WashU weekly Neuroscience publications

The herbicide glyphosate inhibits hippocampal long-term potentiation and learning through activation of pro-inflammatory signaling
(2023) Scientific Reports, 13 (1), art. no. 18005, . 

Izumi, Y.^a b , O’Dell, K.A.^a b , Zorumski, C.F.^a b

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute administration of 10–100 μM glyphosate also inhibited LTP induction. Minocycline, an inhibitor of microglial activation, and TAK-242, an inhibitor of toll-like receptor 4 (TLR4), both overcame the inhibitory effects of 100 µM glyphosate. Similarly, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), a different TLR4 antagonist, overcame the inhibitory effects. In addition, ISRIB (integrated stress response inhibitor) and quercetin, an inhibitor of endoplasmic reticulum stress, overcame the inhibitory effects. We also observed that in vivo glyphosate injection (16.9 mg/kg i.p.) impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by TAK-242. These observations indicate that glyphosate can impair cognitive function through pro-inflammatory signaling in microglia. © 2023, Springer Nature Limited.

Funding details
National Institute of Mental HealthNIMHMH122379
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas
(2023) BMC Research Notes, 16 (1), art. no. 275, . 

Williams, K.B.^a , Marley, A.R.^b , Tibbitts, J.^a , Moertel, C.L.^a , Johnson, K.J.^c , Linden, M.A.^d , Largaespada, D.A.^a , Marcotte, E.L.^a b

^a Department of Pediatrics, Masonic Cancer Center, University of Minnesota – Twin Cities, 515 Delaware St SE, Minneapolis, MN 55455, United States
^b Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota – Twin Cities, 420 Delaware St SE MMC 715, Minneapolis, MN 55455, United States
^c Brown School, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
^d Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota – Twin Cities, 420 Delaware St SE, Minneapolis, MN 55455, United States

Abstract
Objective: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model. Results: We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status. © 2023, BioMed Central Ltd., part of Springer Nature.

Author Keywords
Folate intake;  Murine models;  NF1;  Plexiform-like neurofibromas

Funding details
W81XWH 17-1-0633
National Cancer InstituteNCIT32 CA099936
Division of Cancer Prevention, National Cancer InstituteDCP, NCI
Center for Strategic Scientific Initiatives, National Cancer InstituteCSSI, NCI
Division of Cancer Epidemiology and Genetics, National Cancer InstituteDCEG
Center for Biomedical Informatics and Information Technology, National Cancer InstituteCBIIT, NCI CBIIT

Document Type: Article
Publication Stage: Final
Source: Scopus

Vertebrate-class-specific binding modes of the alphavirus receptor MXRA8
(2023) Cell, 186 (22), pp. 4818-4833.e25. 

Zimmerman, O.^a , Zimmerman, M.I.^b , Raju, S.^b , Nelson, C.A.^b , Errico, J.M.^b , Madden, E.A.^a , Holmes, A.C.^a , Hassan, A.O.^a , VanBlargan, L.A.^a , Kim, A.S.^a b , Adams, L.J.^b , Basore, K.^b , Whitener, B.M.^a , Palakurty, S.^a , Davis-Adams, H.G.^a , Sun, C.^c , Gilliland, T., Jr.^c , Earnest, J.T.^a , Ma, H.^a , Ebel, G.D.^d , Zmasek, C.^e , Scheuermann, R.H.^e f g h , Klimstra, W.B.^c , Fremont, D.H.^b i j , Diamond, M.S.^a b i k

^a Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Center for Vaccine Research, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15260, United States
^d Center for Vector-borne Infectious Diseases, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, United States
^e J. Craig Venter Research Institute, La Jolla, CA 92037, United States
^f Department of Pathology, University of California, San Diego, San Diego, CA 92161, United States
^g Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States
^h Global Virus Network, Baltimore, MD 92037, United States
ⁱ Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^j Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, United States
^k Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
MXRA8 is a receptor for chikungunya (CHIKV) and other arthritogenic alphaviruses with mammalian hosts. However, mammalian MXRA8 does not bind to alphaviruses that infect humans and have avian reservoirs. Here, we show that avian, but not mammalian, MXRA8 can act as a receptor for Sindbis, western equine encephalitis (WEEV), and related alphaviruses with avian reservoirs. Structural analysis of duck MXRA8 complexed with WEEV reveals an inverted binding mode compared with mammalian MXRA8 bound to CHIKV. Whereas both domains of mammalian MXRA8 bind CHIKV E1 and E2, only domain 1 of avian MXRA8 engages WEEV E1, and no appreciable contacts are made with WEEV E2. Using these results, we generated a chimeric avian-mammalian MXRA8 decoy-receptor that neutralizes infection of multiple alphaviruses from distinct antigenic groups in vitro and in vivo. Thus, different alphaviruses can bind MXRA8 encoded by different vertebrate classes with distinct engagement modes, which enables development of broad-spectrum inhibitors. © 2023 Elsevier Inc.

Author Keywords
alphavirus;  birds;  cryoelectron microscopy;  evolution;  inhibitor;  mammals;  pathogenesis;  receptor;  species;  structure;  tropism

Funding details
National Institutes of HealthNIHR01 AI067380, R01 AI095436, R01 AI114816, R01 AI123348
National Institute of Allergy and Infectious DiseasesNIAID75N93022C00035
Defense Threat Reduction AgencyDTRAMCDC2103-011
Vir Biotechnology

Document Type: Article
Publication Stage: Final
Source: Scopus

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb
(2023) Nature, 622 (7984), pp. 802-809. 

Ma, S.^a b , Chen, M.^b c , Jiang, Y.^b c , Xiang, X.^b , Wang, S.^b , Wu, Z.^b , Li, S.^b , Cui, Y.^b , Wang, J.^b , Zhu, Y.^b , Zhang, Y.^b , Ma, H.^b , Duan, S.^b , Li, H.^b , Yang, Y.^b c , Lingle, C.J.^d , Hu, H.^a b c

^a Department of Psychiatry and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
^b Nanhu Brain–Computer Interface Institute, MOE Frontier Science Center for Brain Science and Brain–Machine Integration, State Key Laboratory of Brain–Machine Intelligence, New Cornerstone Science Laboratory, Zhejiang University, Hangzhou, China
^c Department of Affiliated Mental Health Center and Hangzhou Seventh People’s Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China
^d Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2–4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6–9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine. © 2023, The Author(s).

Funding details
2020R01001
SN-ZJU-SIAS-002
National Natural Science Foundation of ChinaNSFC31830032, 32130042, 82288101
Special Project for Research and Development in Key areas of Guangdong Province2018B030331001, 2018B030334001

Document Type: Article
Publication Stage: Final
Source: Scopus

Macrocephaly and developmental delay caused by missense variants in RAB5C
(2023) Human Molecular Genetics, 32 (21), pp. 3063-3077. 

Koop, K.^a , Yuan, W.^b , Tessadori, F.^c , Rodriguez-Polanco, W.R.^d , Grubbs, J.^e , Zhang, B.^b , Osmond, M.^f , Graham, G.^f , Sawyer, S.^g , Conboy, E.^h , Vetrini, F.^h , Treat, K.^h , Płoski, R.ⁱ , Pienkowski, V.M.^i j , Kłosowska, A.^k , Fieg, E.^l m , Krier, J.^l m , Mallebranche, C.ⁿ , Alban, Z.^o , Aldinger, K.A.^p q , Ritter, D.^r , Macnamara, E.^s , Sullivan, B.^t , Herriges, J.^u , Alaimo, J.T.^u , Helbig, C.^v , Ellis, C.A.^w , van Eyk, C.^x , Gecz, J.^x , Farrugia, D.^y , Osei-Owusu, I.^z , Adès, L.^aa , van den Boogaard, M.-J.^ab , Fuchs, S.^a , Bakker, J.^c , Duran, K.^c , Dawson, Z.D.^b , Lindsey, A.^b , Huang, H.^b , Baldridge, D.^b , Silverman, G.A.^b , Grant, B.D.^d , Raizen, D.^e , van Haaften, G.^ab , Pak, S.C.^b , Rehmann, H.^ac , Schedl, T.^b , van Hasselt, P.^a , Undiagnosed Diseases Network^ad

^a Department of Pediatrics, University Medical Center Utrecht, EA, Utrecht 3584, Netherlands
^b Departments of Pediatrics and Genetics, C. elegans Model Organism Screening Center, Washington University in St Louis School of Medicine, St Louis, MO 63110, United States
^c Hubrecht Institute-KNAW and University Medical Center UtrechtUtrecht 3584 CT, Netherlands
^d Department of Molecular Biology and Biochemistry, Rutgers, State University of New Jersey, Piscataway, NJ 08854, United States
^e Department of Neurology and the Chronobiology and Sleep Institute, University of Pennsylvania, Philadelphia, PA 19104, United States
^f Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
^g Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada
^h Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
ⁱ Department of Medical Genetics, Medical University of Warsaw, Warsaw, 02-106, Poland
^j Marseille Medical Genetics U1251, Aix Marseille University, Marseille, 13005, France
^k Department of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, 80-210, Poland
^l Brigham and Women’s Hospital, Boston, MA 02115, United States
^m Harvard Medical School, Boston, MA 02115, United States
ⁿ Unité d’Onco-Hémato-Immunologie pédiatrique, CHU d’Angers, Angers, 49933, France
^o CHU d’Angers, Service de génétique, Angers, 49933, France
^p Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98195, United States
^q Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, United States
^r Department of Pediatrics, Oncology Section, Baylor College of Medicine, Houston, TX 77030, United States
^s Undiagnosed Diseases Program Translational Laboratory, NHGRI, National Institutes of Health, Bethesda, MD 20892, United States
^t Division of Clinical Genetics, Department of Pediatrics, Children’s Mercy-Kansas City, Kansas City, MO 64108, United States
^u Department of Pathology and Laboratory Medicine, Children’s Mercy-Kansas City, Kansas City, MO 64108, United States
^v Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^w Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia PA19104, United States
^x Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5006, Australia
^y Haematology, Mater Dei HospitalMSD2090, Malta
^z Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
^aa Department of Clinical Genetics, Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, 2145, Australia
^ab Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584EA, Utrecht, Netherlands
^ac Department of Energy and Biotechnology, Flensburg University of Applied Sciences, Flensburg, 24943, Germany

Abstract
Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

Recruitment methods and yield rates for a multisite clinical trial exploring risk reduction for Alzheimer’s disease (rrAD)
(2023) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 9 (4), art. no. e12422, . 

Szabo-Reed, A.N.^a b , Hall, T.^c , Vidoni, E.D.^a d , Van Sciver, A.^a , Sewell, M.^e , Burns, J.M.^a d , Cullum, C.M.^f g , Gahan, W.P.^h , Hynan, L.S.^f i , Kerwin, D.R.^j k , Rossetti, H.^f , Stowe, A.M.^k , Vongpatanasin, W.^h , Zhu, D.C.^l , Zhang, R.^c g , Keller, J.N.^h , Binder, E.F.^e

^a KU Alzheimer’s Disease Research Center, University of Kansas Medical Center, Fairway, KS, United States
^b Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States
^c Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, United States
^d Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
^e Department of Internal Medicine, Division of Geriatrics & Nutritional Science, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^f Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States
^g Department of Neurology, UT Southwestern Medical Center, Dallas, TX, United States
^h Institute for Dementia Research and Prevention, Pennington Biomedical Research Center, Baton Rouge, LA, United States
ⁱ Peter O’Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, United States
^j Kerwin Research Center and Memory Care, Dallas, TX, United States
^k Department of Neurology, University of Kentucky, Lexington, KY, United States
^l Department for Radiology, Michigan State University, East Lansing, MI, United States

Abstract
INTRODUCTION: The risk reduction for Alzheimer’s disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer’s disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site’s project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions. The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles. The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants. The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site. The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site. Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements. © 2023 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  brain structure;  cognition;  exercise;  recruitment;  reduction of vascular risk factors

Funding details
National Institutes of HealthNIHKL2TR002367, NCT0291366, R01 AG49749, R24 AG063724

Document Type: Article
Publication Stage: Final
Source: Scopus

Development and evaluation of a wearable peripheral vascular compensation sensor in a swine model of hemorrhage
(2023) Biomedical Optics Express, 14 (10), pp. 5338-5357. 

Bonetta-Misteli, F.^a , Collins, T.^b , Pavek, T.^b , Carlgren, M.^a c , Bashe, D.^a d , Frolova, A.^c , Shmuylovich, L.^d e , O’Brien, C.M.^a c

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
^b Division of Comparative Medicine, Washington University in St. Louis, St. Louis, United States
^c Department of Obstetrics & Gynecology, Washington University in St. Louis, St. Louis, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, United States
^e Department of Dermatology, Washington University in St. Louis, St. Louis, United States

Abstract
Postpartum hemorrhage (PPH) is the leading and most preventable cause of maternal mortality, particularly in low-resource settings. PPH is currently diagnosed through visual estimation of blood loss or monitoring of vital signs. Visual assessment routinely underestimates blood loss beyond the point of pharmaceutical intervention. Quantitative monitoring of hemorrhage-induced compensatory processes, such as the constriction of peripheral vessels, may provide an early alert for PPH. To this end, we developed a low-cost, wearable optical device that continuously monitors peripheral perfusion via laser speckle flow index (LSFI) to detect hemorrhage-induced peripheral vasoconstriction. The measured LSFI signal produced a linear response in phantom models and a strong correlation coefficient with blood loss averaged across subjects (>0.9) in a large animal model, with superior performance to vital sign metrics. © 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.

Funding details
Washington University in St. LouisWUSTL
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR00HD103954

Document Type: Article
Publication Stage: Final
Source: Scopus

Genomic medicine to reduce tobacco and related disorders: Translation to precision prevention and treatment
(2023) Addiction Neuroscience, 7, art. no. 100083, . Cited 1 time.

Chen, L.-S.^a b , Baker, T.B.^c , Ramsey, A.^a b , Amos, C.I.^d e , Bierut, L.J.^a b

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO, United States
^c Center for Tobacco Research and Intervention, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
^d Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
^e Department of Medicine, Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, TX, United States

Abstract
Genomic medicine can enhance prevention and treatment. First, we propose that advances in genomics have the potential to enhance assessment of disease risk, improve prognostic predictions, and guide treatment development and application. Clinical implementation of polygenic risk scores (PRSs) has emerged as an area of active research. The pathway from genomic discovery to implementation is an iterative process. Second, we provide examples on how genomic medicine has the potential to solve problems in prevention and treatment using two examples: Lung cancer screening and evidence-based tobacco treatment are both under-utilized and great opportunities for genomic interventions. Third, we discuss the translational process for developing genomic interventions from evidence to implementation by presenting a model to evaluate genomic evidence for clinical implementation, mechanisms of genomic interventions, and patient desire for genomic interventions. Fourth, we present potential challenges in genomic interventions including a great need for evidence in all diverse populations, little evidence on treatment algorithms, challenges in accommodating a dynamic evidence base, and implementation challenges in real world clinical settings. Finally, we conclude that research to identify genomic markers that are associated with smoking cessation success and the efficacy of smoking cessation treatments is needed to empower people of all diverse ancestry. Importantly, genomic data can be used to help identify patients with elevated risk for nicotine addiction, difficulty quitting smoking, favorable response to specific pharmacotherapy, and tobacco-related health problems. © 2023

Author Keywords
Clinical implementation;  Genomic medicine;  Genomics;  Lung cancer;  Polygenic risk;  Precision prevention;  Precision treatment;  Tobacco

Document Type: Article
Publication Stage: Final
Source: Scopus

Working Title: Smoking cessation, harm reduction, and biomarkers protocols in the PhenX Toolkit: Tools for standardized data collection
(2023) Addiction Neuroscience, 7, art. no. 100081, . Cited 1 time.

Bierut, L.J.^a , Hendershot, T.P.^b , Benowitz, N.L.^c , Cummings, K.M.^d , Mermelstein, R.J.^e , Piper, M.E.^f , Vrieze, S.I.^g , Wagener, T.L.^h , Nelms, M.D.^b , Ives, C.^b , Maiese, D.^b , Hamilton, C.M.^b , Swan, G.E.ⁱ

^a Department of Psychiatry, Founding Director Health and Behavior Research Center, Washington University School of Medicine of St. Louis, 660 South Euclid, Campus Box 8134, St. Louis, MO 63110, United States
^b RTI International, Center for GenOmics, Bioinformatics and Translational Research, Research Triangle Park, NC, United States
^c Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
^d Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States
^e Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
^f Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
^g Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^h Department of Internal Medicine, The Ohio State University, Columbus, OH, United States
ⁱ Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States

Abstract
The use of standard protocols in studies supports consistent data collection, improves data quality, and facilitates cross-study analyses. Funded by the National Institutes of Health, the PhenX (consensus measures for Phenotypes and eXposures) Toolkit is a catalog of recommended measurement protocols that address a wide range of research topics and are suitable for inclusion in a variety of study designs. In 2020, a PhenX Working Group of smoking cessation experts followed a well-established consensus process to identify and recommend measurement protocols suitable for inclusion in smoking cessation and smoking harm reduction studies. The broader scientific community was invited to review and provide feedback on the preliminary recommendation of the Working Group. Fourteen selected protocols for measuring smoking cessation, harm reduction, and biomarkers research associated with smoking cessation were released in the PhenX Toolkit (https://www.phenxtoolkit.org) in February 2021. These protocols complement existing PhenX Toolkit content related to tobacco regulatory research, substance use and addiction research, and other measures of smoking-related health outcomes. Adopting well-established protocols enables consistent data collection and facilitates comparing and combining data across studies, potentially increasing the scientific impact of individual studies. © 2023

Author Keywords
Harm reduction;  PhenX Toolkit;  Smoking cessation;  Standardized data collection

Document Type: Article
Publication Stage: Final
Source: Scopus

Comprehensive Assessment of the Activity Level of the ICF Using Both Capacity and Performance Measures: A Case Report
(2023) Archives of Rehabilitation Research and Clinical Translation, 5 (3), art. no. 100277, . 

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

Abstract
Individuals with neurologic conditions seek physical therapy services to improve mobility in their daily lives. While clinicians commonly track activity capacity, measurement of activity performance in daily life is an emerging yet unstandardized practice within routine clinical physical therapy. The purpose of this case report is to (1) provide an example of the structure, clinical reasoning, and implementation of both activity capacity and activity performance level assessments across an episode of outpatient physical therapy and (2) to describe how objective activity performance in daily life tracking supported the physical therapy intervention and education plan. A 42-year-old woman presented to outpatient neurologic physical therapy with a rare autoimmune-mediated disorder with primary goals of independently caring for her youngest child and grandchild, walking without limitations in the home and community, participating in exercise, and returning to work due to deconditioning and dizziness. The patient participated in 12 visits across a span of 4.5 months targeting performance in daily life (steps per day), aerobic conditioning, and vestibular habituation. Activity capacity measurement served as a standardized assessment of what the patient was able to do in the clinic, and activity performance in daily life tracking via a Samsung wrist worn consumer-grade device provided a quantitative assessment of real-world daily stepping activity. Tracking of activity performance in daily life was an essential component of physical therapy management that provided an objective quantification of daily stepping activity to identify barriers and facilitators to increasing daily performance in an individual with a medical diagnosis of Susac syndrome. © 2023 The Authors

Author Keywords
Capacity;  Measurement;  Performance;  Rehabilitation

Funding details
National Institutes of HealthNIHR01HD068290

Document Type: Article
Publication Stage: Final
Source: Scopus

Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness
(2023) Innovations in Clinical Neuroscience, 20 (7-9), pp. 40-46. 

Lutz, J.^a b c , Pratap, A.^d e f g , Lenze, E.J.^h , Bestha, D.ⁱ , Lipschitz, J.M.^j k , Karantzoulis, S.^l , Vaidyanathan, U.^e m , Robin, J.ⁿ , Horan, W.^o p q , Brannan, S.^p , Mittoux, A.^r , Davis, M.C.^s , Lakhan, S.E.^a t , Keefe, R.^u

^a Click Therapeutics, Inc, New York, NY, United States
^b Biogen Digital Health, Cambridge, MA, United States
^c Boston University School of Medicine, Boston, MA, United States
^d Center for Addiction & Mental Health, Toronto, Canada
^e Boehringer Ingelheim, Ridgefield, CT, United States
^f King’s College London, London, United Kingdom
^g Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, United States
^h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Atrium Health, Charlotte, NC, United States
^j Brigham and Women’s Hospital, Boston, MA, United States
^k Harvard Medical School, Boston, MA, United States
^l IQVIA, New York, NY, United States
^m Sublimus, Ridgefield, CT, United States
ⁿ Winterlight Labs, Inc, Toronto, Canada
^o WCG VeraSci, Durham, NC, United States
^p Karuna Therapeutics, Boston, MA, United States
^q University of California, Los Angeles, CA, United States
^r Lundbeck, Paris, France
^s Usona Institute, Madison, WI, United States
^t School of Neuroscience, Virginia Tech, Blacksburg, VA, United States
^u Department of Psychiatry, Duke University Medical Center, Durham, NC, United States

Abstract
Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption. © 2023, Matrix Medical Communications. All rights reserved.

Author Keywords
Clinical trials;  CNS;  e-consent;  recruitment;  technology;  virtual trials

Funding details
Patient-Centered Outcomes Research InstitutePCORI
Janssen Pharmaceuticals

Document Type: Article
Publication Stage: Final
Source: Scopus

T1 and FLAIR signal intensities are related to tau pathology in dominantly inherited Alzheimer disease
(2023) Human Brain Mapping, .

Rahmani, F.^a , Brier, M.R.^a , Gordon, B.A.^a , McKay, N.^a , Flores, S.^a , Keefe, S.^a , Hornbeck, R.^a , Ances, B.^a , Joseph-Mathurin, N.^a , Xiong, C.^a , Wang, G.^a , Raji, C.A.^a , Libre-Guerra, J.J.^a , Perrin, R.J.^a , McDade, E.^a , Daniels, A.^a , Karch, C.^a , Day, G.S.^b , Brickman, A.M.^c , Fulham, M.^d , Jack, C.R., Jr.^e , la La Fougère, C.^f g h , Reischl, G.^f g h , Schofield, P.R.^i j , Oh, H.^k , Levin, J.^l m n , Vöglein, J.^l m n , Cash, D.M.^o p , Yakushev, I.^l m n , Ikeuchi, T.^q , Klunk, W.E.^r , Morris, J.C.^a , Bateman, R.J.^a , Benzinger, T.L.S.^a

^a Washington University School of Medicine, St. Louis, MO, United States
^b Mayo Clinic, Department of Neurology, Jacksonville, FL, United States
^c Taub Institute for Research on Alzheimer’s Disease & the Aging Brain, and Department of Neurology College of Physicians and Surgeons, Columbia University, New York, NY, United States
^d Royal Prince Alfred Hospital (RPA), Sydney, Australia
^e Mayo Clinic, Rochester, MN, United States
^f Department of Nuclear Medicine and Clinical Molecular Imaging, University Hospital Tuebingen, Tübingen, Germany
^g German Center for Neurodegenerative Diseases (DZNE) Tuebingen, Tübingen, Germany
^h Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
ⁱ Neuroscience Research Australia, Sydney, NSW, Australia
^j School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
^k Brown University, Providence, RI, United States
^l Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^m German Center for Neurodegenerative Diseases (DZNE), site Munich, Munich, Germany
ⁿ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^o UK Dementia Research Institute at University College London, London, United Kingdom
^p Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
^q Niigata University, Brain Research Institute, Niigata, Japan
^r University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-μ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients. © 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
amyloid PET;  dominantly inherited Alzheimer disease;  quantitative MR imaging;  T1 and FLAIR signal intensity;  tau PET

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAU19AG03243808
Alzheimer’s AssociationAA
Foundation for Barnes-Jewish HospitalFBJH
Japan Agency for Medical Research and DevelopmentAMED
UK Research and InnovationUKRIMR/V03863X/1
Avid RadiopharmaceuticalsK23AG064029, U01AG057195, U01NS120901, U19AG032438
Korea Dementia Research CenterKDRC
Medical Research CouncilMRC
Alzheimer’s Society
University College LondonUCL
National Health and Medical Research CouncilNHMRC
Alzheimer’s Research UKARUKARUK‐PG2017‐1946
Korea Health Industry Development InstituteKHIDI
Ministry of Science ICT and Future PlanningMSIP
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNER01AG052550‐01A1
UCLH Biomedical Research CentreNIHR BRC
Fleni
UK Dementia Research InstituteUK DRI

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

Alzheimer’s polygenic risk scores are associated with cognitive phenotypes in Down syndrome
(2023) Alzheimer’s and Dementia, . 

Gorijala, P.^a b , Aslam, M.M.^c , Dang, L.-H.T.^d e , Xicota, L.^e , Fernandez, M.V.^a b , Sung, Y.J.^a b f , Fan, K.-H.^c , Feingold, E.^c , Surace, E.I.^g , Chhatwal, J.P.^h , Hom, C.L.ⁱ , Hartley, S.L.^j , Hassenstab, J.^k , Perrin, R.J.^l m n , Mapstone, M.^o , Zaman, S.H.^p q , Ances, B.M.ⁿ , Kamboh, M.I.^c , Lee, J.H.^d e , Cruchaga, C.^a b l

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Human Genetics, University of Pittsburgh, School of Public Health, Pittsburgh, PA, United States
^d Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, United States
^e Sergievsky Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^f Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^g Laboratory of Neurodegenerative Diseases – Institute of Neurosciences (INEU-Fleni- CONICET), Buenos Aires, Argentina
^h Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
ⁱ Dept. of Psychiatry and Human Behavior, University of California, Irvine School of MedicineCA, United States
^j Waisman Center and School of Human Ecology, University of Wisconsin- Madison, Madison, WI, United States
^k Department of Neurology and Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^l Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States
^m Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
ⁿ Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^o Department of Neurology, University of California-Irvine, Irvine, CA, United States
^p Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge, Douglas House, United Kingdom
^q Cambridgeshire and Peterborough NHS Foundation Trust, Elizabeth House, Fulbourn Hospital, Cambridge, Fulbourn, United Kingdom

Abstract
INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer’s disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
amyloid precursor protein;  apoliprotein E APOE;  area under the curve;  cerebrospinal fluid biomarkers;  cognitive batteries;  Dominantly Inherited Alzheimer Network;  Down syndrome;  early-onset Alzheimer’s disease;  early-onset autosomal dominant;  genetic architecture;  genetic risk factor;  late-onset Alzheimer’s disease;  polygenic risk score;  PSEN1;  PSEN2;  sporadic late-onset Alzheimer’s disease

Funding details
W81XWH‐12‐2‐0012
P50 HD105353, U54 HD087011, U54 HD090256
U24 AG21886
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG066444, R01AG044546, R01AG064877, RF1AG053303, RF1AG058501, RF1AG074007, U01AG058922, U19AG032438
U.S. Department of DefenseDODLI‐W81XWH2010849
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
National Institute of Child Health and Human DevelopmentNICHDP30 AG062421, P30 AG062715, P30 AG066519, P50 AG005133, P50 AG005681, P50 AG008702, P50 AG16537, U01 AG051406, U01 AG051412, U19 AG068054
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAZEN‐22‐848604
Alzheimer’s Drug Discovery FoundationADDF
Biogen
National Center for Advancing Translational SciencesNCATSUL1 TR001414, UL1 TR001857, UL1 TR001873, UL1 TR002345, UL1 TR002373
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
BioClinica
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni

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

COVID-19 Related Facilitators and Barriers to In-Person Learning for Children With Intellectual and Development Disabilities: A Follow-Up
(2023) Journal of School Health, . 

Vestal, L.E.^a , Schmidt, A.M.^a , Dougherty, N.L.^b , Rolf, L.^b , Newland, J.G.^c , Mueller, N.B.^d

^a Evaluation Center, Brown School at Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130, United States
^b Evaluation Center, Brown School at Washington University in St. Louis, MSC 1196-0251-46, One Brookings Drive, St. Louis, MO 63130, United States
^c Pediatric Infectious Diseases, Washington University School of Medicine, 620 South Taylor, Northwest Tower 10113, St. Louis, MO 63130, United States
^d Institutional Effectiveness, Office of the Provost, Washington University in St. Louis, Campus Box 1196-0251-46, One Brookings Drive, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
BACKGROUND: Students with intellectual and developmental disabilities (IDD) and the staff who support them were largely in-person during the 2021-2022 school year, despite their continued vulnerability to infection with SARS-CoV-2. This qualitative study aimed to understand continued perceptions of weekly SARS-CoV-2 screening testing of students and staff amidst increased availability of vaccinations. METHODS: Twenty-three focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2021-2022 school year. Responses were analyzed using a directed thematic content analysis approach. RESULTS: Four principal themes were identified: strengths and opportunities of school- and district-level mitigation policies; experience at school with the return to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; and perceptions of SARS-CoV-2 testing in light of vaccine availability. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Despite the increased availability of vaccines, school staff and families agreed that saliva-based SARS-CoV-2 screening testing helped increase comfort with in-person learning as long as the virus was present in the community. CONCLUSION: To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important. Clearly communicating school policies and mitigation strategies facilitated peace of mind and confidence in the school district. © 2023 The Authors. Journal of School Health published by Wiley Periodicals LLC on behalf of American School Health Association.

Author Keywords
children with IDD;  COVID-19;  COVID-19 school testing;  COVID-19 vaccinations;  intellectual and developmental disabilities;  SARS-CoV-2 testing

Funding details
National Institutes of HealthNIHP50HD103525‐01S1

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

Improving Early Recognition of Treatment-Responsive Causes of Rapidly Progressive Dementia: The STAM3P Score
(2023) Annals of Neurology, . 

Satyadev, N.^a b , Tipton, P.W.^a , Martens, Y.^c , Dunham, S.R.^d , Geschwind, M.D.^e , Morris, J.C.^d , Brier, M.R.^d , Graff-Radford, N.R.^a , Day, G.S.^a

^a Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
^b Georgia Institute of Technology, Atlanta, GA, United States
^c Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, United States
^d Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^e University of California San Francisco, Department of Neurology, Memory and Aging Center, San Francisco, CA, United States

Abstract
Objective: To improve the timely recognition of patients with treatment-responsive causes of rapidly progressive dementia (RPD). Methods: A total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment-responsive or non-responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum-of-Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment-responsive causes of RPD early in the diagnostic evaluation. Results: A total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment-responsive causes. The median (range) age-at-symptom onset in patients with RPD was 68.9 years (range 22.0–90.7 years), with a similar number of men and women. Seizures, tumor (disease-associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3) in cerebrospinal fluid at presentation were independently associated with treatment-responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age-at-symptom onset <50 years (ie, STAM3P), captured 82 of 86 (95.3%) cases of treatment-responsive RPD. The presence of ≥3 STAM3P features had a positive predictive value of 100%. Interpretation: Selected features at presentation reliably identified patients with potentially treatment-responsive causes of RPD. Adaptation of the STAM3P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2023. © 2023 American Neurological Association.

Funding details
National Institutes of HealthNIHK23AG064029
National Institute on AgingNIA

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

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults
(2023) Development and Psychopathology, . 

Su, J.^a , Kuo, S.I.-C.^b , Aliev, F.^b , Rabinowitz, J.A.^c , Jamil, B.^a , Chan, G.^d e , Edenberg, H.J.^f , Francis, M.^g , Hesselbrock, V.^d , Kamarajan, C.^h , Kinreich, S.^h , Kramer, J.^e , Lai, D.^f , McCutcheon, V.^g , Meyers, J.^h , Pandey, A.^h , Pandey, G.^h , Plawecki, M.H.ⁱ , Schuckit, M.^j , Tischfield, J.^k , Dick, D.M.^l

^a Department of Psychology, Arizona State University, Tempe, AZ, United States
^b Department of Psychiatry, Rutgers University, New Brunswick, NJ, United States
^c Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States
^d Department of Psychiatry, University of Connecticut, Farmington, CT, United States
^e Department of Psychiatry, University of Iowa, Iowa City, IA, United States
^f Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, United States
^g Department of Psychiatry, Washington University, St. Louis, MO, United States
^h Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, United States
ⁱ Department of Psychiatry, Indiana University, Bloomington, IN, United States
^j Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
^k Department of Genetics, Rutgers University, New Brunswick, NJ, United States
^l Rutgers Addiction Research Center, Rutgers University, New Brunswick, NJ, United States

Abstract
Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use. © The Author(s), 2023. Published by Cambridge University Press.

Author Keywords
alcohol use;  COGA;  gene-environment interaction;  polygenic scores;  social support

Funding details
National Institutes of HealthNIHU10AA008401
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA

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

An image-based modeling framework for predicting spatiotemporal brain cancer biology within individual patients
(2023) Frontiers in Oncology, 13, art. no. 1185738, .

Bond, K.M.^a b , Curtin, L.^a , Ranjbar, S.^a , Afshari, A.E.^a , Hu, L.S.^a c , Rubin, J.B.^d , Swanson, K.R.^a

^a Mathematical Neuro-Oncology Lab, Department of Neurological Surgery, Mayo Clinic, Phoenix, AZ, United States
^b Hospital of University of Pennsylvania, Department of Neurosurgery, Philadelphia, PA, United States
^c Department of Radiology, Mayo Clinic, Phoenix, AZ, United States
^d Departments of Neuroscience and Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Imaging is central to the clinical surveillance of brain tumors yet it provides limited insight into a tumor’s underlying biology. Machine learning and other mathematical modeling approaches can leverage paired magnetic resonance images and image-localized tissue samples to predict almost any characteristic of a tumor. Image-based modeling takes advantage of the spatial resolution of routine clinical scans and can be applied to measure biological differences within a tumor, changes over time, as well as the variance between patients. This approach is non-invasive and circumvents the intrinsic challenges of inter- and intratumoral heterogeneity that have historically hindered the complete assessment of tumor biology and treatment responsiveness. It can also reveal tumor characteristics that may guide both surgical and medical decision-making in real-time. Here we describe a general framework for the acquisition of image-localized biopsies and the construction of spatiotemporal radiomics models, as well as case examples of how this approach may be used to address clinically relevant questions. Copyright © 2023 Bond, Curtin, Ranjbar, Afshari, Hu, Rubin and Swanson.

Author Keywords
CNS tumor;  glioblastoma;  glioma;  imaging;  machine learning;  MRI;  personalized medicine;  radiomics

Funding details
National Institutes of HealthNIHU01CA22037

Document Type: Article
Publication Stage: Final
Source: Scopus

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement
(2023) Molecular Psychiatry, . 

Mu, L.^a , Liu, X.^a , Yu, H.^a , Vickstrom, C.R.^a c , Friedman, V.^a , Kelly, T.J.^a , Hu, Y.^a , Su, W.^a b , Liu, S.^a , Mantsch, J.R.^a , Liu, Q.-S.^a

^a Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
^b Department of Exercise Physiology, Beijing Sport University, Beijing, 100084, China
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1–4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHF30MH115536, F31DA054759, R01DA035217, R01DA047269
National Institute of General Medical SciencesNIGMST32-GM080202

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

Association of organizational culture and climate with variation in the clinical outcomes of collaborative care for maternal depression in community health centers
(2023) Implementation Research and Practice, 4, . 

Williams, N.J.^a , Russo, J.^b , Vredevoogd, M.^b , Grover, T.^b , Green, P.^c , Proctor, E.^d , Bhat, A.^b , Unützer, J.^b , Bennett, I.M.^b e

^a School of Social Work, Boise State University, Boise, ID, United States
^b Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States
^c Center for Behavioral Health Research, University of Tennessee, Knoxville, TN, United States
^d Brown School of Social Work, Washington University, Saint Louis, MO, United States
^e Department of Family Medicine, University of Washington School of Medicine, Seattle, WA, United States

Abstract
Background: Organizational factors may help explain variation in the effectiveness of evidence-based clinical innovations through implementation and sustainment. This study tested the relationship between organizational culture and climate and variation in clinical outcomes of the Collaborative Care Model (CoCM) for treatment of maternal depression implemented in community health centers. Method: Organizational cultures and climates of 10 community health centers providing CoCM for depression among low-income women pregnant or parenting were assessed using the organizational social context (OSC) measure. Three-level hierarchical linear models tested whether variation in culture and climate predicted variation in improvement in depression symptoms from baseline to 6.5-month post-baseline for N = 468 women with care ±1 year of OSC assessment. Depression symptomology was measured using the Patient Health Questionnaire (PHQ-9). Results: After controlling for patient characteristics, case mix, center size, and implementation support, patients served by centers with more proficient cultures improved significantly more from baseline to 6.5-month post-baseline than patients in centers with less proficient cultures (mean improvement = 5.08 vs. 0.14, respectively, p =.020), resulting in a large adjusted effect size of dadj = 0.78. A similar effect was observed for patients served by centers with more functional climates (mean improvement = 5.25 vs. 1.12, p <.044, dadj = 0.65). Growth models indicated that patients from all centers recovered on average after 4 months of care. However, those with more proficient cultures remained stabilized whereas patients served by centers with less proficient cultures deteriorated by 6.5-month post-baseline. A similar pattern was observed for functional climate. Conclusions: Variation in clinical outcomes for women from historically underserved populations receiving Collaborative Care for maternal depression was associated with the organizational cultures and climates of community health centers. Implementation strategies targeting culture and climate may improve the implementation and effectiveness of integrated behavioral health care for depression. © The Author(s) 2023.

Author Keywords
climate;  collaborative care;  culture;  depression;  integrated behavioral health;  maternal;  Organization;  primary care

Document Type: Article
Publication Stage: Final
Source: Scopus

Kappa-opioid receptor activation reinstates nicotine self-administration in mice
(2022) Addiction Neuroscience, 2, art. no. 100017, . 

Gowrishankar, R.^a c , Gomez, A.^b , Waliki, M.^b , Bruchas, M.R.^a b c

^a Departments of Anesthesiology and Pain Medicine and Pharmacology, University of Washington, Seattle, WA, United States
^b Department of Anesthesiology, Washington University in St. Louis MO, United States
^c Center for the Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA, United States

Abstract
Voluntary drug administration is a key facet of substance use disorder (SUD). Among the substances included under SUD, nicotine is the leading cause of preventable death. Nicotine use is also particularly sensitive to relapse, with stress being the major cause. Intravenous self-administration of nicotine has been the gold standard for accurately modeling SUD in rat and non-human primate models. However, this has been hard to achieve in mice. Here, using previously published protocols, we show that mice develop and maintain intravenous self-administration for nicotine and cocaine. Furthermore, we demonstrate that dynorphin-Kappa opioid receptor signaling, previously established to be necessary for negative affective behavior associated with stress, is sufficient to reinstate nicotine seeking in mice. With a stable model for volitional nicotine-seeking, we will be able to uncover the circuit- and molecular-level adaptations during the development, maintenance, withdrawal and relapse to pathological nicotine use. © 2022 The Author(s)

Author Keywords
Intravenous nicotine self-administration;  Kappa opioid receptor

Document Type: Article
Publication Stage: Final
Source: Scopus