WashU weekly Neuroscience publications | Office of Neuroscience Research

“A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine” (2020) Nature Communications

A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine
(2020) Nature Communications, 11 (1), art. no. 3368, .

Guo, Y.^a ^b ^c , Rist, P.M.^a ^b ^c , Daghlas, I.^a ^b , Giulianini, F.^a , Gormley, P.^e ^f ^g ^h , Anttila, V.^f ^g ⁱ , Winsvold, B.S.^j ^k ^l , Palta, P.^m , Esko, T.^f ⁿ ^o , Pers, T.H.^f ^o ^p ^q , Farh, K.-H.^f ⁱ ^r , Cuenca-Leon, E.^e ^f ^g ^s , Muona, M.^m ^t ^u ^v , Furlotte, N.A.^w , Kurth, T.^x ^y , Ingason, A.^z , McMahon, G.^aa , Ligthart, L.^ab , Terwindt, G.M.^ac , Kallela, M.^ad , Freilinger, T.M.^ae ^af , Ran, C.^ag , Gordon, S.G.^ah , Stam, A.H.^ac , Steinberg, S.^z , Borck, G.^ai , Koiranen, M.^aj , Quaye, L.^ak , Adams, H.H.H.^al ^am , Lehtimäki, T.^an , Sarin, A.-P.^m , Wedenoja, J.^ao , Hinds, D.A.^w , Buring, J.E.^y ^ap , Schürks, M.^aq , Ridker, P.M.^y ^ap , Hrafnsdottir, M.G.^ar , Stefansson, H.^z , Ring, S.M.^aa , Hottenga, J.-J.^ab , Penninx, B.W.J.H.^as , Färkkilä, M.^ad , Artto, V.^ad , Kaunisto, M.^m , Vepsäläinen, S.^ad , Malik, R.^ae , Heath, A.C.^at , Madden, P.A.F.^at , Martin, N.G.^ah , Montgomery, G.W.^ah , Kurki, M.^e ^f ^g , Kals, M.ⁿ , Mägi, R.ⁿ , Pärn, K.ⁿ , Hämäläinen, E.^m , Huang, H.^f ^g ⁱ , Byrnes, A.E.^f ^g ⁱ , Franke, L.^au , Huang, J.^h , Stergiakouli, E.^aa , Lee, P.H.^e ^f ^g , Sandor, C.^av , Webber, C.^av , Cader, Z.^aw ^ax , Muller-Myhsok, B.^ay , Schreiber, S.^az , Meitinger, T.^ba , Eriksson, J.G.^bb ^bc , Salomaa, V.^bc , Heikkilä, K.^bd , Loehrer, E.^al ^be , Uitterlinden, A.G.^bf , Hofman, A.^al , Duijn, C.M.^al , Cherkas, L.^ak , Pedersen, L.M.^j , Stubhaug, A.^bg ^bh , Nielsen, C.S.^bg ^bi , Männikkö, M.^aj , Mihailov, E.ⁿ , Milani, L.ⁿ , Göbel, H.^bj , Esserlind, A.-L.^bk , Christensen, A.F.^bk , Hansen, T.F.^bl , Werge, T.^bm ^bn ^bo , Kaprio, J.^m ^bp ^bq , Aromaa, A.J.^bc , Raitakari, O.^br ^bs , Ikram, M.A.^al ^am ^bs ^bt , Spector, T.^ak , Järvelin, M.-R.^aj ^bu ^bv ^bw , Metspalu, A.ⁿ , Kubisch, C.^bx , Strachan, D.P.^by , Ferrari, M.D.^ac , Belin, A.C.^ag , Dichgans, M.^ah ^bz , Wessman, M.^m ^t , Maagdenberg, A.M.J.M.^ac ^ca , Zwart, J.-A.^j ^k ^l , Boomsma, D.I.^ab , Smith, G.D.^aa , Stefansson, K.^z ^cb , Eriksson, N.^w , Daly, M.J.^f ^g ⁱ , Neale, B.M.^f ^g ⁱ , Olesen, J.^bk , Chasman, D.I.^y ^ap , Nyholt, D.R.^cc , Palotie, A.^e ^f ^g ^h ⁱ ^m ^aa ^cd , Agee, M.^ce , Auton, A.^ce , Bell, R.K.^ce , Bryc, K.^ce , Elson, S.L.^ce , Fontanillas, P.^ce , Furlotte, N.A.^ce , Hinds, D.A.^ce , Huber, K.E.^ce , Kleinman, A.^ce , Litterman, N.K.^ce , McCreight, J.C.^ce , McIntyre, M.H.^ce , Mountain, J.L.^ce , Noblin, E.S.^ce , Northover, C.A.M.^ce , Pitts, S.J.^ce , Sathirapongsasuti, J.F.^ce , Sazonova, O.V.^ce , Shelton, J.F.^ce , Shringarpure, S.^ce , Tian, C.^ce , Tung, J.Y.^ce , Vacic, V.^ce , Kurth, T.^c ^d , Chasman, D.I.^a ^b , The International Headache Genetics Consortium^cf , The 23andMe Research Team^cf

^a Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215, United States
^b Harvard Medical School, Boston, MA 02115, United States
^c Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02215, United States
^d Institute of Public Health, Charité – Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany
^e Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^f Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^g Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^h Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
ⁱ Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^j FORMI, Oslo University Hospital, P.O. 4956 Nydalen, Oslo, 0424, Norway
^k Department of Neurology, Oslo University Hospital, P.O. 4956 Nydalen, Oslo, 0424, Norway
^l Institute of Clinical Medicine, University of Oslo, P.O. 1171 Blindern, Oslo, 0318, Norway
^m Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
ⁿ Estonian Genome Center, University of Tartu, Tartu, Estonia
^o Division of Endocrinology, Boston Children’s Hospital, Boston, MA, United States
^p Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
^q Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
^r Illumina, Illumina Way, San Diego, CA 5200, United States
^s Vall d’Hebron Research Institute, Pediatric Neurology, Barcelona, Spain
^t Folkhälsan Institute of Genetics, Helsinki, FI-00290, Finland
^u Neuroscience Center, University of Helsinki, Helsinki, FI-00014, Finland
^v Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, FI-00014, Finland
^w 23andMe, Inc., 223 N Mathilda Ave, Sunnyvale, CA 94086, United States
^x Inserm Research Center for Epidemiology and Biostatistics (U897), University of Bordeaux, Bordeaux, 33076, France
^y Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215, United States
^z deCODE Genetics, Reykjavik, 101, Iceland
^aa Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
^ab Department of Biological Psychology, VU University Amsterdam, Amsterdam, 1081 BT, Netherlands
^ac Department of Neurology, Leiden University Medical Centre, PO Box 9600, Leiden, 2300 RC, Netherlands
^ad Department of Neurology, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, 00290, Finland
^ae Institute for Stroke and Dementia Research, Klinikum der Universtität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, Munich, 81377, Germany
^af Department of Neurology and Epileptology, Hertie Institute for Clincal Brain Research, University of Tuebingen, Tuebingen, Germany
^ag Department of Neuroscience, Karolinska Institutet, Stockholm, 171 77, Sweden
^ah Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4006, Australia
^ai Institute of Human Genetics, Ulm University, Ulm, 89081, Germany
^aj Center for Life Course Epidemiology and Systems Medicine, University of Oulu, Box 5000, Oulu, FI-90014, Finland
^ak Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
^al Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands
^am Department of Radiology, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands
^an Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, 33520, Finland
^ao Department of Public Health, University of Helsinki, Helsinki, Finland
^ap Harvard Medical School, Boston, MA 02115, United States
^aq University Duisburg Essen, Essen, Germany
^ar Landspitali University Hospital, Reykjavik, 101, Iceland
^as Department of Psychiatry, VU University Medical Centre, Amsterdam, 1081 HL, Netherlands
^at Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, CB 8134, St. Louis, MO 63110, United States
^au University Medical Center Groningen, University of Groningen, Groningen, 9700RB, Netherlands
^av MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, United Kingdom
^aw Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom
^ax Oxford Headache Centre, John Radcliffe Hospital, Oxford, United Kingdom
^ay Max-Planck-Institute of Psychiatry, Munich, Germany
^az Christian Albrechts University, Kiel, Germany
^ba Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany
^bb Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^bc National Institute for Health and Welfare, Helsinki, Finland
^bd Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland
^be Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
^bf Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands
^bg Department of Pain Management and Research, Oslo University Hospital, Oslo, 0424, Norway
^bh Medical Faculty, University of Oslo, Oslo, 0318, Norway
^bi Division of Mental Health, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, Oslo, 0403, Norway
^bj Kiel Pain and Headache Center, Kiel, 24149, Germany
^bk Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
^bl Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
^bm Institute Of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen, 2100, Denmark
^bn Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, 2100, Denmark
^bo iPSYCH – The Lundbeck Foundation’s Initiative for Integrative Psychiatric Research, Copenhagen, 2100, Denmark
^bp Department of Public Health, University of Helsinki, Helsinki, Finland
^bq Department of Health, National Institute for Health and Welfare, Helsinki, Finland
^br Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20521, Finland
^bs Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland
^bt Department of Neurology, Erasmus University Medical Center, Rotterdam, 3015 CN, Netherlands
^bu Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, United Kingdom
^bv Biocenter Oulu, University of Oulu, Box 5000, Oulu, 90014, Finland
^bw Unit of Primary Care, Oulu University Hospital, Box 10, Oulu, FIN-90029, Finland
^bx University Medical Center Hamburg Eppendorf, Institute of Human Genetics, Hamburg, 20246, Germany
^by Population Health Research Institute, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
^bz Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^ca Leiden University Medical Centre, Department of Human Genetics, PO Box 9600, Leiden, 2300 RC, Netherlands
^cb Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
^cc Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD 4059, Australia
^cd Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^ce 23andMe, Inc., 223 N Mathilda Ave, Sunnyvale, CA 94086, United States

Abstract
Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (Ncases/Ncontrols = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, rg = 0.11, P = 3.56 × 10−06) and systolic BP (SBP, rg = 0.06, P = 0.01), but not pulse pressure (PP, rg = −0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10−08), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15–1.25]/10 mmHg; P = 5.57 × 10−25) on migraine than SBP (1.05 [1.03–1.07]/10 mmHg; P = 2.60 × 10−07) and a corresponding opposite effect for PP (0.92 [0.88–0.95]/10 mmHg; P = 3.65 × 10−07). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease” (2020) Nature Communications

Comprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease
(2020) Nature Communications, 11 (1), art. no. 3328, .

Ray, T.A.^a ^b , Cochran, K.^a ^b , Kozlowski, C.^a ^b , Wang, J.^a ^b , Alexander, G.^c , Cady, M.A.^h , Spencer, W.J.^h , Ruzycki, P.A.^d , Clark, B.S.^d ^e , Laeremans, A.^f , He, M.-X.^f , Wang, X.^f , Park, E.^f , Hao, Y.^b , Iannaccone, A.^b , Hu, G.^a ^b , Fedrigo, O.^c ^g , Skiba, N.P.^b , Arshavsky, V.Y.^b , Kay, J.N.^a ^b

^a Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, United States
^b Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, United States
^c Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, United States
^d John F. Hardesty, M.D. Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO 63110, United States
^e Department of Developmental Biology, Washington University, St. Louis, MO 63110, United States
^f Advanced Cell Diagnostics, Newark, CA 94560, United States
^g The Rockefeller University, 1230 York Avenue, New York, NY 10065, United States

Abstract
Genes encoding cell-surface proteins control nervous system development and are implicated in neurological disorders. These genes produce alternative mRNA isoforms which remain poorly characterized, impeding understanding of how disease-associated mutations cause pathology. Here we introduce a strategy to define complete portfolios of full-length isoforms encoded by individual genes. Applying this approach to neural cell-surface molecules, we identify thousands of unannotated isoforms expressed in retina and brain. By mass spectrometry we confirm expression of newly-discovered proteins on the cell surface in vivo. Remarkably, we discover that the major isoform of a retinal degeneration gene, CRB1, was previously overlooked. This CRB1 isoform is the only one expressed by photoreceptors, the affected cells in CRB1 disease. Using mouse mutants, we identify a function for this isoform at photoreceptor-glial junctions and demonstrate that loss of this isoform accelerates photoreceptor death. Therefore, our isoform identification strategy enables discovery of new gene functions relevant to disease. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“A comparative study of sleep and diurnal patterns in house mouse (Mus musculus) and Spiny mouse (Acomys cahirinus)” (2020) Scientific Reports

A comparative study of sleep and diurnal patterns in house mouse (Mus musculus) and Spiny mouse (Acomys cahirinus)
(2020) Scientific Reports, 10 (1), art. no. 10944, .

Wang, C.^a ^c , Guerriero, L.E.^a , Huffman, D.M.^b , Ajwad, A.A.^b , Brooks, T.C.^a , Sunderam, S.^b , Seifert, A.W.^a , O’Hara, B.F.^a ^d

^a Department of Biology, University of Kentucky, Lexington, KY 40506, United States
^b Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40506, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Signal Solutions LLC, 145 Graham Ave., Lexington, KY 40506, United States

Abstract
Most published sleep studies use three species: human, house mouse, or Norway rat. The degree to which data from these species captures variability in mammalian sleep remains unclear. To gain insight into mammalian sleep diversity, we examined sleep architecture in the spiny basal murid rodent Acomys cahirinus. First, we used a piezoelectric system validated for Mus musculus to monitor sleep in both species. We also included wild M. musculus to control for alterations generated by laboratory-reared conditions for M. musculus. Using this comparative framework, we found that A. cahirinus, lab M. musculus, and wild M. musculus were primarily nocturnal, but exhibited distinct behavioral patterns. Although the activity of A. cahirinus increased sharply at dark onset, it decreased sharply just two hours later under group and individual housing conditions. To further characterize sleep patterns and sleep-related variables, we set up EEG/EMG and video recordings and found that A. cahirinus sleep significantly more than M. musculus, exhibit nearly three times more REM, and sleep almost exclusively with their eyes open. The observed differences in A. cahirinus sleep architecture raise questions about the evolutionary drivers of sleep behavior. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Conservation and divergence in NaChBac and NaV1.7 pharmacology reveals novel drug interaction mechanisms” (2020) Scientific Reports

Conservation and divergence in NaChBac and NaV1.7 pharmacology reveals novel drug interaction mechanisms
(2020) Scientific Reports, 10 (1), art. no. 10730, .

Zhu, W.^a ^b , Li, T.^a , Silva, J.R.^b , Chen, J.^a

^a Biochemical and Cellular Pharmacology, Genentech Inc., 103 DNA Way, South San Francisco, CA, United States
^b Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Voltage-gated Na+ (NaV) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial NaV channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of channel gating. However, the pharmacology of bacterial NaV remains largely unexplored. Here we systematically screened 39 NaV modulators on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac and a mammalian channel (human NaV1.7). We found that while many compounds interact with both channels, they exhibit distinct functional effects. For example, the local anesthetics ambroxol and lidocaine block both NaV1.7 and NaChBac but affect activation and inactivation of the two channels to different extents. The voltage-sensing domain targeting toxin BDS-I increases NaV1.7 but decreases NaChBac peak currents. The pore binding toxins aconitine and veratridine block peak currents of NaV1.7 and shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac, they block the peak current by binding to the pore residue F224. Nonetheless, aconitine has no effect on activation or inactivation, while veratridine only modulates activation of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian NaV channels provide insights into the molecular basis of channel gating and will facilitate organism-specific drug discovery. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Brain extraction on MRI scans in presence of diffuse glioma: Multi-institutional performance evaluation of deep learning methods and robust modality-agnostic training” (2020) NeuroImage

Brain extraction on MRI scans in presence of diffuse glioma: Multi-institutional performance evaluation of deep learning methods and robust modality-agnostic training
(2020) NeuroImage, 220, art. no. 117081, .

Thakur, S.^a ^b , Doshi, J.^a ^c , Pati, S.^a ^c , Rathore, S.^a ^c , Sako, C.^a ^c , Bilello, M.^c , Ha, S.M.^a ^c , Shukla, G.^a ^d ^f , Flanders, A.^e , Kotrotsou, A.^g , Milchenko, M.^h , Liem, S.ⁱ , Alexander, G.S.^j , Lombardo, J.^f ⁱ , Palmer, J.D.^f ^k , LaMontagne, P.^h , Nazeri, A.^h , Talbar, S.^b , Kulkarni, U.^b , Marcus, D.^h , Colen, R.^g , Davatzikos, C.^a ^c , Erus, G.^a ^c , Bakas, S.^a ^c ^l

^a Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, PA, United States
^b Shri Guru Gobind Singhji Institute of Engineering and Technology, Nanded, Maharashtra, India
^c Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Radiation Oncology, Christiana Care Health System, Philadelphia, PA, United States
^e Department of Radiology, Thomas Jefferson University, Philadelphia, PA, United States
^f Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
^g Department of Diagnostic Radiology, University of Texas MD Anderson Cancer CenterTX, United States
^h Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
ⁱ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
^j Department of Radiation Oncology, University of Maryland, Baltimore, MD, United States
^k Department of Radiation Oncology, James Cancer Center, The Ohio State University, Columbus, OH, United States
^l Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Brain extraction, or skull-stripping, is an essential pre-processing step in neuro-imaging that has a direct impact on the quality of all subsequent processing and analyses steps. It is also a key requirement in multi-institutional collaborations to comply with privacy-preserving regulations. Existing automated methods, including Deep Learning (DL) based methods that have obtained state-of-the-art results in recent years, have primarily targeted brain extraction without considering pathologically-affected brains. Accordingly, they perform sub-optimally when applied on magnetic resonance imaging (MRI) brain scans with apparent pathologies such as brain tumors. Furthermore, existing methods focus on using only T1-weighted MRI scans, even though multi-parametric MRI (mpMRI) scans are routinely acquired for patients with suspected brain tumors. In this study, we present a comprehensive performance evaluation of recent deep learning architectures for brain extraction, training models on mpMRI scans of pathologically-affected brains, with a particular focus on seeking a practically-applicable, low computational footprint approach, generalizable across multiple institutions, further facilitating collaborations. We identified a large retrospective multi-institutional dataset of n=3340 mpMRI brain tumor scans, with manually-inspected and approved gold-standard segmentations, acquired during standard clinical practice under varying acquisition protocols, both from private institutional data and public (TCIA) collections. To facilitate optimal utilization of rich mpMRI data, we further introduce and evaluate a novel ‘‘modality-agnostic training’’ technique that can be applied using any available modality, without need for model retraining. Our results indicate that the modality-agnostic approach1 obtains accurate results, providing a generic and practical tool for brain extraction on scans with brain tumors. © 2020 The Author(s)

Author Keywords
Brain Extraction; Brain tumor; Deep learning; Evaluation; Glioblastoma; Glioma; Skull-stripping; TCIA

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Examining emotional pain among individuals with chronic physical pain: Nomothetic and idiographic approaches” (2020) Journal of Psychosomatic Research

Examining emotional pain among individuals with chronic physical pain: Nomothetic and idiographic approaches
(2020) Journal of Psychosomatic Research, 136, art. no. 110172, .

Frumkin, M.R.^a , Haroutounian, S.^b , Rodebaugh, T.L.^a

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

Abstract
Objective: Emotional pain (i.e., pain affect in response to psychological experiences such as rejection or loss) may be a component of chronic pain syndromes given high co-occurrence with depression and neurobiological overlaps in pain affect resulting from physical and emotional experiences. In the current set of studies, we examined the relationship between emotional and physical pain using both nomothetic (i.e., group-level) and idiographic (i.e., individual-level) approaches. Methods: Individuals with chronic pain were recruited from the Washington University Pain Center. First, we assessed the relationship between emotional and physical pain at the group level. Then, three individuals from the group-level study completed ecological momentary assessment four times per day for at least four weeks. We assessed relationships between emotional and physical pain using correlations and dynamic structural equation modeling. Results: Emotional pain severity was significantly positively correlated with physical pain at the group level. However, results from idiographic analyses suggested that one individual did not display a significant correlation between physical and emotional pain, and two individuals displayed correlations larger than expected based on the group-level data. Competing models suggested that emotional and physical pain represented distinct constructs for the individuals studied. Conclusions: These results suggest that emotional pain may be an important component of chronic pain syndromes. However, idiographic models revealed heterogeneity that may have important implications for treatment. Further research is needed to understand whether idiographic relationships between emotional and physical pain can help identify effective treatment targets for individuals with co-occurring emotional and physical symptoms. © 2020 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Ingredients of ‘rituals’ and their cognitive underpinnings” (2020) Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences

Ingredients of ‘rituals’ and their cognitive underpinnings
(2020) Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 375 (1805), p. 20190439.

Boyer, P.^a , Liénard, P.^b

^a Departments of Psychology and Anthropology, Washington University in Saint Louis, MISaint Louis, United States
^b Department of Anthropology, University of Nevada Las Vegas, NV, Las Vegas, United States

Abstract
Ritual is not a proper scientific object, as the term is used to denote disparate forms of behaviour, on the basis of a faint family resemblance. Indeed, a variety of distinct cognitive mechanisms are engaged, in various combinations, in the diverse interactions called ‘rituals’ – and each of these mechanisms deserves study, in terms of its evolutionary underpinnings and cultural consequences. We identify four such mechanisms that each appear in some ‘rituals’, namely (i) the normative scripting of actions; (ii) the use of interactions to signal coalitional identity, affiliation, cohesiveness; (iii) magical claims based on intuitive expectations of contagion; and (iv) ritualized behaviour based on a specific handling of the flow of behaviour. We describe the cognitive and evolutionary background to each of these potential components of ‘rituals’, and their effects on cultural transmission. This article is part of the theme issue ‘Ritual renaissance: new insights into the most human of behaviours’.

Author Keywords
conventions; cultural evolution; evolutionary psychology; magic; rituals

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Amyloid (1–42) Evoked Neurotoxicity” (2020) Molecular Neurobiology

Naringenin Upregulates AMPK-Mediated Autophagy to Rescue Neuronal Cells From β-Amyloid (1–42) Evoked Neurotoxicity
(2020) Molecular Neurobiology, 57 (8), pp. 3589-3602.

Ahsan, A.U.^a , Sharma, V.L.^a , Wani, A.^b , Chopra, M.^a

^a Cytogenetics Lab, Department of Zoology, Panjab University, Chandigarh, India
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Deposition of an amyloid-β peptide is one of the first events in the pathophysiology of Alzheimer’s disease (AD) and is clinically characterized by Aβ plaques, tau tangles, and behavioral impairments that lead to neuronal death. A substantial number of studies encourage targeting the skewness in the production and degradation of amyloid-β could be among the promising therapies in the disease. Neuronal autophagy has emerged for an essential role in the degradation of such toxic aggregate-prone proteins in various neurodegenerative diseases. We profiled a small library of common dietary compounds and identified those that can enhance autophagy in neuronal cells. Here we noted naringenin in silico exhibits a robust affinity with AMP-activated protein kinase (AMPK) and upregulated AMPK-mediated autophagy signaling in neurons. Naringenin can induce autophagy promoting proteins such as ULK1, Beclin1, ATG5, and ATG7 in Neuro2a cells and primary mouse neurons as well. The knockdown of AMPK by siRNA-AMPK was complemented by naringenin that restored transcript levels of AMPK. Further, naringenin can reduce the levels of Aβ at a nontoxic concentration from neuronal cells. Moreover, it maintained the mitochondrial membrane potential and resisted reactive oxygen species production, which led to the protection against Aβ1–42 evoked neurotoxicity. This highlights the neuroprotective potential of naringenin that can be developed as an anti-amyloidogenic nutraceutical. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
AICAR; AMPK; Aβ; GFAP; LC3B; MAP 2; mTOR; Naringenin; ULK1

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV (2020) Journal of Acquired Immune Deficiency Syndromes” (1999)

Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV
(2020) Journal of Acquired Immune Deficiency Syndromes (1999), 84 (4), pp. 414-421.

Paul, R.H.^a ^b , Cho, K.S.^b , Luckett, P.^c , Strain, J.F.^c , Belden, A.C.^b , Bolzenius, J.D.^b , Navid, J.^c , Garcia-Egan, P.M.^a ^b , Cooley, S.A.^c , Wisch, J.K.^c , Boerwinkle, A.H.^c , Tomov, D.^c , Obosi, A.^b ^d , Mannarino, J.A.^b , Ances, B.M.^c

^a Department of Psychological Sciences, University of Missouri, MO, Saint Louis, Seychelles
^b Missouri Institute of Mental Health, University of Missouri, MO, Saint Louis, Seychelles
^c Department of Neurology, Washington University School of Medicine, MO, Saint Louis, Seychelles
^d Department of Psychology, University of Ibadan, Ibadan, Nigeria

Abstract
BACKGROUND: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. SETTING: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. METHODS: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. RESULTS: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. CONCLUSIONS: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Early Child Development Outcomes of a Randomized Trial Providing 1 Egg Per Day to Children Age 6 to 15 Months in Malawi” (2020) The Journal of Nutrition

Early Child Development Outcomes of a Randomized Trial Providing 1 Egg Per Day to Children Age 6 to 15 Months in Malawi
(2020) The Journal of Nutrition, 150 (7), pp. 1933-1942.

Prado, E.L.^a , Maleta, K.^b , Caswell, B.L.^a , George, M.^b , Oakes, L.M.^c , DeBolt, M.C.^c , Bragg, M.G.^a , Arnold, C.D.^a , Iannotti, L.L.^d , Lutter, C.K.^e , Stewart, C.P.^a

^a Department of Nutrition and Institute for Global Nutrition, University of California Davis, Davis, CA, USA
^b School of Public Health and Family Medicine, University of Malawi College of Medicine, Blantyre, Malawi
^c Department of Psychology and Center for Mind and Brain, University of California Davis, Davis, CA, USA
^d Brown School, Institute for Public Health, Washington University in St. Louis, St. Louis, MO, USA
^e RTI International, Washington DC, School of Public Health, University of Maryland, MD, College Park, United States

Abstract
BACKGROUND: Eggs are a rich source of nutrients important for brain development, including choline, riboflavin, vitamins B-6 and B-12, folate, zinc, protein, and DHA. OBJECTIVE: Our objective was to evaluate the effect of the consumption of 1 egg per day over a 6-mo period on child development. METHODS: In the Mazira Project randomized controlled trial, 660 children aged 6-9 mo were randomly allocated into an intervention or control group. Eggs were provided to intervention households during twice-weekly home visits for 6 mo. Control households were visited at the same frequency. At enrollment, blinded assessors administered the Malawi Developmental Assessment Tool (MDAT), and 2 eye-tracking tasks using a Tobii-Pro X2-60 eye tracker: a visual paired comparison memory task and an Infant Orienting with Attention task. At endline, 6-mo later, blinded assessors administered the MDAT and eye-tracking tasks plus an additional elicited imitation memory task. RESULTS: At endline, intervention and control groups did not significantly differ in any developmental score, with the exception that a smaller percentage of children were delayed in fine motor development in the intervention group (10.6%) compared with the control group (16.5%; prevalence ratio: 0.59, 95% CI: 0.38-0.91). Among 10 prespecified effect modifiers for the 8 primary developmental outcomes, we found 7 significant interactions demonstrating a consistent pattern that children who were less vulnerable, for example, those with higher household wealth and maternal education, showed positive effects of the intervention. Given multiple hypothesis testing, some findings may have been due to chance. CONCLUSION: The provision of 1 egg per day had no overall effect on child development in this population of children, however, some benefits may be seen among children in less vulnerable circumstances. This trial was registered at clinicaltrials.gov as NCT03385252. Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.

Author Keywords
child development; complementary feeding; eggs; eye tracking; language; memory; motor

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Response to Letter to the Editor: Do Pediatric Cochlear Implant Recipients Display Domain-General Sequencing Difficulties? A Comment on” (2020) Ear and Hearing

Response to Letter to the Editor: Do Pediatric Cochlear Implant Recipients Display Domain-General Sequencing Difficulties? A Comment on
(2020) Ear and Hearing, 41 (4), pp. 1055-1056.

Davidson, L.S.^a , Geers, A.E.^b , Hale, S.^c , Sommers, M.M.^c , Brenner, C.^d , Spehar, B.^a

^a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Behavioral and Brain Sciences, University of Texas Dallas, Dallas, TX, United States
^c Department of Psychology, Washington University, St. Louis, MO, United States
^d Moog Center for Deaf Education, St. Louis, MO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

“A Domain-General Cognitive Core Defined in Multimodally Parcellated Human Cortex” (2020) Cerebral Cortex (New York, N.Y. : 1991)

A Domain-General Cognitive Core Defined in Multimodally Parcellated Human Cortex
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (8), pp. 4361-4380.

Assem, M.^a , Glasser, M.F.^b ^c ^d , Van Essen, D.C.^b , Duncan, J.^a ^e

^a MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, United Kingdom
^b Department of Neuroscience, Washington University in St. Louis, MO, Saint Louis 63110, United States
^c Department of Radiology, Washington University in St. Louis, MO, Saint Louis 63110, United States
^d St. Luke’s Hospital, MO, Saint Louis 63017, United States
^e Department of Experimental Psychology, University of Oxford, Oxford, OX1 3UD, United Kingdom

Abstract
Numerous brain imaging studies identified a domain-general or “multiple-demand” (MD) activation pattern accompanying many tasks and may play a core role in cognitive control. Though this finding is well established, the limited spatial localization provided by traditional imaging methods precluded a consensus regarding the precise anatomy, functional differentiation, and connectivity of the MD system. To address these limitations, we used data from 449 subjects from the Human Connectome Project, with the cortex of each individual parcellated using neurobiologically grounded multimodal MRI features. The conjunction of three cognitive contrasts reveals a core of 10 widely distributed MD parcels per hemisphere that are most strongly activated and functionally interconnected, surrounded by a penumbra of 17 additional areas. Outside cerebral cortex, MD activation is most prominent in the caudate and cerebellum. Comparison with canonical resting-state networks shows MD regions concentrated in the fronto-parietal network but also engaging three other networks. MD activations show modest relative task preferences accompanying strong co-recruitment. With distributed anatomical organization, mosaic functional preferences, and strong interconnectivity, we suggest MD regions are well positioned to integrate and assemble the diverse components of cognitive operations. Our precise delineation of MD regions provides a basis for refined analyses of their functions. © The Author(s) 2020. Published by Oxford University Press.

Author Keywords
cognitive control; domain-general; fronto-parietal; multimodal cortical parcellation; multiple-demand

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision” (2020) Proceedings of the National Academy of Sciences of the United States of America

Thyroid hormone receptors mediate two distinct mechanisms of long-wavelength vision
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (26), pp. 15262-15269.

Volkov, L.I.^a , Kim-Han, J.S.^b , Saunders, L.M.^c ^d , Poria, D.^e , Hughes, A.E.O.^a , Kefalov, V.J.^e , Parichy, D.M.^c ^d , Corbo, J.C.^f

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
^b Department of Pharmacology, A.T. Still University of Health Sciences, Kirksville, MO 63501
^c Department of Biology, University of Virginia, Charlottesville, United States
^d Department of Cell Biology, University of Virginia, Charlottesville, United States
^e Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110
^f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;

Abstract
Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor β (thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, cyp27c1, that converts vitamin A1 into vitamin A2 to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa, thrab, and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three (thraa-/-;thrab-/-;thrb-/- ) completely abrogates its induction and the resulting conversion of A1- to A2-based retinoids. In the retina, loss of thrb resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adult thrb-/- retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the thrb-/- retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.

Author Keywords
cone photoreceptors; retinal development; thyroid hormone; vitamin A2; zebrafish

Document Type: Article
Publication Stage: Final
Source: Scopus

“Robust principal component analysis for accurate outlier sample detection in RNA-Seq data” (2020) BMC Bioinformatics

Robust principal component analysis for accurate outlier sample detection in RNA-Seq data
(2020) BMC Bioinformatics, 21 (1), art. no. 269, .

Chen, X.^a , Zhang, B.^b , Wang, T.^c , Wang, T.^d , Bonni, A.^a , Zhao, G.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Center of Regenerative Medicine, Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^d Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: High throughput RNA sequencing is a powerful approach to study gene expression. Due to the complex multiple-steps protocols in data acquisition, extreme deviation of a sample from samples of the same treatment group may occur due to technical variation or true biological differences. The high-dimensionality of the data with few biological replicates make it challenging to accurately detect those samples, and this issue is not well studied in the literature currently. Robust statistics is a family of theories and techniques aim to detect the outliers by first fitting the majority of the data and then flagging data points that deviate from it. Robust statistics have been widely used in multivariate data analysis for outlier detection in chemometrics and engineering. Here we apply robust statistics on RNA-seq data analysis. Results: We report the use of two robust principal component analysis (rPCA) methods, PcaHubert and PcaGrid, to detect outlier samples in multiple simulated and real biological RNA-seq data sets with positive control outlier samples. PcaGrid achieved 100% sensitivity and 100% specificity in all the tests using positive control outliers with varying degrees of divergence. We applied rPCA methods and classical principal component analysis (cPCA) on an RNA-Seq data set profiling gene expression of the external granule layer in the cerebellum of control and conditional SnoN knockout mice. Both rPCA methods detected the same two outlier samples but cPCA failed to detect any. We performed differentially expressed gene detection before and after outlier removal as well as with and without batch effect modeling. We validated gene expression changes using quantitative reverse transcription PCR and used the result as reference to compare the performance of eight different data analysis strategies. Removing outliers without batch effect modeling performed the best in term of detecting biologically relevant differentially expressed genes. Conclusions: rPCA implemented in the PcaGrid function is an accurate and objective method to detect outlier samples. It is well suited for high-dimensional data with small sample sizes like RNA-seq data. Outlier removal can significantly improve the performance of differential gene detection and downstream functional analysis. © 2020 The Author(s).

Author Keywords
Anomaly detection; High-dimensional data; Outlier detection; PcaGrid; PcaHubert; RNA-seq; Robust principal component analysis

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World” (2020) Cell

How Support of Early Career Researchers Can Reset Science in the Post-COVID19 World
(2020) Cell, 181 (7), pp. 1445-1449.

Gibson, E.M.^a , Bennett, F.C.^b , Gillespie, S.M.^c , Güler, A.D.^d , Gutmann, D.H.^e , Halpern, C.H.^f , Kucenas, S.C.^d , Kushida, C.A.^a , Lemieux, M.^g , Liddelow, S.^h , Macauley, S.L.ⁱ , Li, Q.^j , Quinn, M.A.^k , Roberts, L.W.^a , Saligrama, N.^e , Taylor, K.R.^c , Venkatesh, H.S.^c , Yalçın, B.^c , Zuchero, J.B.^f

^a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA
^b Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States
^c Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA
^d Department of Biology, University of Virginia, Charlottesville, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
^f Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA 94305, USA
^g Salk Institute for Biological Studies, La Jolla, CA, 92037, United States
^h Neuroscience Institute, NYU School of Medicine, NY, NY 10016, United States
ⁱ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, United States
^j Departments of Neuroscience and Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
^k Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, United States

Abstract
The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers. Copyright © 2020 Elsevier Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Predicting Individual Preferences in Mindfulness Techniques Using Personality Traits” (2020) Frontiers in Psychology

Predicting Individual Preferences in Mindfulness Techniques Using Personality Traits
(2020) Frontiers in Psychology, 11, art. no. 1163, .

Tang, R., Braver, T.S.

Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
The growing popularity of mindfulness-based interventions (MBIs) has prompted exciting scientific research investigating their beneficial effects on well-being and health. Most mindfulness programs are provided as multi-faceted packages encompassing a set of different mindfulness techniques, each with distinct focus and mechanisms. However, this approach overlooks potential individual differences, which may arise in response to practicing various mindfulness techniques. The present study investigated preferences for four prototypical mindfulness techniques [focused attention (FA), open monitoring (OM), loving-kindness (LK), and body scan (BS)] and identified factors that may contribute to individual differences in these preferences. Participants without prior mindfulness experiences were exposed to each technique through audio-guided instructions and were asked to rank their preferences at the end of all practices. Results indicated that preferences for loving-kindness were predicted by empathy, and that females tended to prefer loving-kindness more than males. Conversely, preferences for open monitoring were predicted by nonreactivity and nonjudgment of present moment experiences. Additionally, higher state mindfulness was detected for individuals’ preferred technique relative to other alternatives. These findings suggest that individuals tend to prefer techniques compatible with their personalities, as the predictor variables encompass trait capacities specifically relevant to practicing these techniques. Together, our results suggest the possibility that assessing individual difference and then tailoring MBIs to individual needs could be a useful way to improve intervention effectiveness and subsequent outcomes. © Copyright © 2020 Tang and Braver.

Author Keywords
disposition; individual difference; meditation; mindfulness; personality; preferences

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Feasibility and validity of a low-cost racing simulator in driving assessment after stroke” (2020) Geriatrics (Switzerland)

Feasibility and validity of a low-cost racing simulator in driving assessment after stroke
(2020) Geriatrics (Switzerland), 5 (2), art. no. 35, .

Tiu, J.^a , Harmon, A.C.^b , Stowe, J.D.^c , Zwa, A.^d , Kinnear, M.^e , Dimitrov, L.^f , Nolte, T.^g , Carr, D.B.^b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Mid-America Regional Council, Kansas City, MO 64105, United States
^d sOnit, Inc., Potomac, MD 20854, United States
^e Thomas Dunn Learning Center, St. Louis, MO 63118, United States
^f 3 Peak Engineering, Toronto, ON M3C 3P3, Canada
^g Center for Clinical Studies, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
There is amyriad ofmethodologies to assess driving performance after a stroke. These include psychometric tests, driving simulation, questionnaires, and/or road tests. Research-based driving simulators have emerged as a safe, convenient way to assess driving performance after a stroke. Such traditional research simulators are useful in recreating street traffic scenarios, but are often expensive, with limited physics models and graphics rendering. In contrast, racing simulators developed for motorsport professionals and enthusiasts offer high levels of realism, run on consumer-grade hardware, and can provide rich telemetric data. However, most offer limited simulation of traffic scenarios. This pilot study compares the feasibility of research simulation and racing simulation in a sample with minor stroke. We determine that the racing simulator is tolerated well in subjects with a minor stroke. There were correlations between research and racing simulator outcomes with psychometric tests associated with driving performance, such as the Trails Making Test Part A, Snellgrove Maze Task, and the Motricity Index. We found correlations between measures of driving speed on a complex research simulator scenario and racing simulator lap time and maximum tires off track. Finally, we present two models, using outcomes from either the research or racing simulator, predicting road test failure as linked to a previously published fitness-to-drive calculator that uses psychometric screening. © 2020 by the authors.

Author Keywords
Driving assessment; Driving rehabilitation; Driving simulation; Racing simulation; Return to driving; Stroke rehabilitation

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Factors associated with syrinx size in pediatric patients treated for Chiari malformation type I and syringomyelia: A study from the Park-Reeves Syringomyelia research consortium” (2020) Journal of Neurosurgery: Pediatrics

Factors associated with syrinx size in pediatric patients treated for Chiari malformation type I and syringomyelia: A study from the Park-Reeves Syringomyelia research consortium
(2020) Journal of Neurosurgery: Pediatrics, 25 (6), pp. 629-639.

Hale, A.T.^a ^b , David Adelson, P.^c , Albert, G.W.^d , Aldana, P.R.^e , Alden, T.D.^f , Anderson, R.C.E.^g , Bauer, D.F.^h , Bonfield, C.M.^b ⁱ , Brockmeyer, D.L.^j , Chern, J.J.^k , Couture, D.E.^l , Daniels, D.J.^m , Durham, S.R.ⁿ , Ellenbogen, R.G.^o , Eskandari, R.^p , George, T.M.^q , Grant, G.A.^r , Graupman, P.C.^s , Greene, S.^t , Greenfield, J.P.^u , Gross, N.L.^v , Guillaume, D.J.^w , Heuer, G.G.^x , Iantosca, M.^y , Iskandar, B.J.^z , Jackson, E.M.^aa , Johnston, J.M.^ab , Keating, R.F.^ac , Leonard, J.R.^ad , Maher, C.O.^ae , Mangano, F.T.^af , Gordon McComb, J.^ag , Meehan, T.^ah , Menezes, A.H.^ai , O’Neill, B.^aj , Olavarria, G.^ak , Park, T.S.^ah , Ragheb, J.^al , Selden, N.R.^am , Shah, M.N.^an , Smyth, M.D.^ah , Stone, S.S.D.^ao , Strahle, J.M.^ah , Wait, S.D.^ap , Wellons, J.C.^b ⁱ , Whitehead, W.E.^aq , Shannon, C.N.^b ⁱ , Limbrick, D.D., Jr.^ah , Park-Reeves Syringomyelia Research Consortium Investigators^ar

^a Vanderbilt University School of Medicine, Medical Scientist Training Program, Nashville, TN, United States
^b Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States
^c Division of Pediatric Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
^d Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
^e Division of Pediatric Neurosurgery, University of Florida College of Medicine, Jacksonville, FL, United States
^f Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of ChicagoIL, United States
^g Division of Pediatric Neurosurgery, Department of Neurological Surgery, Children’s Hospital of New York, Columbia-Presbyterian, New York, NY, United States
^h Department of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
ⁱ Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States
^j Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
^k Division of Pediatric Neurosurgery, Children’s Healthcare of Atlanta University, Atlanta, GA, United States
^l Department of Neurological Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, United States
^m Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
ⁿ Department of Neurosurgery, University of Vermont, Burlington, VT, United States
^o Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
^p Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
^q Division of Pediatric Neurosurgery, Dell Children’s Medical Center, Austin, TX, United States
^r Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Palo Alto, CA, United States
^s Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
^t Division of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^u Department of Neurological Surgery, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, United States
^v Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^w Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
^x Division of Pediatric Neurosurgery, Children’s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^y Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
^z Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States
^aa Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^ab Division of Pediatric Neurosurgery, University of Alabama, Birmingham, AL, United States
^ac Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
^ad Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^ae Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
^af Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
^ag Division of Pediatric Neurosurgery, Children’s Hospital of Los AngelesCA, United States
^ah Department of Neurological Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^ai Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^aj Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
^ak Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
^al Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
^am Department of Neurological Surgery, Doernbecher Children’s Hospital, OregonHealth & Science University, Portland, OR, United States
^an Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
^ao Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
^ap Carolina Neurosurgery & Spine Associates, Charlotte, NC, United States
^aq Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States

Abstract
OBJECTIVE Factors associated with syrinx size in pediatric patients undergoing posterior fossa decompression (PFD) or PFD with duraplasty (PFDD) for Chiari malformation type I (CM-I) with syringomyelia (SM; CM-I+SM) are not well established. METHODS Using the Park-Reeves Syringomyelia Research Consortium registry, the authors analyzed variables associated with syrinx radiological outcomes in patients (< 20 years old at the time of surgery) with CM-I+SM undergoing PFD or PFDD. Syrinx resolution was defined as an anteroposterior (AP) diameter of ≤ 2 mm or ≤ 3 mm or a reduction in AP diameter of ≥ 50%. Syrinx regression or progression was defined using 1) change in syrinx AP diameter (≥ 1 mm), or 2) change in syrinx length (craniocaudal, ≥ 1 vertebral level). Syrinx stability was defined as a < 1-mm change in syrinx AP diameter and no change in syrinx length. RESULTS The authors identified 380 patients with CM-I+SM who underwent PFD or PFDD. Cox proportional hazards modeling revealed younger age at surgery and PFDD as being independently associated with syrinx resolution, defined as a ≤ 2-mm or ≤ 3-mm AP diameter or ≥ 50% reduction in AP diameter. Radiological syrinx resolution was associated with improvement in headache (p < 0.005) and neck pain (p < 0.011) after PFD or PFDD. Next, PFDD (p = 0.005), scoliosis (p = 0.007), and syrinx location across multiple spinal segments (p = 0.001) were associated with syrinx diameter regression, whereas increased preoperative frontal-occipital horn ratio (FOHR; p = 0.007) and syrinx location spanning multiple spinal segments (p = 0.04) were associated with syrinx length regression. Scoliosis (HR 0.38 [95% CI 0.16–0.91], p = 0.03) and smaller syrinx diameter (5.82 ± 3.38 vs 7.86 ± 3.05 mm; HR 0.60 [95% CI 0.34–1.03], p = 0.002) were associated with syrinx diameter stability, whereas shorter preoperative syrinx length (5.75 ± 4.01 vs 9.65 ± 4.31 levels; HR 0.21 [95% CI 0.12–0.38], p = 0.0001) and smaller pB-C2 distance (6.86 ± 1.27 vs 7.18 ± 1.38 mm; HR 1.44 [95% CI 1.02–2.05], p = 0.04) were associated with syrinx length stability. Finally, younger age at surgery (8.19 ± 5.02 vs 10.29 ± 4.25 years; HR 1.89 [95% CI 1.31–3.04], p = 0.01) was associated with syrinx diameter progression, whereas increased postoperative syrinx diameter (6.73 ± 3.64 vs 3.97 ± 3.07 mm; HR 3.10 [95% CI 1.67–5.76], p = 0.003), was associated with syrinx length progression. PFD versus PFDD was not associated with syrinx progression or reoperation rate. CONCLUSIONS These data suggest that PFDD and age are independently associated with radiological syrinx improvement, although forthcoming results from the PFDD versus PFD randomized controlled trial (NCT02669836, clinicaltrials. gov) will best answer this question. © AANS 2020.

Author Keywords
Chiari malformation type I; Park-Reeves Syringomyelia Research Consortium; Syrinx

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Complex regional pain syndrome type II after a brachial plexus and C6 nerve root injury” (2020) Cutis

Complex regional pain syndrome type II after a brachial plexus and C6 nerve root injury
(2020) Cutis, 105 (5), pp. E14-E16.

Ahn, J.W.^a , Mann, C.^b

^a Department of Dermatology, University of Michigan, Ann Arbor, United States
^b Department of Dermatology, St. Louis School of Medicine, Washington UniversityMO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

“Retinal Biomarkers of Alzheimer Disease” (2020) American Journal of Ophthalmology

Retinal Biomarkers of Alzheimer Disease
(2020) American Journal of Ophthalmology, .

Lee, C.S.^a , Apte, R.S.^b ^c ^d

^a Department of Ophthalmology, University of Washington, Seattle, WA, United States
^b Department of Ophthalmology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Purpose: To address challenges associated with identifying retinal biomarkers for Alzheimer’s disease (AD) and strategies for future investigation of novel ophthalmologic biomarkers. Design: Perspective. Methods: Summarization of the current understanding of retinal changes that have been identified using advances in imaging technology, analysis of current research into how these changes reflect neurodegenerative pathology, and recommendations for further research in this area that will allow for the identification of unique biomarkers for early AD. Results: Some retinal changes detectable using various imaging modalities may reflect neurodegeneration or other AD-related pathology on a cellular level. Structural changes in both the peripapillary and macular retina and changes in vascular parameters have been identified. Some imaging findings correlate with known histopathologic findings, and some are associated with cognitive decline. However, multiple challenges exist, such as identifying retinal biomarkers that are specific to biomarker-positive AD, clinical syndrome of AD, and/or pathologic AD brain, finding features that are highly sensitive and specific to AD in patients with other eye diseases, and validating potential biomarkers in population-based longitudinal cohorts. Conclusions: Further research is needed to validate retinal biomarkers for AD, with accurate classification of patients according to diagnosis and cognitive symptoms. Advances in imaging technology, big data, and machine learning, as well as carefully designed studies, will help to identify and confirm potential biomarkers and may lead to novel treatment approaches. © 2020 Elsevier Inc.

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

“Neurobiology of COVID-19” (2020) Journal of Alzheimer’s Disease: JAD

Neurobiology of COVID-19
(2020) Journal of Alzheimer’s Disease: JAD, 76 (1), pp. 3-19. Cited 1 time.

Fotuhi, M.^a ^b , Mian, A.^c , Meysami, S.^d , Raji, C.A.^c ^e

^a NeuroGrow Brain Fitness Center, VA, McLean, United States
^b Johns Hopkins Medicine, MD, Baltimore, United States
^c Neuroradiology Section, Mallinckrodt Institute of Radiology at Washington University in St. Louis, St. Louis, MO, USA
^d Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
^e Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA

Abstract
Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic “NeuroCovid” classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson’s disease, or Alzheimer’s disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

Author Keywords
Alzheimer’s disease; anosmia; cerebrovascular disease; COVID-19; cytokines; SARS-Cov2; seizure; vasculitis

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV” (2020) Annals of Clinical and Translational Neurology

Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV
(2020) Annals of Clinical and Translational Neurology, .

Ellis, R.J.^a , Diaz, M.^b , Sacktor, N.^c , Marra, C.^d , Collier, A.C.^e , Clifford, D.B.^f , Calcutt, N.^g , Fields, J.A.^h , Heaton, R.K.^h , Letendre, S.L.ⁱ , Franklin, D., Jr.^j , Best, B.^j , Cookson, D.^j , Cushman, C.^j , Dawson, M.^j , Fennema Notestine, C.^j , Weibel, S.G.^j , Grant, I.^j , Marcotte, T.D.^j , Marquie-Beck, J.^j , Vaida, F.^j , Rogalski, V.^j , Morgello, S.^j , Mintz, L.^j , McCutchan, J.A.^j , Storey, S.^j , Gelman, B.^j , Head, E.^j , Teshome, M.^j

^a Departments of Neurosciences and Psychiatry, University of California, San Diego, La Jolla, CA, United States
^b Department of Medicine, University of California, San Diego, La Jolla, CA, United States
^c Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^d Department of Neurology, University of Washington, Seattle, WA, United States
^e Department of Medicine, University of Washington, Seattle, WA, United States
^f Department of Neurology, Washington University, Saint Louis, MO, United States
^g Department of Pathology, University of California, San Diego, La Jolla, CA, United States
^h Department of Psychiatry, University of California, San Diego, La Jolla, CA, United States
ⁱ Departments of Medicine and Psychiatry, University of California, San Diego, La Jolla, CA, United States

Abstract
Objective: Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact. Methods: Ambulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes. Results: Of 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5 years. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free. Interpretation: HIV DSP and neuropathic pain increased in prevalence and severity over 12 years despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

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

“New and emerging treatments for inflammatory itch” (2020) Annals of Allergy, Asthma and Immunology

New and emerging treatments for inflammatory itch
(2020) Annals of Allergy, Asthma and Immunology, .

Erickson, S.^a , Heul, A.V.^b ^c , Kim, B.S.^a ^c ^d ^e

^a Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To summarize recent therapeutic developments for chronic pruritus with a focus on allergic and type 2 inflammatory pathways. Data Sources: Literature search of PubMed, industry websites, and review of the ClinicalTrials.gov database. Study Selection: Peer-reviewed publications and public disclosures by industry relating to chronic pruritus pathophysiology and therapeutics. Results: Histamine and immunoglobulin E remain primary targets for the treatment of itch in the setting of chronic urticaria. More recently, blockade of type 2 immune cell–associated cytokines, including interleukin (IL) 4, IL-13, and IL-31, and the epithelial cell–derived cytokines, specifically IL-33 and thymic stromal lymphopoietin, has and is revolutionizing the treatment of chronic pruritic dermatoses, such as atopic dermatitis and prurigo nodularis. Other novel targets include histamine receptor 4, Janus kinases, κ-opioid receptor, neurokinin 1 receptor, and phosphodiesterase 4. Conclusion: Advances in our understanding of the neuroimmunology of chronic pruritus have led to the identification of new therapeutic targets and the rapid development of cutting-edge clinical trials. Although incredible advances have already been made, chronic itch continues to be an area of great unmet need. © 2020 American College of Allergy, Asthma & Immunology

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

“Incipient alcohol use in childhood: Early alcohol sipping and its relations with psychopathology and personality” (2020) Development and Psychopathology

Incipient alcohol use in childhood: Early alcohol sipping and its relations with psychopathology and personality
(2020) Development and Psychopathology, .

Watts, A.L.^a , Wood, P.K.^a , Jackson, K.M.^b , Lisdahl, K.M.^c , Heitzeg, M.M.^d , Gonzalez, R.^e , Tapert, S.F.^f , Barch, D.M.^g , Sher, K.J.^a

^a Department of Psychological Sciences, University of Missouri, 200 S. 7th Street, Columbia, MI 65211, United States
^b Center for Alcohol and Addiction Studies, Brown University, Providence, United States
^c Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
^d Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
^e Department of Psychology, Florida International University, Miami, FL, United States
^f Department of Psychiatry, University of California San Diego, San Diego, CA, United States
^g Departments of Psychological and Brain Sciences Psychiatry and Radiology, Washington University, St. Louis, MO, United States

Abstract
Prior research has shown that sipping of alcohol begins to emerge during childhood and is potentially etiologically significant for later substance use problems. Using a large, community sample of 9-and 10-year-olds (N = 11,872; 53% female), we examined individual differences in precocious alcohol use in the form of alcohol sipping. We focused explicitly on features that are robust and well-demonstrated correlates of, and antecedents to, alcohol excess and related problems later in the lifespan, including youth-and parent-reported externalizing traits (i.e., impulsivity, behavioral inhibition and activation) and psychopathology. Seventeen percent of the sample reported sipping alcohol outside of a religiously sanctioned activity by age 9 or 10. Several aspects of psychopathology and personality emerged as small but reliable correlates of sipping. Nonreligious sipping was related to youth-reported impulsigenic traits, aspects of behavioral activation, prodromal psychotic-like symptoms, and mood disorder diagnoses, as well as parent-reported externalizing disorder diagnoses. Religious sipping was unexpectedly associated with certain aspects of impulsivity. Together, our findings point to the potential importance of impulsivity and other transdiagnostic indicators of psychopathology (e.g., emotion dysregulation, novelty seeking) in the earliest forms of drinking behavior. © 2020 The Author(s). Published by Cambridge University Press.

Author Keywords
alcohol sipping; novelty seeking; personality; precocious alcohol use; psychopathology

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

“Enantiomerically Pure Quinoline-Based κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation” (2020) ChemMedChem

Enantiomerically Pure Quinoline-Based κ-Opioid Receptor Agonists: Chemoenzymatic Synthesis and Pharmacological Evaluation
(2020) ChemMedChem, .

Martin, B.^a , Schepmann, D.^a , Bernal, F.A.^b , Schmidt, T.J.^b , Che, T.^c , Loser, K.^d ^e , Wünsch, B.^a ^e

^a Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, Münster, 48149, Germany
^b Institut für Pharmazeutische Biologie und Phytochemie der Universität Münster, Corrensstraße 48, Münster, 48149, Germany
^c Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^d Department of Dermatology, University of Münster, von-Esmarch-Street 58, Münster, 48149, Germany
^e Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Münster, 48149, Germany

Abstract
Racemic K-opioid receptor (KOR) agonist 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aSR)-8-(pyrrolidin-1-yl)-3,4,4a,5,6,7,8,8a-octahydroquinolin-1(2H)-yl]ethan-1-one ((±)-4) was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of the silyl ether of 1,2,3,4-tetrahydroquinoin-8-ol ((±)-9) to afford cis,cis-configured perhydroquinoline derivative (±)-10. Removal of the TBDMS protecting group led to a β-aminoalcohol that reacted with SO2Cl2 to form an oxathiazolidine. Nucleophilic substitution with pyrrolidine resulted in the desired cis,trans-configured perhydroquinoline upon inversion of the configuration. In order to obtain enantiomerically pure KOR agonists 4 (99.8 % ee) and ent-4 (99.0 % ee), 1,2,3,4-tetrahydroquinolin-8-ols (R)-8 (99.1 % ee) and (S)-8 (98.4 % ee) were resolved by an enantioselective acetylation catalyzed by Amano lipase PS-IM. The absolute configuration was determined by CD spectroscopy. The 4aR,8S,8aS-configured enantiomer 4 showed sub-nanomolar KOR affinity (Ki=0.81 nM), which is more than 200 times higher than the KOR affinity of its enantiomer ent-4. In the cAMP assay and the Tango β-arrestin-2 recruitment assay, 4 behaved as a KOR agonist. Upon incubation of human macrophages, human dendritic cells, and mouse myeloid immune cells with 4, the number of cells expressing co-stimulatory receptor CD86 and proinflammatory cytokines interleukin 6 and tumor necrosis factor α was significantly reduced; this indicates the strong anti-inflammatory activity of 4. The anti-inflammatory effects correlated well with the KOR affinity: (4aR,8S,8aS)-4 was slightly more potent than the racemic mixture (±)-4, and the distomer ent-4 was almost inactive. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Author Keywords
anti-inflammatory activity; diastereoselective synthesis; KOR agonists; lipase-catalyzed kinetic resolution; perhydroquinolines

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

“In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation” (2020) Molecular Imaging and Biology

In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation
(2020) Molecular Imaging and Biology, .

Liu, H., Luo, Z., Gu, J., Jiang, H., Joshi, S., Shoghi, K.I., Zhou, Y., Gropler, R.J., Benzinger, T.L.S., Tu, Z.

Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States

Abstract
Purpose: The sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four 18F-labeled S1PR1 tracers (18F-TZ43113, 18F-TZ35104, 18F-TZ4877, and 18F-TZ4881) in a rat model of multiple sclerosis (MS). Procedures: MicroPET studies of each tracer’s uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats. Results: All four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was 18F-TZ4877 > 18F-TZ4881 > 18F-TZ35104 > 18F-TZ43113. 18F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of 18F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain. Conclusion: Among these four new PET tracers, 18F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising 18F-labeled tracer for imaging S1PR1 in vivo. © 2020, World Molecular Imaging Society.

Author Keywords
Fluorine-18; Neuroinflammation; PET radioligands; Sphingosine-1-phosphate receptor 1

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

“Connectome mapping with edge density imaging differentiates pediatric mild traumatic brain injury from typically developing controls: proof of concept” (2020) Pediatric Radiology

Connectome mapping with edge density imaging differentiates pediatric mild traumatic brain injury from typically developing controls: proof of concept
(2020) Pediatric Radiology, .

Raji, C.A.^a ^b , Wang, M.B.^a , Nguyen, N.N.^a , Owen, J.P.^a , Palacios, E.M.^a , Yuh, E.L.^a , Mukherjee, P.^a

^a Neural Connectivity Laboratory, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry St., Suite 350, San Francisco, CA 94158, United States
^b Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Although acute neurologic impairment might be transient, other long-term effects can be observed with mild traumatic brain injury. However, when pediatric patients with mild traumatic brain injury present for medical care, conventional imaging with CT and MR imaging often does not reveal abnormalities. Objective: To determine whether edge density imaging can separate pediatric mild traumatic brain injury from typically developing controls. Materials and methods: Subjects were recruited as part of the “Therapeutic Resources for Attention Improvement using Neuroimaging in Traumatic Brain Injury” (TRAIN-TBI) study. We included 24 adolescents (χ=14.1 years of age, σ=1.6 years, range 10–16 years), 14 with mild traumatic brain injury (TBI) and 10 typically developing controls. Neurocognitive assessments included the pediatric version of the California Verbal Learning Test (CVLT) and the Attention Network Task (ANT). Diffusion MR imaging was acquired on a 3-tesla (T) scanner. Edge density images were computed utilizing fiber tractography. Principal component analysis (PCA) and support vector machines (SVM) were used in an exploratory analysis to separate mild TBI and control groups. The diagnostic accuracy of edge density imaging, neurocognitive tests, and fractional anisotropy (FA) from diffusion tensor imaging (DTI) was computed with two-sample t-tests and receiver operating characteristic (ROC) metrics. Results: Support vector machine–principal component analysis of edge density imaging maps identified three white matter regions distinguishing pediatric mild TBI from controls. The bilateral tapetum, sagittal stratum, and callosal splenium identified mild TBI subjects with sensitivity of 79% and specificity of 100%. Accuracy from the area under the ROC curve (AUC) was 94%. Neurocognitive testing provided an AUC of 61% (CVLT) and 71% (ANT). Fractional anisotropy yielded an AUC of 48%. Conclusion: In this proof-of-concept study, we show that edge density imaging is a new form of connectome mapping that provides better diagnostic delineation between pediatric mild TBI and healthy controls than DTI or neurocognitive assessments of memory or attention. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Brain; Children; Concussion; Diffusion tensor imaging; Edge density imaging; Magnetic resonance imaging; Traumatic brain injury

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

“Bioresorbable, Wireless, Passive Sensors as Temporary Implants for Monitoring Regional Body Temperature” (2020) Advanced Healthcare Materials

Bioresorbable, Wireless, Passive Sensors as Temporary Implants for Monitoring Regional Body Temperature
(2020) Advanced Healthcare Materials, .

Lu, D.^a , Yan, Y.^b , Avila, R.^c ^d , Kandela, I.^e ^f , Stepien, I.^e ^f , Seo, M.-H.^a , Bai, W.^a , Yang, Q.^a , Li, C.^c ^d , Haney, C.R.^f ^g , Waters, E.A.^f ^g , MacEwan, M.R.^b , Huang, Y.^c ^d , Ray, W.Z.^b , Rogers, J.A.^a

^a Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL 60208, United States
^b Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
^d Departments of Mechanical Engineering and Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, United States
^e Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208, United States
^f Chemistry Life Processes Institute, Northwestern University, Evanston, IL 60208, United States
^g Center for Advanced Molecular Imaging, Northwestern University, Evanston, IL 60208, United States

Abstract
Measurements of regional internal body temperatures can yield important information in the diagnosis of immune response-related anomalies, for precisely managing the effects of hyperthermia and hypothermia therapies and monitoring other transient body processes such as those associated with wound healing. Current approaches rely on permanent implants that require extraction surgeries after the measurements are no longer needed. Emerging classes of bioresorbable sensors eliminate the requirements for extraction, but their use of percutaneous wires for data acquisition leads to risks for infection at the suture site. As an alternative, a battery-free, wireless implantable device is reported here, which is constructed entirely with bioresorbable materials for monitoring regional internal body temperatures over clinically relevant timeframes. Ultimately, these devices disappear completely in the body through natural processes. In vivo demonstrations indicate stable operation as subcutaneous and intracranial implants in rat models for up to 4 days. Potential applications include monitoring of healing cascades associated with surgical wounds, recovery processes following internal injuries, and the progression of thermal therapies for various conditions. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
biomedical implants; bioresorbable devices; LC-resonance; regional body temperature; wireless sensors

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

“Genome-wide association study of rate of cognitive decline in Alzheimer’s disease patients identifies novel genes and pathways” (2020) Alzheimer’s and Dementia

Genome-wide association study of rate of cognitive decline in Alzheimer’s disease patients identifies novel genes and pathways
(2020) Alzheimer’s and Dementia, .

Sherva, R.^ak , Gross, A.^a , Mukherjee, S.^b , Koesterer, R.^c , Amouyel, P.^d ^e ^f , Bellenguez, C.^d ^e ^f , Dufouil, C.^g , Bennett, D.A.^h ⁱ , Chibnik, L.^j ^k , Cruchaga, C.^l ^m ⁿ ^o , del-Aguila, J.^l ^m ⁿ ^o , Farrer, L.A.^p ^ak ^q ^r ^s ^t ^ak , Mayeux, R.^u ^v ^w , Munsie, L.^x , Winslow, A.^y , Newhouse, S.^z ^aa ^ab ^ac ^ad , Saykin, A.J.^ae , Kauwe, J.S.K.^af , Crane, P.K.^b , Green, R.C.^ag ^ah ^ai ^aj , the Alzheimer’s Disease Genetics Consortium^ak

^a Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Center on Aging and Health, Baltimore, MD, United States
^b Department of Medicine, University of Washington, Seattle, WA, United States
^c Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, United States
^d Inserm, CHU Lille, Institute Pasteur de Lille, U1167 – RID-AGE – Risk factors and molecular determinants of age-related diseases; Institute Pasteur de Lille, University of Lille, Lille Cedex, France
^e Institut Pasteur de Lille, Lille, France
^f DISTALZ Laboratory of Excellence (LabEx), University of Lille, Lille, France
^g Inserm Unit 1219 Bordeaux Population Health, CIC 1401-EC (Clinical Epidemiology), University of Bordeaux, ISPED (Bordeaux School of Public Health), Bordeaux University Hospital, Bordeaux, France
^h Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
ⁱ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^j Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^k Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^l Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ⁿ Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^o NeuroGenomics and Informatics, Washington University School of Medicine, Saint Louis, United States
^p Bioinformatics Graduate Program, Boston University, Boston, MA, United States
^q Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^r Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^s Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
^t Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
^u Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
^v The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^w Department of Neurology, College of Physicians and Surgeons, New York-Presbyterian Hospital, Columbia University Medical Center, New York, NY, United States
^x Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, United States
^y Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, United States
^z Department of Biostatistics and Health Informatics, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
^aa NIHR BioResource Centre Maudsley, Psychology and Neuroscience (IoPPN), King’s College London, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, London, United Kingdom
^ab Health Data Research UK London, University College London, London, United Kingdom
^ac Institute of Health Informatics, University College London, London, United Kingdom
^ad The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, United Kingdom
^ae Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, IU Health Neuroscience Center, Indiana University School of Medicine, Indianapolis, IN, United States
^af Department of Biology, Brigham Young University, Provo, UT, United States
^ag Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^ah The Broad Institute of MIT and Harvard, Cambridge, MA, United States
^ai Harvard Medical School, Boston, MA, United States
^aj Partners HealthCare Personalized Medicine, Boston, MA, United States
^ak Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States

Abstract
Introduction: Variability exists in the disease trajectories of Alzheimer’s disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results: Suggestive associations (P < 1.0 × 10−6) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10−7), chromosome 7 (rs60465337,P = 4.06 × 10−7) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10−7), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10−7), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10−7) and 4 (rs1304013, P = 7.73 × 10−7). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact. © 2020 the Alzheimer’s Association

Author Keywords
cognitive decline; disease progression; genetic association; pathway analysis

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

“A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment” (2020) Alzheimer’s and Dementia

A randomized controlled trial of amyloid positron emission tomography results disclosure in mild cognitive impairment
(2020) Alzheimer’s and Dementia, .

Lingler, J.H.^a ^b , Sereika, S.M.^a , Butters, M.A.^c , Cohen, A.D.^b ^c , Klunk, W.E.^b ^c ^d , Knox, M.L.^a , McDade, E.^e , Nadkarni, N.K.^b ^d ^f , Roberts, J.S.^g , Tamres, L.K.^a , Lopez, O.L.^b ^c ^d

^a Department of Health and Community Systems, School of Nursing, University of Pittsburgh, Pittsburgh, PA, United States
^b Alzheimer’s Disease Research Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^c Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^e Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
^f Department of Medicine (Geriatric Medicine), School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^g University of Michigan School of Public Health, Ann Arbor, MI, United States

Abstract
Introduction: Recent studies suggest that Alzheimer’s disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers. Methods: Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up. Results: Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms. Discussion: These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results. © 2020 the Alzheimer’s Association

Author Keywords
amyloid positron emission tomography; biomarker disclosure; caregiving; ethics; mild cognitive impairment

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

“Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans” (2020) British Journal of Clinical Pharmacology

Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans
(2020) British Journal of Clinical Pharmacology, .

Chiang, M.D.^b , Frey, K.^a , Lee, C.^a , Kharasch, E.D.^c , Tallchief, D.^a , Sawyer, C.^d , Blood, J.^a , Back, H.^b , Kagan, L.^b , Haroutounian, S.^a

^a Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
^c Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
^d Genome Technology Access Center, Washington University School of Medicine, St Louis, MO, United States

Abstract
Aims: Changes in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration. Methods: Fifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS. Results: The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26. Conclusions: After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration–time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain. © 2020 The British Pharmacological Society

Author Keywords
CNS disposition; neuropathic pain; P-glycoprotein; population modelling

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

“Parkinson disease clinical subtypes: key features & clinical milestones” (2020) Annals of Clinical and Translational Neurology

Parkinson disease clinical subtypes: key features & clinical milestones
(2020) Annals of Clinical and Translational Neurology, .

Campbell, M.C.^a ^b , Myers, P.S.^a , Weigand, A.J.^c , Foster, E.R.^a ^d ^e , Cairns, N.J.^a ^f , Jackson, J.J.^c , Lessov-Schlaggar, C.N.^e , Perlmutter, J.S.^a ^b ^d ^g ^h

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^d Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f College of Medicine and Health, University of Exeter, Exeter, United Kingdom
^g Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^h Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objectives: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones. Methods: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality. Results: LCA identified distinct subtypes: “motor only” (N = 63) characterized by primary motor deficits; “psychiatric & motor” (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; “cognitive & motor” (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the “cognitive & motor” subtype. Surprisingly, mortality risk was similarly elevated for both “cognitive & motor” and “psychiatric & motor” subtypes compared to the “motor only” subtype (relative risk = 3.15, 2.60). Interpretation: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

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

“The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS)” (2020) Neurourology and Urodynamics

The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS)
(2020) Neurourology and Urodynamics, .

Clemens, J.Q.^a , Kutch, J.J.^b , Mayer, E.A.^c , Naliboff, B.D.^c , Rodriguez, L.V.^d , Klumpp, D.J.^e , Schaeffer, A.J.^e , Kreder, K.J.^f , Clauw, D.J.^g , Harte, S.E.^g , Schrepf, A.D.^g , Williams, D.A.^g , Andriole, G.L.^h , Lai, H.H.^h , Buchwald, D.ⁱ , Lucia, M.S.^j , van Bokhoven, A.^j , Mackey, S.^k , Moldwin, R.M.^l , Pontari, M.A.^m , Stephens-Shields, A.J.ⁿ , Mullins, C.^o , Landis, J.R.ⁿ

^a Department of Urology, Michigan Medicine, Ann Arbor, MI, United States
^b Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, United States
^c Department of Medicine, David Geffen School of Medicine at The University of California, Los Angeles, CA, United States
^d Departments of Urology & Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, United States
^e Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^f Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^g Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI, United States
^h Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Epidemiology and Medicine, Washington State University Institute for Research and Education to Advance Community Health, Seattle, WA, United States
^j Department of Pathology, University of Colorado Denver, Aurora, CO, United States
^k Department of Anesthesiology, Perioperative, and Pain Medicine, Division of Pain Medicines, Stanford University School of Medicine, Stanford, CA, United States
^l Department of Urology, Hofstra University School of Medicine, The Arthur Smith Institute for Urology, New Hyde Park, NY, United States
^m Department of Urology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
ⁿ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^o Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States

Abstract
Aims: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study—the Symptom Patterns Study (SPS)—to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments. Methods: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol. Results: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing. Conclusions: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions. © 2020 Wiley Periodicals LLC

Author Keywords
chronic; interstitial cystitis; plasma biomarkers; prostatitis; urine biomarkers; urological chronic pelvic pain syndromes

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

“Validation of Parkinson’s Disease-Related Questionnaires in South Africa” (2020) Parkinson’s Disease

Validation of Parkinson’s Disease-Related Questionnaires in South Africa
(2020) Parkinson’s Disease, 2020, art. no. 7542138, .

Nelson, G.^a , Nelson, G.^b , Ndlovu, N.^a , Christofides, N.^a , Hlungwani, T.M.^a , Faust, I.^c , Racette, B.A.^a , Racette, B.A.^c

^a School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 St.Andrews Rd, Parktown, 2193, South Africa
^b UCL Institute for Global Health, Research Department of Infection and Population Health, University College London, London, United Kingdom
^c Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, Missouri 63110, United States

Abstract
Background. There are very few epidemiological studies investigating Parkinson’s disease (PD) in Africa. The hundreds of local languages and dialects make traditional screening and clinical evaluation tools difficult to use. Objective. The objective of the study was to validate two commonly used PD questionnaires in an African population. Methods. The PD Screening Questionnaire (PDSQ) and Parkinson’s Disease Questionnaire (PDQ-39) were modified and translated into Afrikaans, Setswana, and isiZulu and administered to a sample of healthy local residents. We assessed the internal consistencies and cluster characteristics of the questionnaires, using a Cronbach’s alpha test and exploratory factor analysis. The questionnaires were then administered to a population-based sample of 416 research participants. We evaluated the correlations between the questionnaires and both a timed motor task and the Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3), using locally weighted scatterplot smoothing (LOWESS) regression analysis and Spearman’s rank correlation. Results. Both questionnaires had high overall internal consistency (Cronbach’s alpha = 0.86 and 0.95, respectively). The modified PDQ-39 had evidence of five subscales, with Factor 1 explaining 57% and Factor 2 explaining 14%, of the variance in responses. The PDSQ and PDQ-39 scores were correlated with the UPDRS3 score (ρ = 0.35, P<0.001; and ρ = 0.28, P<0.001, respectively). Conclusion. The translated PDSQ and PDQ-39 questionnaires demonstrated high internal consistency and correlations with clinical severity of parkinsonism and a timed motor task, suggesting that they are valid tools for field-based epidemiological studies. © 2020 Gill Nelson et al.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults” (2020) Clinical Pharmacology and Therapeutics

Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults
(2020) Clinical Pharmacology and Therapeutics, .

Kharasch, E.D.^a , Neiner, A.^b , Kraus, K.^b , Blood, J.^b , Stevens, A.^c , Miller, J.P.^d , Lenze, E.J.^c

^a Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
^b Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The antidepressant bupropion is stereoselectively metabolized and metabolite enantiomers have differential pharmacologic effects, but steady-state enantiomeric disposition is unknown. Controversy persists about bupropion XL 300 mg generic equivalence to brand product, and whether generics might have different stereoselective disposition leading to enantiomeric non-bioequivalence and, thus, clinical nonequivalence. This preplanned follow-on analysis of a prospective, randomized, double-blinded, crossover study of brand and 3 generic bupropion XL 300 mg products measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations and evaluated bioequivalence and pharmacokinetics. Steady-state plasma and urine bupropion disposition was markedly stereoselective, with up to 40-fold differences in plasma concentrations of the active metabolite S,S-hydroxybupropion vs. R,R,-hydroxybupropion. Urine metabolite glucuronides were prominent, but glucuronidation was metabolite-specific and enantioselective. There were no differences between any generic and brand, or between generics, in plasma enantiomer concentrations of bupropion or the major metabolites. All generic products satisfied formal bioequivalence criteria (peak plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC0–24)) using enantiomers for bupropion as well as for metabolites, and generics were comparable to each other, and were considered bioequivalent, based on enantiomeric analysis. Enantiomeric bioequivalence explains the previously observed therapeutic equivalence of bupropion generics and brand in treating major depression. These results have important implications for understanding the clinical therapeutic effects of bupropion based on complex and stereoselective metabolism. © 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics

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