“Using polygenic scores for identifying individuals at increased risk of substance use disorders in clinical and population samples” (2020) Translational Psychiatry
Using polygenic scores for identifying individuals at increased risk of substance use disorders in clinical and population samples
(2020) Translational Psychiatry, 10 (1), art. no. 196, .
Barr, P.B.a , Ksinan, A.b , Su, J.c , Johnson, E.C.d , Meyers, J.L.e , Wetherill, L.f , Latvala, A.g h , Aliev, F.a i , Chan, G.j , Kuperman, S.k , Nurnberger, J.f l m , Kamarajan, C.e , Anokhin, A.d , Agrawal, A.d , Rose, R.J.n , Edenberg, H.J.f o , Schuckit, M.p , Kaprio, J.g q , Dick, D.M.a r
a Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
b Department of Health Behavior and Policy, Virginia Commonwealth University, Richmond, VA, United States
c Department of Psychology, Arizona State University, Tempe, AZ, United States
d Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO, United States
e Department of Psychiatry & Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, United States
f Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, United States
g Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
h Institute of Criminology and Legal Policy, University of Helsinki, Helsinki, Finland
i Faculty of Business, Karabük University, Karabük, Turkey
j Department of Psychiatry, School of Medicine, University of Connecticut, Farmington, CT, United States
k Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
l Department of Psychiatry, School of Medicine, Indiana University, Indianapolis, IN, United States
m Stark Neurosciences Research Institute, School of Medicine, Indiana University, Indianapolis, IN, United States
n Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
o Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN, United States
p Department of Psychiatry, School of Medicine, University of California, San Diego, San Diego, CA, United States
q Department of Public Health, University of Helsinki, Helsinki, Finland
r Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
Abstract
Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a population-based sample [the FinnTwin12 (FT12) study] and a high-risk sample [the Collaborative Study on the Genetics of Alcoholism (COGA)], we examined the association between PRSs derived from genome-wide association studies (GWASs) of (1) alcohol dependence/alcohol problems, (2) alcohol consumption, and (3) risky behaviors with AUD and other substance use disorder (SUD) criteria. These PRSs explain ~2.5–3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. Calculations of area under the curve (AUC) show PRS provide only a slight improvement over a model with age, sex, and ancestral principal components as covariates. While individuals in the top 20, 10, and 5% of the PRS distribution had greater odds of having an AUD compared to the lower end of the continuum in both COGA and FT12, the point estimates at each threshold were statistically indistinguishable. Those in the top 5% reported greater levels of licit (alcohol and nicotine) and illicit (cannabis and opioid) SUD criteria. PRSs are associated with risk for SUD in independent samples. However, usefulness for identifying those at increased risk in their current form is modest, at best. Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples. © 2020, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Clinical trials in REM sleep behavioural disorder: Challenges and opportunities” (2020) Journal of Neurology, Neurosurgery and Psychiatry
Clinical trials in REM sleep behavioural disorder: Challenges and opportunities
(2020) Journal of Neurology, Neurosurgery and Psychiatry, 91 (7), pp. 740-749.
Videnovic, A.a , Ju, Y.-E.S.b , Arnulf, I.c , Arnulf, I.d , Cochen-De Cock, V.e , Cochen-De Cock, V.f , Högl, B.g , Kunz, D.h , Provini, F.i , Provini, F.j , Ratti, P.-L.k , Schiess, M.C.l , Schenck, C.H.m , Schenck, C.H.n , Trenkwalder, C.o , Trenkwalder, C.p
a Department of Neurology, Massachusetts General Hospital, Boston, MA 02114-2696, United States
b Department of Neurology, Washington University in Saint Louis, Saint Louis, MO, United States
c Assistance Publique Hôpitaux de Paris, Service des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Paris, France
d UMR S 1127, CNRS UMR 7225, ICM, Sorbonne Universités, UPMC University Paris, Paris, France
e Neurologie et Sommeil, Clinique Beau Soleil, Montpellier, France
f Laboratoire Movement to Health (M2H), EuroMov, Université Montpellier, Montpellier, France
g Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
h Clinic for Sleep and Chronomedicine, Berlin, Germany
i IRCCS Institute of Neurological Sciences of Bologna, University of Bologna, Bologna, Italy
j Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
k Neurocenter of Southern Switzerland, Lugano, Switzerland
l Department of Neurology, University of Texas Medical School at Houston, Houston, TX, United States
m Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
n Minnesota Regional Sleep Disorders Center, Minneapolis, MN, United States
o Paracelsus Elena Klinik, Kassel, Germany
p Department of Neurosurgery, University Medical Center, Göttingen, Germany
Abstract
The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
Lewy body dementia; Parkinson’s disease; randomised trials; sleep disorders
Document Type: Review
Publication Stage: Final
Source: Scopus
“The CINRG Becker Natural History Study: Baseline Characteristics” (2020) Muscle & Nerve
The CINRG Becker Natural History Study: Baseline Characteristics
(2020) Muscle & Nerve, .
Clemens, P.R.a , Niizawa, G.b , Feng, J.c , Florence, J.d , D’Alessandro, A.S.b , Morgenroth, L.P.e , Gorni, K.f , Guglieri, M.g , Connolly, A.d , Wicklund, M.h , Bertorini, T.i , Mah, J.K.j , Thangarajh, M.c , Smith, E.k , Kuntz, N.l , McDonald, C.M.m , Henricson, E.K.m , Upadhyayula, S.n , Byrne, B.o , Manousakis, G.p , Harper, A.q , Bravver, E.q , Iannaccone, S.r , Spurney, C.c , Cnaan, A.c , Gordish-Dressman, H.c , CINRG BNHS Investigatorss
a University of Pittsburgh School of Medicine and Department of Veterans Affairs Medical Center, Pittsburgh, United States
b University of Pittsburgh School of Medicine, Pittsburgh, United States
c Children’s National Medical Center, DCWA
d Washington University, St. Louis, MO
e Pittsburgh, United States
f Centro Clinico Nemo Hospital, Milan, Italy
g Newcastle University, Newcastle, United Kingdom
h Hershey Medical Center, Hershey, United States
i University of Tennessee, TN, Memphis, United States
j Alberta Children’s Hospital, Calgary, AB, Canada
k Duke University Medical Center, Durham
l Lurie Children’s Hospital, Chicago, Mexico
m University of California, Davis, Sacramento, CA
n Children’s Healthcare of Atlanta, Atlanta, United States
o University of Florida, FL, Gainesville, United States
p University of Minnesota, MN, Minneapolis, United States
q Carolinas Medical CenterCharlotte, Saint Vincent and the Grenadines
r University of Texas Southwestern Medical Center, TX, Dallas, United States
Abstract
INTRODUCTION: We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). METHODS: A prospective natural history study collected longitudinal medical, strength and timed function assessments. RESULTS: Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6 to 75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. DISCUSSION: A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Author Keywords
Becker muscular dystrophy; clinical features; dystrophinopathy; musculoskeletal
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Image-Forming Visual Basis of Empathy for Pain in Mice” (2020) Neuroscience Bulletin
Image-Forming Visual Basis of Empathy for Pain in Mice
(2020) Neuroscience Bulletin, .
Geng, K.-W.a b d e , Du, R.a b , Wei, N.a b , Li, C.-L.a b , Wang, Y.a b , Sun, W.a b , Chen, T.c , Wei, D.-Y.c , Yu, Y.a b , He, T.a b , Luo, W.-J.a b , Wang, R.-R.a b , Chen, Z.-F.d e f g , Chen, J.a b
a Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, China
b Key Laboratory of Brain Stress and Behavior, People’s Liberation Army, Xi’an, 710038, China
c Center of Clinical Aerospace Medicine, The Fourth Military Medical University, Xi’an, 710032, China
d Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
Document Type: Letter
Publication Stage: Article in Press
Source: Scopus
“Surgical resource utilization after initial treatment of infant hydrocephalus: comparing ETV, early experience of ETV with choroid plexus cauterization, and shunt insertion in the Hydrocephalus Clinical Research Network” (2020) Journal of Neurosurgery. Pediatrics
Surgical resource utilization after initial treatment of infant hydrocephalus: comparing ETV, early experience of ETV with choroid plexus cauterization, and shunt insertion in the Hydrocephalus Clinical Research Network
(2020) Journal of Neurosurgery. Pediatrics, pp. 1-9.
Pindrik, J.a , Riva-Cambrin, J.b , Kulkarni, A.V.c , Alvey, J.S.d , Reeder, R.W.d , Pollack, I.F.e , Wellons, J.C.f , Jackson, E.M.g , Rozzelle, C.J.h , Whitehead, W.E.i , Limbrick, D.D.j , Naftel, R.P.f , Shannon, C.f , McDonald, P.J.k , Tamber, M.S.k , Hankinson, T.C.l , Hauptman, J.S.m , Simon, T.D.m , Krieger, M.D.n , Holubkov, R.o , Kestle, J.R.W.d , Hydrocephalus Clinical Research Networkp
a 1Division of Pediatric Neurosurgery, Department of Neurological Surgery, Ohio State University College of Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
b 2Section of Pediatric Neurosurgery, Division of Neurosurgery, Alberta Children’s Hospital, University of CalgaryAB, Canada
c 3Division of Neurosurgery, Hospital for Sick Children, University of TorontoON, Canada
d Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
e Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
f 6Division of Pediatric Neurosurgery, Department of Neurosurgery, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, United States
g Department of Neurosurgery, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
h 8Division of Pediatric Neurosurgery, Department of Neurosurgery, Children’s of Alabama, University of Alabama School of Medicine, Birmingham, AL
i Department of Neurosurgery, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
j 10Division of Pediatric Neurosurgery, Departments of Neurological Surgery and Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine in St. LouisMO
k 11Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
l 12Departments of Neurosurgery and Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
m 13Division of Pediatric Neurosurgery, Department of Neurosurgery, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
n 14Department of Surgery, Children’s Hospital of Los Angeles, California; and
o 15Hydrocephalus Clinical Research Network Data Coordinating Center, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
Abstract
OBJECTIVE: Few studies have addressed surgical resource utilization-surgical revisions and associated hospital admission days-following shunt insertion or endoscopic third ventriculostomy (ETV) with or without choroid plexus cauterization (CPC) for CSF diversion in hydrocephalus. Study members of the Hydrocephalus Clinical Research Network (HCRN) investigated differences in surgical resource utilization between CSF diversion strategies in hydrocephalus in infants. METHODS: Patients up to corrected age 24 months undergoing initial definitive treatment of hydrocephalus were reviewed from the prospectively maintained HCRN Core Data Project (Hydrocephalus Registry). Postoperative courses (at 1, 3, and 5 years) were studied for hydrocephalus-related surgeries (primary outcome) and hospital admission days related to surgical revision (secondary outcome). Data were summarized using descriptive statistics and compared using negative binomial regression, controlling for age, hydrocephalus etiology, and HCRN center. The study population was organized into 3 groups (ETV alone, ETV with CPC, and CSF shunt insertion) during the 1st postoperative year and 2 groups (ETV alone and CSF shunt insertion) during subsequent years due to limited long-term follow-up data. RESULTS: Among 1090 patients, the majority underwent CSF shunt insertion (CSF shunt, 83.5%; ETV with CPC, 10.0%; and ETV alone, 6.5%). Patients undergoing ETV with CPC had a higher mean number of revision surgeries (1.2 ± 1.6) than those undergoing ETV alone (0.6 ± 0.8) or CSF shunt insertion (0.7 ± 1.3) over the 1st year after surgery (p = 0.005). At long-term follow-up, patients undergoing ETV alone experienced a nonsignificant lower mean number of revision surgeries (0.7 ± 0.9 at 3 years and 0.8 ± 1.3 at 5 years) than those undergoing CSF shunt insertion (1.1 ± 1.9 at 3 years and 1.4 ± 2.6 at 5 years) and exhibited a lower mean number of hospital admission days related to revision surgery (3.8 ± 10.3 vs 9.9 ± 27.0, p = 0.042). CONCLUSIONS: Among initial treatment strategies for hydrocephalus, ETV with CPC yielded a higher surgical revision rate within 1 year after surgery. Patients undergoing ETV alone exhibited a nonsignificant lower mean number of surgical revisions than CSF shunt insertion at 3 and 5 years postoperatively. Additionally, the ETV-alone cohort demonstrated significantly fewer hospital admission days related to surgical management of hydrocephalus within 3 years after surgery. These findings suggest a time-dependent benefit of ETV over CSF shunt insertion regarding surgical resource utilization.
Author Keywords
AS = aqueductal stenosis; cerebrospinal fluid; choroid plexus cauterization; CPC = choroid plexus cauterization; endoscopic third ventriculostomy; ETV = endoscopic third ventriculostomy; HCRN; HCRN = Hydrocephalus Clinical Research Network; Hydrocephalus Clinical Research Network; IIHS = International Infant Hydrocephalus Study; IVH = intraventricular hemorrhage; resource utilization; shunt
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer’s Disease” (2020) The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer’s Disease
(2020) The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 75 (7), pp. 1232-1241. Cited 1 time.
Seo, D.-O., Holtzman, D.M.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
More than 300 years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed “animalcules,” examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high-throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer’s disease (AD) is the most common cause of dementia characterized by a progressive decline in memory and thinking severe enough to interfere with daily life. Despite the great progress in linking genetic risk factors with AD pathogenesis, treatments targeted at AD pathology and its modifiers have not yet resulted in a disease-modifying therapy. There is mounting evidence that the gut microbiota interacts with AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis-the gut microbiota has gone from being the forgotten organ to a potential key player in the AD pathology. © The Gerontological Society of America 2019.
Author Keywords
Amyloid; Bacteria; Microbiome; Neurodegeneration; Tau
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial” (2020) Neurology
Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial
(2020) Neurology, .
Salter, A.a , Kowalec, K.b c , Fitzgerald, K.d , Cutter, G.e , Marrie, R.A.f
a Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, USA
b College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, CAN
c Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Sweden
d Department of Neurology, Johns Hopkins School of Medicine, MD, Baltimore, United States
e Department of Biostatistics, University of Alabama in Birmingham School of Public Health, Birmingham, AL, USA
f Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, CAN
Abstract
OBJECTIVE: To determine whether comorbidity is associated with clinical (relapses, disability worsening) and MRI outcomes in multiple sclerosis (MS), we conducted a secondary analysis of the CombiRx clinical trial. METHODS: CombiRx compared interferon-beta-1a, glatiramer acetate and the combination of these agents. For participants eligible for evaluation of 6-month confirmed disability worsening, we used medical history, concomitant medications and adverse events to ascertain comorbidity status. Comorbidities evaluated included hypertension, dyslipidemia, diabetes, depression, anxiety disorders, and migraine. Clinical outcomes included disease activity consisting of protocol-defined relapses, disability worsening and MRI activity. We summarized the prevalence of these comorbidities and their association with disease activity and its components using multivariable Cox regression. RESULTS: Of the 1008 participants randomized, 959 (95.1%) were eligible for assessment of 6-month disability worsening; for this subgroup the median length of follow-up was 3.4 years (range 0.5-6.9 years). Overall, 55.1% of participants had ≥1 comorbidity at enrollment. After adjustment, anxiety (hazard ratio [HR]: 1.25; 95%CI: 1.01-1.55), and dyslipidemia (HR 1.32; 95%CI: 1.01-1.72) were associated with an increased hazard of any disease activity, while migraine (HR 0.80; 95%CI: 0.67-0.96) was associated with a decreased hazard. CONCLUSIONS: In this large trial population with rigorously obtained outcomes, comorbidities were common among participants and influenced disease outcomes, including relapses. The comorbidity burden of clinical trial participants with MS may be an important factor in the outcome of clinical trials. Additional investigations of the impact of comorbidity on clinical trial outcomes, and response to disease-modifying therapies is warranted. © 2020 American Academy of Neurology.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner” (2020) Journal of Neuroinflammation
25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
(2020) Journal of Neuroinflammation, 17 (1), p. 192.
Wong, M.Y.a , Lewis, M.b , Doherty, J.J.b , Shi, Y.c , Cashikar, A.G.d , Amelianchik, A.a , Tymchuk, S.a , Sullivan, P.M.e , Qian, M.f , Covey, D.F.f , Petsko, G.A.a , Holtzman, D.M.c , Paul, S.M.b d , Luo, W.g
a Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, NY, NY, United States
b Sage Therapeutics, Cambridge, MA, United States
c Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
d Departments of Neurology and Psychiatry, Hope Center for Neurological Disorders, Taylor Family Institute, Washington University School of Medicine, St. Louis, MO, USA
e Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center’s Geriatric Research, Education and Clinical Center, Durham, United States
f Departments of Developmental Biology, Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
g Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, NY, NY, United States
Abstract
BACKGROUND: Genome-wide association studies of Alzheimer’s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. METHODS: We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. RESULTS: We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. CONCLUSION: 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.
Author Keywords
25-Hydroxycholesterol; Alzheimer’s disease; Apolipoprotein E; Cholesterol 25-hydroxylase; Inflammasome; Inflammation; Interleukin-1β; Lipid metabolism; Lipopolysaccharide; Microglia; Oxysterol
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Organ of Corti size is governed by yap/tead-mediated progenitor self-renewal” (2020) Proceedings of the National Academy of Sciences of the United States of America
Organ of Corti size is governed by yap/tead-mediated progenitor self-renewal
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (24), pp. 13552-13561.
Gnedeva, K.a b , Wang, X.a b , McGovern, M.M.c , Barton, M.d , Tao, L.a b , Trecek, T.a b , Monroe, T.O.e f , Llamas, J.a b , Makmura, W.a b , Martin, J.F.f g h , Groves, A.K.c g i , Warchol, M.d , Segil, N.a b
a Department of Stem Cell Biology and Regenerative Medicine, Keck Medicine of University of Southern California, Los Angeles, CA 90033, United States
b Caruso Department of Otolaryngology-Head and Neck Surgery, Keck Medicine of University of Southern California, Los Angeles, CA 90033, United States
c Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
d Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO 63130, United States
e Advanced Center for Translational and Genetic Medicine, Lurie Children’s Hospital of Chicago, Chicago, IL 60611, United States
f Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, United States
g Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, United States
h Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, TX 77030, United States
i Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
Abstract
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2- positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration. © 2020 National Academy of Sciences. All rights reserved.
Author Keywords
Hippo signaling pathway; Inner ear; Organ of corti; Taz; Yap
Document Type: Article
Publication Stage: Final
Source: Scopus
“The Curing Coma Campaign: Framing Initial Scientific Challenges—Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting” (2020) Neurocritical Care
The Curing Coma Campaign: Framing Initial Scientific Challenges—Proceedings of the First Curing Coma Campaign Scientific Advisory Council Meeting
(2020) Neurocritical Care, .
Provencio, J.J.a , Hemphill, J.C.b , Claassen, J.c , Edlow, B.L.d , Helbok, R.e , Vespa, P.M.f , Diringer, M.N.g , Polizzotto, L.h , Shutter, L.i , Suarez, J.I.j , Stevens, R.D.j , Hanley, D.F.k , Akbari, Y.l , Bleck, T.P.m , Boly, M.n , Foreman, B.o , Giacino, J.T.p , Hartings, J.A.q , Human, T.r , Kondziella, D.s , Ling, G.S.F.t , Mayer, S.A.u , McNett, M.v , Menon, D.K.w , Meyfroidt, G.x , Monti, M.M.y , Park, S.c , Pouratian, N.z , Puybasset, L.aa , Rohaut, B.ab , Rosenthal, E.S.d , Schiff, N.D.ac , Sharshar, T.ad ae , Wagner, A.af , Whyte, J.ag , Olson, D.W.M.ah , on behalf of the Neurocritical Care Society Curing Coma Campaignai
a Department of Neurology and Neuroscience, University of Virginia, Charlottesville, VA, United States
b Department of Neurology, Zuckerberg San Francisco General Hospital, University of California, San Francisco, Building 1, Room 101, 1001 Potrero Avenue, San Francisco, CA 94110, United States
c Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY, United States
d Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
e Department of Neurology, Neurocritical Care, Medical University of Innsbruck, Innsbruck, Austria
f Departments of Neurology and Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
g Department of Neurology, Washington University, Barnes-Jewish Hospital, St Louis, MO, United States
h Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, United States
i Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh/UPMC Health System, Pittsburgh, PA, United States
j Departments of Anesthesiology and Critical Care Medicine, Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
k Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD, United States
l Departments of Neurology, Neurosurgery and the Beckman Laser Institute, University of California-Irvine, Irvine, CA, United States
m Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
n Department of Neurology, University of Wisconsin-Madison, Madison, WI, United States
o Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, University of Cincinnati College of Medicine, Cincinnati, OH, United States
p Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States
q Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, United States
r Departments of Neurology and Neurosurgery, Washington University, Barnes-Jewish Hospital, St Louis, MO, United States
s Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
t Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
u Departments of Neurology and Neurosurgery, New York Medical College, Valhalla, NY, United States
v College of Nursing, The Ohio State University, Columbus, OH, United States
w Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
x Department and Laboratory of Intensive Care Medicine, University Hospitals Leuven and KU Leuven, Leuven, Belgium
y Department of Psychology, University of California, Los Angeles, CA, United States
z Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
aa Department of Anesthesiology and Critical Care, Sorbonne University, GRC 29, AP-HP, DMU DREAM, Pitié-Salpêtrière Hospital, Paris, 75013, France
ab Department of Neurology, Neuro-ICU, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France
ac Departments of Neurology, Neuroscience, and Medical Ethics, Weill Cornell Medicine, New York, NY, United States
ad Neuro-anesthesiology and Intensive Care Medicine, Sainte-Anne Hospital, Paris-Descartes University, Paris, France
ae Experimental Neuropathology, Infection and Epidemiology Department, Institut Pasteur, Paris, France
af Department of Physical Medicine and Rehabilitation, Department of Neuroscience, Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, United States
ag Moss Rehabilitation Research Institute, Elkins Park, PA, United States
ah Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, United States
Abstract
Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the “grand challenge” of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the “curing coma community” to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients. © 2020, The Author(s).
Author Keywords
Biomarker; Coma; Consciousness; Endotype; Recovery
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Assessing Stakeholder Perceptions of the Utility of Genetic Information for the Clinical Care of Mental Health Disorders: We Have a Will but Need to See the Way” (2020) Administration and Policy in Mental Health and Mental Health Services Research
Assessing Stakeholder Perceptions of the Utility of Genetic Information for the Clinical Care of Mental Health Disorders: We Have a Will but Need to See the Way
(2020) Administration and Policy in Mental Health and Mental Health Services Research, .
Bourdon, J.L.a , Hettema, J.M.b c , Prom-Wormley, E.C.d , Southam-Gerow, M.A.e
a Brown School of Social Work and Department of Psychiatry, Washington University in ST. Louis, 4560 Clayton Avenue, St. Louis, MO 63110, United States
b Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, 800 E. Leigh Street, Biotech One, Richmond, VA 23298, United States
c Department of Psychiatry, Texas A&M College of Medicine, 8447 Riverside Parkway, Bryan, TX 77807, United States
d Division of Epidemiology, Department of Family Medicine and Population Health, Virginia Commonwealth University, 830 E. Main Street, Richmond, VA 23298, United States
e Department of Psychology, Virginia Commonwealth University, 806 West Franklin Street, Richmond, VA 23284, United States
Abstract
Academic stakeholders’ (primarily mental health researchers and clinicians) practices and attitudes related to the translation of genetic information into mental health care were assessed. A three-part survey was administered at two large, urban universities. Response frequencies were calculated. Participants (N = 64) reported moderate levels of translational practice, adequate levels of genetic knowledge, and variable levels of genetic competence. They held positive attitudes toward translating genetic information about mental health broadly but negative attitudes about the impact that such information would have on specific aspects of care. The current study lays the groundwork for further inquiry into translating genetic information to mental health care. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Genetics; Mental health; Practice; Translational science
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types” (2020) Nature Neuroscience
Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types
(2020) Nature Neuroscience, .
Laszlovszky, T.a b , Schlingloff, D.b c , Hegedüs, P.a b , Freund, T.F.c , Gulyás, A.c , Kepecs, A.d e , Hangya, B.a
a Lendület Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary
b János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary
c Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Budapest, Hungary
d Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
e Departments of Neuroscience and Psychiatry, Washington University in St Louis, St Louis, MO, United States
Abstract
Basal forebrain cholinergic neurons (BFCNs) modulate synaptic plasticity, cortical processing, brain states and oscillations. However, whether distinct types of BFCNs support different functions remains unclear. Therefore, we recorded BFCNs in vivo, to examine their behavioral functions, and in vitro, to study their intrinsic properties. We identified two distinct types of BFCNs that differ in their firing modes, synchronization properties and behavioral correlates. Bursting cholinergic neurons (Burst-BFCNs) fired synchronously, phase-locked to cortical theta activity and fired precisely timed bursts after reward and punishment. Regular-firing cholinergic neurons (Reg-BFCNs) were found predominantly in the posterior basal forebrain, displayed strong theta rhythmicity and responded with precise single spikes after behavioral outcomes. In an auditory detection task, synchronization of Burst-BFCNs to the auditory cortex predicted the timing of behavioral responses, whereas tone-evoked cortical coupling of Reg-BFCNs predicted correct detections. We propose that differential recruitment of two basal forebrain cholinergic neuron types generates behavior-specific cortical activation. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Standards for Socially-and Achievement-Oriented Roles in Major Depressive Disorder and Generalized Anxiety Disorder” (2020) Cognitive Therapy and Research
Standards for Socially-and Achievement-Oriented Roles in Major Depressive Disorder and Generalized Anxiety Disorder
(2020) Cognitive Therapy and Research, .
Thompson, R.J.a , Borenstein, J.B.a , Kircanski, K.b , Gotlib, I.H.c
a Department of Psychological and Brain Sciences, Washington University in St. Louis, 1 Brookings Dr., Campus, Box 1125, St. Louis, MO 63130, United States
b Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, United States
c Department of Psychology, Stanford University, Stanford, CA, United States
Abstract
Background: People with major depressive disorder (MDD) and generalized anxiety disorder (GAD) have elevated trait perfectionism. We tested whether they hold perfectionistic standards for specific life roles and examined the extent to which they met their own expectations for, gained satisfaction from, and expended effort in these roles. Methods: Seventy-four women with MDD, GAD, both disorders, or no mental disorders (CTL) described their standards for a socially-and achievement-oriented roles, coded for perfectionism. Using ecological momentary assessment, participants reported the extent to which they met, how much satisfaction they gained from, and how much effort they expended in each role. Results: Although the clinical groups endorsed elevated trait perfectionism, they did not differ from CTLs in their role-specific standards. Compared to CTLs, the clinical groups reported meeting their standards to a lesser extent and receiving less satisfaction from both roles. The two MDD groups reported expending less effort in achievement-oriented, but not socially-oriented, roles than the other two groups. Conclusion: Despite similar standards for socially- and achievement-oriented roles, people with MDD and/or GAD are less likely to meet their standards and gain satisfaction from these roles. Having MDD, independent of GAD, is associated with putting less effort into achievement-oriented roles. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Effort; GAD; MDD; Motivation; Perfectionism; Roles; Standards
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Behavior- and Modality-General Representation of Confidence in Orbitofrontal Cortex” (2020) Cell
Behavior- and Modality-General Representation of Confidence in Orbitofrontal Cortex
(2020) Cell, .
Masset, P.a b , Ott, T.a c , Lak, A.d , Hirokawa, J.a , Kepecs, A.a b c
a Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring HarborNY 11724, United States
b Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring HarborNY 11724, United States
c Department of Neuroscience and Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Abstract
Neurons in the orbitofrontal cortex signal decision confidence across sensory modalities to support multiple confidence-guided behaviors, revealing the neural architecture for metacognitive abilities in rats. © 2020 Elsevier Inc.
Every decision we make is accompanied by a sense of confidence about its likely outcome. This sense informs subsequent behavior, such as investing more—whether time, effort, or money—when reward is more certain. A neural representation of confidence should originate from a statistical computation and predict confidence-guided behavior. An additional requirement for confidence representations to support metacognition is abstraction: they should emerge irrespective of the source of information and inform multiple confidence-guided behaviors. It is unknown whether neural confidence signals meet these criteria. Here, we show that single orbitofrontal cortex neurons in rats encode statistical decision confidence irrespective of the sensory modality, olfactory or auditory, used to make a choice. The activity of these neurons also predicts two confidence-guided behaviors: trial-by-trial time investment and cross-trial choice strategy updating. Orbitofrontal cortex thus represents decision confidence consistent with a metacognitive process that is useful for mediating confidence-guided economic decisions. © 2020 Elsevier Inc.
Author Keywords
behavior; confidence; decision-making; electrophysiology; metacognition; neuroscience; orbitofrontal cortex; reinforcement learning; reward value; uncertainty
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition” (2020) Journal of Cerebral Blood Flow and Metabolism
Opposed hemodynamic responses following increased excitation and parvalbumin-based inhibition
(2020) Journal of Cerebral Blood Flow and Metabolism, .
Lee, J.a , Stile, C.L.a , Bice, A.R.a , Rosenthal, Z.P.b , Yan, P.b , Snyder, A.Z.a , Lee, J.-M.b c , Bauer, A.Q.a c
a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Understanding cellular contributions to hemodynamic activity is essential for interpreting blood-based brain mapping signals. Optogenetic studies examining cell-specific influences on local hemodynamics have reported that excitatory activity results in cerebral perfusion and blood volume increase, while inhibitory activity contributes to both vasodilation and vasoconstriction. How specific subpopulations of interneurons regulate the brain’s blood supply is less examined. Parvalbumin interneurons are the largest subpopulation of GABAergic neurons in the brain, critical for brain development, plasticity, and long-distance excitatory neurotransmission. Despite their essential role in brain function, the contribution of parvalbumin neurons to neurovascular coupling has been relatively unexamined. Using optical intrinsic signal imaging and laser speckle contrast imaging, we photostimulated awake and anesthetized transgenic mice expressing channelrhodopsin under a parvalbumin promoter. Increased parvalbumin activity reduced local oxygenation, cerebral blood volume, and cerebral blood flow. These “negative” hemodynamic responses were consistent within and across mice and reproducible across a broad range of photostimulus parameters. However, the sign and magnitude of the hemodynamic response resulting from increased parvalbumin activity depended on the type and level of anesthesia used. Opposed hemodynamic responses following increased excitation or parvalbumin-based inhibition suggest unique contributions from different cell populations to neurovascular coupling. © The Author(s) 2020.
Author Keywords
Excitatory; inhibitory; neurovascular coupling; optogenetics; parvalbumin
Document Type: Article
Publication Stage: Article in Press
Source: Scopus