WashU weekly Neuroscience publications

Plasma MCP-1 and changes on cognitive function in community-dwelling older adults
(2022) Alzheimer’s Research and Therapy, 14 (1), art. no. 5, . 

Sanchez-Sanchez, J.L.^a b , Giudici, K.V.^a , Guyonnet, S.^a c , Delrieu, J.^a c , Li, Y.^d e , Bateman, R.J.^d e f g , Parini, A.^h , Vellas, B.^a c , de Souto Barreto, P.^a c , Vellas, B.ⁱ , Guyonnet, S.ⁱ , Carrié, I.ⁱ , Brigitte, L.ⁱ , Faisant, C.ⁱ , Lala, F.ⁱ , Delrieu, J.ⁱ , Villars, H.ⁱ , Combrouze, E.ⁱ , Badufle, C.ⁱ , Zueras, A.ⁱ , Andrieu, S.ⁱ , Cantet, C.ⁱ , Morin, C.ⁱ , Van Kan, G.A.ⁱ , Dupuy, C.ⁱ , Rolland, Y.ⁱ , Caillaud, C.ⁱ , Ousset, P.-J.ⁱ , Lala, F.ⁱ , Willis, S.ⁱ , Belleville, S.ⁱ , Gilbert, B.ⁱ , Fontaine, F.ⁱ , Dartigues, J.-F.ⁱ , Marcet, I.ⁱ , Delva, F.ⁱ , Foubert, A.ⁱ , Cerda, S.ⁱ , Marie-Noëlle-Cuffiⁱ , Costes, C.ⁱ , Rouaud, O.ⁱ , Manckoundia, P.ⁱ , Quipourt, V.ⁱ , Marilier, S.ⁱ , Franon, E.ⁱ , Bories, L.ⁱ , Pader, M.-L.ⁱ , Basset, M.-F.ⁱ , Lapoujade, B.ⁱ , Faure, V.ⁱ , Tong, M.L.Y.ⁱ , Malick-Loiseau, C.ⁱ , Cazaban-Campistron, E.ⁱ , Desclaux, F.ⁱ , Blatge, C.ⁱ , Dantoine, T.ⁱ , Laubarie-Mouret, C.ⁱ , Saulnier, I.ⁱ , Clément, J.-P.ⁱ , Picat, M.-A.ⁱ , Bernard-Bourzeix, L.ⁱ , Willebois, S.ⁱ , Désormais, I.ⁱ , Cardinaud, N.ⁱ , Bonnefoy, M.ⁱ , Livet, P.ⁱ , Rebaudet, P.ⁱ , Gédéon, C.ⁱ , Burdet, C.ⁱ , Terracol, F.ⁱ , Pesce, A.ⁱ , Roth, S.ⁱ , Chaillou, S.ⁱ , Louchart, S.ⁱ , Sudres, K.ⁱ , Lebrun, N.ⁱ , Barro-Belaygues, N.ⁱ , Touchon, J.ⁱ , Bennys, K.ⁱ , Gabelle, A.ⁱ , Romano, A.ⁱ , Touati, L.ⁱ , Marelli, C.ⁱ , Pays, C.ⁱ , Robert, P.ⁱ , Le Duff, F.ⁱ , Gervais, C.ⁱ , Gonfrier, S.ⁱ , Gasnier, Y.ⁱ , Bordes, S.ⁱ , Begorre, D.ⁱ , Carpuat, C.ⁱ , Khales, K.ⁱ , Lefebvre, J.-F.ⁱ , El Idrissi, S.M.ⁱ , Skolil, P.ⁱ , Salles, J.-P.ⁱ , Dufouil, C.ⁱ , Lehéricy, S.ⁱ , Chupin, M.ⁱ , Mangin, J.-F.ⁱ , Bouhayia, A.ⁱ , Allard, M.ⁱ , Ricolfi, F.ⁱ , Dubois, D.ⁱ , Martel, M.P.B.ⁱ , Cotton, F.ⁱ , Bonafé, A.ⁱ , Chanalet, S.ⁱ , Hugon, F.ⁱ , Bonneville, F.ⁱ , Cognard, C.ⁱ , Chollet, F.ⁱ , Payoux, P.ⁱ , Voisin, T.ⁱ , Peiffer, S.ⁱ , Hitzel, A.ⁱ , Zanca, M.ⁱ , Monteil, J.ⁱ , Darcourt, J.ⁱ , Molinier, L.ⁱ , Derumeaux, H.ⁱ , Costa, N.ⁱ , Perret, B.ⁱ , Vinel, C.ⁱ , Caspar-Bauguil, S.ⁱ , Olivier-Abbal, P.ⁱ , Coley, N.ⁱ , for the MAPT/DSA Groupⁱ

^a Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalier-Universitaire de Toulouse, 37 allées Jules Guesde, Toulouse, 31000, France
^b Faculty of Sport Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, 28670, Spain
^c CERPOP, Inserm 1295, Université de Toulouse, UPS, Toulouse, France
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^f Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^g Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
^h Institut des Maladies Métaboliques et Cardiovasculaires, Inserm/Université Paul Sabatier UMR 1048 – I2MC 1, Toulouse, France

Abstract
Background: Monocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma MCP-1 levels (alone and in combination with β-amyloid deposition—Aβ42/40) with overall and domain-specific cognitive evolution among older adults. Methods: Secondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aβ42/40 (lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1+)) were used, as well as a dichotomy of Aβ42/40. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT – memory). Results: Plasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1+ was associated with worse evolution in the CCS (4-year between-group difference: β = −0.14, 95%CI = −0.26, −0.02) and the CDR sum of boxes (2-year: β = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1+ was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aβ42/40, MCP-1+ was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aβ42/40× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables. Conclusions: Baseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aβ42/40 to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aβ42/40. © 2022, The Author(s).

Author Keywords
Alzheimer’s disease;  Cognitive function;  Episodic memory;  MCP-1;  Older adults

Funding details
1901175
Avid Radiopharmaceuticals
Ministère des Affaires Sociales et de la Santé
European Regional Development FundERDFMP0022856

Associations between cognition and polygenic liability to substance involvement in middle childhood: Results from the ABCD study
(2022) Drug and Alcohol Dependence, 232, art. no. 109277, . 

Paul, S.E.^a , Hatoum, A.S.^b , Barch, D.M.^a b c , Thompson, W.K.^d , Agrawal, A.^b , Bogdan, R.^a , Johnson, E.C.^b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, 6411 Forsyth Blvd, St. Louis, MO 63105, United States
^b Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave., St Louis, MO 63110, United States
^c Department of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, St. Louis, MO 63110, United States
^d Division of Biostatistics and Department of Radiology, UCSD, La JollaCA 92093, United States

Abstract
Background: Cognition is robustly associated with substance involvement. This relationship is attributable to multiple factors, including genetics, though such contributions show inconsistent patterns in the literature. For instance, genome-wide association studies point to potential positive relationships between educational achievement and common substance use but negative relationships with heavy and/or problematic substance use. Methods: We estimated associations between polygenic risk for substance involvement (i.e., alcohol, tobacco, and cannabis use and problematic use) and cognition subfacets (i.e., general ability, executive function, learning/memory) derived from confirmatory factor analysis among 3205 substance naïve children (ages 9–10) of European ancestry who completed the baseline session of the Adolescent Brain Cognitive Development (ABCD) Study. Findings: Polygenic risk for lifetime cannabis use was positively associated with all three facets of cognitive ability (Bs ≥ 0.045, qs ≤ 0.044). No other substance polygenic risk scores showed significant associations with cognition after adjustment for multiple testing (|Bs|≤0.033, qs ≥ 0.118). Conclusions: Polygenic liability to lifetime cannabis use, but not use disorder, was positively associated with cognitive performance among substance-naïve children, possibly reflecting shared genetic overlap with openness to experience or the influence of genetic variance associated with socioeconomic status. Our lack of findings for the other polygenic scores may reflect ascertainment differences between the genome-wide association study (GWAS) samples and the current sample and/or the young age of the present sample. As longitudinal data in ABCD are collected, this sample may be useful for disentangling putatively causal or predispositional influences of substance use and misuse on cognition. © 2022 Elsevier B.V.

Author Keywords
Cognitive ability;  Polygenic risk;  Substance use;  Substance use disorder

Funding details
National Institutes of HealthNIH1K01DA051759, F31-AA029934-01, K02DA032573, R01 MH120025, R01 MH122688, R01-AG045231, R01-AG052564, R01-DA046224, R01-HD083614, R01-MH066031, R01-MH090786, R01-MH113883, R21-AA027827, T32-DA007261, U01-A005020803, U01-MH109589

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C
(2022) Pediatric Neurology, 128, pp. 33-44. 

Fink, E.L.^a , Robertson, C.L.^b , Wainwright, M.S.^c , Roa, J.D.^d , Lovett, M.E.^e , Stulce, C.^f , Yacoub, M.^g , Potera, R.M.^h , Zivick, E.ⁱ , Holloway, A.^j , Nagpal, A.^k , Wellnitz, K.^l , Czech, T.^m , Even, K.M.ⁿ , Brunow de Carvalho, W.^o , Rodriguez, I.S.^o , Schwartz, S.P.^p , Walker, T.C.^p , Campos-Miño, S.^q , Dervan, L.A.^r , Geneslaw, A.S.^s , Sewell, T.B.^s , Pryce, P.^t , Silver, W.G.^u , Lin, J.E.^u , Vargas, W.S.^u , Topjian, A.^v , Alcamo, A.M.^v , McGuire, J.L.^w , Domínguez Rojas, J.A.^x , Muñoz, J.T.^x , Hong, S.J.^y , Muller, W.J.^y , Doerfler, M.^y , Williams, C.N.^z , Drury, K.^aa , Bhagat, D.^ab , Nelson, A.^ab , Price, D.^ab , Dapul, H.^ac , Santos, L.^ac , Kahoud, R.^ad , Francoeur, C.^ae , Appavu, B.^af , Guilliams, K.P.^ag , Agner, S.C.^ag , Walson, K.H.^ah , Rasmussen, L.^ai , Janas, A.^ai , Ferrazzano, P.^aj , Farias-Moeller, R.^ak , Snooks, K.C.^al , Chang, C.-C.H.^am , Yun, J.^am , Schober, M.E.^an , Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) Investigators^ao

^a Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Pittsburgh, Pennsylvania; Safar Center for Resuscitation Research, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States
^b Departments of Anesthesiology and Critical Care Medicine, and Pediatrics of The Johns Hopkins University SOM, Baltimore, Maryland
^c Division of Pediatric Neurology, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
^d Department of Pediatrics, Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
^e Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States
^f Department of Pediatrics, University of Chicago, Chicago, Illinois
^g Division of Critical Care, Department of Pediatrics, UMC Children’s Hospital, Las Vegas, Nevada
^h Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
ⁱ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
^j Division of Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, Maryland
^k Department of Pediatrics, Section of Critical Care Medicine, Oklahoma Children’s Hospital at OU health, Oklahoma University College of Medicine, Oklahoma City, OK, United States
^l Division of Pediatric Critical Care, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^m Division of Pediatric Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, United States
ⁿ Division of Pediatric Critical Care Medicine, Penn State College of Medicine, Hershey, Pennsylvania
^o Department of Pediatrics, University of São Paulo, São Paulo, Brazil
^p Department of Pediatrics, University of North Carolina at Chapel Hill Hospitals, Chapel Hill, NC, United States
^q Pediatric Intensive Care Unit, Hospital Metropolitano, Quito, Ecuador
^r Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
^s Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York
^t Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, Morgan Stanley Children’s Hospital New York-Presbyterian Hospital, New York, New York
^u Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, New York
^v Division of Critical Care Medicine at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Anesthesiology and Critical Care Medicine and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
^w Division of Neurology at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
^x Division of Pediatric Critical Care, Department of Pediatrics, Hospital de Emergencia Villa El Salvador, Lima, Peru
^y Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, Illinois
^z Division of Pediatric Critical Care, Department of Pediatrics, Pediatric Critical Care and Neurotrauma Recovery Program Portland, Oregon Health & Science UniversityOregon
^aa Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon
^ab Department of Neurology, NYU Langone Health, New York, New York
^ac Division of Pediatric Critical Care, Department of Pediatrics, Hassenfeld Children’s Hospital at NYU Langone Health, New York, New York
^ad Division of Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
^ae Department of Pediatrics, CHU de Québec – Université Laval Research Center, Quebec City, Quebec, Canada
^af Division of Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital, University of Arizona, College of Medicine, Phoenix, Arizona
^ag Departments of Neurology, Pediatrics, and Radiology, Washington University in St. Louis, St. Louis, Missouri
^ah Department of Pediatric Critical Care Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, United States
^ai Pediatric Critical Care Medicine, Lucile Packard Children’s Hospital, Stanford University, Stanford, California
^aj Department of Pediatrics, University of Wisconsin, Madison, WI, United States
^ak Division Child Neurology, Department of Neurology, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, WI, United States
^al Department of Pediatrics, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, WI, United States
^am Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^an Division of Critical Care of the University of Utah, Department of Pediatrics, Salt Lake City, Utah

Abstract
Background: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). Methods: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. Results: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. Conclusions: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed. © 2021 Elsevier Inc.

Author Keywords
Child development;  Neurological manifestations;  Pediatrics;  SARS-CoV-2

Funding details
Ohio State UniversityOSU
Johns Hopkins UniversityJHU
University of Texas Southwestern Medical CenterUTSW
University of OklahomaOU
School of Medicine, Johns Hopkins UniversitySOM, JHU
Medizinische Universität InnsbruckMUI

Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN
(2022) The Journal of Cell Biology, 221 (2), . 

Li, Y.^a b , Pazyra-Murphy, M.F.^a b , Avizonis, D.^c , de Sá Tavares Russo, M.^c , Tang, S.^b , Chen, C.-Y.^d , Hsueh, Y.-P.^d , Bergholz, J.S.^b e f , Jiang, T.^b , Zhao, J.J.^b e f , Zhu, J.^g , Ko, K.W.^h , Milbrandt, J.^g i , DiAntonio, A.^h i , Segal, R.A.^a b

^a Department of Neurobiology, Harvard Medical School, MA, Boston
^b Department of Cancer Biology, Dana-Farber Cancer Institute, MA, Boston
^c Metabolomics Innovation Resource, Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
^d Institute of Molecular Biology, Academia Sinica, Republic of ChinaTaipei, Taiwan
^e Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA, Boston
^f Broad Institute of Harvard and Massachusetts Institute of Technology, MA, Cambridge
^g Department of Genetics, Washington University School of Medicine, St. Louis, MO
^h Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO
ⁱ Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO

Abstract
Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN). © 2021 Li et al.

Resting EEG spectral slopes are associated with age-related differences in information processing speed
(2022) Biological Psychology, 168, art. no. 108261, . 

Pathania, A.^a , Euler, M.J.^b , Clark, M.^a , Cowan, R.L.^a , Duff, K.^c , Lohse, K.R.^a d

^a Department of Health and Kinesiology, University of Utah, United States
^b Department of Psychology, University of Utah, United States
^c Department of Neurology, University of Utah, United States
^d Program in Physical Therapy and Department of Neurology, Washington University School of Medicine in Saint Louis, United States

Abstract
Background: Previous research has shown the slope of the EEG power spectrum differentiates between older and younger adults in various experimental cognitive tasks. We extend that work, assessing the relation between the EEG power spectrum and performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Methods: Twenty-one younger and twenty-three older adults completed the RBANS with EEG data collected at rest. Using spectral parameterization, we tested the mediating effect of the spectral slope on differences in subsequent cognitive task performance. Results: Older adults performed reliably worse on the RBANS overall, and on the Attention and Delayed Memory domains specifically. However, evidence of mediation was only found for the Coding subtest. Conclusions: The slope of the resting EEG power spectrum mediated age-related differences in cognition, but only in a task requiring speeded processing. Mediation was not statistically significant for delayed memory, even though age-related differences were present. © 2022 Elsevier B.V.

Author Keywords
1/f noise;  Aging;  Cognition;  EEG;  Spectral slope

FASN-dependent de novo lipogenesis is required for brain development
(2022) Proceedings of the National Academy of Sciences of the United States of America, 119 (2), art. no. e2112040119, . 

Gonzalez-Bohorquez, D.^a , Gallego Lopez, I.M.^a , Jaeger, B.N.^a , Pfammatter, S.^b , Bowers, M.^a , Semenkovich, C.F.^c , Jessberger, S.^a

^a Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich 8057, Zurich, Switzerland
^b Functional, Genomics Center Zurich, University of Zurich, Eidgenossiche € Technische Hochschule Zurich, Zurich, 8057, Switzerland
^c Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63108, United States

Abstract
Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cremediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell–derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism. © 2022 National Academy of Sciences. All rights reserved.

Author Keywords
Lipogenesis;  Neural stem cell;  Neurogenesis;  Polarity

Funding details
European Research CouncilERC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF310030_196869, BSCGI0_157859
Universität ZürichUZH
Neuroscience Center Zurich, University of ZurichZNZ

Invariant odor recognition with ON–OFF neural ensembles
(2022) Proceedings of the National Academy of Sciences of the United States of America, 119 (2), art. no. e2023340118, . 

Nizampatnam, S.^a , Zhang, L.^a , Chandak, R.^b , Li, J.^b , Raman, B.^a b

^a Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Invariant stimulus recognition is a challenging pattern-recognition problem that must be dealt with by all sensory systems. Since neural responses evoked by a stimulus are perturbed in a multitude of ways, how can this computational capability be achieved? We examine this issue in the locust olfactory system. We find that locusts trained in an appetitive-conditioning assay robustly recognize the trained odorant independent of variations in stimulus durations, dynamics, or history, or changes in background and ambient conditions. However, individual- and population-level neural responses vary unpredictably with many of these variations. Our results indicate that linear statistical decoding schemes, which assign positive weights to ON neurons and negative weights to OFF neurons, resolve this apparent confound between neural variability and behavioral stability. Furthermore, simplification of the decoder using only ternary weights (f+1, 0, 21g) (i.e., an “ON-minus-OFF” approach) does not compromise performance, thereby striking a fine balance between simplicity and robustness. © 2022 National Academy of Sciences. All rights reserved.

Author Keywords
Antennal lobe;  Behavioral recognition;  Computational neuroscience;  Olfaction;  Sensory invariance

Funding details
National Science FoundationNSF1453022, 1724218, 2021795
Office of Naval ResearchONRN000141912049
Washington University in St. LouisWUSTL

Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis
(2022) Cancer Discovery, 12 (1), pp. 154-171. 

Schaettler, M.O.^a b , Richters, M.M.^c d e , Wang, A.Z.^a b , Skidmore, Z.L.^c d e , Fisk, B.^c d e , Miller, K.E.^f , Vickery, T.L.^g , Kim, A.H.^a , Chicoine, M.R.^a , Osbun, J.W.^a , Leuthardt, E.C.^a , Dowling, J.L.^a , Zipfel, G.J.^a , Dacey, R.G.^a , Lu, H.-C.^b , Johanns, T.M.^c g , Griffith, O.L.^c d e , Mardis, E.R.^f h , Griffith, M.^c d e , Dunn, G.P.^a b g

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^e The McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, United States
^f The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
^g Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, United States

Abstract
Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell–intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through wholeexome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. © 2021 The Authors; Published by the American Association for Cancer Research.

Funding details
National Institutes of HealthNIH2T32HG000045–21, R00HG007940, T32 AI007163, T32 GM 7200–43
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCIU01CA248235
Damon Runyon Cancer Research FoundationDRCRF94-17
V Foundation for Cancer ResearchVFCRV2018–007

The T1-tetramerisation domain of Kv1.2 rescues expression and preserves function of a truncated NaChBac sodium channel
(2022) FEBS Letters, . 

D’Avanzo, N.^a , Miles, A.J.^b , Powl, A.M.^b , Nichols, C.G.^c , Wallace, B.A.^b , O’Reilly, A.O.^d

^a Department of Pharmacology and Physiology, Université de Montréal, Canada
^b Institute of Structural and Molecular Biology, Birkbeck, University of London, United Kingdom
^c Department of Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, United States
^d School of Biological & Environmental Sciences, Liverpool John Moores University, United Kingdom

Abstract
Cytoplasmic domains frequently promote functional assembly of multimeric ion channels. To investigate structural determinants of this process, we generated the ‘T1-chimera’ construct of the NaChBac sodium channel by truncating its C-terminal domain and splicing the T1-tetramerisation domain of the Kv1.2 channel to the N terminus. Purified T1-chimera channels were tetrameric, conducted Na+ when reconstituted into proteoliposomes, and were functionally blocked by the drug mibefradil. Both the T1-chimera and full-length NaChBac had comparable expression levels in the membrane, whereas a NaChBac mutant lacking a cytoplasmic domain had greatly reduced membrane expression. Our findings support a model whereby bringing the transmembrane regions into close proximity enables their tetramerisation. This phenomenon is found with other channels, and thus, our findings substantiate this as a common assembly mechanism. © 2022 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Funding details
National Institutes of HealthNIHR35 HL140024
Canadian Institutes of Health ResearchIRSCFRN 173388
Natural Sciences and Engineering Research Council of CanadaNSERC
Medical Research CouncilMRCMR/W002159/1
Biotechnology and Biological Sciences Research CouncilBBSRCBB/L006790, BB/P024092
Rosetrees TrustCF2/100001, RGPIN‐2019‐00373

Sharper in the morning: Cognitive time of day effects revealed with high-frequency smartphone testing
(2022) Journal of Clinical and Experimental Neuropsychology, . 

Wilks, H.^a , Aschenbrenner, A.J.^a b , Gordon, B.A.^b c , Balota, D.A.^b , Fagan, A.M.^a , Musiek, E.^a , Balls-Berry, J.^a , Benzinger, T.L.S.^c , Cruchaga, C.^d , Morris, J.C.^a , Hassenstab, J.^a b

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

Abstract
Decades of research has established a shift from an “eveningness” preference to a “morningness” preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61–94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a “cognitive sundowning” in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Aging;  Alzheimer’s disease;  circadian rhythms;  neuropsychological tests;  smartphone-based cognitive testing

Routine culture and study of adult human brain cells from neurosurgical specimens
(2022) Nature Protocols, . 

Park, T.I.-H.^a b , Smyth, L.C.D.^c , Aalderink, M.^a , Woolf, Z.R.^a , Rustenhoven, J.^d , Lee, K.^e , Jansson, D.^f , Smith, A.^a , Feng, S.^a , Correia, J.^b g , Heppner, P.^b g , Schweder, P.^b g , Mee, E.^b g , Dragunow, M.^a b

^a Hugh Green Biobank & Department of Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
^b Neurosurgical Research Unit, Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
^c Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand
^d Center for Brain Immunology and Glia (BIG), Washington University, St. Louis, MO, United States
^e Department of Physiology, Faculty of Medical Science and Health Sciences, The University of Auckland, Auckland, New Zealand
^f Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine VISN 20 Mental Illness Research, Education and Clinical Centre (MIRECC), VA Puget Sound Health Care System, Seattle, WA, United States
^g Department of Neurosurgery, Auckland City Hospital, Auckland, New Zealand

Abstract
When modeling disease in the laboratory, it is important to use clinically relevant models. Patient-derived human brain cells grown in vitro to study and test potential treatments provide such a model. Here, we present simple, highly reproducible coordinated procedures that can be used to routinely culture most cell types found in the human brain from single neurosurgically excised brain specimens. The cell types that can be cultured include dissociated cultures of neurons, astrocytes, microglia, pericytes and brain endothelial and neural precursor cells, as well as explant cultures of the leptomeninges, cortical slice cultures and brain tumor cells. The initial setup of cultures takes ~2 h, and the cells are ready for further experiments within days to weeks. The resulting cells can be studied as purified or mixed population cultures, slice cultures and explant-derived cultures. This protocol therefore enables the investigation of human brain cells to facilitate translation of neuroscience research to the clinic. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
Hugh Green FoundationHGF
Health Research Council of New ZealandHRC

Gene–environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution
(2022) Multiple Sclerosis Journal, . 

Ziaei, A.^a , Lavery, A.M.^b , Shao, X.M.A.^c , Adams, C.^c , Casper, T.C.^d , Rose, J.^d , Candee, M.^d , Weinstock-Guttman, B.^e , Aaen, G.^f , Harris, Y.^g , Graves, J.^h , Benson, L.ⁱ , Gorman, M.ⁱ , Rensel, M.^j , Mar, S.^k , Lotze, T.^l , Greenberg, B.^m , Chitnis, T.ⁿ , Hart, J.^a , Waldman, A.T.^b , Barcellos, L.F.^c , Waubant, E.^a

^a University of California, San Francisco, CA, United States
^b Division of Child Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^c Genetic Epidemiology and Genomics Laboratory, Divisions of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA, United States
^d The University of Utah, Salt Lake City, UT, United States
^e Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, United States
^f Loma Linda University Children’s Hospital, Loma Linda, CA, United States
^g The University of Alabama, Tuscaloosa, AL, United States
^h University of California, San Diego, CA, United States
ⁱ Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children’s Hospital, Boston, MA, United States
^j Cleveland Clinic, Cleveland, OH, United States
^k Washington University in St. Louis, St. Louis, MO, United States
^l Texas Children’s Hospital, Houston, TX, United States
^m University of Texas Southwestern Medical Center, Dallas, TX, United States
ⁿ Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA-DRB1*15, the strongest genetic variant associated with POMS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC’s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 (DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother’s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk. © The Author(s), 2022.

Author Keywords
CD86;  DRB1*15;  gene–environment interaction;  multiple sclerosis;  ozone pollution;  Pediatric onset

Funding details
HC-1509-06233
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSS
Pfizer
Genentech
Novartis
Roche
Pennsylvania Department of Health
Biogen
Patient-Centered Outcomes Research InstitutePCORI
Guthy-Jackson Charitable Foundation
Capital Medical UniversityCCMU
Multiple Sclerosis International FederationMSIF

The Role of the Human Brain Neuron–Glia–Synapse Composition in Forming Resting-State Functional Connectivity Networks
(2021) Brain Sciences, 11 (12), art. no. 1565, . 

Kahali, S.^a , Raichle, M.E.^a b , Yablonskiy, D.A.^a

^a Department of Radiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
^b Department of Neurology, Washington University in Saint Louis, Saint Louis, MO 63110, United States

Abstract
While significant progress has been achieved in studying resting-state functional networks in a healthy human brain and in a wide range of clinical conditions, many questions related to their relationship to the brain’s cellular constituents remain. Here, we use quantitative Gradient-Recalled Echo (qGRE) MRI for mapping the human brain cellular composition and BOLD (blood–oxygen level-dependent) MRI to explore how the brain cellular constituents relate to resting-state functional networks. Results show that the BOLD signal-defined synchrony of connections between cellular circuits in network-defined individual functional units is mainly associated with the regional neuronal density, while the between-functional units’ connectivity strength is also influenced by the glia and synaptic components of brain tissue cellular constituents. These mechanisms lead to a rather broad distribution of resting-state functional network properties. Visual networks with the highest neuronal density (but lowest density of glial cells and synapses) exhibit the strongest coherence of the BOLD signal as well as the strongest intra-network connectivity. The Default Mode Network (DMN) is positioned near the opposite part of the spectrum with relatively low coherence of the BOLD signal but with a remarkably balanced cellular contents, enabling DMN to have a prominent role in the overall organization of the brain and hierarchy of functional networks. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Brain cellular composition;  Default mode network;  Functional connectivity networks;  MRI;  QGRE;  Quantitative Gradient-Recalled Echo

Funding details
R01 AG054513
1U54MH091657
National Institutes of HealthNIH
NIH Blueprint for Neuroscience Research
McDonnell Center for Systems Neuroscience

A prospective examination of sex differences in posttraumatic autonomic functioning
(2021) Neurobiology of Stress, 15, art. no. 100384, . Cited 1 time.

Seligowski, A.V.^a b , Steuber, E.R.^c , Hinrichs, R.^d , Reda, M.H.^e , Wiltshire, C.N.^f , Wanna, C.P.^e , Winters, S.J.^e , Phillips, K.A.^g h , House, S.L.ⁱ , Beaudoin, F.L.^j , An, X.^k , Stevens, J.S.^d , Zeng, D.^l , Neylan, T.C.^m , Clifford, G.D.^n o , Linnstaedt, S.D.^k , Germine, L.T.^a p q , Bollen, K.A.^r , Guffanti, G.^a b , Rauch, S.L.^a p s , Haran, J.P.^t , Storrow, A.B.^u , Lewandowski, C.^v , Musey, P.I., Jr.^w , Hendry, P.L.^x , Sheikh, S.^x , Jones, C.W.^y , Punches, B.E.^z aa , Kurz, M.C.^ab ac ad , Murty, V.P.^ae , McGrath, M.E.^af , Hudak, L.A.^ag , Pascual, J.L.^ah ai , Seamon, M.J.^ai aj , Datner, E.M.^ak al , Chang, A.M.^am , Pearson, C.^an , Peak, D.A.^ao , Merchant, R.C.^ap , Domeier, R.M.^aq , Rathlev, N.K.^ar , O’Neil, B.J.^an , Sanchez, L.D.^ap as , Bruce, S.E.^at , Miller, M.W.^au av , Pietrzak, R.H.^aw ax , Joormann, J.^ay , Barch, D.M.^az , Pizzagalli, D.A.^a b , Sheridan, J.F.^ba bb , Luna, B.^bc , Harte, S.E.^bd be , Elliott, J.M.^bf bg bh , Koenen, K.C.^bi , Kessler, R.C.^bj , McLean, S.A.^k bk , Ressler, K.J.^a b , Jovanovic, T.^e

^a Department of Psychiatry, Harvard Medical School, Boston, MA 02115, United States
^b Division of Depression and Anxiety, McLean Hospital, Belmont, MA 02478, United States
^c Department of Psychiatry, Johns Hopkins Hospital, Baltimore, MD 21287, United States
^d Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30329, United States
^e Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MA 48202, United States
^f Wayne State University, Detroit, MA 48202, United States
^g McLean Hospital, Belmont, MA 02478, United States
^h Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States
ⁱ Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Department of Emergency Medicine & Department of Health Services, Policy, and Practice, The Alpert Medical School of Brown University, Rhode Island Hospital and the Miriam Hospital, Providence, RI 02930, United States
^k Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel HillNC 27559, United States
^l Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel HillNC 27559, United States
^m Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA 94143, United States
ⁿ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30332, United States
^o Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, United States
^p Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA 02478, United States
^q The Many Brains Project, Belmont, MA 02478, United States
^r Department of Psychology and Neuroscience & Department of Sociology, University of North Carolina at Chapel Hill, Chapel HillNC 27559, United States
^s Department of Psychiatry, McLean Hospital, Belmont, MA 02478, United States
^t Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA 01655, United States
^u Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States
^v Department of Emergency Medicine, Henry Ford Health System, Detroit, MI 48202, United States
^w Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
^x Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL 32209, United States
^y Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
^z Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
^aa College of Nursing, University of Cincinnati, Cincinnati, OH 45221, United States
^ab Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, AL 35294, United States
^ac Department of Surgery, Division of Acute Care Surgery, University of Alabama School of Medicine, Birmingham, AL 35294, United States
^ad Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL 35294, United States
^ae Department of Psychology, Temple University, Philadelphia, PA 19121, United States
^af Department of Emergency Medicine, Boston Medical Center, Boston, MA 02118, United States
^ag Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA 30329, United States
^ah Department of Surgery, Department of Neurosurgery, University of Pennsylvania, PennsylvaniaPA 19104, United States
^ai Perelman School of Medicine, University of Pennsylvania, PennsylvaniaPA 19104, United States
^aj Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, PennsylvaniaPA 19104, United States
^ak Department of Emergency Medicine, Einstein Healthcare Network, PennsylvaniaPA 19141, United States
^al Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, PennsylvaniaPA 19107, United States
^am Department of Emergency Medicine, Jefferson University Hospitals, PennsylvaniaPA 19107, United States
^an Department of Emergency Medicine, Wayne State University, Detroit, MA 48202, United States
^ao Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
^ap Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA 02115, United States
^aq Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI 48197, United States
^ar Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA 01107, United States
^as Department of Emergency Medicine, Harvard Medical School, Boston, MA 02115, United States
^at Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO 63121, United States
^au National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA 02130, United States
^av Department of Psychiatry, Boston University School of Medicine, Boston, MA 02118, United States
^aw National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West HavenCT 06516, United States
^ax Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, United States
^ay Department of Psychology, Yale School of Medicine, New Haven, CT 06510, United States
^az Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
^ba Department of Biosciences, OSU Wexner Medical Center, Columbus, OH 43210, United States
^bb Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH 43211, United States
^bc Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States
^bd Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^be Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^bf Kolling Institute of Medical Research, University of Sydney, St LeonardsNSW 2065, Australia
^bg Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health DistrictNSW 2006, Australia
^bh Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, United States
^bi Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, United States
^bj Department of Health Care Policy, Harvard Medical School, Boston, MA 02115, United States
^bk Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel HillNC 27559, United States

Abstract
Background: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning. Methods: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma. Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD. Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted. © 2021 The Authors

Author Keywords
Autonomic;  Cardiovascular;  PTSD;  Sex;  Trauma

Funding details
R33AG05654
National Science FoundationNSF
National Institutes of HealthNIHR01HD079076, R03HD094577, U01 MH110925
National Institute of Mental HealthNIMH
Substance Abuse and Mental Health Services AdministrationSAMHSA1H79TI083101-01
Medical Research and Materiel CommandMRMC
Bill and Melinda Gates FoundationBMGF
Brain and Behavior Research FoundationBBRF
Gordon and Betty Moore FoundationGBMF
Dana Foundation
Blue Cross and Blue Shield of Florida Foundation
Allergan Foundation
Microsoft ResearchMSR
Google
National Center for Medical Rehabilitation ResearchNCMRR
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
MathWorks
NSW Ministry of Health

Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease
(2021) Alzheimer Disease and Associated Disorders, . 

Levine, T.F.^a , Roe, C.M.^b c , Babulal, G.M.^b c f , Fagan, A.M.^b c d , Head, D.^a b e

^a Department of Psychological and Brain Sciences, Washington University, United States
^b Charles F. and Joanne Knight Alzheimer Disease Research Center, United States
^c Department of Neurology, United States
^d Hope Center for Neurological Disorders, United States
^e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa

Abstract
Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aβ42, p-tau181, p-tau181/Aβ42ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps&gt;0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps&gt;0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD. © 2021 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
allocentric navigation;  cognitive mapping;  subjective cognitive complaints

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHP01 AG026276, P01 AG03991, P30 AG066444, R01AG056466, R01AG067428, R01AG068183
BrightFocus FoundationBFFA2021142S

Neurocognitive functioning in preschool children with sickle cell disease
(2021) Pediatric Blood and Cancer, . 

Heitzer, A.M.^a , Cohen, D.L.^a , Okhomina, V.I.^b , Trpchevska, A.^a , Potter, B.^a , Longoria, J.^a , Porter, J.S.^a , Estepp, J.H.^c , King, A.^d , Henley, M.^c , Kang, G.^b , Hankins, J.S.^c

^a Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Program in Occupational Therapy and Department of Pediatrics and Medicine, Washington University, St. Louis, MO, United States

Abstract
Background: Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. Procedure: Sixty-two patients with SCD (60% HbSS/HbSβ0-thalassemia; 40% HbSC/HbSβ+-thalassemia) between the ages of 3 and 6 years (mean = 4.77 years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSβ0-thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45) years of age. The average dose was 28.8 mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. Results: Patients with HbSS/HbSβ0-thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR] &lt;.05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR &gt;.05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR &lt;.05). Greater household socioeconomic status was positively associated with academic readiness. Conclusions: Preschoolers with severe SCD (HbSS/HbSβ0-thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed. © 2021 Wiley Periodicals LLC

Funding details
American Lebanese Syrian Associated CharitiesALSAC