WashU weekly Neuroscience publications

Touch engages visual spatial contextual processing
(2018) Scientific Reports, 8 (1), art. no. 16637, . 

Pérez-Bellido, A.^{a b} , Pappal, R.D.^{a c} , Yau, J.M.^a

^a Department of Neuroscience, Baylor College of Medicine, Houston, One Baylor Plaza, Houston, TX 77030, United States
^b Radboud University, Donders Institute for Brain, Cognition and Behavior, Nijmegen, Netherlands
^c Washington University School of Medicine in St. Louis, St. Louis, MO 63108, United States

Abstract
The spatial context in which we view a visual stimulus strongly determines how we perceive the stimulus. In the visual tilt illusion, the perceived orientation of a visual grating is affected by the orientation signals in its surrounding context. Conceivably, the spatial context in which a visual grating is perceived can be defined by interactive multisensory information rather than visual signals alone. Here, we tested the hypothesis that tactile signals engage the neural mechanisms supporting visual contextual modulation. Because tactile signals also convey orientation information and touch can selectively interact with visual orientation perception, we predicted that tactile signals would modulate the visual tilt illusion. We applied a bias-free method to measure the tilt illusion while testing visual-only, tactile-only or visuo-tactile contextual surrounds. We found that a tactile context can influence visual tilt perception. Moreover, combining visual and tactile orientation information in the surround results in a larger tilt illusion relative to the illusion achieved with the visual-only surround. These results demonstrate that the visual tilt illusion is subject to multisensory influences and imply that non-visual signals access the neural circuits whose computations underlie the contextual modulation of vision. © 2018, The Author(s).

Document Type: Article Source: 

Scopus Access Type: Open Access

Child Neurology: Brown-Vialetto-Van Laere syndrome: Dramatic visual recovery after delayed riboflavin therapy
(2018) Neurology, 91 (20), pp. 938-941. 

Bamaga, A.K., Maamari, R.N., Culican, S.M., Shinawi, M., Golumbek, P.T.

From the Departments of Neurology (A.K.B., P.T.G.) and Ophthalmology and Visual Sciences (R.N.M., S.M.C.) and Division of Genetics and Genomic Medicine, Department of Pediatrics (M.S.), Washington University School of Medicine, St Louis, MO; and Department of Pediatrics (A.K.B.), King Abdulaziz University, Jeddah, Saudi Arabia

Document Type: Article

Source: Scopus

Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US
(2018) Neurology, 91 (19), pp. e1778-e1787. 

Krysko, K.M., Graves, J., Rensel, M., Weinstock-Guttman, B., Aaen, G., Benson, L., Chitnis, T., Gorman, M., Goyal, M., Krupp, L., Lotze, T., Mar, S., Rodriguez, M., Rose, J., Waltz, M., Charles Casper, T., Waubant, E., US Network of Pediatric MS Centers

From the Department of Neurology (K.M.K., J.G., E.W.), University of California San Francisco; Department of Neurology (M. Rensel), Cleveland Clinic, OH; Department of Neurology (B.W.-G.), State University of New York at Buffalo; Department of Pediatrics (G.A.), Loma Linda University, CA; Department of Neurology (L.B., M. Gorman), Boston Children’s Hospital, MA; Department of Neurology (T.C.), Massachusetts General Hospital, Boston; Department of Neurology (M. Goyal, S.M.), Washington University in Saint Louis, MO; Department of Neurology (L.K.), New York University Langone Medical Center, NY; Department of Neurology (T.L.), Texas Children’s Hospital, Houston; Department of Neurology (M. Rodriguez), Mayo Clinic, Rochester, MN; and Department of Neurology (J.R.), Biostatistician II (M.W.), and Department of Pediatrics (T.C.C.), University of Utah, Salt Lake City

Abstract
OBJECTIVE: To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age. METHODS: This is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005. RESULTS: As of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults. CONCLUSION: Newer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management. © 2018 American Academy of Neurology.

Document Type: Article

Source: Scopus

Exchange Rate and Risk of Noise-Induced Hearing Loss in Construction Workers
(2018) Annals of work exposures and health, 62 (9), pp. 1176-1178. 

Dobie, R.A.^a , Clark, W.W.^b , Kallogjeri, D.^c , Spitznagel, E.L.^d

^a Department of Otolaryngology – Head and Neck Surgery, University of Texas Health Science Center, San Antonio, TX, United States
^b Program in Audiology and Communication Sciences, Washington University, St. Louis, MO, United States
^c Department of Otolaryngology, Washington University, St. Louis, MO, United States
^d Department of Mathematics and Statistics, Washington University, St. Louis, MO, United States

Document Type: Article

Source: Scopus Access

Type: Open Access

CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
(2018) Nature communications, 9 (1), p. 4619. 

Snijders Blok, L.^{a b c} , Rousseau, J.^d , Twist, J.^e , Ehresmann, S.^d , Takaku, M.^e , Venselaar, H.^f , Rodan, L.H.^g , Nowak, C.B.^g , Douglas, J.^g , Swoboda, K.J.^h , Steeves, M.A.ⁱ , Sahai, I.ⁱ , Stumpel, C.T.R.M.^j , Stegmann, A.P.A.^j , Wheeler, P.^k , Willing, M.^l , Fiala, E.^l , Kochhar, A.^m , Gibson, W.T.^{n o} , Cohen, A.S.A.^{n o} , Agbahovbe, R.^{n o} , Innes, A.M.^p , Au, P.Y.B.^p , Rankin, J.^q , Anderson, I.J.^r , Skinner, S.A.^s , Louie, R.J.^s , Warren, H.E.^s , Afenjar, A.^t , Keren, B.^{u v} , Nava, C.^{u v w} , Buratti, J.^u , Isapof, A.^x , Rodriguez, D.^y , Lewandowski, R.^z , Propst, J.^z , van Essen, T.^aa , Choi, M.^ab , Lee, S.^ab , Chae, J.H.^ac , Price, S.^ad , Schnur, R.E.^ae , Douglas, G.^ae , Wentzensen, I.M.^ae , Zweier, C.^af , Reis, A.^af , Bialer, M.G.^ag , Moore, C.^ag , Koopmans, M.^ah , Brilstra, E.H.^ah , Monroe, G.R.^ah , van Gassen, K.L.I.^ah , van Binsbergen, E.^ah , Newbury-Ecob, R.^ai , Bownass, L.^ai , Bader, I.^aj , Mayr, J.A.^ak , Wortmann, S.B.^{ak al am} , Jakielski, K.J.^an , Strand, E.A.^ao , Kloth, K.^ap , Bierhals, T.^ap , Roberts, J.D.^e , Petrovich, R.M.^e , Machida, S.^aq , Kurumizaka, H.^aq , Lelieveld, S.^a , Pfundt, R.^a , Jansen, S.^{a c} , Deriziotis, P.^b , Faive, L.^{ar as} , Thevenon, J.^{ar as} , Assoum, M.^{ar as} , Shriberg, L.^at , Kleefstra, T.^{a c} , Brunner, H.G.^{a c j} , Wade, P.A.^e , Fisher, S.E.^{b c} , Campeau, P.M.^{d au}

^a Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6500HB, Netherlands
^b Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
^c Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, 6500HE, Netherlands
^d CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada
^e National Institute of Environmental Health Sciences, Research Triangle ParkNC 27709, United States
^f Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500HB, Netherlands
^g Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
^h Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
ⁱ Department of Medical Genetics, Massachusetts General Hospital, Boston, MA 02114, United States
^j Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202AZ, Netherlands
^k Nemours Childrens Clinic, Orlando, FL 32827, United States
^l Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^m Valley Children’s Hospital, Madera, CA 93636, United States
ⁿ British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
^o Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
^p Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
^q Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust (Heavitree), Exeter, EX2 5DW, United Kingdom
^r Division of Genetics, Department of Medicine, University of Tennessee Medical Center, Knoxville, TN 37920, United States
^s Greenwood Genetic Center, Greenwood, SC 29646, United States
^t GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris ; Department of Medical Genetics and Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, Armand Trousseau Hospital, GHUEP, AP-HP, Paris, 75012, France
^u AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, 75013, France
^v Groupe de Recherche Clinique (GRC) ‘déficience intellectuelle et autisme’ UPMC, Paris, 75005, France
^w INSERM, 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, UPMC Univ Paris 06 UMR S 1127, Sorbonne Universités, Paris, 75013, France
^x GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department Child Neurology and Reference Center for Neuromuscular Diseases “Nord/Est/Ile-de-France”, FILNEMUS, Armand Trousseau Hospital, GHUEP, AP-HP, Paris, 75012, France
^y GRC ConCer-LD, Sorbonne Universités, UPMC Univ Paris 06; Department of Child Neurology and National Reference Center for Neurogenetic Disorders, Armand Trousseau Hospital, GHUEP, AP-HP, INSERM U1141, 75012, Paris, France
^z Clinical Genetics Division, Virginia Commonwealth University Health System, Richmond, VA 23298, United States
^aa Clinical Genetics Department, University Medical Center Groningen, Groningen, 9700RB, Netherlands
^ab Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 08826, North Korea
^ac Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, 08826, North Korea
^ad Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7HE, United Kingdom
^ae GeneDx, Gaithersburg, MD 20877, United States
^af Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^ag Division of Medical Genetics and Genomics, Northwell Health, Great Neck, NY 11021, United States
^ah Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, 3508AB, Netherlands
^ai University Hospitals Bristol, Department of Clinical Genetics, St Michael’s Hospital, Bristol, BS2 8EG, United Kingdom
^aj Department of Clinical Genetics, University Children’s Hospital, Paracelsus Medical UniversitySalzburg A-5020, Austria
^ak Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical UniversitySalzburg A-5020, Austria
^al Institute of Human Genetics, Technische Universität München, Munich, 81675, Germany
^am Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, 85764, Germany
^an Communication Sciences and Disorders, Augustana College, Rock Island, IL 61201, United States ^ao Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States ^ap Institute of Human Genetics, University Medical Center Hamburg-EppendorfHamburg 20246, Germany
^aq Waseda UniversityTokyo 169-8050, Japan
^ar Equipe Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, 21070, France
^as Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’Enfants, CHU Dijon et Université de Bourgogne, Dijon, 21079, France
^at Waisman Center, Phonology Project, Madison, WI 53705-2280, United States
^au Sainte-Justine Hospital, University of Montreal, Montreal, QC H3T 1C5, Canada

Abstract
Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Document Type: Article

Source: Scopus Access

Type: Open Access

Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer’s disease
(2018) Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 14 (11), pp. 1427-1437. 

Müller, S.^a , Preische, O.^b , Sohrabi, H.R.^c , Gräber, S.^d , Jucker, M.^e , Ringman, J.M.^f , Martins, R.N.^c , McDade, E.^g , Schofield, P.R.^h , Ghetti, B.ⁱ , Rossor, M.^j , Fox, N.N.^j , Graff-Radford, N.R.^k , Levin, J.^l , Danek, A.^l , Vöglein, J.^l , Salloway, S.^m , Xiong, C.ⁿ , Benzinger, T.^o , Buckles, V.^o , Masters, C.L.^p , Sperling, R.^q , Bateman, R.J.^o , Morris, J.C.^o , Laske, C.^d , Dominantly Inherited Alzheimer Network (DIAN)^r

^a Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
^b Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^c Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia
^d Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^e German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^f Memory and Aging Center, Keck School of Medicine of USC, Los Angeles, CA, United States
^g University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh, PA, United States
^h Neuroscience Research Australia, Randwick, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
ⁱ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, United States
^j Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, United Kingdom
^k Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
^l German Center for Neurodegenerative Diseases (DZNE), München, Germany; Department of Neurology, Ludwig-Maximilians University Munich, Munich, Germany
^m Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States ⁿ Division of Biostatistics, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
^o Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^p Florey Institute, University of Melbourne, Parkville, Victoria, Australia
^q Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Abstract
INTRODUCTION: Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer’s disease (AD). METHODS: A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. RESULTS: Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD-like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. DISCUSSION: These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD. Copyright © 2018 the Alzheimer’s Association. All rights reserved.

Author Keywords
Cerebrospinal fluid biomarkers; Cognitive function; Dominantly inherited Alzheimer’s disease; Functional status; Mutation carrier; Physical activity

Document Type: Article

Source: Scopus

A randomized controlled trial of parent-child psychotherapy targeting emotion development for early childhood depression
(2018) American Journal of Psychiatry, 175 (11), pp. 1102-1110. Cited 1 time.

Luby, J.L., Barch, D.M., Whalen, D., Tillman, R., Freedland, K.E.

Department of Psychiatry, Washington University, St. Louis, United States

Abstract
Objective: Clinical depression in children as young as age 3 has been validated, and prevalence rates are similar to the school-age disorder. Homotypic continuity between early and later childhood depression has been observed, with alterations in brain function and structure similar to those reported in depressed adults. These findings highlight the importance of identifying and treating depression as early as developmentally possible, given the relative treatment resistance and small effect sizes for treatments later in life. The authors conducted a randomized controlled trial of a dyadic parent-child psychotherapy for early childhood depression that focuses on enhancing the child’s emotional competence and emotion regulation. Method: A modified version of the empirically tested parent-child interaction therapy with a novel “emotion development” module (PCIT-ED) was compared with a waiting list condition in a randomized controlled trial in 229 parent-child dyads with children 3-6.11 years of age. Both study arms lasted 18 weeks. Results: Children in the PCIT-ED group had lower rates of depression (primary outcome), lower depression severity, and lower impairment compared with those in the waiting list condition (Cohen’s d values, 1.0). Measures of child emotional functioning and parenting stress and depression were significantly improved in the PCIT-ED group. Conclusions: The findings from this randomized controlled trial of a parent-child psychotherapy for early childhood depression suggest that earlier identification and intervention in this chronic and relapsing disorder represents a key new pathway for more effective treatment. Manualized PCIT-ED, administered by master’s-level clinicians, is feasible for delivery in community health settings. © 2018 American Journal of Psychiatry. All rights reserved.

Document Type: Article

Source: Scopus

Pharmacogenetic guidelines and decision support tools for depression treatment: Application to late-life
(2018) Pharmacogenomics, 19 (16), pp. 1269-1284. 

Chang, D.D.^a , Eyreeuro, H.A.^{b c d e} , Abbott, R.^{f g} , Coudreaut, M.^h , Baune, B.T.^e , Shaman, J.A.ⁱ , Lavretsky, H.^g , Lenze, E.J.^j , Merrill, D.A.^g , Singh, A.B.^c , Mulsant, B.H.^{k l} , Reynolds, C.F.^m , Müller, D.J.^{k l} , Bousman, C.ⁿ

^a School of Medicine, University of Queensland, Ochsner Clinical School, Brisbane, QLD 4072, Australia
^b Innovation Institute, Texas Medical Center, Houston, TX 77006, United States
^c IMPACT SRC, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
^d Department of Psychiatry, University of Melbourne, Melbourne, VIC 3003, Australia
^e Discipline of Psychiatry, University of Adelaide, Adelaide, SA 5055, Australia
^f University of SurreyGU27XH, United Kingdom
^g David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA 90095, United States
^h Department of Psychiatry, Intermountain Healthcare, Salt Lake City, UT 84102, United States
ⁱ Coriell Life Sciences, Philadelphia, PA 19112, United States
^j Department of Psychiatry, Washington University, St Louis, MO 63130, United States
^k Department of Psychiatry, University of Toronto, Toronto, ON M5S3H7, Canada
^l Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5S3H7, Canada
^m Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, United States
ⁿ Departments of Medical Genetics, Psychiatry, and Physiology and Pharmacology, University of Calgary, Calgary, AB ANT2N1N4, Canada

Abstract
Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines. © 2018 Future Medicine Ltd.

Author Keywords
decision support tools; late-life depression; major depression; pharmacogenomics;  precision medicine

Document Type: Review

Source: Scopus

The APOE e4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the long life family study
(2018) PLoS ONE, 13 (11), art. no. e0206873, . 

Kulminski, A.M.^a , Barochia, A.V.^b , Loika, Y.^a , Raghavachari, N.^c , Arbeev, K.G.^a , Wojczynski, M.K.^d , Thyagarajan, B.^e , Vardarajan, B.N.^f , Christensen, K.^{g h} , Yashin, A.I.^a , Levine, S.J.^b

^a Biodemography of Aging Research Unit, Social Sciences Research Institute, Duke University, Durham, NC, United States
^b Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, United States
^c National Institute on Aging, Gateway Building, Suite, Bethesda, MD, United States
^d Division of Statistical Genomics, Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
^f Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
^g Danish Aging Research Center, University of Southern Denmark, Odense C, Denmark ^h Department of Clinical Genetics, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense C, Denmark

Abstract
Introduction Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function. Objectives We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study. Methods Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ε2, ε3, and ε4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ε2 allele, defined as ε2/2 or ε2/3 genotypes, and the ε4 allele, defined as ε3/4 or ε4/4 genotypes, which were compared to the ε3/3 genotype. Results The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ε4 allele as compared to women with the ε3/3 genotype or the ε2 allele. Carriage of the APOE ε4 allele was associated with FEV1/ FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease. Conclusions This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ε4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Document Type: Article

Source: Scopus Access

Type: Open Access

Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease
(2018) Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 14 (11), pp. 1505-1521. 

Shaw, L.M.^a , Arias, J.^b , Blennow, K.^c , Galasko, D.^d , Molinuevo, J.L.^e , Salloway, S.^f , Schindler, S.^g , Carrillo, M.C.^h , Hendrix, J.A.^h , Ross, A.^h , Illes, J.ⁱ , Ramus, C.ⁱ , Fifer, S.^j

^a Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA, United States
^b Department of Neurology, University of California, San Francisco, CA, United States
^c Department of Psychiatry and Neurochemistry, University of Gothenberg, Molndal, Sweden
^d Department of Neuroscience, University of California, San Diego, CA, United States
^e Barcelonabeta Brain Research Center, Barcelona, Spain
^f Butler Hospital Memory and Aging Program, Warren Alpert Medical School of Brown University, Brown University, Providence, RI, United States
^g Department of Neurology, Washington University St. Louis
^h Alzheimer’s Association, Chicago, IL, United States
ⁱ Avalere HealthWA, United States ^j San Francisco, CA, United States

Abstract
INTRODUCTION: The Alzheimer’s Association convened a multidisciplinary workgroup to develop appropriate use criteria to guide the safe and optimal use of the lumbar puncture procedure and cerebrospinal fluid (CSF) testing for Alzheimer’s disease pathology detection in the diagnostic process. METHODS: The workgroup, experienced in the ethical use of lumbar puncture and CSF analysis, developed key research questions to guide the systematic review of the evidence and developed clinical indications commonly encountered in clinical practice based on key patient groups in whom the use of lumbar puncture and CSF may be considered as part of the diagnostic process. Based on their expertise and interpretation of the evidence from systematic review, members rated each indication as appropriate or inappropriate. RESULTS: The workgroup finalized 14 indications, rating 6 appropriate and 8 inappropriate. DISCUSSION: In anticipation of the emergence of more reliable CSF analysis platforms, the manuscript offers important guidance to health-care practitioners and suggestions for implementation and future research. Copyright © 2018 the Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.

Author Keywords
Alzheimer’s disease pathology; Amyloid PET; AUC;  CSF Aβ-42, diagnostic utilities; MCI; Modified Delphi; p-tau181; PICOTS (population, interventions, comparisons, outcomes, timing, and settings) framework; SCD; t-tau, LP

Document Type: Review

Source: Scopus

Psychotic like experiences as part of a continuum of psychosis: Associations with effort-based decision-making and reward responsivity 
(2018) Schizophrenia Research, . Article in Press. 

Ermel, J.A.^a , Moran, E.K.^b , Culbreth, A.J.^a , Barch, D.M.^{a b c}

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Research examining psychotic disorders typically involves comparison between individuals with a clinical disorder and healthy controls. However, research suggests that psychotic symptoms, such as delusions and hallucinations, may exist on a continuum ranging from variation in healthy individuals to diagnosable psychotic disorders. On this continuum, some individuals endorse occasional psychotic like experiences (PLEs) that do not cause sufficient impairment or distress to warrant a clinical diagnosis. Given this continuum model, one might expect to observe impairments in those with PLEs in the same behavioral domains impaired in schizophrenia. Thus, we examined two domains typically impaired in schizophrenia, effort allocation and reward responsivity, in a large university sample (n = 126). Participants completed tasks assessing effort-based decision-making, reward responsivity, and questionnaires assessing PLEs. Greater PLEs were associated with greater effort expenditure regardless of probability of receiving a reward or reward value. Higher PLEs were related to greater positive feelings when receiving rewards. Importantly, these relationships remained the same when controlling for other symptoms such as depression, anhedonia, and anxiety. These findings suggest that PLEs may be associated with hypersensitivity to reward at the less severe end of the psychotic continuum, with effort to attain a reward expended in a potentially inefficient manner. This pattern is consistent with models of hyperdopaminergic states in psychotic individuals not taking antipsychotic medications, given the role of dopamine in modulating effort allocation and reward anticipation. © 2018 Elsevier B.V.

Author Keywords
Continuum of psychosis; Effort-based decision-making;  Psychosis;  Psychotic-like experiences; Reward responsivity

Document Type: Article in Press

Source: Scopus

Understanding multi-pill ingestion of prescription opioids: Prevalence, characteristics, and motivation 
(2018) Pharmacoepidemiology and Drug Safety, . Article in Press. 

Ellis, M.S.^a , Cicero, T.J.^a , Dart, R.C.^b , Green, J.L.^b

^a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^b Denver Health and Hospital Authority, Rocky Mountain Poison and Drug Center, Denver, CO, United States

Abstract
Purpose: Oral use is the primary route of administration among non-medical prescription opioid users. While progression to non-oral routes and shifts to stronger opioids have been previously studied as ways to cope with tolerance, the prevalence and patterns of those who cope by increasing the number of pills/tablets ingested at one time (ie, multi-pill use) has not been assessed. Methods: A subset (N = 231) of treatment-seeking opioid users from a national opioid surveillance system, participating in the Researchers and Participants Interacting Directly (RAPID) Program, completed an online survey centered on multi-pill use. Results: Over two-thirds of non-medical prescription opioid users had a history of multi-pill use (67.7%), defined as ingesting four or more of the same pill, intact and at the same time. Among these (n = 154), the median maximum number of pills taken at one time was eight, with over 20% ingesting 11 or more pills in a single instance. Nearly half engaged in multi-pill ingestion more than once a day in the past month (43.8%), with accessibility to lower dose pills being the primary motivator (85.4%). Hydrocodone immediate-release (IR) compounds were by far the most frequently endorsed (90.3%), followed by oxycodone IR tablets with acetaminophen (76.0%) and oxycodone IR tablets containing no acetaminophen/ibuprofen (56.5%). Conclusions: These results indicate that the ingestion of multiple opioid pills/tablets is extremely common among treatment-seeking opioid users. This, and other forms of non-medical oral use of prescription opioids, should be taken under consideration when developing prevention and intervention efforts targeting the opioid epidemic. © 2018 John Wiley & Sons, Ltd.

Author Keywords
multi-pill ingestion; non-medical opioid use; opioid surveillance;  pharmacoepidemiology; prescription opioids; survey data collection

Document Type: Article in Press

Source: Scopus

Optimizing Neurocritical Care Follow-Up Through the Integration of Neuropsychology
(2018) Pediatric Neurology, . Article in Press. 

Dodd, J.N.^a , Hall, T.A.^b , Guilliams, K.^{c d} , Guerriero, R.M.^c , Wagner, A.^b , Malone, S.^e , Williams, C.N.^f , Hartman, M.E.^d , Piantino, J.^g

^a St. Louis Children’s Hospital/Washington University School of Medicine, Department of Psychology, St. Louis, MO, United States
^b Doernbecher Children’s Hospital/Oregon Health & Science University, Department of Pediatrics, Portland, OR, United States
^c St. Louis Children’s Hospital/Washington University School of Medicine, Division of Pediatric and Developmental Neurology, Department of Neurology, St. Louis, MO, United States
^d St. Louis Children’s Hospital/Washington University School of Medicine, Division of Critical Care Medicine, Department of Pediatrics, St. Louis, MO, United States
^e St. Louis Children’s Hospital/Washington University School of Medicine, School of Social Work, St. Louis, MO, United States
^f Doernbecher Children’s Hospital/Oregon Health and Science University, Division of Pediatric Critical Care, Portland, OR, United States
^g Doernbecher Children’s Hospital/Oregon Health and Science University, Division of Child Neurology, Portland, OR, United States

Abstract
Background: Pediatric critical care survivors often suffer persisting multisystem health problems and are left with treatment needs that go unmet due to limits in current care models. We proposed that integration of neuropsychology into neurocritical care follow-up provides incremental benefit to the identification and treatment of persisting complications and reduction in co-morbidities. Basic Procedures: The aims of this study were three-fold. First, we described pilot programs at two pediatric hospitals as models for implementing systematic follow-up care with interdisciplinary clinic teams consisting of critical care, neurology, and neuropsychology. Second, we described working models specific to neuropsychological service delivery in these programs. Third, we presented preliminary data from the first six months of one of the pilot programs in order to examine incremental benefit of neuropsychology in improving patient care and parent satisfaction. Main Findings: A total of 16 patients (age range three to 17 years) were seen by neuropsychology within the first six months of the program. Results showed that integration of neuropsychology into follow-up care resulted in recommendations being made for services or concerns not already addressed in 81% of cases. Parents reported high satisfaction, endorsing the highest possible rating on 96% of all items. Parents reported that neuropsychological consultation improved their understanding and communication with their child, and helped them know what to expect from their child during postacute recovery. Conclusions: Results of this pilot study suggest that integration of neuropsychology into neurocritical care follow-up programs contributes to parent satisfaction and may provide incremental benefit to patient care. © 2018 Elsevier Inc.

Author Keywords
neurocritical care; neurology; neuropsychology; outcome; parent satisfaction; pediatric; PICS

Document Type: Article in Press

Source: Scopus

Prevalence of carpal tunnel syndrome presenting with symptoms in an ulnar nerve distribution: A prospective study
(2018) Muscle and Nerve, . Article in Press. 

Colorado, B.S.^{a b} , Osei, D.A.^a

^a Department of Orthopedic Surgery, Washington University School of Medicine, Campus Box 8233, 425 South Euclid Avenue, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Patients presenting with symptoms of pain/paresthesias primarily in an ulnar nerve distribution may be noted to have exclusive median mononeuropathy at the wrist on subsequent electrodiagnostic testing. There has been limited research looking at the prevalence of this clinical presentation. Methods: A cohort of adults were surveyed to assess for severity and localization of hand symptoms using the Katz hand diagram and Boston Carpal Tunnel Questionnaire Symptoms Severity Scale. Thirty volunteers met our case definition for ulnar neuropathy and underwent a standardized physical examination, electrodiagnostic testing, and nerve ultrasound. Results: Eleven of 30 subjects (37%) were found to have exclusive median mononeuropathy at the wrist. Discussion: Carpal tunnel syndrome should remain high on the differential for patients presenting with symptoms of pain/paresthesias primarily in an ulnar nerve distribution. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

Author Keywords
carpal tunnel syndrome;  diagnosis;  extra-median symptoms;  prevalence;  ulnar neuropathy;  ultrasound

Document Type: Article in Press

Source: Scopus

Prevalence of five lifestyle risk factors among U.S. adults with and without stroke
(2018) Disability and Health Journal, . Article in Press. 

Bailey, R.R.^a , Phad, A.^a , McGrath, R.^b , Haire-Joshu, D.^a

^a Washington University in St. Louis, Brown School of Social Work, Campus Box 1196, One Brookings Drive, St. Louis, MO 63110, United States
^b North Dakota State University, Department of Health, Nutrition, and Exercise Sciences, NDSU Dept. 2620, PO Box 6050, Fargo, ND 58108, United States

Abstract
Background: History of stroke increases cardiometabolic risk, which can be exacerbated by the presence of unhealthy lifestyle factors. Population-based estimates of lifestyle risk factors in people with stroke are lacking but could be used to inform research, policy, and healthcare practice. Objective: To compare population-based estimates of the prevalence of five lifestyle risk factors—low fruit and vegetable consumption, insufficient physical activity, smoking, heavy alcohol consumption, and overweight/obesity—among U.S. adults with and without stroke. Methods: Representative data from noninstitutionalized adults aged ≥18 years (stroke, n = 37,225; no stroke, n = 851,607) from the 2015 and 2017 Behavioral Risk Factor Surveillance System (BRFSS) were used to estimate prevalence of individual and total number of risk factors. Logistic regression models were used to determine the odds of lifestyle risk factors in adults with stroke, adjusting for sex, age, ethnicity, marital status, education, income, and disability. Results: Prevalence and adjusted odds ratios (AOR) were higher in individuals with stroke compared to those without stroke for insufficient physical activity (56.5% vs. 49.5%, AOR: 1.14) and smoking (30.1% vs. 16.6%, AOR: 1.16), but lower for heavy alcohol consumption (5.4% vs. 6.1%, AOR: 0.76). Prevalence for low fruit and vegetable consumption (51.7% vs. 46.0%) and overweight/obesity (70.2% vs. 64.5%) was higher among adults with stroke, but differences were attenuated by demographic characteristics. Additionally, clustering of 4–5 lifestyle risk factors was higher in adults with stroke (9.0% vs. 5.3%, AOR: 1.12). Conclusion: Additional research and healthcare interventions are needed to improve lifestyle risk factors in adults with stroke. © 2018 Elsevier Inc.

Author Keywords
BRFSS;  Health behaviors;  Physical activity;  Prevalence;  Stroke

Document Type: Article in Press

Source: Scopus

Maternal immune activation, central nervous system development and behavioral phenotypes
(2018) Birth Defects Research, . Article in Press. 

Minakova, E., Warner, B.B.

Department of Pediatrics, School of Medicine, Washington University in St Louis, Saint Louis, MO, United States

Abstract
Maternal immune activation (MIA) refers to a maternal immune system triggered by infectious or infectious-like stimuli. A cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes most notably in the central nervous system. Epidemiologic studies implicate maternal infections in a variety of neuropsychiatric disorders, most commonly autism spectrum disorders and schizophrenia. In animal models, MIA causes neurochemical and anatomic changes in the brain that correspond to those found in humans with the disorders. As our understanding of the interactions between environment, genetics, and immune system grows, the role of alternative, noninfectious risk factors, such as prenatal stress, obesity, and the gut microbiome also becomes clearer. This review considers how infectious and noninfectious etiologies activate the maternal immune system. Their impact on fetal programming and neuropsychiatric disorders in offspring is examined in the context of human and animal studies. © 2018 Wiley Periodicals, Inc.

Author Keywords
autism;  gut microbiome;  maternal immune activation;  prenatal stress

Document Type: Article in Press

Source: Scopus

Individual Variation in Memory and Cognition
(2018) Journal of Applied Research in Memory and Cognition, . Article in Press. 

Wahlheim, C.N.^a , Zacks, J.M.^b

^a University of North Carolina at Greensboro, United States
^b Washington University in St. Louis, United States

Document Type: Article in Press

Source: Scopus

Accuracy of Dementia Screening Instruments in Emergency Medicine: A Diagnostic Meta-analysis
(2018) Academic Emergency Medicine, . Article in Press. 

Carpenter, C.R.^a , Banerjee, J.^{c d} , Keyes, D.^{e f} , Eagles, D.^g , Schnitker, L.^h , Barbic, D.ⁱ , Fowler, S.^b , LaMantia, M.A.^j

^a Division of Emergency Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Becker Medical Library, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Emergency Medicine, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
^d Department of Health Sciences, University of Leicester, Leicester, United Kingdom
^e Emergency Medicine, St. Mary Mercy Hospital, Livonia, MI, United States
^f Michigan State University School of Osteopathic Medicine, East Lansing, MI, United States
^g Department of Emergency Medicine, University of Ottawa, Ottawa, ON, Canada
^h School of Nursing, Queensland University of Technology, Brisbane, QLD, Australia ⁱ Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada
^j Geriatric Medicine, University of Vermont College of Medicine, Burlington, VT, United States

Abstract
Background: Dementia is underrecognized in older adult emergency department (ED) patients, which threatens operational efficiency, diagnostic accuracy, and patient satisfaction. The Society for Academic Emergency Medicine geriatric ED guidelines advocate dementia screening using validated instruments. Objectives: The objective was to perform a systematic review and meta-analysis of the diagnostic accuracy of sufficiently brief screening instruments for dementia in geriatric ED patients. A secondary objective was to define an evidence-based pretest probability of dementia based on published research and then estimate disease thresholds at which dementia screening is most appropriate. This systematic review was registered with PROSPERO (CRD42017074855). Methods: PubMed, EMBASE, CINAHL, CENTRAL, DARE, and SCOPUS were searched. Studies in which ED patients ages 65 years or older for dementia were included if sufficient details to reconstruct 2 × 2 tables were reported. QUADAS-2 was used to assess study quality with meta-analysis reported if more than one study evaluated the same instrument against the same reference standard. Outcomes were sensitivity, specificity, and positive and negative likelihood ratios (LR+ and LR–). To identify test and treatment thresholds, we employed the Pauker-Kassirer method. Results: A total of 1,616 publications were identified, of which 16 underwent full text-review; nine studies were included with a weighted average dementia prevalence of 31% (range, 12%–43%). Eight studies used the Mini Mental Status Examination (MMSE) as the reference standard and the other study used the MMSE in conjunction with a geriatrician’s neurocognitive evaluation. Blinding to the index test and/or reference standard was inadequate in four studies. Eight instruments were evaluated in 2,423 patients across four countries in Europe and North America. The Abbreviated Mental Test (AMT-4) most accurately ruled in dementia (LR+ = 7.69 [95% confidence interval {CI} = 3.45–17.10]) while the Brief Alzheimer’s Screen most accurately ruled out dementia (LR– = 0.10 [95% CI = 0.02–0.28]). Using estimates of diagnostic accuracy for AMT-4 from this meta-analysis as one trigger for more comprehensive geriatric vulnerability assessments, ED dementia screening benefits patients when the prescreening probability of dementia is between 14 and 36%. Conclusions: ED-based diagnostic research for dementia screening is limited to a few studies using an inadequate criterion standard with variable masking of interpreter’s access to the index test and the criterion standard. Standardizing the geriatric ED cognitive assessment methods, measures, and nomenclature is necessary to reduce uncertainties about diagnostic accuracy, reliability, and relevance in this acute care setting. The AMT-4 is currently the most accurate ED screening instrument to increase the probability of dementia and the Brief Alzheimer’s Screen is the most accurate to decrease the probability of dementia. Dementia screening as one marker of vulnerability to initiate comprehensive geriatric assessment is warranted based on test–treatment threshold calculations. © 2018 by the Society for Academic Emergency Medicine

Document Type: Article in Press

Source: Scopus

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease
(2018) Acta Neuropathologica, . Article in Press. 

Broce, I.J.^a , Tan, C.H.^{a b} , Fan, C.C.^c , Jansen, I.^d , Savage, J.E.^d , Witoelar, A.^e , Wen, N.^f , Hess, C.P.^a , Dillon, W.P.^a , Glastonbury, C.M.^a , Glymour, M.^g , Yokoyama, J.S.^h , Elahi, F.M.^h , Rabinovici, G.D.^h , Miller, B.L.^h , Mormino, E.C.ⁱ , Sperling, R.A.^{j k} , Bennett, D.A.^l , McEvoy, L.K.^m , Brewer, J.B.^{m n o} , Feldman, H.H.ⁿ , Hyman, B.T.^j , Pericak-Vance, M.^p , Haines, J.L.^{q r} , Farrer, L.A.^{s t u v w} , Mayeux, R.^{x y z} , Schellenberg, G.D.^aa , Yaffe, K.^{g h ab} , Sugrue, L.P.^a , Dale, A.M.^{c m n} , Posthuma, D.^d , Andreassen, O.A.^e , Karch, C.M.^f , Desikan, R.S.^a

^a Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, United States ^b Division of Psychology, Nanyang Technological University, Singapore, Singapore
^c Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, United States
^d Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, Netherlands ^e Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^f Department of Psychiatry, Washington University in St Louis, 425 S Euclid Ave, Campus Box 8134, St Louis, MO 63110, United States
^g Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States
^h Department of Neurology, University of California, San Francisco, CA, United States
ⁱ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, United States
^j Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^k Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^l Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^m Department of Radiology, University of California, San Diego, La Jolla, CA, United States
ⁿ Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
^o Shiley-Marcos Alzheimer’s Disease Research Center, University of California, La Jolla, San Diego, CA, United States
^p John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
^q Department of Epidemiology and Biostatistics, Case Western University, Cleveland, OH, United States
^r Institute for Computational Biology, Case Western University, Cleveland, OH, United States
^s Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
^t Department of Neurology, Boston University School of Medicine, Boston, MA, United States ^u Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States
^v Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^w Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
^x Department of Neurology, Columbia University, New York, NY, United States
^y Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
^z Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
^aa Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ab Department of Psychiatry, University of California, San Francisco, CA, United States

Abstract
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR &lt; 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Alzheimer’s disease; Cardiovascular;  Genetic pleiotropy; Lipids; Polygenic enrichment

Document Type: Article in Press

Source: Scopus

Toward consilience in the use of task-level feedback to promote learning
(2018) Psychology of Learning and Motivation – Advances in Research and Theory, . Article in Press. 

Butler, A.C.^a , Woodward, N.R.^b

^a Washington University in St. Louis, St. Louis, MO, United States ^b University of Texas at Austin, Austin, TX, United States

Abstract
Over the past 50 years, the effects of task-level feedback on learning have been investigated within three relatively isolated research traditions: experimental laboratory research, applied research in the classroom, and research on using computers for individual instruction. Within each of these areas, the accumulation of empirical findings has far outpaced the development of theory. In addition, numerous discrepancies have emerged within and among these research traditions, which is problematic for existing theory and making recommendations for educational practice. The goal of this review is to make sense of a fragmented feedback literature that is rife with (seemingly) contradictory findings by introducing theoretical ideas from other areas of human learning. We begin by providing some context through a brief history of feedback research and then describe some common flaws in feedback research that have caused much confusion in the literature. Next, we discuss three well-replicated findings from the literature that are critical to understanding how people learn from feedback and introduce new theoretical ideas that may help to explain these phenomena. Finally, we describe a few future directions for feedback research and some guidelines for how feedback can be used to promote learning in educational practice. © 2018 Elsevier Inc.

Author Keywords
Feedback; Learning; Task-level

Document Type: Article in Press

Source: Scopus

What defines asymmetric sensorineural hearing loss?
(2018) Laryngoscope, . Article in Press. 

Durakovic, N., Valente, M., Goebel, J.A., Wick, C.C.

Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Author Keywords
acoustic neuroma;  asymmetry;  audiogram;  retrocochlear;  Sensorineural hearing loss;  vestibular schwannoma

Document Type: Article in Press

Source: Scopus

iPLA2β and its role in male fertility, neurological disorders, metabolic disorders, and inflammation
(2018) Biochimica et Biophysica Acta – Molecular and Cell Biology of Lipids, . Article in Press. 

Turk, J.^a , White, T.D.^{b c} , Nelson, A.J.^{b c} , Lei, X.^{b c} , Ramanadham, S.^{b c}

^a Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States ^b Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States ^c Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
The Ca2+-independent phospholipases, designated as group VI iPLA2s, also referred to as PNPLAs due to their shared homology with patatin, include the β γ δ ε ζ and η forms of the enzyme. The iPLA2s are ubiquitously expressed, share a consensus GXSXG catalytic motif, and exhibit organelle/cell-specific localization. Among the iPLA2s, iPLA2β has received wide attention as it is recognized to be involved in membrane remodeling, cell proliferation, cell death, and signal transduction. Ongoing studies implicate participation of iPLA2β in a variety of disease processes including cancer, cardiovascular abnormalities, glaucoma, and peridonditis. This review will focus on iPLA2β and its links to male fertility, neurological disorders, metabolic disorders, and inflammation. © 2018 Elsevier B.V.

Author Keywords
Diabetes;  Immune responses;  iPLA2β-derived lipids;  Membrane remodeling;  Signaling

Document Type: Article in Press

Source: Scopus

234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8–10 December 2017
(2018) Neuromuscular Disorders, . Article in Press. 

Weihl, C.C.^a , Udd, B.^b , Hanna, M.^c , Ben-Zvi, A.^d , Blaettler, T.^e , Bryson-Richardson, R.^f , Carra, S.^g , Dimachkie, M.^h , Findlay, A.ⁱ , Greensmith, L.^j , Greenspan, S.^k , Hanna, M.^j , Höhfled, J.^l , Jonson, P.H.^m , Kampinga, H.ⁿ , Larsson, L.^o , Linke, W.^p , Lynch, G.^f , Machado, P.^q , Orlando, L.^r , Richard, I.^s , Roos, A.^t , Sarparanta, J.^m , Timmerman, V.^u , Udd, B.^v , Weihl, C.^w , Zah, L.^k

^a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, Saint Louis, MO 63110, United States ^b Tampere Neuromuscular Center and Folkhalsan Genetic Institute, Helsinki, Finland ^c UCL Institute of Neurology, Queen Square, London, United Kingdom ^d Israel ^e Denmark ^f Melbourne, Australia ^g Modena, Italy ^h Kansas City, United States ⁱ St. Louis, MD, United States ^j London, United Kingdom ^k Sheffield, MA, United States ^l Bonn, Germany ^m Finland ⁿ Groningen, Netherlands ^o Stockholm, Sweden ^p Munster, Germany ^q United Kingdom ^r United States ^s Paris, France ^t Dortmund, Germany ^u Antwerpen, Belgium ^v Tampere, Finland ^w Saint Louis, MO, United States

Document Type: Article in Press

Source: Scopus