNTRICs. This work reports on the progress and current directions in the evaluation and optimization carried out by CNTRaCS of the tasks identified as part of the original CNTRICs process, as well as subsequent extensions into the Positive Valence systems domain of Research Domain Criteria (RDoC). We also describe the current focus of CNTRaCS, which involves taking a computational psychiatry approach to measuring cognitive and motivational function across the spectrum of psychosis. Specifically, the current iteration of CNTRaCS is using computational modeling to isolate parameters reflecting potentially more specific cognitive and visual processes that may provide greater interpretability in understanding shared and distinct impairments across psychiatric disorders. © 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.

Author Keywords
CNTRaCS;  CNTRICS;  Cognitive neuroscience;  Positive valence systems;  Schizophrenia

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive Dysfunction as a Risk Factor for Psychosis
(2023) Current Topics in Behavioral Neurosciences, 63, pp. 173-203. 

Karcher, N.R.^a , Merchant, J.^b , Pine, J.^b , Kilciksiz, C.M.^a

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

Abstract
The current chapter summarizes recent evidence for cognition as a risk factor for the development of psychosis, including the range of cognitive impairments that exist across the spectrum of psychosis risk symptoms. The chapter examines several possible theories linking cognitive deficits with the development of psychotic symptoms, including evidence that cognitive deficits may be an intermediate risk factor linking genetic and/or neural metrics to psychosis spectrum symptoms. Although there is not strong evidence for unique cognitive markers associated specifically with psychosis compared to other forms of psychopathology, psychotic disorders are generally associated with the greatest severity of cognitive deficits. Cognitive deficits precede the development of psychotic symptoms and may be detectable as early as childhood. Across the psychosis spectrum, both the presence and severity of psychotic symptoms are associated with mild to moderate impairments across cognitive domains, perhaps most consistently for language, cognitive control, and working memory domains. Research generally indicates the size of these cognitive impairments worsens as psychosis symptom severity increases. The chapter points out areas of unclarity and unanswered questions in each of these areas, including regarding the mechanisms contributing to the association between cognition and psychosis, the timing of deficits, and whether any cognitive systems can be identified that function as specific predictors of psychosis risk symptoms. © 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.

Author Keywords
Clinical high risk;  Cognition;  Cognitive systems;  Neurocognitive;  Psychosis risk;  Psychotic-like experiences

Document Type: Article
Publication Stage: Final
Source: Scopus

Gene-environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures
(2023) Journal of Neurology, Neurosurgery and Psychiatry, art. no. jnnp-2022-330713, . 

Nasr, Z.^a , Schoeps, V.A.^a , Ziaei, A.^a , Virupakshaiah, A.^a , Adams, C.^b , Casper, T.C.^c , Waltz, M.^c , Rose, J.^c , Rodriguez, M.^d , Tillema, J.-M.^d , Chitnis, T.^e , Graves, J.S.^f , Benson, L.^g , Rensel, M.^h , Krupp, L.ⁱ , Waldman, A.T.^j , Weinstock-Guttman, B.^k , Lotze, T.^l , Greenberg, B.^m , Aaen, G.ⁿ , Mar, S.^o , Schreiner, T.^p , Hart, J.^a , Simpson-Yap, S.^q r s , Mesaros, C.^t , Barcellos, L.F.^b u , Waubant, E.^a

^a UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94117, United States
^b Genetic Epidemiology and Genomics Laboratory, Divisions of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, United States
^c University of Utah Health, Salt Lake City, UT, United States
^d Mayo Clinic, Rochester, MN, United States
^e Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^f University of California San Diego, San Diego, CA, United States
^g Childrens Hospital Boston, Boston, MA, United States
^h Cleveland Clinic, Cleveland, OH, United States
ⁱ New York University Medical Center, New York City, NY, United States
^j Division of Child Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^k Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY, United States
^l Texas Children’s Hospital, Houston, TX, United States
^m University of Texas Southwestern Medical Center, Dallas, TX, United States
ⁿ Loma Linda University Children’s Hospital, Loma Linda, CA, United States
^o Washington University in St. Louis, St Louis, MO, United States
^p Denver Children’s Hospital, Denver, CO, United States
^q Neuroepidemiology Unit, University of Melbourne School of Population and Global Health, Carlton, Melbourne, Australia
^r Clinical Outcomes Research Unit (CORe), Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne, Australia
^s Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
^t Department of Systems Pharmacology and Translational Therapeutics (SPATT), University of Pennsylvania, Philadelphia, PA, United States
^u Department of Integrative Biology, University of California Berkeley, Berkeley, CA, United States

Abstract
Background: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. Methods: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated. Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1∗15 and the absence of A∗02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). Results: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A∗02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. Conclusions: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis. © 2023 Author(s). Published by BMJ.

Author Keywords
genetics;  multiple sclerosis;  paediatric neurology

Funding details
National Institutes of HealthNIH
National Multiple Sclerosis SocietyNMSSHC-1509-06233
Patient-Centered Outcomes Research InstitutePCORI
Multiple Sclerosis International FederationMSIF

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

Adverse childhood experiences and association with poorer health and health-harming behaviours in adulthood among the Americans
(2023) Child: Care, Health and Development, . 

Islam, M.M.^a , Rashid, M.^b , Rashid, M.^c

^a Department of Statistics, College of Science, Sultan Qaboos University, Muscat, Oman
^b Washington University in St. Louis, St. Louis, MO, United States
^c Department of Mathematical Sciences, DePauw University, Greencastle, IN, United States

Abstract
Background: Adverse childhood experiences (ACEs) such as abuse and neglect have an immediate impact on children and are associated with poorer health and behavioural outcomes in adulthood. This study examined the prevalence of ACEs and their association with socio-demographic factors, physical and mental health, morbidity and health-harming behaviours in adulthood among Americans. Method: Data for the study come from the 2019 Behavioral Risk Factor Surveillance System (BRFSS), covering a sample of 116 032 adult respondents from 22 states of the United States. Descriptive and inferential statistical techniques, including multiple logistic regression models, were employed to analyse the data. Results: At least one kind of ACE was found to be quite common among American adults, as 60% of adults had at least one kind of ACE, 22.5% had one ACE and 17% had four or more ACEs during 0–17 years of life. Of the total ACEs, 42.2% were due to abuse (physical, emotional or sexual), and 46% were due to any kind of household dysfunction. There is an increasing trend in ACEs in the United States. Adults with low socio-economic status, female, living in urban areas, gay or bisexual orientation, minority other than White and unemployed had a significantly higher prevalence of ACEs than their counterparts. ACEs were found to be significantly associated with poor physical and mental health; health-harming behaviours such as binge drinking, heavy drinking and smoking; and chronic morbidities. Conclusion: Programmes aimed at reducing ACEs and mitigating the harms of ACEs among those who have already experienced them should be strengthened to improve public health and quality of life and reduce health-harming behaviours. © 2023 John Wiley & Sons Ltd.

Author Keywords
abuse;  adverse childhood experience;  behaviour;  health-harming;  morbidity

Funding details
Sultan Qaboos UniversitySQU

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

Choline Intake and Cognitive Function Among U.S. Older Adults
(2023) Journal of Nutrition in Gerontology and Geriatrics, . 

An, R.^a , Li, D.^b , Xiang, X.^b

^a Brown School, Washington University, St. Louis, MO, United States
^b School of Social Work, University of Michigan, Ann Arbor, MI, United States

Abstract
Choline is an essential nutrient affects brain development in early life. However, evidence is lacking regarding its potential neuroprotective effects in later life from community-based cohorts. This study assessed the relationship between choline intake and cognitive functioning in a sample of older adults 60 years + from the National Health and Nutrition Examination Survey 2011–2012 and 2013–2014 waves (n = 2,796). Choline intake was assessed using two nonconsecutive 24-hour dietary recalls. Cognitive assessments included immediate and delayed word recalls, Animal Fluency, and Digit Symbol Substitution Test. The average daily dietary choline intake was 307.5 mg, and the total intake (including intake from dietary supplements) was 330.9 mg, both below the Adequate Intake level. Neither dietary OR = 0.94, 95% CI (0.75, 1.17) nor total choline intake OR = 0.87, 95% CI (0.70, 1.09) was associated with changes in cognitive test scores. Further investigation adopting longitudinal or experimental designs may shed light on the issue. © 2023 Taylor & Francis Group, LLC.

Author Keywords
Choline;  cognition;  diet;  older adult

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

One-Year Hearing Preservation and Speech Outcomes Comparing Slim Modiolar and Lateral Wall Arrays
(2023) Otolaryngology – Head and Neck Surgery (United States), . 

Zhan, K.Y., Walia, A., Durakovic, N., Wick, C.C., Buchman, C.A., Shew, M.A., Herzog, J.A.

Department of Otolaryngology-Head and Neck Surgery, Division of Otology and Neurotology, Washington University in St Louis, St Louis, MO, United States

Abstract
Objective: Compare postoperative speech outcomes in hearing preservation (HP) cochlear implantation (CI) patients with a low-frequency pure-tone average (LFPTA) ≤ 60 dB using 2 electrode array designs. Study Design: Retrospective cohort study. Setting: Large academic cochlear implant referral center. Methods: We reviewed adult HP CI cases using either the slim modiolar electrode (SME) (CI 532/CI 632) or th slim lateral wall electrode (SLWE) (CI 624). One-year speech outcomes and HP status were the primary outcomes. Results: A total of 132 implanted ears were analyzed (mean age 73.1 years, standard deviation [SD] 12.6), with 72% (N = 95) with CI 532/632 and 28% (N = 37) with CI 624. The mean preoperative LFPTA was 44.8 dB, SD 11.8. One-year functional HP was 27.2% (mean LFPTA shift 46.1 dB, SD 22.1) and was as follows: SME 23.9% and SLWE 36.4%, p =.168. The mean age at implantation was significantly younger only in SLWE patients with preserved hearing (66.9 vs 80.3 years, p =.008). At 6 months, speech measures were significantly better in all outcomes in HP patients with an SLWE than nonpreserved SLWE patients; this effect abated at 1 year as performance among nonpreserved SLWE patients became equivalent to the remaining cohort. Speech outcomes in SME patients were similar regardless of HP status. Age at implantation and datalogging was correlated with speech outcomes. Conclusion: In this cohort of HP patients, a 1-year functional HP rate of 23.9% (SME) and 36.4% (SLWE) was observed (p = 0.168). This was initially 57.1% (SME) and 70.3% (SLWE) at activation, p =.172. Datalogging and age at implantation were correlated with postoperative speech outcomes. © 2023 American Academy of Otolaryngology–Head and Neck Surgery Foundation.

Author Keywords
cochlear implants;  electrode array;  hearing preservation;  speech outcomes

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

Genetic Variants Associated with Opioid Use Disorder
(2023) Clinical Pharmacology and Therapeutics, . 

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

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

Abstract
Genetics are presumed to contribute 30–40% to opioid use disorder (OUD), allowing for the possibility that genetic markers could be used to identify personal risk for developing OUD. We aimed to test the potential association among 180 candidate single nucleotide polymorphisms (SNPs), 120 of which were related to the dopamine reward pathway and 60 related to pharmacokinetics. Participants were randomly recruited in 2020–2021 in a cross-sectional genetic association study. Self-reported health history including Diagnostic and Statistical Manual of Mental Disorders (DSM-5) OUD criteria and buccal swabs were collected. A total of 1,301 participants were included in the analyses for this study. Of included participants, 250 met the DSM-5 criteria for ever having OUD. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and DSM-5 criteria consistent with OUD. Six SNPs found in 4 genes were associated with OUD: increased odds with CYP3A5 (rs15524 and rs776746) and DRD3 (rs324029 and rs2654754), and decreased odds with CYP3A4 (rs2740574) and CYP1A2 (rs2069514). Homozygotic CYP3A5 (rs15524 and rs776746) had the highest adjusted odds ratio of 2.812 (95% confidence interval (CI) 1.737, 4.798) and 2.495 (95% CI 1.670, 3.835), respectively. Variants within the dopamine reward and opioid metabolism pathways have significant positive (DRD3 and CYP3A5) and negative (CYP3A4 and CYP1A2) associations with OUD. Identification of these variants provides promising possibilities for genetic prognostic and therapeutic targets for future investigation. © 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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

Rural–urban differences in personality traits and well-being in adulthood
(2023) Journal of Personality, . 

Atherton, O.E.^a b , Willroth, E.C.^c , Graham, E.K.^b , Luo, J.^b , Mroczek, D.K.^b d , Lewis-Thames, M.W.^b

^a Department of Psychology, University of Houston, Houston, TX, United States
^b Department of Medical Social Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology, Northwestern University, Evanston, IL, United States

Abstract
Objective: One large focus of personality psychology is to understand the biopsychosocial factors responsible for adult personality development and well-being change. However, little is known about how macro-level contextual factors, such as rurality–urbanicity, are related to personality development and well-being change. Method: The present study uses data from two large longitudinal studies of U.S. Americans (MIDUS, HRS) to examine whether there are rural–urban differences in levels and changes in the Big Five personality traits and well-being (i.e., psychological well-being, and life satisfaction) in adulthood. Results: Multilevel models showed that Americans who lived in more rural areas tended to have lower levels of openness, conscientiousness, and psychological well-being, and higher levels of neuroticism. With the exception of psychological well-being (which replicated across MIDUS and HRS), rural–urban differences in personality traits were only evident in the HRS sample. The effect of neuroticism was fully robust to the inclusion of socio-demographic and social network covariates, but other effects were partially robust (i.e., conscientiousness and openness) or were not robust at all (i.e., psychological well-being). In both samples, there were no rural–urban differences in Big Five or well-being change. Conclusions: We discuss the implications of these findings for personality and rural health research. © 2023 Wiley Periodicals LLC.

Author Keywords
Big Five;  HRS;  life satisfaction;  longitudinal;  MIDUS;  psychological well-being;  rurality

Funding details
National Institute on AgingNIAP01‐AG020166, P30‐AG059988, R01‐AG018436, U19‐AG051426
National Cancer InstituteNCIK01‐CA262342
John D. and Catherine T. MacArthur FoundationJDCTMF
Respiratory Health Association of Metropolitan ChicagoRHAMCRHA2020‐01
Northwestern UniversityNUUL1TR001422

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

The Role of Thyroid Dysfunction in Alzheimer’s Disease: A Systematic Review and Meta-Analysis
(2023) Journal of Prevention of Alzheimer’s Disease, . 

Salehipour, A.^a c , Dolatshahi, M.^b c , Haghshomar, M.^c d , Amin, J.^e

^a Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
^b Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
^c NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
^d Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
^e Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom

Abstract
Imbalances in thyroid hormones have been linked with Alzheimer’s dementia. Several studies have reported an association between thyroid disorders, such as hyper- or hypothyroidism, with Alzheimer’s disease. However, there remains no consensus about the precise role of thyroid dysfunction in Alzheimer’s disease. In this study we systematically searched PubMed, Embase and Scopus for clinical studies which reported the prevalence of hyper- or hypothyroidism in people with Alzheimer’s disease compared to controls. Meta-analysis was performed to compare thyroid disorder prevalence in Alzheimer’s disease and controls. Subgroup analysis was performed to assess the clinical and subclinical thyroid dysfunction, separately. Seven studies, including 1189 people with Alzheimer’s disease and 72711 controls, were included in our sample. Hypothyroidism was significantly more prevalent in Alzheimer’s disease compared with controls (6.4% vs 2.4%, p=0.01). Subgroup analysis showed that clinical hypothyroidism was not significantly different between Alzheimer’s disease compared to controls (10.0% vs 5.3%, p=0.35). There was no difference in the crude overall prevalence of clinical and subclinical hyperthyroidism in Alzheimer’s disease versus controls (2.4 vs 1.9%, p=0.73). Our analyses revealed a higher prevalence of hypothyroidism in Alzheimer’s disease. Whether this finding is explained by hypothyroidism being a risk factor for, or consequence of, Alzheimer’s disease requires longitudinal analysis. Our review supports further work into a potential role for treatment of hypothyroidism in the prevention or delay of Alzheimer’s disease. © 2023, The Authors.

Author Keywords
Alzheimer’s disease;  hyperthyroidism;  hypothyroidism;  meta-analysis;  thyroid

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

Cognitive function following diabetic ketoacidosis in young children with type 1 diabetes
(2023) Endocrinology, Diabetes and Metabolism, . 

Ghetti, S.^a b , Kuppermann, N.^c d , Rewers, A.^e , Myers, S.R.^f , Schunk, J.E.^g , Stoner, M.J.^h , Garro, A.ⁱ , Quayle, K.S.^j , Brown, K.M.^k , Trainor, J.L.^l , Tzimenatos, L.^c , DePiero, A.D.^m , McManemy, J.K.ⁿ , Nigrovic, L.E.^o , Kwok, M.Y.^p , Olsen, C.S.^g , Casper, T.C.^g , Glaser, N.S.^d , Lewis, R.^q , Blumer, J.^q , Bremer, A.^q , Cook, T.^q , Slomine, B.^q , Meert, K.^q , Zimmerman, J.^q , Hickey, R.^q , Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group^q

^a Department of Psychology, University of California, Davis, Davis, CA, United States
^b Center for Mind and Brain, University of California, Davis, Davis, CA, United States
^c Department of Emergency Medicine, University of California Davis Health, University of California Davis, School of Medicine, Davis, CA, United States
^d Department of Pediatrics, University of California Davis Health, University of California Davis, School of Medicine, Davis, CA, United States
^e Division of Emergency Medicine, Department of Pediatrics, The Colorado Children’s Hospital, University of Colorado-Denver School of Medicine, Aurora, CO, United States
^f Division of Emergency Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^g Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, United States
^h Division of Emergency Medicine, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University School of Medicine, Columbus, OH, United States
ⁱ Departments of Emergency Medicine and Pediatrics, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, United States
^j Division of Emergency Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^k Division of Emergency Medicine, Department of Pediatrics, Children’s National Medical Center, The George Washington School of Medicine and Health Sciences, Washington, District of Columbia, United States
^l Division of Emergency Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^m Division of Emergency Medicine, Nemours/A.I. DuPont Hospital for Children, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
ⁿ Division of Emergency Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^o Division of Emergency Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^p Division of Emergency Medicine, Department of Pediatrics, New York Presbyterian Morgan Stanley Children’s Hospital, Columbia University College of Physicians and Surgeons, New York City, NY, United States

Abstract
Introduction: Young children with type 1 diabetes (T1D) may be at particularly high risk of cognitive decline following diabetic ketoacidosis (DKA). However, studies of cognitive functioning in T1D typically examine school-age children. The goal of this study was to examine whether a single experience of DKA is associated with lower cognitive functioning in young children. We found that recently diagnosed 3- to 5-year-olds who experienced one DKA episode, regardless of its severity, exhibited lower IQ scores than those with no DKA exposure. Methods: We prospectively enrolled 46 3- to 5-year-old children, who presented with DKA at the onset of T1D, in a randomized multi-site clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 22 children and mild in 24 children. Neurocognitive function was assessed once 2–6 months after the DKA episode. A comparison group of 27 children with T1D, but no DKA exposure, was also assessed. Patient groups were matched for age and T1D duration at the time of neurocognitive testing. Results: Children who experienced DKA, regardless of its severity, exhibited significantly lower IQ scores than children who did not experience DKA, F(2, 70) = 6.26, p =.003, partial η2 =.15. This effect persisted after accounting for socioeconomic status and ethnicity. Conclusions: A single DKA episode is associated with lower IQ scores soon after exposure to DKA in young children. © 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

Author Keywords
cognitive function;  diabetic ketoacidosis;  early childhood;  intelligence;  type 1 diabetes

Funding details
Health Resources and Services AdministrationHRSA
Maternal and Child Health BureauMCHBU03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC00008, U03MC22684, U03MC22685
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

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

Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses
(2022) Frontiers in Neurology, 13, art. no. 1061363, . 

Ostergaard, J.R.^a , Nelvagal, H.R.^b c , Cooper, J.D.^b d e

^a Department of Child and Adolescencet, Centre for Rare Diseases, Aarhus, Denmark
^b Department of Pediatrics, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^c UCL School of Pharmacy, University College London, London, United Kingdom
^d Department of Genetics, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^e Department of Neurology, School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
Background: The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation. Methods: We have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of PPT1 function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively. Results: Despite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and postmortem studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence/early twenties, with the extrapyramidal system also affected during this time course. Discussion: The propagation of disease in these two NCLs therefore has much in common with the “Brain-first” vs. “Body-first” models of alpha-synuclein propagation in Parkinson’s disease. CLN1 disease represents a “Body-first” or bottom-up disease propagation and CLN3 disease having a “Brain-first” and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood (juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in the outer retinal layers, i.e., identical to classical Juvenile NCL disease. Copyright © 2022 Ostergaard, Nelvagal and Cooper.

Author Keywords
Body-first;  Brain-first;  CLN1;  CLN3;  connectome;  disease propagation;  neurodegeneration;  neuronal ceroid lipofuscinoses

Document Type: Article
Publication Stage: Final
Source: Scopus