“Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury” (2021) Nature Communications
Improving hindlimb locomotor function by Non-invasive AAV-mediated manipulations of propriospinal neurons in mice with complete spinal cord injury
(2021) Nature Communications, 12 (1), art. no. 781, .
Brommer, B.a , He, M.a , Zhang, Z.a , Yang, Z.a , Page, J.C.a , Su, J.a , Zhang, Y.a , Zhu, J.a , Gouy, E.a , Tang, J.a , Williams, P.a b , Dai, W.a , Wang, Q.a , Solinsky, R.c d , Chen, B.e , He, Z.a
a F.M. Kirby Neurobiology Center, Boston Children’s Hospital, and Departments of Neurology and Ophthalmology, Harvard Medical School, Boston, MA, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Spaulding Rehabilitation Hospital, Boston, MA, United States
d Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, United States
e Department of Neuroscience, Cell Biology, & Anatomy, University of Texas Medical Branch, Galveston, TX, United States
Abstract
After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI. © 2021, The Author(s).
Funding details
National Institute of Neurological Disorders and StrokeNINDS
National Center for Complementary and Integrative HealthNCCIHF32AT011155
Dr. Miriam and Sheldon G. Adelson Medical Research FoundationAMRF
National Institutes of HealthNIHHD018655, P30EY012196
Document Type: Article
Publication Stage: Final
Source: Scopus
“Sex, ApoE4 and Alzheimer’s disease: Rethinking drug discovery in the era of precision medicine” (2021) Neural Regeneration Research
Sex, ApoE4 and Alzheimer’s disease: Rethinking drug discovery in the era of precision medicine
(2021) Neural Regeneration Research, 16 (9), pp. 1764-1765.
Paranjpe, M.D.a , Wang, J.K.a , Zhou, Y.b
a Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, United States
b Mallinckrodt Institute of Radiology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
Document Type: Review
Publication Stage: Final
Source: Scopus
“Consistent differences in lumbar spine alignment between low back pain subgroups and genders during clinical and functional activity sitting tests” (2021) Musculoskeletal Science and Practice
Consistent differences in lumbar spine alignment between low back pain subgroups and genders during clinical and functional activity sitting tests
(2021) Musculoskeletal Science and Practice, 52, art. no. 102336, .
Hooker, Q.L., Lanier, V.M., van Dillen, L.R.
Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Subgroups of people with low back pain display differences in their lumbar alignment during tests from a clinical examination. However, it is unknown if subgroups display the same patterns during a functional activity test and if gender influences subgroup-related differences. Objectives: Test if differences in lumbar alignment between two LBP subgroups are 1) present during a functional activity test of preferred sitting and 2) independent of gender. Design: Cross-sectional. Method: 154 participants with chronic low back pain were classified based on the Movement System Impairment Classification System by a physical therapist. Participants performed a functional activity test of preferred sitting and clinical tests of maximum flexed and extended sitting. 3D marker co-ordinate data were collected. Sagittal plane lumbar alignment, indexed by lumbar curvature angle, was calculated. A three-way mixed effect analysis of variance was used to examine effects of test, subgroup, gender, subgroup × test, gender × test and subgroup × gender. Results/findings: The lumbar rotation with extension subgroup [LCA = −8.0° (−9.5,-6.5)] displayed a more extended lumbar alignment than lumbar rotation [LCA = −5.9° (−7.4,-4.4)]. Women [LCA = −10.7° (−12.3,-9.2)] displayed a more extended lumbar alignment than men [LCA = −3.2° (−4.7,-1.7)]. There was a significant gender × test interaction (p = 0.01). The subgroup × test (p = 0.99) and subgroup × gender (p = 0.76) interactions were not significant. Conclusions: LBP subgroup differences in lumbar alignment are present during preferred sitting. Gender-related differences in lumbar alignment are not driving subgroup differences. These findings highlight the need to use patient-specific clinical characteristics to guide treatment of a functional activity of preferred sitting limited due to low back pain. © 2021 Elsevier Ltd
Author Keywords
Chronic; Classification; Low back pain; Lumbar spine alignment
Funding details
National Institutes of HealthNIHR01 HD047709, R01 HD047709, TR002344, TR002344, R01 HD047709, R01 HD047709, TR002344, TR002344
National Institutes of HealthNIHR01 HD047709, R01 HD047709, TR002344, TR002344, R01 HD047709, R01 HD047709, TR002344, TR002344
Document Type: Article
Publication Stage: Final
Source: Scopus
“Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice” (2021) Molecular Therapy – Methods and Clinical Development
Intracranial delivery of AAV9 gene therapy partially prevents retinal degeneration and visual deficits in CLN6-Batten disease mice
(2021) Molecular Therapy – Methods and Clinical Development, 20, pp. 497-507.
White, K.A.a , Nelvagal, H.R.b e , Poole, T.A.b , Lu, B.c , Johnson, T.B.a d , Davis, S.a , Pratt, M.A.a , Brudvig, J.a , Assis, A.B.e , Likhite, S.f , Meyer, K.g i , Kaspar, B.K.g i , Cooper, J.D.b e , Wang, S.c , Weimer, J.M.a d h
a Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, United States
b Pediatric Storage Disorders Laboratory, Division of Genetics and Genomics, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
d Amicus Therapeutics, Philadelphia, PA 19104, United States
e Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center and David Geffen School of Medicine, UCLA, Torrance, CA 90502, United States
f Nationwide Children’s Hospital., He was involved in AAV9 construct development
g The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, United States
h Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57069, United States
i Department of Pediatrics, The Ohio State University, Columbus, OH 43210, United States
Abstract
Recently, the benefits of AAV9 gene therapy were reported in a mouse model of CLN6-Batten disease, a rare neuropediatric disease. Here, the authors show that intracerebroventricularly delivered AAV9 prevents disease pathology in the visual centers of the brain, expresses in the retina, and partially preserves vision in Cln6nclf mice. © 2021 The Authors
Batten disease is a family of rare, fatal, neuropediatric diseases presenting with memory/learning decline, blindness, and loss of motor function. Recently, we reported the use of an AAV9-mediated gene therapy that prevents disease progression in a mouse model of CLN6-Batten disease (Cln6nclf), restoring lifespans in treated animals. Despite the success of our viral-mediated gene therapy, the dosing strategy was optimized for delivery to the brain parenchyma and may limit the therapeutic potential to other disease-relevant tissues, such as the eye. Here, we examine whether cerebrospinal fluid (CSF) delivery of scAAV9.CB.CLN6 is sufficient to ameliorate visual deficits in Cln6nclf mice. We show that intracerebroventricular (i.c.v.) delivery of scAAV9.CB.CLN6 completely prevents hallmark Batten disease pathology in the visual processing centers of the brain, preserving neurons of the superior colliculus, thalamus, and cerebral cortex. Importantly, i.c.v.-delivered scAAV9.CB.CLN6 also expresses in many cells throughout the central retina, preserving many photoreceptors typically lost in Cln6nclf mice. Lastly, scAAV9.CB.CLN6 treatment partially preserved visual acuity in Cln6nclf mice as measured by optokinetic response. Taken together, we report the first instance of CSF-delivered viral gene reaching and rescuing pathology in both the brain parenchyma and retinal neurons, thereby partially slowing visual deterioration. © 2021 The Authors
Author Keywords
AAV9; Batten disease; CLN6; Gene therapy; ICV; NCL; retina; vision
Funding details
Foundation for Barnes-Jewish Hospital3770, 4642
National Institutes of HealthNIHR01NS082283, P20GM103548, P20GM103620
CDI-CORE-2019-813, CDI-CORE-2015-505
Document Type: Article
Publication Stage: Final
Source: Scopus
“Identifying challenges and recommendations for advancing global mental health implementation research: A key informant study of the National Institute of Mental Health Scale-Up Hubs” (2021) Asian Journal of Psychiatry
Identifying challenges and recommendations for advancing global mental health implementation research: A key informant study of the National Institute of Mental Health Scale-Up Hubs
(2021) Asian Journal of Psychiatry, 57, art. no. 102557, .
Naslund, J.A.a , Kalha, J.b , Restivo, J.L.a , Amarreh, I.c , Callands, T.d , Chen, H.e , Gomez-Restrepo, C.f g , Hamoda, H.M.h , Kapoor, A.b , Levkoff, S.i , Masiye, J.j , Oquendo, M.A.k , Patel, V.a l , Petersen, I.m , Sensoy Bahar, O.n , Shields-Zeeman, L.o , Ssewamala, F.M.n , Tugnawat, D.p , Uribe-Restrepo, J.M.g , Vijayakumar, L.q , Wagenaar, B.H.r , Wainberg, M.L.s , Wissow, L.t u , Wurie, H.R.v , Zimba, C.w , Pathare, S.b
a Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, United States
b Centre for Mental Health Law and Policy, Indian Law Society, Pune, India
c National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
d Health Promotion and Behavior, College of Public Health, The University of Georgia, Athens, GA, United States
e Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, United States
f Faculty of Medicine, Department of Clinical Epidemiology, Pontificia Universidad Javeriana, Bogota, Colombia
g Department of Psychiatry and Mental Health, Pontificia Universidad Javeriana, Bogota, Colombia
h Department of Psychiatry and Behavioral Sciences, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
i College of Social Work, University of South Carolina, Columbia, SC, United States
j Ministry of Health, Malawi, Lilongwe, Malawi
k Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
l Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, United States
m Centre for Rural Health, School of Nursing and Public Health, University of KwaZulu-Natal, South Africa
n Brown School, Washington University in St. Louis, St. Louis, MO, United States
o Trimbos Institute, Netherlands Institute for Mental Health and Addiction, Utrecht, Netherlands
p Sangath, Bhopal, India
q Voluntary Health Services, Chennai, India
r Department of Global Health, University of Washington, Seattle, WA, United States
s Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY, United States
t Division of Child and Adolescent Psychiatry, University of Washington School of Medicine, Seattle, United States
u Department of Psychiatry and Behavioral Medicine, Seattle Children’s Hospital, Seattle, United States
v Faculty of Nursing, Biochemistry, College of Medicine and Allied Health Sciences, University of Sierra Leone, Freetown, Sierra Leone
w University of North Carolina Project Malawi, Lilongwe, Malawi
Abstract
Objective: This study explored perspectives of researchers working with the National Institute of Mental Health (NIMH) Scale-Up Hubs, consisting of research partnerships for scaling up mental health interventions in low- and middle-income countries (LMICs), to: 1) identify common barriers to conducting impactful research on the implementation of evidence-based mental health services; and 2) provide recommendations to overcome these implementation challenges. Methods: A sequential qualitative approach was employed. First, an open-ended survey was distributed to the 10 Scale-Up Hubs and NIMH program staff asking informants to identify challenges in conducting mental health implementation research in LMICs. Second, survey findings guided an in-person workshop to generate implementation recommendations to inform the field. Results: In total, 46 respondents completed surveys, and 101 researchers attended the workshop. The workshop produced implementation recommendations for low-resource settings: 1) identifying impact of research on policy and practice; 2) sustaining careers of early researchers in global mental health; 3) engaging policymakers and donors to value mental health research; 4) supporting the workforce for delivering evidence-based treatments for mental disorders; and 5) promoting sustainability of programs. Conclusions: These findings can strengthen collaboration between researchers and key stakeholders, and highlight important targets for improving mental health implementation research in LMICs. © 2021 Elsevier B.V.
Author Keywords
Capacity building; Global health; Implementation research; Low-resource settings; Mental health; Scale up
Funding details
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Final
Source: Scopus
“Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons” (2021) Immunity
Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons
(2021) Immunity, 54 (2), pp. 225-234.e6. Cited 1 time.
Klawonn, A.M.a b , Fritz, M.a h , Castany, S.a , Pignatelli, M.c d , Canal, C.e , Similä, F.a , Tejeda, H.A.c , Levinsson, J.a , Jaarola, M.a , Jakobsson, J.f , Hidalgo, J.e , Heilig, M.a , Bonci, A.g , Engblom, D.a
a Department of Biomedical and Clinical Sciences, Linköping University, Linköping, 58185, Sweden
b Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, United States
c Synaptic Plasticity Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, MD 21224, United States
d Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO 63110, United States
e Institute of Neurosciences and Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, Barcelona, 08028, Spain
f Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, 22184, Sweden
g Global Institutes on Addictions, Miami, FL 33132, United States
h Present address: Department of Forensic Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany
Abstract
Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation. © 2020 Elsevier Inc.
Many pathological conditions are accompanied by microglial activation and negative mood, but it is unclear if the microglia contribute causally to the aversive state. Klawonn et al. reveal that striatal microglial activation induces negative affect and that IL-6 and prostaglandin dependent signaling in microglia is critical for inflammation-induced aversion. © 2020 Elsevier Inc.
Author Keywords
anhedonia; aversion; depression; DREADDs; interleukin-6; Microglia; neuroinflammation; prostaglandin; striatum
Funding details
Medicinska ForskningsrådetMFR
RTI2018-101105-B-I00, SAF2014-56546-R, B18P0023
Stiftelsen Lars Hiertas Minne
Knut och Alice Wallenbergs Stiftelse
Document Type: Article
Publication Stage: Final
Source: Scopus
“Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction” (2021) American Journal of Human Genetics
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
(2021) American Journal of Human Genetics, 108 (2), pp. 346-356.
den Hoed, J.a b , de Boer, E.c d , Voisin, N.e , Dingemans, A.J.M.c d , Guex, N.e f , Wiel, L.c g h , Nellaker, C.i j k , Amudhavalli, S.M.l m , Banka, S.n o , Bena, F.S.p , Ben-Zeev, B.q , Bonagura, V.R.r s , Bruel, A.-L.t u , Brunet, T.v , Brunner, H.G.c d bs , Chew, H.B.x , Chrast, J.e , Cimbalistienė, L.y , Coon, H.z , Délot, E.C.aa , Démurger, F.ab , Denommé-Pichon, A.-S.t u , Depienne, C.ac , Donnai, D.n o , Dyment, D.A.ad , Elpeleg, O.ae , Faivre, L.t af ag , Gilissen, C.c g , Granger, L.ah , Haber, B.ai , Hachiya, Y.aj , Abedi, Y.H.ak al , Hanebeck, J.ai , Hehir-Kwa, J.Y.am , Horist, B.an , Itai, T.ao , Jackson, A.n , Jewell, R.ap , Jones, K.L.aq ar , Joss, S.as , Kashii, H.aj , Kato, M.at , Kattentidt-Mouravieva, A.A.au , Kok, F.av aw , Kotzaeridou, U.ai , Krishnamurthy, V.an , Kučinskas, V.y , Kuechler, A.ac , Lavillaureix, A.ax , Liu, P.ay az , Manwaring, L.ba , Matsumoto, N.ao , Mazel, B.af , McWalter, K.bb , Meiner, V.ae , Mikati, M.A.bc , Miyatake, S.ao , Mizuguchi, T.ao , Moey, L.H.bd , Mohammed, S.be , Mor-Shaked, H.ae , Mountford, H.bf , Newbury-Ecob, R.bg , Odent, S.ax , Orec, L.ai , Osmond, M.ad , Palculict, T.B.bb , Parker, M.bh , Petersen, A.K.ah , Pfundt, R.c , Preikšaitienė, E.y , Radtke, K.bi , Ranza, E.p bj , Rosenfeld, J.A.ay , Santiago-Sim, T.bb , Schwager, C.l m , Sinnema, M.w bk , Snijders Blok, L.a c d , Spillmann, R.C.bl , Stegmann, A.P.A.c w , Thiffault, I.l bm bn , Tran, L.bc , Vaknin-Dembinsky, A.bt , Vedovato-dos-Santos, J.H.av , Schrier Vergano, S.A.aq , Vilain, E.aa , Vitobello, A.t u , Wagner, M.v bo , Waheeb, A.ad bp , Willing, M.ba , Zuccarelli, B.bq , Kini, U.br , Newbury, D.F.bf , Kleefstra, T.c d , Reymond, A.e , Fisher, S.E.a d , Vissers, L.E.L.M.c d , The DDD Studybu
a Language and Genetics Department, Max Planck Institute for Psycholinguistics, AH Nijmegen, 6500, Netherlands
b International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, AH Nijmegen, 6500, Netherlands
c Department of Human Genetics, Radboudumc, HB Nijmegen, 6500, Netherlands
d Donders Institute for Brain, Cognition and Behaviour, Radboud University, GL Nijmegen, 6500, Netherlands
e Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland
f Bioinformatics Competence Center, University of Lausanne, Lausanne, 1015, Switzerland
g Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, HB Nijmegen, 6500, Netherlands
h Center for Molecular and Biomolecular Informatics of the Radboudumc, HB Nijmegen, 6500, Netherlands
i Nuffield Department of Women’s and Reproductive Health, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom
j Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, OX3 7DQ, United Kingdom
k Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7LF, United Kingdom
l University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, United States
m Department of Pediatrics, Division of Clinical Genetics, Children’s Mercy Hospital, Kansas City, MO 64108, United States
n Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, United Kingdom
o Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, M13 9WL, United Kingdom
p Service of Genetic Medicine, University Hospitals of Geneva, Geneva, 1205, Switzerland
q Edmomd and Lilly Safra Pediatric Hospital, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel
r Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, United States
s Pediatrics and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
t UMR1231-Inserm, Génétique des Anomalies du développement, Université de Bourgogne Franche-ComtéDijon 21070, France
u Laboratoire de Génétique chromosomique et moléculaire, UF6254 Innovation en diagnostic génomique des maladies rares, Centre Hospitalier Universitaire de DijonDijon 21070, France
v Institute of Human Genetics, Technical University of Munich, Munich, 81675, Germany
w Department of Clinical Genetics, Maastricht University Medical Center+, azM, AZ Maastricht, 6202, Netherlands
x Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, Kuala Lumpur, 50586, Malaysia
y Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, 08661, Lithuania
z Department of Psychiatry, University of Utah School of Medicine, Salt Lake CityUT 84112, United States
aa Center for Genetic Medicine Research, Children’s National Hospital, Children’s Research Institute and Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20010, United States
ab Department of clinical genetics, Vannes hospital, Vannes, 56017, France
ac Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany
ad Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
ae Department of Genetics, Hadassah Medical Center, Hebrew University Medical CenterJerusalem 91120, Israel
af Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, 21079, France
ag Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, 21079, France
ah Department of Rehabilitation and Development, Randall Children’s Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, United States
ai Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, 69120, Germany
aj Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, 183-0042, Japan
ak Division of Allergy and Immunology, Northwell Health, Great Neck, NY 11021, United States
al Departments of Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, United States
am Princess Máxima Center for Pediatric Oncology, CS Utrecht, 3584, Netherlands
an Pediatrics & Genetics, Alpharetta, GA 30005, United States
ao Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
ap Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, LS7 4SA, United Kingdom
aq Division of Medical Genetics & Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA 23507, United States
ar Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA 23507, United States
as West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, G51 4TF, United Kingdom
at Department of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo, 142-8666, Japan
au Zuidwester, 3240AA Middelharnis, Netherlands
av Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil
aw University of Sao Paulo, School of Medicine, Sao Paulo, SP 01246-903, Brazil
ax CHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, Rennes, 35033, France
ay Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
az Baylor Genetics, Houston, TX 77021, United States
ba Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, United States
bb GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States
bc Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, United States
bd Department of Genetics, Penang General Hospital, Jalan Residensi, Georgetown, Penang 10990, Malaysia
be Clinical Genetics, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom
bf Department of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford, OX3 0BP, United Kingdom
bg Clinical Genetics, St Michael’s Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8EG, United Kingdom
bh Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, S5 7AU, United Kingdom
bi Clinical Genomics Department, Ambry Genetics, Aliso Viejo, CA 92656, United States
bj Medigenome, Swiss Institute of Genomic Medicine, Geneva, 1207, Switzerland
bk Department of Genetics and Cell Biology, Faculty of Health Medicine Life Sciences, Maastricht University Medical Center+, Maastricht University, ER Maastricht, 6229, Netherlands
bl Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27713, United States
bm Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO 64108, United States
bn Department of Pathology and Laboratory Medicine, Children’s Mercy Hospital, Kansas City, MO 64108, United States
bo Institute of Neurogenomics, Helmholtz Zentrum München, Munich, 85764, Germany
bp Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
bq The University of Kansas School of Medicine Salina Campus, Salina, KS 67401, United States
br Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, United Kingdom
bs Maastricht University Medical Center, Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, and MHeNS School for Mental health and Neuroscience, PO Box 5800Maastricht 6202AZ, Netherlands
bt Department of Neurology and Laboratory of Neuroimmunology, The Agnes Ginges Center for Neurogenetics, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel
bu Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom
Abstract
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability. © 2021 American Society of Human Genetics
Author Keywords
cell-based functional assays; de novo variants; HPO-based analysis; intellectual disability; neurodevelopmental disorders; SATB1; seizures; teeth abnormalities
Funding details
91718310
Fondation Jérôme Lejeune
Max-Planck-GesellschaftMPG
British Academy
Oxford Brookes University
015.014.066, 015.014.036
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF31003A_182632
Leverhulme Trust
779257
Document Type: Article
Publication Stage: Final
Source: Scopus
“Discovering New Imaging Biomarkers of Stroke Etiology” (2021) Radiology
Discovering New Imaging Biomarkers of Stroke Etiology
(2021) Radiology, 298 (2), pp. 382-383.
Kansagra, A.P., Goyal, M.S.
From the Mallinckrodt Institute of Radiology (A.P.K., M.S.G.), Department of Neurological Surgery (A.P.K.), Department of Neurology (A.P.K., M.S.G.), and Department of Neuroscience (M.S.G.), Washington University School of Medicine, 510 Kingshighway Blvd, CB 8131, St Louis, MO 63110
Document Type: Editorial
Publication Stage: Final
Source: Scopus
“Thalamic deep brain stimulation for acquired dystonia in children and young adults: A phase 1 clinical trial” (2021) Journal of Neurosurgery: Pediatrics
Thalamic deep brain stimulation for acquired dystonia in children and young adults: A phase 1 clinical trial
(2021) Journal of Neurosurgery: Pediatrics, 27 (2), pp. 203-212.
Luciano, M.S.a , Robichaux-Viehoever, A.c , Dodenhoff, K.A.a , Gittings, M.L.a , Viser, A.C.a , Racine, C.A.b , Bledsoe, I.O.a , Pereira, C.W.a , Wang, S.S.a , Starr, P.A.b , Ostrem, J.L.a
a Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, United States
b Department of Neurological Surgery, University of California, San Francisco, CA, United States
c Department of Neurology, Division of Child Neurology, Washington University in St. LouisMO, United States
Abstract
OBJECTIVE: The aim of this study was to evaluate the feasibility and preliminary efficacy and safety of combined bilateral ventralis oralis posterior/ventralis intermedius (Vop/Vim) deep brain stimulation (DBS) for the treatment of acquired dystonia in children and young adults. Pallidal DBS is efficacious for severe, medication-refractory isolated dystonia, providing 50%-60% long-term improvement. Unfortunately, pallidal stimulation response rates in acquired dystonia are modest and unpredictable, with frequent nonresponders. Acquired dystonia, most commonly caused by cerebral palsy, is more common than isolated dystonia in pediatric populations and is more recalcitrant to standard treatments. Given the limitations of pallidal DBS in acquired dystonia, there is a need to explore alternative brain targets. Preliminary evidence has suggested that thalamic stimulation may be efficacious for acquired dystonia. METHODS Four participants, 3 with perinatal brain injuries and 1 with postencephalitic symptomatic dystonia, underwent bilateral Vop/Vim DBS and bimonthly evaluations for 12 months. The primary efficacy outcome was the change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) scores between the baseline and 12-month assessments. Video documentation was used for blinded ratings. Secondary outcomes included evaluation of spasticity (Modified Ashworth Scale score), quality of life (Pediatric Quality of Life Inventory [PedsQL] and modified Unified Parkinson’s Disease Rating Scale Part II [UPDRS-II] scores), and neuropsychological assessments. Adverse events were monitored for safety. RESULTS All participants tolerated the procedure well, and there were no safety concerns or serious adverse events. There was an average improvement of 21.5% in the BFMDRS motor subscale score, but the improvement was only 1.6% according to the BADS score. Following blinded video review, dystonia severity ratings were even more modest. Secondary outcomes, however, were more encouraging, with the BFMDRS disability subscale score improving by 15.7%, the PedsQL total score by 27%, and the modified UPDRS-II score by 19.3%. Neuropsychological assessment findings were unchanged 1 year after surgery. CONCLUSIONS Bilateral thalamic neuromodulation by DBS for severe, medication-refractory acquired dystonia was well tolerated. Primary and secondary outcomes showed highly variable treatment effect sizes comparable to those of pallidal stimulation in this population. As previously described, improvements in quality of life and disability were not reflected in dystonia severity scales, suggesting a need for the development of scales specifically for acquired dystonia. © AANS 2021, except where prohibited by US copyright law
Author Keywords
DBS; Deep brain stimulation; Dystonia; Functional neurosurgery; Pediatric; Thalamic
Document Type: Article
Publication Stage: Final
Source: Scopus
“Functional Connectivity Network Disruption Underlies Domain-Specific Impairments in Attention for Children Born Very Preterm” (2021) Cerebral Cortex
Functional Connectivity Network Disruption Underlies Domain-Specific Impairments in Attention for Children Born Very Preterm
(2021) Cerebral Cortex, 31 (2), pp. 1383-1394.
Wheelock, M.D.a , Lean, R.E.b , Bora, S.c , Melzer, T.R.d , Eggebrecht, A.T.a , Smyser, C.D.a e f , Woodward, L.J.g
a Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63108, United States
c Mothers, Babies, and Women’s Health Program, Mater Research Institute, University of Queensland, South Brisbane, Australia
d Department of Medicine, University of Otago, New Zealand Brain Research Institute, Christchurch, 8011, New Zealand
e Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
f Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, United States
g School of Health Sciences and Child Wellbeing Research Institute, University of Canterbury, Christchurch, 8041, New Zealand
Abstract
Attention problems are common in school-age children born very preterm (VPT; < 32 weeks gestational age), but the contribution of aberrant functional brain connectivity to these problems is not known. As part of a prospective longitudinal study, brain functional connectivity (fc) was assessed alongside behavioral measures of selective, sustained, and executive attention in 58 VPT and 65 full-term (FT) born children at corrected-age 12 years. VPT children had poorer sustained, shifting, and divided attention than FT children. Within the VPT group, poorer attention scores were associated with between-network connectivity in ventral attention, visual, and subcortical networks, whereas between-network connectivity in the frontoparietal, cingulo-opercular, dorsal attention, salience and motor networks was associated with attention functioning in FT children. Network-level differences were also evident between VPT and FT children in specific attention domains. Findings contribute to our understanding of fc networks that potentially underlie typical attention development and suggest an alternative network architecture may help support attention in VPT children. © 2020 The Author(s). Published by Oxford University Press. All rights reserved.
Author Keywords
attention; functional connectivity; networks; outcome; preterm
Document Type: Article
Publication Stage: Final
Source: Scopus
“Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy” (2021) Journal of Neuropathology and Experimental Neurology
Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy
(2021) Journal of Neuropathology and Experimental Neurology, 80 (2), pp. 102-111.
Walker, J.M.a b , Richardson, T.E.a b c , Farrell, K.d e f , Iida, M.A.d e f , Foong, C.g , Shang, P.g , Attems, J.h , Ayalon, G.i , Beach, T.G.j , Bigio, E.H.k , Budson, A.l , Cairns, N.J.m , Corrada, M.n , Cortes, E.d , Dickson, D.W.o , Fischer, P.p , Flanagan, M.E.k , Franklin, E.m , Gearing, M.q , Glass, J.q , Hansen, L.A.r , Haroutunian, V.s , Hof, P.R.d e f , Honig, L.t , Kawas, C.n , Keene, C.D.u , Kofler, J.v , Kovacs, G.G.p , Lee, E.B.w , Lutz, M.I.x , Mao, Q.j , Masliah, E.r , McKee, A.C.l , McMillan, C.T.y , Mesulam, M.M.k , Murray, M.o , Nelson, P.T.z , Perrin, R.m , Pham, T.aa , Poon, W.n , Purohit, D.P.d , Rissman, R.A.r , Sakai, K.ab , Sano, M.s , Schneider, J.A.ac , Stein, T.D.l , Teich, A.F.ad , Trojanowski, J.Q.w , Troncoso, J.C.ae , Vonsattel, J.-P.ad , Weintraub, S.k , Wolk, D.A.y , Woltjer, R.L.aa , Yamada, M.ab , Yu, L.ac , White, C.L.g , Crary, J.F.d e f
a From the Department of Pathology, University of Texas Health Science Center, San Antonio, TX, United States
b Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, United States
c Department of Pathology, State University of New York, Upstate Medical University, Syracuse, NY, United States
d Department of Pathology and Nash Family Neuroscience, Icahn School of Medicine at Mount SinaiNY, United States
e Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, Neuropathology Brain Bank & Research CoreNY, United States
f Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount SinaiNY, United States
g Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
h Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom
i Department of Neuroscience, Genentech Inc., South San Francisco, CA, United States
j Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, United States
k Department of Pathology, Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
l Department of Pathology, VA Medical Center & Boston University School of Medicine, Boston, MA, United States
m Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
n Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, United States
o Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
p Department of Laboratory Medicine and Pathobiology, University of Toronto, Laboratory Medicine Program, Tanz Centre for Research in Neurodegenerative Disease, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
q Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, United States
r Departments of Neurosciences and Pathology, University of California, La Jolla, San Diego, CA, United States
s Department of Psychiatry and Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount SinaiNY, United States
t Department of Neurology, Columbia University Irving Medical CenterNY, United States
u Department of Pathology, University of Washington, Seattle, WA, United States
v Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
w Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Institute of Neurology, Medical University of ViennaVienna, Austria
y Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
z Department of Pathology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
aa Department of Pathology, Oregon Health Sciences University, Portland, Oregon, USA
ab Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
ac Departments of Pathology and Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
ad Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical CenterNY, United States
ae Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Abstract
Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART. © 2020 American Association of Neuropathologists, Inc. All rights reserved.
Author Keywords
Alzheimer disease; CA2; Cognitive status; Cornu ammonis; Hippocampal subfields; Neurodegenerative disease; Primary age-related tauopathy
Document Type: Article
Publication Stage: Final
Source: Scopus
“Implications of Oligomeric Amyloid-Beta (oAβ42) Signaling through α7β2-Nicotinic Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic Excitability and Cognitive Decline” (2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Implications of Oligomeric Amyloid-Beta (oAβ42) Signaling through α7β2-Nicotinic Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic Excitability and Cognitive Decline
(2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 41 (3), pp. 555-575.
George, A.A.a , Vieira, J.M.b , Xavier-Jackson, C.c , Gee, M.T.d , Cirrito, J.R.e , Bimonte-Nelson, H.A.b , Picciotto, M.R.f , Lukas, R.J.a , Whiteaker, P.a
a Department of Neurobiology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, United States
b Department of Psychology, Arizona State University, Tempe, AZ 87110, Italy
c Department of Pharmacology, University of Bath, Bath, BA2 7AY, United Kingdom
d Department of Physiology, Banner-University Medical Center, University of Arizona, Tucson, AZ 85724, United States
e Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO 63110, United States
f Department of Psychiatry, Yale School of Medicine, New Haven, CT 06519, United States
Abstract
Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) and contribute to cognitive deficits associated with Alzheimer’s disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-β (oAβ42), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α7β2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oAβ42 showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band and horizontal diagonal band, but not the nucleus basalis. Last, aged male and female APP/PS1 transgenic mice, genetically null for the β2 nAChR subunit gene, showed improved spatial reference memory compared with APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for α7β2-nAChR in mediating the effects of oAβ42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7β2-nAChR in oAβ42-induced cognitive decline. Copyright © 2021 the authors.
Author Keywords
basal forebrain cholinergic neurons; medium afterhyperpolarization; neuronal intrinsic excitability; oligomeric amyloid-beta; single-channel electrophysiology; spatial reference memory
Document Type: Article
Publication Stage: Final
Source: Scopus
“Detection of the SQSTM1 Mutation in a Patient with Early-Onset Hippocampal Amnestic Syndrome” (2021) Journal of Alzheimer’s Disease: JAD
Detection of the SQSTM1 Mutation in a Patient with Early-Onset Hippocampal Amnestic Syndrome
(2021) Journal of Alzheimer’s Disease: JAD, 79 (2), pp. 477-481.
Carandini, T.a , Sacchi, L.a b , Ghezzi, L.b c , Pietroboni, A.M.a , Fenoglio, C.a b , Arighi, A.a , Fumagalli, G.G.a , De Riz, M.A.a , Serpente, M.a b , Rotondo, E.a , Scarpini, E.a b , Galimberti, D.a b
a Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
b University of Milan, Dino Ferrari Center, Milan, Italy
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Abstract
Genetics has a major role in early-onset dementia, but the correspondence between genotype and phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1. The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer’s disease-but biomarkers were not-and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1, which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report suggests that the clinical spectrum of SQSTM1 variants is wider.
Author Keywords
Alzheimer’s disease; early-onset dementia; next-generation sequencing; p62; SQSTM1
Document Type: Letter
Publication Stage: Final
Source: Scopus
“Communicating 5-Year Risk of Alzheimer’s Disease Dementia: Development and Evaluation of Materials that Incorporate Multiple Genetic and Biomarker Research Results” (2021) Journal of Alzheimer’s Disease: JAD
Communicating 5-Year Risk of Alzheimer’s Disease Dementia: Development and Evaluation of Materials that Incorporate Multiple Genetic and Biomarker Research Results
(2021) Journal of Alzheimer’s Disease: JAD, 79 (2), pp. 559-572.
Mozersky, J.a , Hartz, S.b , Linnenbringer, E.c , Levin, L.a , Streitz, M.d , Stock, K.e , Moulder, K.d , Morris, J.C.d
a Bioethics Research Center, Division of General Medical Sciences, Washington University School of Medicine, St. Louis, MO, USA
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
c Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA
d Department of Neurology, Washington University School of Medicine, St. Louis, MO; and Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
e Washington University Danforth College of Arts and Sciences (post-baccalaureate program) and Music Speaks, LLC
Abstract
BACKGROUND: Cognitively normal (CN) older adults participating in Alzheimer’s disease (AD) research increasingly ask for their research results-including genetic and neuroimaging findings-to understand their risk of developing AD dementia. AD research results are typically not returned for multiple reasons, including possible psychosocial harms of knowing one is at risk of a highly feared and untreatable disease. OBJECTIVE: We developed materials that convey information about 5-year absolute risk of developing AD dementia based on research results. METHODS: 20 CN older adults who received a research brain MRI result were interviewed regarding their wishes for research results to inform material development (Pilot 1). Following material development, 17 CN older adults evaluated the materials for clarity and acceptability (Pilot 2). All participants were community-dwelling older adults participating in longitudinal studies of aging at a single site. RESULTS: Participants want information on their risk of developing AD dementia to better understand their own health, satisfy curiosity, inform family, and future planning. Some articulated concerns, but the majority wanted to know their risk despite the limitations of information. Participants found the educational materials and results report clear and acceptable, and the majority would want to know their research results after reviewing them. CONCLUSION: These materials will be used in a clinical study examining the psychosocial and cognitive effects of offering research results to a cohort of CN older adults. Future AD research may incorporate the return of complex risk information to CN older adults, and materials are needed to communicate this information.
Author Keywords
Alzheimer’s disease dementia; biomarkers; cognitively normal older adults; genetics; health communication; imaging; pre-symptomatic; research ethics; return of research results; risk
Document Type: Article
Publication Stage: Final
Source: Scopus
“Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome” (2021) Journal of Alzheimer’s disease: JAD
Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome
(2021) Journal of Alzheimer’s disease: JAD, 79 (2), pp. 671-681.
Petersen, M.E.a , Rafii, M.S.b , Zhang, F.a , Hall, J.c , Julovich, D.c , Ances, B.M.d , Schupf, N.e f g h , Krinsky-McHale, S.J.i , Mapstone, M.j , Silverman, W.k , Lott, I.k , Klunk, W.l , Head, E.m , Christian, B.n , Foroud, T.o , Lai, F.p , Diana Rosas, H.q , Zaman, S.r s , Wang, M.-C.t , Tycko, B.u , Lee, J.H.e , Handen, B.l , Hartley, S.v , Fortea, J.w x , O’Bryant, S.c , Alzheimer’s Biomarker Consortium -Down Syndrome (ABC-DS)y
a University of North Texas Health Science Center, Department of Family Medicine and Institute for Translational Research, TX, Fort Worth, United States
b Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA
c University of North Texas Health Science Center, Institute for Translational Research and Department of Pharmacology and Neuroscience, TX, Fort Worth, United States
d Washington University School of Medicine in St. Louis, Center for Advanced Medicine Neuroscience, St. Louis, MO, USA
e Columbia University Irving Medical Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain/G.H. Sergievsky Center, NY, NY, United States
f Columbia University, Mailman School of Public Health, Department of Epidemiology, NY, NY, United States
g Columbia University Irving Medical Center, Department of Neurology, Neurological Institute, NY, NY, United States
h Columbia University Medical Center, Department of Psychiatry, NY, NY, United States
i NYS Institute for Basic Research in Developmental Disabilities, Department of Psychology, Staten Island, NY, United States
j University of California, Irvine, Department of Neurology, Irvine, CA, USA
k University of California, Irvine, School of Medicine, Department of Pediatrics, Orange, CA, USA
l University of Pittsburgh, Department of Psychiatry, Pittsburgh, United States
m University of California, Irvine, Department of Pathology, Irvine, CA, USA
n University of Wisconsin Madison, Department of Medical Physics and Psychiatry, WI, Madison, United States
o Indiana University School of Medicine, Department of Medical & Molecular Genetics, IN, Indianapolis, United States
p Massachusetts General Hospital, Department of Neurology, Harvard Medical School, MA, Charlestown, United States
q Massachusetts General Hospital, Departments of Neurology and Radiology, Harvard Medical School, MA, Charlestown, United States
r University of Cambridge, School of Clinical Medicine, Department of Psychiatry, Cambridge, United Kingdom
s Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, United Kingdom
t Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, United States
u Columbia University Irving Medical Center, Department of Pathology and Cell Biology, NY, NY, United States
v University of Wisconsin, School of Human Ecology and Waisman Center, WI, Madison, United States
w Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain
x Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Aut`onoma de Barcelona, Barcelona, Spain
Abstract
BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer’s Biomarker Consortium -Down Syndrome. RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.
Author Keywords
Neurofilament light chain; proteomics; sensitivity; specificity; total-tau; trisomy 21
Document Type: Article
Publication Stage: Final
Source: Scopus
“Pain, negative affective states and opioid-based analgesics: Safer pain therapies to dampen addiction” (2021) International Review of Neurobiology
Pain, negative affective states and opioid-based analgesics: Safer pain therapies to dampen addiction
(2021) International Review of Neurobiology, .
Massaly, N.a b c , Markovic, T.a b c , Creed, M.a b c d e f , Al-Hasani, R.a b c g h , Cahill, C.M.i j k , Moron, J.A.a b c d e
a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
b Washington University in St Louis, Pain Center, St. Louis, MO, United States
c Washington University in St Louis, School of Medicine, St. Louis, MO, United States
d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
g Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, United States
h Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, MO, United States
i Department of Psychiatry and Biobehavioural Sciences, University of California, Los Angeles, CA, United States
j Shirley and Stefan Hatos Center for Neuropharmacology, University of California Los Angeles, Los Angeles, CA, United States
k Jane & Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, United States
Abstract
Across centuries and civilizations opioids have been used to relieve pain. In our modern societies, opioid-based analgesics remain one of the most efficient treatments for acute pain. However, the long-term use of opioids can lead to the development of analgesic tolerance, opioid-induced hyperalgesia, opioid use disorders, and overdose, which can ultimately produce respiratory depressant effects with fatal consequences. In addition to the nociceptive sensory component of pain, negative affective states arising from persistent pain represent a risk factor for developing an opioid use disorder. Several studies have indicated that the increase in prescribed opioid analgesics since the 1990s represents the root of our current opioid epidemic. In this review, we will present our current knowledge on the endogenous opioid system within the pain neuroaxis and the plastic changes occurring in this system that may underlie the occurrence of pain-induced negative affect leading to misuse and abuse of opioid medications. Dissecting the allostatic neuronal changes occurring during pain is the most promising avenue to uncover novel targets for the development of safer pain medications. We will discuss this along with current and potential approaches to treat pain-induced negative affective states that lead to drug misuse. Moreover, this chapter will provide a discussion on potential avenues to reduce the abuse potential of new analgesic drugs and highlight a basis for future research and drug development based on recent advances in this field. © 2020 Elsevier Inc.
Author Keywords
Addiction; Analgesia; Negative affect; Opioid use disorders; Opioids; Pain
Document Type: Book Chapter
Publication Stage: Article in Press
Source: Scopus
“Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations” (2021) Journal of Alzheimer’s Disease
Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations
(2021) Journal of Alzheimer’s Disease, 79 (2), pp. 895-903.
Chatterjee, P.a b , Fagan, A.M.c d , Xiong, C.d e , McKay, M.f , Bhatnagar, A.f , Wu, Y.f , Singh, A.K.g , Taddei, K.b h , Martins, I.b , Gardener, S.L.b , Molloy, M.P.f i , Multhaup, G.j , Masters, C.L.k , Schofield, P.R.l m , Benzinger, T.L.S.d n , Morris, J.C.c d , Bateman, R.J.c d , Greenberg, S.M.o , Wermer, M.J.H.p , Van Buchem, M.A.p , Sohrabi, H.R.a b h q r , Martins, R.N.a b h r s
a Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia
b School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
c Department of Neurology, Washington University, St. Louis, MO, United States
d Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
e Division of Biostatistics, Washington University, St. Louis, MO, United States
f Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia
g Macquarie Business School, Macquarie University, North Ryde, NSW, Australia
h Australian Alzheimer’s Research Foundation, Nedlands, WA, Australia
i Bowel Cancer and Biomarker Laboratory, Kolling Institute, The University of Sydney, St Leonards, NSW, Australia
j Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
k The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VA, Australia
l Neuroscience Research Australia, Sydney, NSW, Australia
m School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
n Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
o Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA, United States
p Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
q Centre for Healthy Ageing, School of Psychology and Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA, Australia
r School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia
s The KaRa Institute of Neurological Diseases, Macquarie Park, NSW, Australia
Abstract
Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ϵ4 (p < 0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs =-0.527, p = 0.030). Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia. © 2021-IOS Press. All rights reserved.
Author Keywords
Blood biomarkers; cerebral amyloid angiopathy; early diagnosis; hereditary cerebral hemorrhage with amyloidosis-dutch type; intracerebral hemorrhage; metabolomics; vascular dementia
Document Type: Article
Publication Stage: Final
Source: Scopus
“Attempted recall of biographical information influences face attractiveness” (2021) Psychonomic Bulletin and Review
“TERT promoter mutation analysis for blood-based diagnosis and monitoring of gliomas” (2021) Clinical Cancer Research
TERT promoter mutation analysis for blood-based diagnosis and monitoring of gliomas
(2021) Clinical Cancer Research, 27 (1), pp. 169-178.
Muralidharan, K.a , Yekula, A.a , Small, J.L.a , Rosh, Z.S.a , Kang, K.M.a b , Wang, L.a , Lau, S.a , Zhang, H.c , Lee, H.d , Bettegowda, C.e , Chicoine, M.R.f , Kalkanis, S.N.g , Shankar, G.M.a , Nahed, B.V.a , Curry, W.T.a , Jones, P.S.a , Cahill, D.P.a , Balaj, L.a , Carter, B.S.a
a Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
b School of Medicine, University of California, San Diego, San diego, CA, United States
c Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
d Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
e Department of Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, MD, United States
f Department of Neurosurgery, Washington University Medicine in St. Louis, St. Louis, MO, United States
g Department of Neurosurgery, Henry Ford Health System, Detroit, MI, United States
Abstract
Purpose: Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors). Experimental Design: Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of patients with glioma. Results: In baseline performance in tumor tissue, the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples [95% confidence interval (CI), 94%–100%]. Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI, 52%–73%) and a specificity of 90% (95% CI, 80%–96%) compared with the gold-standard tumor tissue–based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT-mutant allele frequency reflects the clinical course of the disease, with levels decreasing after surgical intervention and therapy and increasing with tumor progression. Conclusions: Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in patients with glioma with clinically relevant sensitivity and specificity. © 2020 American Association for Cancer Research.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants” (2021) Molecular Psychiatry
Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants
(2021) Molecular Psychiatry, .
Saarentaus, E.C.a , Havulinna, A.S.a b , Mars, N.a , Ahola-Olli, A.a c d , Kiiskinen, T.T.J.a , Partanen, J.a , Ruotsalainen, S.a , Kurki, M.a c d , Urpa, L.M.a , Chen, L.e f , Perola, M.b , Salomaa, V.b , Veijola, J.g , Männikkö, M.h , Hall, I.M.e f , Pietiläinen, O.c i j , Kaprio, J.a k , Ripatti, S.a c d k , Daly, M.a c d , Palotie, A.a c l
a Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
b Finnish Institute for Health and Welfare, Helsinki, Finland
c Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States
d Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States
e Department of Genetics, Yale School of Medicine, New Haven, CT, United States
f McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
g Research Unit of Clinical Neuroscience, University of Oulu & Oulu University Hospital, Oulu, Finland
h Northern Finland Birth Cohorts, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
i Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
j Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
k Department of Public Health, University of Helsinki, Helsinki, Finland
l Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
Abstract
Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation. © 2021, The Author(s).
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal)” (2021) Progress in Brain Research
Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal)
(2021) Progress in Brain Research, .
De Ridder, D.a , Schlee, W.b , Vanneste, S.c , Londero, A.d , Weisz, N.e , Kleinjung, T.f , Shekhawat, G.S.g h i , Elgoyhen, A.B.j , Song, J.-J.k , Andersson, G.l m , de Azevedo, A.A.n , Baguley, D.M.o p , Biesinger, E.q , Binetti, A.C.r , Del Bo, L.s , Cederroth, C.R.p t u , Cima, R.v w x , Eggermont, J.J.y , Figueiredo, R.z aa , Fuller, T.E.v ab , Gallus, S.ac , Gilles, A.ad ae , Hall, D.A.af ag ah ai , Van de Heyning, P.aj , Hoare, D.J.ak , Khedr, E.M.al , Kikidis, D.am , Kleinstaeuber, M.an , Kreuzer, P.M.b , Lai, J.-T.ao , Lainez, J.M.ap , Landgrebe, M.aq , Li, L.P.-H.ar , Lim, H.H.as , Liu, T.-C.at , Lopez-Escamez, J.A.au av aw , Mazurek, B.ax , Moller, A.R.ay , Neff, P.az , Pantev, C.ba , Park, S.N.bb , Piccirillo, J.F.bc , Poeppl, T.B.bd , Rauschecker, J.P.be bf , Salvi, R.bg , Sanchez, T.G.bh bi , Schecklmann, M.b , Schiller, A.b , Searchfield, G.D.bj bk bl , Tyler, R.bm , Vielsmeier, V.bn , Vlaeyen, J.W.S.w bo , Zhang, J.bp , Zheng, Y.bq , de Nora, M.i , Langguth, B.b , Adhia, D.a
a Department of Surgery, Section of Neurosurgery, University of Otago, Dunedin, New Zealand
b Department of Psychiatry and Psychotherapy, Bezirksklinikum, University of Regensburg, Regensburg, Germany
c Lab for Integrative and Clinical Neuroscience, Global Brain Health Institute & Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland
d Service ORL CCF, Hôpital Européen Georges Pompidou, Paris, France
e Centre for Cognitive Neuroscience, University of Salzburg, Salzburg, Austria
f Department of Otorhinolaryngology—Head and Neck Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
g College of Nursing & Health Sciences, Flinders University, Adelaide, SA, Australia
h Ear Institute, UCL, London, United Kingdom
i Tinnitus Research Initiative Foundation (TRI), Regensburg, Germany
j Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres” (INGEBI), Buenos Aires, Argentina
k Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
l Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden
m Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
n OTOSUL, otorrinolaringologia Sul Fluminense, Volta Redonda, Brazil
o Otology and Hearing Group, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
p NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, United Kingdom
q Otolaryngological Practice, Lindenberg, Germany
r Buenos Aires, Buenos Aires British Hospital, Argentina
s Del Bo Tecnologia per l’ascolto srl, Milan, Italy
t Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
u Laboratory of Experimental Audiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
v Department of Clinical Psychological Science, Maastricht University, Maastricht, Netherlands
w Department of Health Psychology, KU Leuven, Leuven, Belgium
x Adelante, Centre of Expertise in Rehabilitation and Audiology, Hoensbroek, Netherlands
y Department of Psychology, University of Calgary, Calgary, AB, Canada
z Centro Universitário de Valença, Faculdade de Medicina, Valença, Brazil
aa OTOSUL, Clinical and Research Tinnitus Center, Volta Redonda, Brazil
ab Spine and Biologics, Medtronic, Maastricht, Netherlands
ac Laboratory of Lifestyle Epidemiology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
ad Department of otorhinolaryngology and Head & Neck Surgery, Antwerp University Hospital, Edegem, Belgium
ae Faculty of Medicine, Antwerp University, Wilrijk, Belgium
af Hearing Sciences, Division of Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
ag National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham, United Kingdom
ah Nottingham University Hospitals NHS Trust, Queens Medical Centre, Nottingham, United Kingdom
ai University of Nottingham Malaysia, Semenyih, Malaysia
aj Univ Dept of Otorhinolaryngology and head and neck surgery, Antwerp University Hospital, Department of Translational Neurosciences, University of Antwerp, Antwerpen, Belgium
ak NIHR Nottingham Biomedical Research Centre, Hearing Sciences, Division of Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom
al Department of Neurology, Assiut University Hospital, Assiut, Egypt
am 1st Department of Otolaryngology—Head and Neck Surgery, National and Kapodistrian University of Athens, Athens, Greece
an Department of Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
ao Department of Otolaryngology, Kuang-Tien General Hospital, Taichung, Taiwan
ap Department of Neurology, University Clinic Hospital, Catholic University of Valencia, Valencia, Spain
aq kbo-Lech-Mangfall-Kliniken Agatharied, Hausham, Germany
ar Department of Otolaryngology, Cheng Hsin General Hospital, Taipei, Taiwan
as Department of Otolaryngology, Head and Neck Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, United States
at Department of Otolaryngology, National Taiwan University, Taipei, Taiwan
au Center for Genomics and Oncology Research (GENYO), Granada, Spain
av Department of Otolaryngology, Hospital Universitario Virgen de las Nieves, Instituto de Investigacion Biosanitario (ibs.GRANADA), Granada, Spain
aw Department of Surgery, Division of Otolaryngology, Univerdad de Granada, Granada, Spain
ax Tinnitus Center, Charité Universitätsmedizin Berlin, Berlin, Germany
ay School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, TX, United States
az URPP “Dynamics of Healthy Ageing”, University of Zurich, Zurich, Switzerland
ba Institute for Biomagnetism and Analysis of Biosignals, University of Muenster, Muenster, Germany
bb Department of Otorhinolaryngology—Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
bc Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
bd Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
be Department of Neuroscience, Georgetown University, Washington, DC, United States
bf Hans Fischer Senior Fellow and TUM Ambassador, Institute for Advanced Study and Klinikum Rechts der Isar, TUM, Munich, Germany
bg SUNY Distinguished Professor, Center for Hearing and Deafness, 137 Cary Hall, University at Buffalo, Buffalo, NY, United States
bh Department Otolaryngology, University of São Paulo School of Medicine, São Paulo, Brazil
bi Institute Ganz Sanchez, São Paulo, Brazil
bj Section of Audiology, The University of Auckland, Auckland, New Zealand
bk Eisdell Moore Centre, The University of Auckland, Auckland, New Zealand
bl Centre for Brain Research, The University of Auckland, Auckland, New Zealand
bm Department of Communication Sciences and Disorders, Department of Otolaryngology—Head and Neck Surgery, Iowa City, IA, United States
bn Department of Otolaryngology, University of Regensburg, Regensburg, Germany
bo Department of Experimental Health Psychology, Maastricht University, Maastricht, Netherlands
bp Department of Communication Sciences & Disorders, Department of Otolaryngology, Wayne State University, Detroit, MI, United States
bq Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
Abstract
As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO’s ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association’s DSM-V doesn’t mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: “Tinnitus” for the former and “Tinnitus Disorder” for the latter. The proposed definition then becomes “Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder “when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.”. In other words “Tinnitus” describes the auditory or sensory component, whereas “Tinnitus Disorder” reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder. © 2021 Elsevier B.V.
Author Keywords
Affective; Definition; Operational; Pain; Phantom; Sound; Theoretical; Tinnitus
Document Type: Book Chapter
Publication Stage: Article in Press
Source: Scopus
“A Chemomechanical Model for Regulation of Contractility in the Embryonic Brain Tube” (2021) Journal of Elasticity
A Chemomechanical Model for Regulation of Contractility in the Embryonic Brain Tube
(2021) Journal of Elasticity, .
Oltean, A., Taber, L.A.
Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
Abstract
Morphogenesis is regulated by genetic, biochemical, and biomechanical factors, but the feedback controlling the interactions between these factors remains poorly understood. A previous study has found that compressing the brain tube of the early chick embryo induces changes in contractility and nuclear shape in the neuroepithelial wall. Assuming this response involves mechanical feedback, we used experiments and computational modeling to investigate a hypothetical mechanism behind the observed behavior. First, we measured nuclear circularity in embryonic chick brains subjected to transverse compression. Immediately after loading, the circularity varied regionally and appeared to reflect the local state of stress in the wall. After three hours of culture with sustained compression, however, the nuclei became rounder. Exposure to a gap junction blocker inhibited this response, suggesting that it requires intercellular diffusion of a biochemical signal. We speculate that the signal regulates the contraction that occurs near the lumen, altering stress distributions and nuclear geometry throughout the wall. Simulating compression using a chemomechanical finite-element model based on this idea shows that our hypothesis is consistent with most of the experimental data. This work provides a foundation for future investigations of chemomechanical feedback in epithelia during embryonic development. © 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.
Author Keywords
Chick embryo; Epithelia; Gap junctions; Mechanical feedback; Morphogenesis; Nucleus
Funding details
National Institutes of HealthNIH
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus