"A 2020 view of tension-based cortical morphogenesis" (2021) Proceedings of the National Academy of Sciences of the United States of America
A 2020 view of tension-based cortical morphogenesis
(2021) Proceedings of the National Academy of Sciences of the United States of America, 117 (52), pp. 32868-32879.
van Essen, D.C.
Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
Abstract
Mechanical tension along the length of axons, dendrites, and glial processes has been proposed as a major contributor to morphogenesis throughout the nervous system [D. C. Van Essen, Nature 385, 313–318 (1997)]. Tension-based morphogenesis (TBM) is a conceptually simple and general hypothesis based on physical forces that help shape all living things. Moreover, if each axon and dendrite strive to shorten while preserving connectivity, aggregate wiring length would remain low. TBM can explain key aspects of how the cerebral and cerebellar cortices remain thin, expand in surface area, and acquire their distinctive folds. This article reviews progress since 1997 relevant to TBM and other candidate morphogenetic mechanisms. At a cellular level, studies of diverse cell types in vitro and in vivo demonstrate that tension plays a major role in many developmental events. At a tissue level, I propose a differential expansion sandwich plus (DES+) revision to the original TBM model for cerebral cortical expansion and folding. It invokes tangential tension and “sulcal zipping” forces along the outer cortical margin as well as tension in the white matter core, together competing against radially biased tension in the cortical gray matter. Evidence for and against the DES+ model is discussed, and experiments are proposed to address key tenets of the DES+ model. For cerebellar cortex, a cerebellar multilayer sandwich (CMS) model is proposed that can account for many distinctive features, including its unique, accordion-like folding in the adult, and experiments are proposed to address its specific tenets. © 2020 National Academy of Sciences. All rights reserved.
Author Keywords
Biomechanics; Cerebellum; Cerebral cortex; Folding; Gyrification
Funding details
1U54MH091657
NIH Blueprint for Neuroscience Research
National Institutes of HealthNIHMH060974-26
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
"Determinants of using children’s mental health research in policymaking: variation by type of research use and phase of policy process" (2021) Implementation Science
Determinants of using children’s mental health research in policymaking: variation by type of research use and phase of policy process
(2021) Implementation Science, 16 (1), art. no. 13, .
Purtle, J.a , Nelson, K.L.a , Horwitz, S.M.C.b , McKay, M.M.c , Hoagwood, K.E.b
a Department of Health Management & Policy, Drexel University Dornsife School of Public Health, 3215 Market St, Philadelphia, PA 19104, United States
b Department of Child and Adolescent Psychiatry, New York University School of Medicine, 1 Park Avenue, New York, NY 10016, United States
c Brown School at Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
Abstract
Background: Research use in policymaking is multi-faceted and has been the focus of extensive study. However, virtually no quantitative studies have examined whether the determinants of research use vary according to the type of research use or phase of policy process. Understanding such variation is important for selecting the targets of implementation strategies that aim to increase the frequency of research use in policymaking. Methods: A web-based survey of US state agency officials involved with children’s mental health policymaking was conducted between December 2019 and February 2020 (n = 224, response rate = 33.7%, 49 states responding (98%), median respondents per state = 4). The dependent variables were composite scores of the frequency of using children’s mental health research in general, specific types of research use (i.e., conceptual, instrumental, tactical, imposed), and during different phases of the policy process (i.e., agenda setting, policy development, policy implementation). The independent variables were four composite scores of determinants of research use: agency leadership for research use, agency barriers to research use, research use skills, and dissemination barriers (e.g., lack of actionable messages/recommendations in research summaries, lack of interaction/collaboration with researchers). Separate multiple linear regression models estimated associations between determinant and frequency of research use scores. Results: Determinants of research use varied significantly by type of research use and phase of policy process. For example, agency leadership for research use was the only determinant significantly associated with imposed research use (β = 0.31, p < 0.001). Skills for research use were the only determinant associated with tactical research use (β = 0.17, p = 0.03) and were only associated with research use in the agenda-setting phase (β = 0.16, p = 0.04). Dissemination barriers were the most universal determinants of research use, as they were significantly and inversely associated with frequency of conceptual (β = −0.21, p = 0.01) and instrumental (β = −0.22, p = 0.01) research use and during all three phases of policy process. Conclusions: Decisions about the determinants to target with policy-focused implementation strategies—and the strategies that are selected to affect these targets—should reflect the specific types of research use that these strategies aim to influence. © 2021, The Author(s).
Author Keywords
Children; Mental health; Policy; Research use in policymaking; United States
Document Type: Article
Publication Stage: Final
Source: Scopus
"Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction" (2021) Fluids and Barriers of the CNS
Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 4, .
Harris, C.A.a , Morales, D.M.b , Arshad, R.a , McAllister, J.P., IIb , Limbrick, D.D., Jr.c
a Wayne State University Dept. of Chemical Engineering and Materials Science, 6135 Woodward Avenue, Rm 1413, Detroit, MI 48202, United States
b Department of Neurosurgery, Washington University in St. Louis, 425 S. Euclid, St. Louis, MO 63110, United States
c Division of Pediatric Neurosurgery, and Department of Pediatrics, Department of Neurosurgery, Washington University in St. Louis, 425 S. Euclid, St. Louis, MO 63110, United States
Abstract
Background: Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods: Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results: Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion: Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested. © 2021, The Author(s).
Author Keywords
Cytokines; Hydrocephalus; Mmps; Multiplex ELISA; Neuroinflammation; Revisions
Document Type: Article
Publication Stage: Final
Source: Scopus
"Effects of aging on emotion recognition from dynamic multimodal expressions and vocalizations" (2021) Scientific Reports
Effects of aging on emotion recognition from dynamic multimodal expressions and vocalizations
(2021) Scientific Reports, 11 (1), art. no. 2647, .
Cortes, D.S.a , Tornberg, C.a , Bänziger, T.b , Elfenbein, H.A.c , Fischer, H.a , Laukka, P.a
a Department of Psychology, Stockholm University, Stockholm, Sweden
b Department of Psychology, Mid Sweden University, Östersund, Sweden
c Olin Business School, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Age-related differences in emotion recognition have predominantly been investigated using static pictures of facial expressions, and positive emotions beyond happiness have rarely been included. The current study instead used dynamic facial and vocal stimuli, and included a wider than usual range of positive emotions. In Task 1, younger and older adults were tested for their abilities to recognize 12 emotions from brief video recordings presented in visual, auditory, and multimodal blocks. Task 2 assessed recognition of 18 emotions conveyed by non-linguistic vocalizations (e.g., laughter, sobs, and sighs). Results from both tasks showed that younger adults had significantly higher overall recognition rates than older adults. In Task 1, significant group differences (younger > older) were only observed for the auditory block (across all emotions), and for expressions of anger, irritation, and relief (across all presentation blocks). In Task 2, significant group differences were observed for 6 out of 9 positive, and 8 out of 9 negative emotions. Overall, results indicate that recognition of both positive and negative emotions show age-related differences. This suggests that the age-related positivity effect in emotion recognition may become less evident when dynamic emotional stimuli are used and happiness is not the only positive emotion under study. © 2021, The Author(s).
Funding details
VetenskapsrådetVR2012-801
Document Type: Article
Publication Stage: Final
Source: Scopus
"Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling" (2021) Respiratory Research
Bitter taste receptor agonists regulate epithelial two-pore potassium channels via cAMP signaling
(2021) Respiratory Research, 22 (1), art. no. 31, .
Kohanski, M.A.a , Brown, L.b , Orr, M.b , Tan, L.H.a , Adappa, N.D.a , Palmer, J.N.a , Rubenstein, R.C.b c d , Cohen, N.A.a e f
a Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, University of Pennsylvania Medical Center, Perelman School of Medicine, 5th Floor Ravdin Building, 3400 Spruce Street, Philadelphia, PA, United States
b Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
c Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
d Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
e Corporal Michael J. Crescenz Veterans Administration Medical Center, Philadelphia, PA, United States
f Monell Chemical Senses Institute, Philadelphia, PA, United States
Abstract
Background: Epithelial solitary chemosensory cell (tuft cell) bitter taste signal transduction occurs through G protein coupled receptors and calcium-dependent signaling pathways. Type II taste cells, which utilize the same bitter taste signal transduction pathways, may also utilize cyclic adenosine monophosphate (cAMP) as an independent signaling messenger in addition to calcium. Methods: In this work we utilized specific pharmacologic inhibitors to interrogate the short circuit current (Isc) of polarized nasal epithelial cells mounted in Ussing chambers to assess the electrophysiologic changes associated with bitter agonist (denatonium) treatment. We also assessed release of human β-defensin-2 from polarized nasal epithelial cultures following treatment with denatonium benzoate and/or potassium channel inhibitors. Results: We demonstrate that the bitter taste receptor agonist, denatonium, decreases human respiratory epithelial two-pore potassium (K2P) current in polarized nasal epithelial cells mounted in Ussing chambers. Our data further suggest that this occurs via a cAMP-dependent signaling pathway. We also demonstrate that this decrease in potassium current lowers the threshold for denatonium to stimulate human β-defensin-2 release. Conclusions: These data thus demonstrate that, in addition to taste transducing calcium-dependent signaling, bitter taste receptor agonists can also activate cAMP-dependent respiratory epithelial signaling pathways to modulate K2P currents. Bitter-agonist regulation of potassium currents may therefore serve as a means of rapid regional epithelial signaling, and further study of these pathways may provide new insights into regulation of mucosal ionic composition and innate mechanisms of epithelial defense. © 2021, The Author(s).
Author Keywords
Antimicrobial peptide; Chronic rhinosinusitis; Defensin; Denatonium; K2P; Potassium channel; SCC; Tuft cell
Document Type: Article
Publication Stage: Final
Source: Scopus
"'It’s way more than just writing a prescription': A qualitative study of preferences for integrated versus non-integrated treatment models among individuals with opioid use disorder" (2021) Addiction Science and Clinical Practice
“It’s way more than just writing a prescription”: A qualitative study of preferences for integrated versus non-integrated treatment models among individuals with opioid use disorder
(2021) Addiction Science and Clinical Practice, 16 (1), art. no. 8, .
Saunders, E.C.a , Moore, S.K.a , Walsh, O.a , Metcalf, S.A.a , Budney, A.J.a , Cavazos-Rehg, P.b , Scherer, E.a , Marsch, L.A.a
a Center for Technology and Behavioral Health, Geisel School of Medicine At Dartmouth College, 46 Centerra Parkway, Suite 301, Lebanon, NH 03766, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Increasingly, treatment for opioid use disorder (OUD) is offered in integrated treatment models addressing both substance use and other health conditions within the same system. This often includes offering medications for OUD in general medical settings. It remains uncertain whether integrated OUD treatment models are preferred to non-integrated models, where treatment is provided within a distinct treatment system. This study aimed to explore preferences for integrated versus non-integrated treatment models among people with OUD and examine what factors may influence preferences. Methods: This qualitative study recruited participants (n = 40) through Craigslist advertisements and flyers posted in treatment programs across the United States. Participants were 18 years of age or older and scored a two or higher on the heroin or opioid pain reliever sections of the Tobacco, Alcohol, Prescription Medications, and Other Substances (TAPS) Tool. Each participant completed a demographic survey and a telephone interview. The interviews were coded and content analyzed. Results: While some participants preferred receiving OUD treatment from an integrated model in a general medical setting, the majority preferred non-integrated models. Some participants preferred integrated models in theory but expressed concerns about stigma and a lack of psychosocial services. Tradeoffs between integrated and non-integrated models were centered around patient values (desire for anonymity and personalization, fear of consequences), the characteristics of the provider and setting (convenience, perceived treatment effectiveness, access to services), and the patient-provider relationship (disclosure, trust, comfort, stigma). Conclusions: Among this sample of primarily White adults, preferences for non-integrated versus integrated OUD treatment were mixed. Perceived benefits of integrated models included convenience, potential for treatment personalization, and opportunity to extend established relationships with medical providers. Recommendations to make integrated treatment more patient-centered include facilitating access to psychosocial services, educating patients on privacy, individualizing treatment, and prioritizing the patient-provider relationship. This sample included very few minorities and thus findings may not be fully generalizable to the larger population of persons with OUD. Nonetheless, results suggest a need for expansion of both OUD treatment in specialty and general medical settings to ensure access to preferred treatment for all. © 2021, The Author(s).
Author Keywords
Integrated treatment; Opioid use disorder; Patient preference; Treatment model
Funding details
National Institute on Drug AbuseNIDAT32 DA037202
National Institute on Drug AbuseNIDAP30 DA029926
Document Type: Article
Publication Stage: Final
Source: Scopus
"Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle" (2021) Scientific Reports
Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle
(2021) Scientific Reports, 11 (1), art. no. 2140, .
Borse, V.a , Barton, M.a , Arndt, H.a , Kaur, T.b , Warchol, M.E.a
a Department of Otolaryngology, School of Medicine, Washington University in Saint Louis, 660 South Euclid Ave, Box 8115, St Louis, MO 63110, United States
b Department of Biomedical Sciences, Creighton University School of Medicine, Nebraska, United States
Abstract
The Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHR01 DC006283, T32 DC000022
Document Type: Article
Publication Stage: Final
Source: Scopus
"Activity competence among infants and toddlers with developmental disabilities: Rasch analysis of the Infant Toddler Activity Card Sort (ITACS)" (2021) Journal of Patient-Reported Outcomes
Activity competence among infants and toddlers with developmental disabilities: Rasch analysis of the Infant Toddler Activity Card Sort (ITACS)
(2021) Journal of Patient-Reported Outcomes, 5 (1), art. no. 14, .
Hoyt, C.R.a , L’Hotta, A.J.a , Bauer, A.H.a , Chang, C.-H.a b c , Varughese, T.E.a , Abel, R.A.a c , King, A.A.a c d e f
a Program in Occupational Therapy, Washington University School of Medicine, 4444 Forest Park Blvd, MSC 8505-66-1, St. Louis, MO 63108, United States
b Institute of Informatics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
f Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Development is rapid in the first years of life. Developmental delays appearing during this critical period have the potential to persist throughout the child’s life. Available standardized assessments for this age record a child’s ability to successfully complete discrete skills but fail to capture whether the child incorporates those skills into daily routines that are meaningful to the child and family. The Infant Toddler Activity Card Sort (ITACS) is a newly developed photograph-based early intervention tool to measure the participation-related concept of activity competence using caregiver report. The purpose of the present study was to use Rasch analysis to determine if ITACS items comprehensively measure the construct of child activity competence. Results: A total of 60 child/caregiver dyads participated. The dichotomous caregiver-reported responses (present vs. absent) on the 40 individual ITACS items were used in Rasch analysis, and three iterations of the model were completed. The final model included 51 child/caregiver dyads and 67 ITACS assessments with a good spread of individual ability measure (6.47 logits). All items demonstrated adequate infit except for “sleeping” (range 0.68–1.54). Five items (sleeping, eating at restaurants, brushing teeth, crawling, and interact with pets) demonstrated high Mean Square (MNSQ) outfit statistics and one (take a bath) demonstrated low MNSQ outfit. ITACS items demonstrated a good spread of item difficulty measures (6.27 logits), and a clear ceiling was observed. Three activity items (smiling, breastfeeding, and playing with adults) were rarely endorsed as concerns. The activities most likely to be reported as challenging were “crying/communicating” and “going to school”. Person and item reliability statistics were adequate (0.79 and 0.80, respectively). The separation between individuals and between items were adequate to good (1.96 and 1.99, respectively). Conclusions: Findings indicate that ITACS items are measuring a unidimensional construct–activity competence in early childhood. The Rasch analysis of caregiver responses suggest that some activities are more likely to be considered challenging and may be important targets for intervention. These results provide evidence to further validate the ITACS as a caregiver report measure and support its use in the early intervention setting to facilitate caregiver driven goal development. © 2021, The Author(s).
Author Keywords
Activity; Caregiver reported outcome; Competence; Developmental delay; Participation; Rasch analysis
Document Type: Article
Publication Stage: Final
Source: Scopus
"Precision functional mapping of human memory systems" (2021) Current Opinion in Behavioral Sciences
Precision functional mapping of human memory systems
(2021) Current Opinion in Behavioral Sciences, 40, pp. 52-57.
Gilmore, A.W.a , Nelson, S.M.b c d , McDermott, K.B.e f
a Laboratory of Brain and Cognition, National Institute of Mental Health, United States
b VISN 17 Center of Excellence for Research on Returning War Veterans, United States
c University of Texas at Dallas Center for Vital Longevity, United States
d Baylor University, Department of Psychology and Neuroscience, United States
e Washington University, Department of Psychological and Brain Sciences, St Louis, MO 63130, United States
f Department of Radiology, United States
Abstract
Precision functional MRI has enabled identification of individual-specific network configurations. A comparison of these individual-specific maps with group-average maps has yielded novel insights into network organization of memory-related brain systems. For example, the default mode network was previously thought to be comprised of three subsystems, but precision fMRI has demonstrated that one of those three subsystems may have arisen as an artifact of group averaging. Further, understanding of a second network—the parietal memory network—has been enhanced through precision fMRI. Specifically, one of the three canonical regions of this network—the posterior inferior parietal lobule—is identifiable within only about half of participants using current methods. In addition, ‘network variants’ have been identified, which are the existence of islands of network membership outside the typical configuration or regions that do not fall within the typical network assignment. The behavioral significance of such variants remains a topic for future consideration. © 2021 Elsevier Ltd
Funding details
National Institute of Mental HealthNIMHZIAMH002920
Document Type: Review
Publication Stage: Final
Source: Scopus
"Clinical Characteristics of Idiopathic Intracranial Hypertension in Patients Over 50 Years of Age: A multicenter clinical cohort study" (2021) American Journal of Ophthalmology
Clinical Characteristics of Idiopathic Intracranial Hypertension in Patients Over 50 Years of Age: A multicenter clinical cohort study
(2021) American Journal of Ophthalmology, 224, pp. 96-101.
Downie, P.A.a , Chen, J.J.b , Bhatti, M.T.b , Melson, A.T.c , Van Stavern, G.P.d , McClelland, C.M.a , Lindgren, B.R.a , Sharieff, J.A.c , Lee, M.S.a
a Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States
b Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States
c Department of Ophthalmology, University of Oklahoma, Oklahoma City, OK, United States
d Department of Ophthalmology, Washington University St. Louis, St. Louis, MO, United States
Abstract
Purpose: To characterize the clinical features of idiopathic intracranial hypertension (IIH) in patients >50 years of age compared to the typical IIH population and existing data for this older cohort. Design: Retrospective, clinical cohort study. Methods: Medical records of 65 patients >50 years of age at first diagnosis of IIH were reviewed based on the Modified Dandy Criteria from 4 academic centers. Each center provided randomly selected controls from IIH patients <50 years of age for each study patient at their location. Data recorded included patient demographics, presenting symptoms, medications, coexisting medical conditions, cerebrospinal fluid (CSF) opening pressure, treatments, and neuro-ophthalmic data from initial and final visits. Results: Compared to controls, the older cohort showed the following characteristics: fewer females (n = 51 [78.5%] vs. controls: n = 60 [92.3%]; P =.045), fewer headaches (n = 33 [50.8%] vs. controls: 52 [80.0%]; P =.001), more frequent incidental discoveries of papilledema (n = 19 [29.2%] vs. controls: 7 [10.8%]; P =.015), and lower CSF opening pressure [median: 33 cm H2O [range: 21-58 cm H2O] vs. the median for controls: 34 cm H2O [range: 24-67 cm H2O; P =.029). Conclusions: Patients with IIH diagnosed at >50 years of age were less often female and had lower CSF opening pressure, fewer headaches, a higher chance of incidentally identified papilledema, and body mass index similar to that of younger IIH patients. Older IIH onset was not associated with worse visual outcome. © 2020 Elsevier Inc.
Funding details
National Center for Advancing Translational SciencesNCATSUL1TR002494
Document Type: Article
Publication Stage: Final
Source: Scopus
"Quantitative endophenotypes as an alternative approach to understanding genetic risk in neurodegenerative diseases" (2021) Neurobiology of Disease
Quantitative endophenotypes as an alternative approach to understanding genetic risk in neurodegenerative diseases
(2021) Neurobiology of Disease, 151, art. no. 105247, .
Farias, F.H.G.a b , Benitez, B.A.a b , Cruchaga, C.a b c d e
a Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
b NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, United States
c Hope Center for Neurologic Diseases, Washington University, St. Louis, MO 63110, United States
d The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
e Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States
Abstract
Endophenotypes, as measurable intermediate features of human diseases, reflect underlying molecular mechanisms. The use of quantitative endophenotypes in genetic studies has improved our understanding of pathophysiological changes associated with diseases. The main advantage of the quantitative endophenotypes approach to study human diseases over a classic case-control study design is the inferred biological context that can enable the development of effective disease-modifying treatments. Here, we summarize recent progress on biomarkers for neurodegenerative diseases, including cerebrospinal fluid and blood-based, neuroimaging, neuropathological, and clinical studies. This review focuses on how endophenotypic studies have successfully linked genetic modifiers to disease risk, disease onset, or progression rate and provided biological context to genes identified in genome-wide association studies. Finally, we review critical methodological considerations for implementing this approach and future directions. © 2021 The Author(s)
Funding details
National Institute of Neurological Disorders and StrokeNINDSR01NS118146
Document Type: Review
Publication Stage: Final
Source: Scopus
"The chiari severity index and the role of external validation" (2021) Journal of Neurosurgery: Pediatrics
The chiari severity index and the role of external validation
(2021) Journal of Neurosurgery: Pediatrics, 27 (2), pp. 241-242.
Greenberg, J.K., Limbrick, D.D., Jr.
Washington University School of Medicine, St. Louis, MO, United States
Funding details
Thrasher Research FundTRF
Agency for Healthcare Research and QualityAHRQ
Document Type: Letter
Publication Stage: Final
Source: Scopus
"Psychotic Like Experiences are Associated with Suicide Ideation and Behavior in 9 to 10 Year Old Children in the United States" (2021) Research on Child and Adolescent Psychopathology
Psychotic Like Experiences are Associated with Suicide Ideation and Behavior in 9 to 10 Year Old Children in the United States
(2021) Research on Child and Adolescent Psychopathology, 49 (2), pp. 255-265.
Grattan, R.E.a , Karcher, N.R.b , Maguire, A.M.a , Hatch, B.a , Barch, D.M.b , Niendam, T.A.a
a Department of Psychiatry & Behavioral Sciences, University of California-Davis, 4701 X St, Sacramento, CA 95817, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Those experiencing psychotic like experiences (PLEs) are at higher risk for suicide ideation and behavior. However, it is unclear if PLEs are related to suicide ideation and behavior in children, and whether other factors such as impulsivity or emotion dysregulation might moderate the relationship. We hypothesize that PLEs are associated with suicide ideation and behavior, with impulsivity and emotion dysregulation moderating this relationship, in middle childhood. History of PLEs, suicide ideation and behavior, depression, emotion dysregulation, and impulsivity were assessed for 10,624 children aged 9 to 10.9 years (47.8% female, 34.4% minority race, 20.0% Hispanic) as part of the Adolescent Brain Cognitive Development℠ study. Hypotheses about associations between variables were assessed using hierarchical linear modeling. PLEs were associated with suicide ideation and suicide behavior even when controlling for depression severity. Emotion dysregulation and impulsivity were also associated with suicide ideation and moderated the relationship between PLEs and suicide ideation. Variation in suicide ideation due to impulsivity and emotion dysregulation appears to be strongest when people are experiencing low levels to no PLEs. Only impulsivity and PLEs were associated with suicide behavior. Depression was associated with suicide ideation, but not suicide behavior. PLEs may be an important risk factor for suicide ideation and behavior in 9 to 10-year-old children, comparable to adult and adolescent populations. When considering prevention of suicidality, these data suggest that considering the relations between PLEs, impulsivity and emotion dysregulation may be important. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Emotion dysregulation; Impulsivity; Psychotic like experiences; Suicide behavior; Suicide ideation
Funding details
National Institutes of HealthNIHU01DA041022, U01DA041028, U01DA041025, U01DA041174, U01DA041156, U01DA041093, U01DA041048, U24DA041147, U24DA041123, U01DA041106, U01DA041148, U01DA041134, U01DA041117, U01DA041089, U01DA041120
National Institute on Drug AbuseNIDAU01 DA041120
MH014677
Document Type: Article
Publication Stage: Final
Source: Scopus
"Multiple domain interfaces mediate SARM1 autoinhibition" (2021) Proceedings of the National Academy of Sciences of the United States of America
Multiple domain interfaces mediate SARM1 autoinhibition
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (4), art. no. e2023151118, .
Shen, C.a b , Vohra, M.c , Zhang, P.a b , Mao, X.c , Figley, M.D.d , Zhu, J.c , Sasaki, Y.c , Wu, H.a b , DiAntonio, A.d e , Milbrandt, J.c e
a Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States
b Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Axon degeneration is an active program of self-destruction mediated by the protein SARM1. In healthy neurons, SARM1 is autoinhibited and, upon injury autoinhibition is relieved, activating the SARM1 enzyme to deplete NAD+ and induce axon degeneration. SARM1 forms a homomultimeric octamer with each monomer composed of an N-terminal autoinhibitory ARM domain, tandem SAM domains that mediate multimerization, and a C-terminal TIR domain encoding the NADase enzyme. Here we discovered multiple intramolecular and intermolecular domain interfaces required for SARM1 autoinhibition using peptide mapping and cryo-electron microscopy (cryo-EM). We identified a candidate autoinhibitory region by screening a panel of peptides derived from the SARM1 ARM domain, identifying a peptide mediating high-affinity inhibition of the SARM1 NADase. Mutation of residues in full-length SARM1 within the region encompassed by the peptide led to loss of autoinhibition, rendering SARM1 constitutively active and inducing spontaneous NAD+ and axon loss. The cryo-EM structure of SARM1 revealed 1) a compact autoinhibited SARM1 octamer in which the TIR domains are isolated and prevented from oligomerization and enzymatic activation and 2) multiple candidate autoinhibitory interfaces among the domains. Mutational analysis demonstrated that five distinct interfaces are required for autoinhibition, including intramolecular and intermolecular ARM-SAM interfaces, an intermolecular ARM-ARM interface, and two ARM-TIR interfaces formed between a single TIR and two distinct ARM domains. These autoinhibitory regions are not redundant, as point mutants in each led to constitutively active SARM1. These studies define the structural basis for SARM1 autoinhibition and may enable the development of SARM1 inhibitors that stabilize the autoinhibited state. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Axonopathy; Metabolism; Neurodegeneration; Neuropathy; NMN
Funding details
GM103310
National Institutes of HealthNIHRO1NS087632, AI050872, RF1AG013730, R01CA219866
Cancer Research InstituteCRI
Document Type: Article
Publication Stage: Final
Source: Scopus
"Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion" (2021) Neurology
Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion
(2021) Neurology, 96 (3), pp. e387-e398.
Mac Donald, C.L.a , Barber, J.b , Patterson, J.b , Johnson, A.M.b , Parsey, C.b , Scott, B.b , Fann, J.R.b , Temkin, N.R.b
a From the Departments of Neurological Surgery (C.L.M., J.B., J.P., B.S., N.R.T.), Neurology (C.P.), and Psychiatry (J.R.F.), School of Medicine, and Department of Biostatistics (N.R.T.), School of Public Health, University of Washington, Seattle; and Center for Clinical Studies (A.M.J.), Washington University School of Medicine, St. Louis, MO. cmacd@uw.edu
b From the Departments of Neurological Surgery (C.L.M., J.B., J.P., B.S., N.R.T.), Neurology (C.P.), and Psychiatry (J.R.F.), School of Medicine, and Department of Biostatistics (N.R.T.), School of Public Health, University of Washington, Seattle; and Center for Clinical Studies (A.M.J.), Washington University School of Medicine, St. Louis, MO
Abstract
OBJECTIVE: To compare 1-year and 5-year clinical outcomes in 2 groups of combat-deployed service members without brain injury to those of 2 groups with combat-related concussion to better understand long-term clinical outcome trajectories. METHODS: This prospective, observational, longitudinal multicohort study examined 4 combat-deployed groups: controls without head injury with or without blast exposure and patients with combat concussion arising from blast or blunt trauma. One-year and 5-year clinical evaluations included identical batteries for neurobehavioral, psychiatric, and cognitive outcomes. A total of 347 participants completed both time points of evaluation. Cross-sectional and longitudinal comparisons were assessed. Overall group effect was modeled as a 4-category variable with rank regression adjusting for demographic factors using a 2-sided significance threshold of 0.05, with post hoc Tukey p values calculated for the pairwise comparisons. RESULTS: Significant group differences in both combat concussion groups were identified cross-sectionally at 5-year follow-up compared to controls in neurobehavioral (Neurobehavioral Rating Scale-Revised [NRS]; Cohen d, -1.10 to -1.40, confidence intervals [CIs] [-0.82, -1.32] to [-0.97, -1.83] by group) and psychiatric domains (Clinician-Administered PTSD Scale for DSM-IV [CAPS]; Cohen d, -0.91 to -1.19, CIs [-0.63, -1.19] to [-0.76, -1.62] by group) symptoms with minimal differences in cognitive performance. Both combat concussion groups also showed clinically significant decline from 1- to 5-year evaluation (66%-76% neurobehavioral NRS; 41%-54% psychiatric CAPS by group). Both control groups fared better but a subset also had clinically significant decline (37%-50% neurobehavioral NRS; 9%-25% psychiatric CAPS by group). CONCLUSIONS: There was an evolution, not resolution, of symptoms from 1- to 5-year evaluation, challenging the assumption that chronic stages of concussive injury are relatively stable. Even some of the combat-deployed controls worsened. The evidence supports new considerations for chronic trajectories of concussion outcome in combat-deployed service members. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Document Type: Article
Publication Stage: Final
Source: Scopus
"Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease" (2021) Proceedings of the National Academy of Sciences of the United States of America
Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (3), .
Ellwanger, D.C.a , Wang, S.b , Brioschi, S.b , Shao, Z.c , Green, L.d , Case, R.e , Yoo, D.f , Weishuhn, D.d , Rathanaswami, P.d , Bradley, J.g , Rao, S.c , Cha, D.g , Luan, P.h , Sambashivan, S.a , Gilfillan, S.b , Hasson, S.A.g , Foltz, I.N.d , van Lookeren Campagne, M.i , Colonna, M.j
a Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080
b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110
c Department of Inflammation and Oncology, Amgen Research, Amgen Inc., South San Francisco, CA 94080
d Department of Biologics Discovery, Amgen Research, Amgen Inc., Burnaby, V5A1V7, Canada
e Discovery Attribute Sciences, Amgen Research, Amgen Inc., South San Francisco, CA 94080
f Department of Biologics Optimization, Amgen Research, Amgen Inc., Thousand Oaks, CA, 91320, Italy
g Department of Neuroscience, Amgen Research, Amgen Inc., Cambridge, MA 02142
h Department of Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc., Thousand Oaks, CA, 91320, Italy
i Department of Inflammation and Oncology, Amgen Research, Amgen Inc., South San Francisco, CA 94080; mvanlook@amgen.com mcolonna@wustl.edu
j Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110; mvanlook@amgen.com mcolonna@wustl.edu
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.
Author Keywords
Alzheimer’s disease; amyloid beta; microglia; monoclonal antibody; TREM2
Document Type: Article
Publication Stage: Final
Source: Scopus
"Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data from the Park-Reeves Syringomyelia Research Consortium" (2021) Neurosurgery
Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data from the Park-Reeves Syringomyelia Research Consortium
(2021) Neurosurgery, 88 (2), pp. 332-341.
Crevecoeur, T.S.a , Yahanda, A.T.a , Maher, C.O.b , Johnson, G.W.a , Ackerman, L.L.c , David Adelson, P.D.d , Ahmed, R.e , Albert, G.W.f , Aldana, P.R.g , Alden, T.D.h i , Anderson, R.C.E.j , Baird, L.k , Bauer, D.F.l , Bierbrauer, K.S.m , Brockmeyer, D.L.n , Chern, J.J.o , Couture, D.E.p , Daniels, D.J.q , Dauser, R.C.r , Durham, S.R.s , Ellenbogen, R.G.t , Eskandari, R.u , Fuchs, H.E.v , George, T.M.w , Grant, G.A.x , Graupman, P.C.y , Greene, S.z , Greenfield, J.P.aa , Gross, N.L.ab , Guillaume, D.J.ac , Haller, G.a , Hankinson, T.C.ad , Heuer, G.G.ae , Iantosca, M.af , Iskandar, B.J.e , Jackson, E.M.ag , Jea, A.H.c , Johnston, J.M.ah , Keating, R.F.ai , Kelly, M.P.aj , Khan, N.ak , Krieger, M.D.al , Leonard, J.R.am , Mangano, F.T.m , Mapstone, T.B.a , Gordon McComb, J.b , Menezes, A.H.an , Muhlbauer, M.ao , Jerry Oakes, W.b , Olavarria, G.c , O’Neill, B.R.d , Park, T.S.b , Ragheb, J.ai , Selden, N.R.aj , Shah, M.N.ak , Shannon, C.al , Shimony, J.S.al , Smith, J.an , Smyth, M.D.ao , Stone, S.S.D.ap , Strahle, J.M.aq , Tamber, M.S.ar , Torner, J.C.as , Tuite, G.F.at , Wait, S.D.au , Wellons, J.C.av , Whitehead, W.E.r , Limbrick, D.D.a
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, University of Michigan School of Medicine, Ann Arbor, MI, United States
c Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
d Division of Pediatric Neurosurgery, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
e Department of Neurological Surgery, University of Wisconsin at Madison, Madison, WI, United States
f Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
g Division of Pediatric Neurosurgery, University of Florida College of Medicine, Jacksonville, FL, United States
h Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
i Division of Pediatric Neurosurgery, Department of Neurological Surgery, Children’s Hospital of New York, Columbia-Presbyterian, New York, NY, United States
j Department of Neurological Surgery, Doernbecher Children’s Hospital, Oregon Health & Science University, Portland, OR, United States
k Department of Neurosurgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
l Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
m Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
n Division of Pediatric Neurosurgery, Children’s Healthcare of Atlanta, Atlanta, GA, United States
o Department of Neurological Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, United States
p Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
q Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States
r Department of Neurosurgery, University of Vermont, Burlington, VT, United States
s Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
t Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
u Department of Neurosurgery, Duke University, Durham, NC, United States
v Division of Pediatric Neurosurgery, Dell Children’s Medical Center, Austin, TX, United States
w Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital at Stanford, Stanford University School of Medicine, Palo Alto, CA, United States
x Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
y Divsion of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
z Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, United States
aa Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK, United States
ab Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
ac Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
ad Division of Pediatric Neurosurgery, Children’s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ae Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
af Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ag Division of Pediatric Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States
ah Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
ai Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
aj Department of Neurosurgery, Le Bonheur Children’s Hospital, Memphis, TN, United States
ak Department of Neurosurgery, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
al Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
am Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
an Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
ao Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, United States
ap Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
aq Division of Pediatric Neurosurgery, Monroe Carell Jr Children’s Hospital of Vanderbilt University, Nashville, TN, United States
ar Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
as Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
at Department of Neurosurgery, The University of British Columbia, Vancouver, Canada
au Department of Neurosurgery, Neuroscience Institute, All Children’s Hospital, St. Petersburg, FL, United States
av Carolina Neurosurgery & Spine Associates, Charlotte, NC, United States
Abstract
BACKGROUND: Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology. OBJECTIVE: To examine factors influencing the use of OCF and OCF/VD in a multicenter cohort of pediatric CM-1 and SM subjects treated with PFD. METHODS: The Park-Reeves Syringomyelia Research Consortium registry was used to examine 637 subjects with cerebellar tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and at least 1 yr of follow-up after their index PFD. Comparisons were made between subjects who received PFD alone and those with PFD + OCF or PFD + OCF/VD. RESULTS: All 637 patients underwent PFD, 505 (79.2%) with and 132 (20.8%) without duraplasty. A total of 12 subjects went on to have OCF at some point in their management (PFD + OCF), whereas 4 had OCF and VD (PFD + OCF/VD). Of those with complete data, a history of platybasia (3/10, P =. 011), Klippel-Feil (2/10, P =. 015), and basilar invagination (3/12, P <. 001) were increased within the OCF group, whereas only basilar invagination (1/4, P <. 001) was increased in the OCF/VD group. Clivo-axial angle (CXA) was significantly lower for both OCF (128.8 ± 15.3°, P =. 008) and OCF/VD (115.0 ± 11.6°, P =. 025) groups when compared to PFD-only group (145.3 ± 12.7°). pB-C2 did not differ among groups. CONCLUSION: Although PFD alone is adequate for treating the vast majority of CM-1/SM patients, OCF or OCF/VD may be occasionally utilized. Cranial base and spine pathologies and CXA may provide insight into the need for OCF and/or OCF/VD. Copyright © 2020 by the Congress of Neurological Surgeons.
Author Keywords
Chiari malformation; Clivo-axial angle; Craniovertebral junction; Occipital-cervical fusion; pB-C2; Syringomyelia; Ventral brainstem compression
Document Type: Article
Publication Stage: Final
Source: Scopus
"Opioid Use Disorder and Associated Infectious Disease: The Role of the Laboratory in Addressing Health Disparities" (2021) The Journal of Applied Laboratory Medicine
Opioid Use Disorder and Associated Infectious Disease: The Role of the Laboratory in Addressing Health Disparities
(2021) The Journal of Applied Laboratory Medicine, 6 (1), pp. 180-193.
Farnsworth, C.W.a , Lloyd, M.a , Jean, S.b
a Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University, St. Louis, MO
b Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH
Abstract
BACKGROUND: Opioid use disorder, defined as a pattern of problematic opioid use leading to clinically significant impairment, has resulted in considerable morbidity and mortality throughout the world. This is due, at least in part, to the marginalized status of patients with opioid use disorder, limiting their access to appropriate laboratory testing, diagnosis, and treatment. Infections have long been associated with illicit drug use and contribute considerably to morbidity and mortality. However, barriers to testing and negative stigmas associated with opioid use disorder present unique challenges to infectious disease testing in this patient population. CONTENT: This review addresses the associations between opioid use disorder and infectious organisms, highlighting the health disparities encountered by patients with opioid use disorder, and the important role of laboratory testing for diagnosing and managing these patients. SUMMARY: Infections are among the most frequent and adverse complications among patients with opioid use disorder. As a result of health disparities and systemic biases, patients that misuse opioids are less likely to receive laboratory testing and treatment. However, laboratories play a crucial in identifying patients that use drugs illicitly and infections associated with illicit drug use. © American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Author Keywords
infectious disease; injection drug use; Opioid use disorder
Document Type: Article
Publication Stage: Final
Source: Scopus
"Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV" (2021) JAMA Network Open
Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV
(2021) JAMA Network Open, 4 (1), p. e2031190.
Nir, T.M.a , Fouche, J.-P.b , Ananworanich, J.c d e , Ances, B.M.f , Boban, J.g , Brew, B.J.h i j , Chaganti, J.R.k , Chang, L.l m n o , Ching, C.R.K.a , Cysique, L.A.p , Ernst, T.l n o , Faskowitz, J.a , Gupta, V.a , Harezlak, J.q , Heaps-Woodruff, J.M.r , Hinkin, C.H.s , Hoare, J.b , Joska, J.A.t , Kallianpur, K.J.u v , Kuhn, T.s , Lam, H.Y.a , Law, M.w , Lebrun-Frénay, C.x , Levine, A.J.y , Mondot, L.z , Nakamoto, B.K.n , Navia, B.A.aa , Pennec, X.ab ac , Porges, E.C.ad , Salminen, L.E.a , Shikuma, C.M.u , Surento, W.a , Thames, A.D.ae , Valcour, V.af ag , Vassallo, M.ah , Woods, A.J.ad , Thompson, P.M.a , Cohen, R.A.ad , Paul, R.ai , Stein, D.J.aj , Jahanshad, N.a
a Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey
b Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
c Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
d Thai Red Cross AIDS Research Centre, South East Asian Research Collaboration in HIVBangkok, Thailand
e AIGHD, University of Amsterdam, Amsterdam, Netherlands
f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
g Faculty of Medicine, Department of Radiology, University of Novi Sad, Novi Sad, Serbia
h Department of Neurology, St Vincent’s Hospital ,St Vincent’s Health Australia and University of New South Wales, Sydney, NSW, Australia
i Department of Immunology, St Vincent’s Hospital ,St Vincent’s Health Australia and University of New South Wales, Sydney, NSW, Australia
j Peter Duncan Neurosciences Unit, St Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
k Department of Medical Imaging, University of New South Wales, St Vincent’s Hospital, Sydney, NSW, Australia
l Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, United States
m Department of Neurology, University of Maryland School of Medicine, Baltimore, United States
n Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, United States
o Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
p School of Psychology, University of New South Wales, Sydney, NSW, Australia
q Department of Epidemiology and Biostatistics, Indiana University School of Public Health, Bloomington, United States
r Missouri Institute of Mental Health, University of Missouri, St Louis, United States
s Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Mexico
t HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
u Hawaii Center for AIDS, University of Hawaii, Honolulu, United States
v Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii, Honolulu, United States
w Department of Radiology, Monash University, Alfred Health, Melbourne, VIC, Australia
x Neurology, UR2CA, Centre Hospitalier Universitaire Pasteur 2, Université Nice Côte d’Azur, Nice, France
y Department of Neurology, University of California, Los Angeles, Mexico
z Department of Radiology, UR2CA, Centre Hospitalier Universitaire Pasteur 2, Université Nice Côte d’Azur, Nice, France
aa Infection Unit, School of Public Health, Tufts University Medical School, Boston, MA
ab Cote d’Azur University, Sophia Antipolis, France
ac Inria, Sophia Antipolis, France
ad Center for Cognitive Aging and Memory, Department of Clinical and Health Psychology, McKnight Brain Institute, University of Florida, Gainesville, United States
ae Department of Psychology, University of Southern California, Los Angeles, Mexico
af Memory and Aging Center, Department of Neurology, University of California, San Francisco, Mexico
ag Global Brain Health Institute, San Francisco, CA, Mexico
ah Internal Medicine/Infectious Diseases, Centre Hospitalier de Cannes, Cannes, France
ai Psychological Sciences, Missouri Institute of Mental Health, University of Missouri, St Louis, United States
aj SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa
Abstract
Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
Document Type: Article
Publication Stage: Final
Source: Scopus
"Racial Attitudes, Accumulation Mechanisms, and Disparities" (2021) Review of Philosophy and Psychology
Racial Attitudes, Accumulation Mechanisms, and Disparities
(2021) Review of Philosophy and Psychology, .
Mallon, R.
Department of Philosophy & Philosophy-Neuroscience-Psychology program, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, United States
Abstract
Some psychologists aim to secure a role for psychological explanations in understanding contemporary social disparities, a concern that plays out in debates over the relevance of the Implicit Association Test (IAT). Meta-analysts disagree about the predictive validity of the IAT and about the importance of implicit attitudes in explaining racial disparities. Here, I use the IAT to articulate and explore one route to establishing the relevance of psychological attitudes with small effects: an appeal to a process of “accumulation” that aggregates small effects into large harms. After characterizing mechanisms of accumulation and considering some candidate examples, I argue that such mechanisms suggest how a contemporary attitude with small effects could figure in the explanation of large disparities, but they do not vindicate the importance of such an attitude since such mechanisms are typically also determined by competing causes. I close by sketching several strategies for advancing a defense of the relevance of attitudes with small effects. © 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Pupil dilation signals recognition salience" (2021) Psychonomic Bulletin and Review
Pupil dilation signals recognition salience
(2021) Psychonomic Bulletin and Review, .
Dobbins, I.G.
Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO 63130, United States
Abstract
Stimuli that are recognized from a prior encounter elicit larger pupil dilations than those that are not. This study tests an account of this recognition dilation response (RDR) that assumes newly encountered recognition signals, like new percepts, elicit attentional orienting responses. Because orienting is moderated by motivational significance and expectation, the RDR was tested for these properties; manipulating incentives for “old” versus “new” judgments, and isolating the effects of runs of “old” versus “new” decisions on the subsequent RDR, in two experiments. Whereas incentivizing “new” decisions largely eliminated the RDR, incentivizing “old” decisions amplified it. Moreover, the RDR was prominent following runs of “new” decisions, yet minimal following runs of “old” decisions. Thus, the pupil dilates more as recognition memory becomes more valuable and/or unexpected. This recognition-orienting response was functionally separate from an additional, late dilation linked to feedback expectancy. Thus, the pupil separately signals the salience of recognition evidence, and the expectation of post-decision feedback. © 2021, The Psychonomic Society, Inc.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Modeling autosomal dominant Alzheimer's disease with machine learning" (2021) Alzheimer's and Dementia
Modeling autosomal dominant Alzheimer’s disease with machine learning
(2021) Alzheimer’s and Dementia, .
Luckett, P.H.a , McCullough, A.a , Gordon, B.A.a , Strain, J.a , Flores, S.a , Dincer, A.a , McCarthy, J.a , Kuffner, T.a , Stern, A.a , Meeker, K.L.a , Berman, S.B.b , Chhatwal, J.P.c , Cruchaga, C.a , Fagan, A.M.a , Farlow, M.R.d , Fox, N.C.e , Jucker, M.f , Levin, J.g h i , Masters, C.L.j , Mori, H.k , Noble, J.M.l , Salloway, S.m , Schofield, P.R.n o , Brickman, A.M.p , Brooks, W.S.n o , Cash, D.M.e , Fulham, M.J.q r , Ghetti, B.d , Jack, C.R., Jr.s , Vöglein, J.h , Klunk, W.b , Koeppe, R.t , Oh, H.m , Su, Y.u , Weiner, M.v , Wang, Q.a , Swisher, L.a , Marcus, D.a , Koudelis, D.a , Joseph-Mathurin, N.a , Cash, L.a , Hornbeck, R.a , Xiong, C.a , Perrin, R.J.a , Karch, C.M.a , Hassenstab, J.a , McDade, E.a , Morris, J.C.a , Benzinger, T.L.S.a , Bateman, R.J.a , Ances, B.M.a , for the Dominantly Inherited Alzheimer Network (DIAN)w
a Washington University in St. Louis, St. Louis, MO, United States
b University of Pittsburgh, Pittsburgh, PA, United States
c Brigham and Women’s Hospital, Massachusetts General Hospital, Boston, MA, United States
d Indiana University, Bloomington, IN, United States
e Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
f German Center for Neurodegenerative Disease, Tübingen, Germany
g Ludwig Maximilian University of Munich, Munich, Germany
h German Center for Neurodegenerative Diseases, Munich, Germany
i Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
j Florey Institute, The University of Melbourne, Parkville, VIC, Australia
k Osaka City University, Sumiyoshi Ward, Osaka, Japan
l Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, G.H. Sergievsky Center and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
m Brown University, Providence, RI, United States
n Neuroscience Research Australia, Randwick, NSW, Australia
o University of New South Wales, Sydney, NSW, Australia
p Columbia University, New York, NY, United States
q Department of Molecular Imaging, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, Australia
r University of Sydney, Sydney, NSW, Australia
s Mayo Clinic, Rochester, MN, United States
t University of Michigan, Ann Arbor, MI, United States
u Banner Alzheimer Institute, Phoenix, AZ, United States
v University of California, La Jolla, CA, United States
Abstract
Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer’s disease. Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non-carriers. Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions. © 2021 the Alzheimer’s Association
Author Keywords
autosomal dominant Alzheimer’s disease (ADAD); fluorodeoxyglucose (FDG); machine learning; magnetic resonance imaging (MRI); Pittsburgh compound B (PiB)
Funding details
Mayo Clinic
Biogen
National Institute on AgingNIA
National Institutes of HealthNIH
National Institutes of HealthNIHP01AG003991, P50AG005681, P01AG026276, UF1AG032438
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Gaining clarity about emotion differentiation" (2021) Social and Personality Psychology Compass
Gaining clarity about emotion differentiation
(2021) Social and Personality Psychology Compass, .
Thompson, R.J.a , Springstein, T.a , Boden, M.b
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychological and Brain Sciences, VA Palo Alto Health Care System, Palo Alto, CA, United States
Abstract
Emotion differentiation captures the detail with which people describe their emotional experiences. A compelling body of research has linked low and negative emotion differentiation to a host of adverse psychological outcomes, yet conceptual and methodological questions and issues remain. We think that the time is right to review and reflect on this growing literature to gain clarity that can be applied to future research. We first review assessment of emotion differentiation while highlighting the methodological variation across studies. Then supported by the literature review, we discuss disconnections between the conceptualization and measurement of differentiation. Finally, to motivate future research, we propose factors that we hypothesize are associated with potentially beneficial effects of emotion differentiation in a given situation (i.e., related to state emotion differentiation) and more generally across time (i.e., related to trait emotion differentiation). © 2021 John Wiley & Sons Ltd.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"The importance of advancing research on aging and driving" (2021) Geriatrics (Switzerland)
The importance of advancing research on aging and driving
(2021) Geriatrics (Switzerland), 6 (1), art. no. 7, pp. 1-3.
Murphy, S.A., Babulal, G.M., Roe, C.M.
Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
Funding details
BrightFocus FoundationBFFA2021142S
R01-AG056466, R01AG067428, R01-AG068183
Document Type: Editorial
Publication Stage: Final
Source: Scopus
"Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status" (2021) NeuroImage: Clinical
Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status
(2021) NeuroImage: Clinical, 29, art. no. 102553, .
Koenig, L.N.a , McCue, L.M.b , Grant, E.b , Massoumzadeh, P.a , Roe, C.M.c , Xiong, C.b , Moulder, K.L.c , Wang, L.a , Zazulia, A.R.a c , Kelly, P.c , Dincer, A.a , Zaza, A.a , Shimony, J.S.a , Benzinger, T.L.S.a , Morris, J.C.c
a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship. Methods: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical β-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke. Results: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049). Conclusion: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in β-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI. © 2020
Author Keywords
African American; Amyloid PET; MRI; Preclinical Alzheimer Disease; Stroke
Funding details
National Institute on AgingNIAP01AG003991, U19AG032438, P50AG005681, P01AG026276
National Institutes of HealthNIH
Eli Lilly and Company
Document Type: Article
Publication Stage: Final
Source: Scopus
"Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC" (2021) Alzheimer's and Dementia
Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC
(2021) Alzheimer’s and Dementia, .
Gianattasio, K.Z.a , Bennett, E.E.a , Wei, J.a , Mehrotra, M.L.b , Mosley, T.c , Gottesman, R.F.d , Wong, D.F.e , Stuart, E.A.f , Griswold, M.E.g , Couper, D.h , Glymour, M.M.b , Power, M.C.a , for the Alzheimer’s Disease Neuroimaging Initiativei
a Department of Epidemiology, George Washington University, Washington, DC, United States
b Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, United States
c Department of Neurology, University of Mississippi Medical Center, Jackson, MS, United States
d Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, United States
e Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
g Department of Biostatistics, University of Mississippi Medical Center, Jackson, MS, United States
h Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States
Abstract
Introduction: Clinic-based study samples, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings. Methods: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates. Results: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6). Discussion: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples. © 2021 the Alzheimer’s Association
Author Keywords
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; Atherosclerosis Risk in Communities; dementia; generalizability
Funding details
National Institute on AgingNIA
AbbVie
Alzheimer’s Drug Discovery FoundationADDF
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
Biogen
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s Disease Neuroimaging InitiativeADNI
BioClinica
Alzheimer’s AssociationAA
National Institute on AgingNIAR01AG040282
National Heart, Lung, and Blood InstituteNHLBI
National Institutes of HealthNIH
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBIHHSN268201700003I, 2U01HL096917, 2U01HL096902, HHSN268201700004I, 2U01HL096899, 2U01HL096814, HHSN268201700002I, HHSN268201700001I, U01 2U01HL096812, HHSN268201700005I
National Institute of Neurological Disorders and StrokeNINDS
National Institute on Deafness and Other Communication DisordersNIDCDR01‐HL70825
Avid Radiopharmaceuticals
H. Lundbeck A/S
National Institutes of HealthNIH
Roche Diagnostics
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"The Relationship Between Depression Symptoms and Adolescent Neural Response During Reward Anticipation and Outcome Depends on Developmental Timing: Evidence From a Longitudinal Study" (2021) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
The Relationship Between Depression Symptoms and Adolescent Neural Response During Reward Anticipation and Outcome Depends on Developmental Timing: Evidence From a Longitudinal Study
(2021) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, .
Luking, K.R.a , Gilbert, K.b , Kelly, D.b , Kappenman, E.S.c , Hajcak, G.d , Luby, J.L.b , Barch, D.M.a b
a Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychology, San Diego State University, San Diego, CA, United States
d Departments of Psychology and Neuroscience, Florida State University, Tallahassee, FL, United States
Abstract
Background: Blunted neural reward responsiveness (RR) is observed in youth depression. However, it is unclear whether symptoms of depression experienced early in development relate to adolescent RR beyond current symptoms and, further, whether such relationships with RR differ during two key components of reward processing: anticipation and outcome. Methods: Within a prospective longitudinal study oversampled for early depression, children and caregivers completed semiannual diagnostic assessments beginning in preschool. In later adolescence, mean age = 16.49 years (SD = 0.94), youths’ (N = 100) neurophysiological responses to cues signaling likely win and loss and these outcomes were assessed. Longitudinally assessed dimensional depression and externalizing symptoms (often comorbid with depression as well as associated with RR) experienced at different developmental periods (preschool [age 3–5.11 years], school age [6–9.11 years], early adolescence [10–14.11 years], current) were used as simultaneous predictors of event-related potentials indexing anticipatory cue processing (cue-P3) and outcome processing (reward positivity/feedback negativity and feedback-P3). Results: Blunted motivated attention to cues signaling likely win (cue-P3) was specifically predicted by early-adolescent depression symptoms. Blunted initial response to win (reward positivity) and loss (feedback negativity) outcomes was specifically predicted by preschool depression symptoms. Blunted motivational salience of win and loss outcomes (feedback-P3) was predicted by cumulative depression, not specific to any developmental stage. Conclusions: Although blunted anticipation and outcome RR is a common finding in depression, specific deficits related to motivated attention to cues and initial outcome processing may map onto the developmental course of these symptoms. © 2020 Society of Biological Psychiatry
Author Keywords
Adolescent; Depression; Development; EEG/evoked potentials; Preschool; Reward
Funding details
National Institutes of HealthNIHR01 MH098454, 2R01 MH064769-06
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Srf is required for maintenance of astrocytes in non-reactive state in the mammalian brain" (2021) eNeuro
Srf is required for maintenance of astrocytes in non-reactive state in the mammalian brain
(2021) eNeuro, 8 (1), art. no. ENEURO.0447-19.2020, pp. 1-15.
Jain, M.a , Das, S.a , Lu, P.P.Y.b , Virmani, G.a , Soman, S.a , Thumu, S.C.R.a , Gutmann, D.H.c , Ramanan, N.a
a Centre for Neuroscience, Indian Institute of Science, Bangalore, Karnataka, 560012, India
b Jiangsu Hengrui Medicine, Cambridge, MA 02139, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Astrocytes play several critical roles in the normal functioning of the mammalian brain, including ion homeosta-sis, synapse formation, and synaptic plasticity. Following injury and infection or in the setting of neurodegener-ation, astrocytes become hypertrophic and reactive, a process termed astrogliosis. Although acute reactive gliosis is beneficial in limiting further tissue damage, chronic gliosis becomes detrimental for neuronal recovery and regeneration. Several extracellular factors have been identified that generate reactive astrocytes; however, very little is known about the cell-autonomous transcriptional mechanisms that regulate the maintenance of astrocytes in the normal non-reactive state. Here, we show that conditional deletion of the stimulus-dependent transcription factor, serum response factor (SRF) in astrocytes (SrfGFAP CKO) results in astrogliosis marked by hypertrophic morphology and increased expression of GFAP, vimentin, and nestin. These reactive astrocytes were not restricted to any specific brain region and were seen in both white and gray matter in the entire brain. This astrogliosis persisted throughout adulthood concomitant with microglial activation. Importantly, the Srf mutant mouse brain did not exhibit any cell death or blood brain barrier (BBB) deficits suggesting that apo-ptosis and leaky BBB are not the causes for the reactive phenotype. The mutant astrocytes expressed more A2 reactive astrocyte marker genes and the SrfGFAP CKO mice exhibited normal neuronal numbers indicating that SRF-deficient gliosis astrocytes are not neurotoxic. Together, our findings suggest that SRF plays a critical role in astrocytes to maintain them in a non-reactive state. © 2021 Jain et al.
Author Keywords
Astrogliosis; Gliosis; Reactive astrocytes; Serum response factor
Funding details
Department of Science and Technology, Ministry of Science and Technology, Indiaडीएसटी
Council for Scientific and Industrial Research, South AfricaCSIR
University Grants CommissionUGC
BT/PR26216/GET/119/234/2017
Document Type: Article
Publication Stage: Final
Source: Scopus
"Electric Field Stimulation for the Functional Assessment of Isolated Dorsal Root Ganglion Neuron Excitability" (2021) Annals of Biomedical Engineering
Electric Field Stimulation for the Functional Assessment of Isolated Dorsal Root Ganglion Neuron Excitability
(2021) Annals of Biomedical Engineering, .
Berke, I.M.a , McGrath, T.M.a , Stivers, J.J.b , Gui, C.a , Barcellona, M.N.a , Gayoso, M.G.a , Tang, S.Y.b c , Cao, Y.-Q.d , Gupta, M.C.c , Setton, L.A.a b c
a Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, Campus Box 1097, St. Louis, MO 63130, United States
b Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
c Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Genetically encoded calcium indicators have proven useful for characterizing dorsal root ganglion neuron excitability in vivo. Challenges persist in achieving high spatial–temporal resolutions in vivo, however, due to deep tissue imaging and motion artifacts that may be limiting technical factors in obtaining measurements. Here we report an ex vivo imaging method, using a peripheral neuron-specific Advillin-GCaMP mouse line and electric field stimulation of dorsal root ganglion tissues, to assess the sensitivity of neurons en bloc. The described method rapidly characterizes Ca2+ activity in hundreds of dorsal root ganglion neurons (221 ± 64 per dorsal root ganglion) with minimal perturbation to the in situ soma environment. We further validate the method for use as a drug screening platform with the voltage-gated sodium channel inhibitor, tetrodotoxin. Drug treatment led to decreased evoked Ca2+ activity; half-maximal response voltage (EV50) increased from 13.4 V in untreated tissues to 21.2, 23.3, 51.5 (p < 0.05), and 60.6 V (p < 0.05) at 0.01, 0.1, 1, and 10 µM doses, respectively. This technique may help improve an understanding of neural signaling while retaining tissue structural organization and serves as a tool for the rapid ex vivo recording and assessment of neural activity. © 2021, Biomedical Engineering Society.
Author Keywords
Calcium imaging; Drug screening; GCaMP; GECI; High content imaging; Nervous system
Funding details
National Institutes of HealthNIHAR077678, AR070975, AR074441, AR069588
National Science FoundationNSFDGE-1745038
Orthopaedic Research and Education FoundationOREFP20-03413
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Ketamine for Depression in Older Adults" (2021) American Journal of Geriatric Psychiatry
Ketamine for Depression in Older Adults
(2021) American Journal of Geriatric Psychiatry, .
Subramanian, S., Lenze, E.J.
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus
"Implantable Optofluidic Systems for Wireless In Vivo Photopharmacology" (2021) ChemPhotoChem
Implantable Optofluidic Systems for Wireless In Vivo Photopharmacology
(2021) ChemPhotoChem, .
Qazi, R.a b , Yeon Kim, C.a , Kang, I.a , Binazarov, D.a , G. McCall, J.c , Jeong, J.-W.a
a School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
b Department of Electrical, Computer and Energy Engineering, University of Colorado, Boulder, CO, United States
c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
The front cover artwork is provided by the Jeong Group at the School of Electrical Engineering at Korea Advanced Institute of Science and Technology (KAIST; South Korea). The image illustrates an ultrathin, soft and biocompatible optofluidic probe, which can deliver both light and drugs for in vivo photopharmacology. Read the full text of the Minireview at 10.1002/cptc.2020000217. © 2021 Wiley-VCH GmbH
Document Type: Note
Publication Stage: Article in Press
Source: Scopus
"Alteplase and Adjuvant Therapies for Acute Ischemic Stroke" (2021) Seminars in Neurology
Alteplase and Adjuvant Therapies for Acute Ischemic Stroke
(2021) Seminars in Neurology, .
Gottula, A.L.a , Barreto, A.D.b , Adeoye, O.c
a Department of Emergency Medicine, University of Cincinnati, 231 Albert Sabin Way, MSB 1654, Cincinnati, OH 45267-0769, United States
b Department of Neurology, University of Texas Houston, Houston, TX, United States
c Department of Emergency Medicine, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
Acute ischemic stroke (AIS) is a time sensitive medical emergency and a leading cause of morbidity and mortality worldwide. Intravenous (IV) recombinant tissue plasminogen activator (IV alteplase) is currently the only proven effective medication for the treatment of AIS with promising adjuvant medications currently under investigation. Recent advances in endovascular thrombectomy have broadened therapeutic options in specific patient populations, with modern treatment strategies utilizing advanced imaging modalities to extend the window for treatment. In all cases, rapid treatment remains a priority. The future of IV alteplase and the changing standard for treatment of AIS remain unwritten with the increasing evidence for imaging selection for both endovascular thrombectomy and IV alteplase, while novel adjuncts are under investigation. In this article, we review the history of IV alteplase investigations for stroke, evidence for thrombectomy as an adjunct to IV alteplase, and the potential of novel adjuvant therapeutics currently under investigation. © 2021 S. Karger AG. All rights reserved.
Author Keywords
alteplase; argatroban; eptifibatide; ischemic; stroke; thrombectomy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients" (2021) Journal of Human Genetics
Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients
(2021) Journal of Human Genetics, .
Wongkittichote, P.a , Wegner, D.J.b , Shinawi, M.S.a
a Division of Genetics and Genomic Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
b Division of Newborn Medicine, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
Abstract
HCFC1, a global transcriptional regulator, has been shown to associate with MMACHC expression. Pathogenic variants in HCFC1 cause X-linked combined methylmalonic acidemia and hyperhomocysteinemia, CblX type (MIM# 309541). Recent studies showed that certain variants in HCFC1 are associated with X-linked intellectual disability with mild or absent metabolic abnormalities. Here, we report five subjects (three males, two females) from the same family with a novel predicted loss of function HCFC1 variant. All five patients exhibit developmental delay or intellectual disability/learning difficulty and some dysmorphic features; findings were milder in the female as compared to male subjects. Biochemical studies in all patients did not show methylmalonic acidemia or hyperhomocysteinemia but revealed elevated vitamin B12 levels. Trio exome sequencing of the proband and his parents revealed a maternally inherited novel variant in HCFC1 designated as c.1781_1803 + 3del26insCA (NM_005334). Targeted testing confirmed the presence of the same variant in two half-siblings and maternal great uncle. In silico analysis showed that the variant is expected to reduce the quality of the splice donor site in intron 10 and causes abnormal splicing. Sequencing of proband’s cDNA revealed exon 10 skipping. Further molecular studies in the two manifesting females revealed moderate and high skewing of X inactivation. Our results support previous observation that HCFC1 variants located outside the Kelch domain exhibit dissociation of the clinical and biochemical phenotype and cause milder or no metabolic changes. We also show that this novel variant can be associated with a phenotype in females, although with milder severity, but further studies are needed to understand the role of skewed X inactivation among females in this rare disorder. Our work expands the genotypes and phenotypes associated with HCFC1-related disorder. © 2021, The Author(s), under exclusive licence to The Japan Society of Human Genetics.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow-up study" (2021) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow-up study
(2021) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, .
Soundararajan, S.a b c , Agrawal, A.d , Purushottam, M.c e , Anand, S.D.b , Shankarappa, B.c , Sharma, P.b f , Jain, S.c e , Murthy, P.b e
a Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
b Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
c Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
f Department of Clinical Pharmacology and Neurotoxicology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
Abstract
Treatment strategies for alcohol use disorder (AUD) aim for abstinence or harm reduction. While deranged biochemical parameters reverse with alcohol abstinence, whether molecular changes at the epigenetic level reverse is not clearly understood. We investigated whether the reduction from high alcohol use reflects DNA methylation at the gene-specific and global level. In subjects seeking treatment for severe AUD, we assessed gene-specific (aldehyde dehydrogenase [ALDH2]/methylene tetrahydrofolate reductase [MTHFR]) and global (long interspersed elements [LINE-1]) methylation across three-time points (baseline, after detoxification and at an early remission period of 3 months), in peripheral blood leukocytes. We observed that both gene-specific and global DNA methylation did not change over time, irrespective of the drinking status at 3 months (52% abstained from alcohol). Further, we also compared DNA methylation in AUD subjects with healthy controls. At baseline, there was a significantly higher gene-specific DNA methylation (ALDH2: p <.001 and MTHFR: p =.001) and a significant lower global methylation (LINE-1: p =.014) in AUD as compared to controls. Our results suggest that epigenetic changes at the DNA methylation level associated with severe AUD persist for at least 3 months of treatment. © 2021 Wiley Periodicals LLC
Author Keywords
alcohol abstinence; alcohol use disorder; DNA methylation; long interspersed nucleotide elements; pyrosequencing
Funding details
National Institutes of HealthNIH
Indian Council of Medical ResearchICMR
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Serotonin 5-HT1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant" (2021) Psychopharmacology
Serotonin 5-HT1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant
(2021) Psychopharmacology, .
O’Reilly, K.C.a , Connor, M.b c , Pierson, J.d , Shuffrey, L.C.a , Blakely, R.D.e , Ahmari, S.E.d , Veenstra-VanderWeele, J.a c
a Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Dr., Unit 78, New York, NY 10032, United States
b Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, United States
c Vanderbilt University, Nashville, TN 37232, United States
d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219, United States
e Brain Institute and Department of Biomedical Science, Florida Atlantic University, Jupiter, FL 33458, United States
Abstract
Rationale: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. Objectives: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. Methods: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. Results: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. Conclusions: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
Author Keywords
5-HT1B; ASD; Autism spectrum disorder; Obsessive-compulsive disorder; OCD; Orbitofrontal cortex; Prepulse inhibition of startle; RU24969; Sensorimotor gating; Serotonin
Funding details
National Institutes of HealthNIHMH081066, MH114296, T32MH016434, MH094604
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Herpesvirus Infections and Risk of Parkinson's Disease" (2021) Neurodegenerative Diseases
Herpesvirus Infections and Risk of Parkinson’s Disease
(2021) Neurodegenerative Diseases, .
Camacho-Soto, A.a , Faust, I.a , Racette, B.A.a b , Clifford, D.B.a , Checkoway, H.c d , Searles Nielsen, S.a
a Department of Neurology, Washington University, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
c Department of Family Medicine and Public Health, University of California, San Diego, CA, United States
d Department of Neurosciences, University of California, San Diego, CA, United States
Abstract
Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson’s disease. Methods: We conducted a population-based case-control study of incident Parkinson’s disease in 2009 Medicare beneficiaries age 66-90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for “herpes simplex”and/or “herpes zoster”in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson’s disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care. Results: Parkinson’s disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74-0.84), herpes zoster (OR 0.88, 95% CI 0.85-0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80-0.96). Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson’s disease, but future studies will be required to explore whether this inverse association is causal. © 2021 Cambridge University Press. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder" (2021) Molecular Psychiatry
Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
(2021) Molecular Psychiatry, .
Jia, X.a , Goes, F.S.b , Locke, A.E.c , Palmer, D.d , Wang, W.e , Cohen-Woods, S.f g , Genovese, G.d , Jackson, A.U.h , Jiang, C.i , Kvale, M.j , Mullins, N.k , Nguyen, H.e , Pirooznia, M.l , Rivera, M.g m , Ruderfer, D.M.n , Shen, L.i , Thai, K.i , Zawistowski, M.h , Zhuang, Y.h , Abecasis, G.h , Akil, H.o , Bergen, S.p , Burmeister, M.o q r s , Champion, S.d , DelaBastide, M.t , Juréus, A.p , Kang, H.M.h , Kwok, P.-Y.j , Li, J.Z.q r , Levy, S.E.u , Monson, E.T.v , Moran, J.w , Sobell, J.x , Watson, S.o , Willour, V.v , Zöllner, S.h s , Adolfsson, R.y , Blackwood, D.z , Boehnke, M.h , Breen, G.g aa , Corvin, A.ab , Craddock, N.ac , DiFlorio, A.ac , Hultman, C.M.p , Landen, M.p ad , Lewis, C.g ae , McCarroll, S.A.af , Richard McCombie, W.t , McGuffin, P.g , McIntosh, A.z ag , McQuillin, A.ah , Morris, D.ab ai , Myers, R.M.u , O’Donovan, M.ac , Ophoff, R.aj ak , Boks, M.ak , Kahn, R.al , Ouwehand, W.am , Owen, M.ac , Pato, C.x an , Pato, M.x ao , Posthuma, D.ap aq , Potash, J.B.b , Reif, A.ar , Sklar, P.e , Smoller, J.d as , Sullivan, P.F.at , Vincent, J.au av , Walters, J.ac , Neale, B.d aw , Purcell, S.ax ay , Risch, N.j , Schaefer, C.i , Stahl, E.A.e , Zandi, P.P.b , Scott, L.J.h
a Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, United States
b Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States
c Division of Genomics & Bioinformatics, Department of Medicine and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, United States
d Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
e Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
f Discipline of Psychology and Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, Australia
g Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
h Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, United States
i Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, United States
j Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, United States
k Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
l Bioinformatics and Computational Core, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, United States
m Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
n Departments of Medicine, Psychiatry, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, United States
o Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States
p Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
q Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United States
r Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, United States
s Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States
t Division of Research, Cold Spring Harbor Laboratory, Cold Spring, Harbor, NY 11797, United States
u HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
v Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
w Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, United States
x Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA 90033, United States
y Departments of Clinical Sciences and Psychiatry, Umea University, Umea, Sweden
z Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
aa NIHR BRC for Mental Health, King’s College London, London, United Kingdom
ab Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
ac Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, United Kingdom
ad Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
ae Department of Medical & Molecular Genetics, King’s College London, London, United Kingdom
af Department of Genetics, Harvard Medical School, Boston, MA 02115, United States
ag Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
ah Division of Psychiatry, University College London, London, United Kingdom
ai Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland Galway, Galway, Ireland
aj Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095, United States
ak Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, Netherlands
al Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
am Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
an SUNY Downstate Medical Center, Brooklyn, NY 11203, United States
ao Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY 11203, United States
ap Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
aq Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, Netherlands
ar Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
as Department of Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States
at Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, United States
au Molecular Neuropsychiatry and Development Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction & Mental Health, Toronto, ON, Canada
av Department of Psychiatry and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
aw Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
ax Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, United States
ay Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
Abstract
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ. © 2021, The Author(s).
Funding details
Kaiser Permanente Washington Health Research InstituteKPWHRI
National Institutes of HealthNIHGERA RC2 AG036607, R01 MH 085543
National Institute of Mental HealthNIMHR01 MH 110437, R01 MH 094145, UO1 MH105653
Dalio Foundation
R01MH077139, R01 MH 087979, R01MH106531, R01MH106527, MH 087992, R01MH095034
Takeda Pharmaceuticals North AmericaTPNA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
"Dynamic 18F-FDOPA-PET/MRI for the preoperative evaluation of gliomas: Correlation with stereotactic histopathology" (2020) Neuro-Oncology Practice
Dynamic 18F-FDOPA-PET/MRI for the preoperative evaluation of gliomas: Correlation with stereotactic histopathology
(2020) Neuro-Oncology Practice, 7 (6), pp. 656-667.
Ponisio, M.R.a , McConathy, J.E.b , Dahiya, S.M.c , Miller-Thomas, M.M.a , Rich, K.M.d , Salter, A.e , Wang, Q.a , LaMontagne, P.J.a , Guzmán Pérez-Carrillo, G.J.a , Benzinger, T.L.S.a
a Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St Louis, MO, United States
b Department of Radiology, Division of Molecular Imaging andTherapeutics, University of Alabama at Birmingham, Birmingham, AL, United States
c Department of Pathology and Immunology, Washington University, School of Medicine, St Louis, MO, United States
d Department of Neurosurgery, Washington University, School of Medicine, St Louis, MO, United States
e Department of Biostatistics, Washington University, School of Medicine, St Louis, MO, United States
Abstract
Background. MRI alone has limited accuracy for delineating tumor margins and poorly predicts the aggressiveness of gliomas, especially when tumors do not enhance.This study evaluated simultaneous 3,4-dihydroxy-6-[18F] fluoro-L-phenylalanine (FDOPA)-PET/MRI to define tumor volumes compared to MRI alone more accurately, assessed its role in patient management, and correlated PET findings with histopathology. Methods. Ten patients with known or suspected gliomas underwent standard of care surgical resection and/or stereotactic biopsy. FDOPA-PET/MRI was performed prior to surgery, allowing for precise co-registration of PET, MR, and biopsies.The biopsy sites were modeled as 5-mm spheres, and the local FDOPA uptake at each site was determined. Correlations were performed between measures of tumor histopathology, and static and dynamic PET values: standardized uptake values (SUVs), tumor to brain ratios, metabolic tumor volumes, and tracer kinetics at volumes of interest (VOIs) and biopsy sites. Results. Tumor FDOPA-PET uptake was visualized in 8 patients. In 2 patients, tracer uptake was similar to normal brain reference with no histological findings of malignancy. Eight biopsy sites confirmed for glioma had FDOPA uptake withoutT1 contrast enhancement.The PET parameters were highly correlated only with the cell proliferation marker, Ki-67 (SUVmax: r = 0.985, P =.002). In this study, no statistically significant difference between high-grade and low-grade tumors was demonstrated.The dynamic PET analysis of VOIs and biopsy sites showed decreasing time-activity curves patterns. FDOPA-PET imaging directly influenced patient management. Conclusions. Simultaneous FDOPA-PET/MRI allowed for more accurate visualization and delineation of gliomas, enabling more appropriate patient management and simplified validation of PET findings with histopathology. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Adult gliomas; Dynamic FDOPA-PET; Glioma delineation; PET/MRI; Stereotactic biopsy
Document Type: Article
Publication Stage: Final
Source: Scopus
"Serum neurofilament light chain uncovers neurodegeneration early in the course of Alzheimer's disease" (2020) Brain
Serum neurofilament light chain uncovers neurodegeneration early in the course of Alzheimer’s disease
(2020) Brain, 143 (12), pp. 3521-3522.
Brier, M.R.a , Day, G.S.b
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
Document Type: Note
Publication Stage: Final
Source: Scopus
"Pediatric Ischemic Stroke: An Infrequent Complication of SARS-CoV-2" (2020) Annals of Neurology
Pediatric Ischemic Stroke: An Infrequent Complication of SARS-CoV-2
(2020) Annals of Neurology, .
Beslow, L.A.a , Linds, A.B.b , Fox, C.K.c , Kossorotoff, M.d , Zuñiga Zambrano, Y.C.e , Hernández-Chávez, M.f , Hassanein, S.M.A.g , Byrne, S.h i , Lim, M.h j , Maduaka, N.k , Zafeiriou, D.l , Dowling, M.M.m , Felling, R.J.n , Rafay, M.F.o , Lehman, L.L.p , Noetzel, M.J.q , Bernard, T.J.r , Dlamini, N.b s , International Pediatric Stroke Study Groupt
a Division of Neurology, Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
b Division of Neurology, Department of Paediatrics, and Child Health Evaluative Sciences Program, The Hospital for Sick Children, Toronto, ON, Canada
c Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA, United States
d French Center for Pediatric Stroke, Pediatric Neurology Department, APHP University Hospital Necker-Enfants Maladies, Paris, France
e Unit of Pediatric Neurology, Fundación, Hospital de la Misericordia, Bogotá, Colombia
f Unit of Neurology, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
g Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
h Evelina London Children’s Hospital, London, United Kingdom
i FutureNeuro, Royal College of Surgeons, Dublin, Ireland
j Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
k Paediatric Department, King’s College Hospital, London, United Kingdom
l Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
m Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
n Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
o Section of Neurology, Department of Pediatrics and Child Health, Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada
p Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
q Departments of Neurology and Pediatrics, Division of Pediatric and Developmental Neurology, Washington University School of Medicine, Neurorehabilitation Program, St. Louis Children’s Hospital, St. Louis, MO, United States
r Section of Child Neurology, Children’s Hospital Colorado, Departments of Pediatrics and Neurology, Hemophilia and Thrombosis Center, University of Colorado School of Medicine, Aurora, CO, United States
s Department of Paediatrics, University of Toronto, Toronto, ON, Canada
Abstract
Objective: Severe complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include arterial ischemic stroke (AIS) in adults and multisystem inflammatory syndrome in children. Whether stroke is a frequent complication of pediatric SARS-CoV-2 is unknown. This study aimed to determine the proportion of pediatric SARS-CoV-2 cases with ischemic stroke and the proportion of incident pediatric strokes with SARS-CoV-2 in the first 3 months of the pandemic in an international cohort. Methods: We surveyed 61 international sites with pediatric stroke expertise. Survey questions included: numbers of hospitalized pediatric (≤ 18 years) patients with SARS-CoV-2; numbers of incident neonatal and childhood ischemic strokes; frequency of SARS-CoV-2 testing for pediatric patients with stroke; and numbers of stroke cases positive for SARS-CoV-2 from March 1 to May 31, 2020. Results: Of 42 centers with SARS-CoV-2 hospitalization numbers, 8 of 971 (0.82%) pediatric patients with SARS-CoV-2 had ischemic strokes. Proportions of stroke cases positive for SARS-CoV-2 from March to May 2020 were: 1 of 108 with neonatal AIS (0.9%), 0 of 33 with neonatal cerebral sinovenous thrombosis (CSVT; 0%), 6 of 166 with childhood AIS (3.6%), and 1 of 54 with childhood CSVT (1.9%). However, only 30.5% of neonates and 60% of children with strokes were tested for SARS-CoV-2. Therefore, these proportions represent 2.9, 0, 6.1, and 3.0% of stroke cases tested for SARS-CoV-2. Seven of 8 patients with SARS-CoV-2 and stroke had additional established stroke risk factors. Interpretation: As in adults, pediatric stroke is an infrequent complication of SARS-CoV-2, and SARS-CoV-2 was detected in only 4.6% of pediatric patients with ischemic stroke tested for the virus. However, < 50% of strokes were tested. To understand the role of SARS-CoV-2 in pediatric stroke better, SARS-CoV-2 testing should be considered in pediatric patients with stroke as the pandemic continues. ANN NEUROL 2021. © 2020 American Neurological Association
Document Type: Article
Publication Stage: Article in Press
Source: Scopus