“The mechanism of Annexin A1 to modulate TRPV1 and nociception in dorsal root ganglion neurons” (2021) Cell and Bioscience
The mechanism of Annexin A1 to modulate TRPV1 and nociception in dorsal root ganglion neurons
(2021) Cell and Bioscience, 11 (1), art. no. 167, .
Zhang, Y.a b f , Ma, S.a b , Ke, X.a b , Yi, Y.a b , Yu, H.a b , Yu, D.a b , Li, Q.c , Shang, Y.b d , Lu, Y.b e , Pei, L.a b f
a Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
b Collaborative Innovation Center for Brain Science, The Institute for Brain Research (IBR), Huazhong University of Science and Technology, Wuhan, 430030, China
c Exchange, Development & Service Center for Science & Technology Talents, The Ministry of Science and Technology (Most), Beijing, 100045, China
d Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
e Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
f Department of Anesthesiology, School of Medicine, Washington University in Saint Loius, St. Loius, MO 63110, United States
Abstract
Background: Annexin A1 (ANXA1) exerts anti-nociceptive effect through ANXA1 receptor formyl peptide receptor 2 (FPR2/ALX (receptor for lipoxin A4), FPR2) at the dorsal root ganglia (DRG) level. However, the mechanisms remain elucidated. By using radiant heat, hot/cold plate, tail flick, von Frey, and Randall-Selitto tests to detect nociception in intact and chemical (capsaicin, menthol, mustard oil, formalin or CFA) injected AnxA1 conditional knockout (AnxA1−/−) mice, applying calcium imaging and patch clamp recordings in cultured DRG neurons to measure neuronal excitability, conducting immunofluorescence and western blotting to detect the protein levels of TRPV1, FPR2 and its downstream molecules, and performing double immunofluorescence and co-immunoprecipitation to investigate the interaction between Calmodulin (CaM) and TRPV1; we aim to uncover the molecular and cellular mechanisms of ANXA1’s role in antinociception. Results: AnxA1−/− mice exhibited significant sensitivity to noxious heat (mean ± SD, 6.2 ± 1.0 s vs. 9.9 ± 1.6 s in Hargreaves test; 13.6 ± 1.5 s vs. 19.0 ± 1.9 s in hot plate test; n = 8; P < 0.001), capsaicin (101.0 ± 15.3 vs. 76.2 ± 10.9; n = 8; P < 0.01), formalin (early phase: 169.5 ± 32.8 s vs. 76.0 ± 21.9 s; n = 8; P < 0.05; late phase: 444.6 ± 40.1 s vs. 320.4 ± 33.6 s; n = 8; P < 0.01) and CFA (3.5 ± 0.8 s vs. 5.9 ± 1.4 s; n = 8; P < 0.01). In addition, we found significantly increased capsaicin induced Ca2+ response, TRPV1 currents and neuronal firing in AnxA1 deficient DRG neurons. Furthermore, ANXA1 mimic peptide Ac2-26 robustly increased intracellular Ca2+, inhibited TRPV1 current, activated PLCβ and promoted CaM-TRPV1 interaction. And these effects of Ac2-26 could be attenuated by FPR2 antagonist Boc2. Conclusions: Selective deletion of AnxA1 in DRG neurons enhances TRPV1 sensitivity and deteriorates noxious heat or capsaicin induced nociception, while ANXA1 mimic peptide Ac2-26 desensitizes TRPV1 via FPR2 and the downstream PLCβ-Ca2+-CaM signal. This study may provide possible target for developing new analgesic drugs in inflammatory pain. © 2021, The Author(s).
Author Keywords
Annexin A1; Formyl peptide receptor; Neuronal sensitivity; Nociceptive sensation; Transient receptor potential vanilloid 1
Funding details
Washington University School of Medicine in St. Louis
National Natural Science Foundation of ChinaNNSFC81200863, 81571078, 81870932
Document Type: Article
Publication Stage: Final
Source: Scopus
“Physical activity and cognitive and imaging biomarkers of Alzheimer’s disease in down syndrome” (2021) Neurobiology of Aging
Physical activity and cognitive and imaging biomarkers of Alzheimer’s disease in down syndrome
(2021) Neurobiology of Aging, 107, pp. 118-127.
Fleming, V.a b , Piro-Gambetti, B.a b , Patrick, A.a c , Zammit, M.a c , Alexander, A.a c , Christian, B.T.a c , Handen, B.d , Cohen, A.d , Klunk, W.d , Laymon, C.e , Ances, B.M.f , Plante, D.T.g , Okonkwo, O.g h , Hartley, S.L.a b
a Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
b School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States
c Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
g Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States
h Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
Abstract
Adults with Down syndrome (DS) are at risk for Alzheimer’s disease. Despite sharing trisomy 21, however, there is variability in the age of disease onset. This variability may mean that other factors, such as lifestyle, influence cognitive aging and disease timing. The present study assessed the association between everyday life physical activity using an actigraph accelerometer and cognitive functioning and early Alzheimer’s disease pathology via positron emission tomography amyloid-β and tau and diffusion tension imaging measures of white matter integrity in 61 non-demented adults with DS. Percent time in sedentary behavior and in moderate-to-vigorous activity were associated (negatively and positively, respectively) with cognitive functioning (r = -.472 to.572, p < 0.05). Neither sedentary behavior nor moderate-to-vigorous activity were associated with amyloid-β or tau, but both were associated with white matter integrity in the superior and inferior longitudinal fasciculus (Fractional Anisotropy: r = -.397 to -.419, p < 0.05; Mean Diffusivity: r =.400, p < 0.05). Longitudinal studies are needed to determine if physical activity promotes healthy aging in DS. © 2021 Elsevier Inc.
Author Keywords
Alzheimer’s disease; Biomarkers; Cognitive functioning; Down syndrome; Physical activity
Funding details
National Institute on AgingNIAR01 AG031110, R01 AG070028, U01 AG051406, U19 AG068054
National Institute of Child Health and Human DevelopmentNICHDU54 HD09025
Document Type: Article
Publication Stage: Final
Source: Scopus
“A cohort study of neuropsychological functioning in spouses of U.S. Gulf War veterans” (2021) Life Sciences
A cohort study of neuropsychological functioning in spouses of U.S. Gulf War veterans
(2021) Life Sciences, 284, art. no. 119894, .
Toomey, R.a , Alpern, R.E.b , Reda, D.J.b , Baker, D.G.c d , Vasterling, J.J.e f , Blanchard, M.S.g , Eisen, S.A.h
a Department of Psychological and Brain Sciences, Boston University, Boston, MA, United States
b Cooperative Study Program Coordinating Center, Edward Hines Jr. VA Hospital, Hines, IL, United States
c Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
d VA Center of Excellence for Stress and Mental Health and VA San Diego Healthcare System, San Diego, CA, United States
e Department of Psychiatry, School of Medicine, Boston University, Boston, MA, United States
f National Center for PTSD and Psychology Service, VA Boston Healthcare System, Boston, MA, United States
g Greater Baltimore Medical Center, Baltimore, MD, United States
h School of Medicine, Washington University, St. Louis, MO, United States
Abstract
Aims: Veterans of the 1991 Gulf War reported symptoms in their spouses that mirrored veterans’ symptoms following their return from the war, including problems with attention and memory. Neuropsychological functioning in these spouses has not been examined with objective tests. This study sought to determine if these spouses exhibited deficits in neuropsychological functioning. Main methods: Spouses of a national cohort of 1991 Gulf War deployed (n = 470) and non-deployed veterans (n = 524) were examined with neuropsychological tests in 1999-2001. Key findings: Neuropsychological tests were factor analyzed yielding five factors: verbal memory, visual memory, attention/working memory, visual organization, and motor speed. Spouses of deployed and nondeployed veterans did not differ on mean factor scores, percentage of impaired factors, or individual test scores. Spouse attention/working memory was related to their having diagnoses of PTSD or anxiety disorders, or self-reported symptoms of current anxiety. Spouse visual memory was related to a diagnosis of current depression. Spouse motor speed was related to their own status of having chronic multisymptom illness (CMI). Significance: Spouses of Gulf War deployed and nondeployed veterans demonstrated similar neuropsychological functioning, although spouses with psychiatric diagnoses and symptoms, or CMI demonstrated neuropsychological impairments characteristic of those conditions, suggesting that monitoring spouses for these conditions and impairments may be warranted. This pattern of relative weaknesses mirrors some of the previously reported findings for Gulf War veterans, although the veterans displayed neuropsychological impairments beyond what was accounted for by these conditions. © 2021
Author Keywords
Cognitive; Gulf war; Military; Neurocognitive; Spouse
Funding details
U.S. Department of Veterans AffairsVA
Office of Research and DevelopmentORD
Document Type: Article
Publication Stage: Final
Source: Scopus
“Implementing family-based behavioral treatment in the pediatric primary care setting: Design of the PLAN study” (2021) Contemporary Clinical Trials
Implementing family-based behavioral treatment in the pediatric primary care setting: Design of the PLAN study
(2021) Contemporary Clinical Trials, 109, art. no. 106497, .
Epstein, L.H.a , Schechtman, K.B.b , Kilanowski, C.a , Ramel, M.c , Moursi, N.A.c , Quattrin, T.a , Cook, S.R.d , Eneli, I.U.e , Pratt, C.f , Geller, N.f , Campo, R.f , Lew, D.b , Wilfley, D.E.c
a Department of Pediatrics, Jacobs School of Medicine, and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
b Department of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, United States
e Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
f National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
Abstract
Family-based behavioral treatment (FBT) is an evidence-based treatment for pediatric obesity. FBT has primarily been implemented in specialty clinics, with highly trained interventionists. The goal of this study is to assess effectiveness of FBT implemented in pediatric primary care settings using newly trained interventionists who might implement FBT in pediatric practices. The goal is to randomize 528 families with a child with overweight/obesity (≥85th BMI percentile) and parent with overweight/obesity (BMI ≥ 25) across four sites (Buffalo and Rochester, New York; Columbus, Ohio; St. Louis, Missouri) to FBT or usual care and obtain assessments at 6-month intervals over 24 months of treatment. FBT is implemented using a mastery model, which provides quantity of treatment tailored to family progress and following the United States Preventive Services Task Force recommendations for effective dose and duration of treatment. The primary outcome of the trial is change in relative weight for children, and secondarily, for parents and siblings who are overweight/obese. Between group differences in the tendency to prefer small immediate rewards over larger, delayed rewards (delay discounting) and how this is related to treatment outcome is also evaluated. Challenges in translation of group-based interventions to individualized treatments in primary care settings, and in study implementation that arose due to the COVID-19 pandemic are discussed. It is hypothesized that the FBT intervention will be associated with better changes in relative weight for children, parents, and siblings than usual care. The results of this study can inform future dissemination and implementation of FBT into primary care settings. © 2021 Elsevier Inc.
Author Keywords
Behavioral intervention in primary care setting; Childhood obesity; Dissemination of evidence-based treatment; Effectiveness trial; Family-based obesity treatment; Generalization of treatment to siblings
Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBINCT02873715, U01HL131552
Document Type: Article
Publication Stage: Final
Source: Scopus
“Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis” (2021) Neurology(R) Neuroimmunology & Neuroinflammation
Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis
(2021) Neurology(R) Neuroimmunology & Neuroinflammation, 8 (5), .
Greenberg, B.M., Casper, T.C., Mar, S.S., Ness, J.M., Plumb, P., Liang, S., Goyal, M., Weinstock-Guttman, B., Rodriguez, M., Aaen, G.S., Belman, A., Barcellos, L.F., Rose, J.W., Gorman, M.P., Benson, L.A., Candee, M., Chitnis, T., Harris, Y.C., Kahn, I.L., Roalstad, S., Hart, J., Lotze, T.E., Rensel, M., Rubin, J.P., Schreiner, T.L., Tillema, J.-M., Waldman, A.T., Krupp, L., Graves, J., Drake, K., Waubant, E.
From the University of Texas Southwestern (B.M.G.), Department of Neurology, Department of Pediatrics, Dallas; Data Coordinating and Analysis Center (T.C.C., S.S.R., K.D.), University of Utah, Salt Lake City; Washington University (S.S.M.), St. Louis, MO; University of Alabama Birmingham (J.M.N.); The University of Texas Southwestern (P.P.), Department of Neurology, Dallas; Department of Radiology (S.L., M.G.), Washington University in St. Louis, MO; Jacobs Pediatric Multiple Sclerosis Center (B.W.-G.), State University of New York at Buffalo, NY; Mayo Clinic Pediatric Multiple Sclerosis Center (M.R., J.-M.T.), Mayo Clinic, Rochester, MN; Pediatric Multiple Sclerosis Center (G.S.A.), Loma Linda University Children’s Hospital, CA; Lourie Center for Pediatric Multiple Sclerosis (A.B.), Stony Brook University Hospital, NY; Epidemiology (L.F.B.), University of California, Berkeley; Department of Neurology (J.W.R.), University of Utah, Salt Lake City; Pediatric Multiple Sclerosis and Related Disorders Program (M.P.G., L.A.B.), Boston Children’s Hospital, MA; Primary Children’s Hospital (M.C.), University of Utah, Salt Lake City; Partners Pediatric Multiple Sclerosis Center (T.C.)
Abstract
BACKGROUND AND OBJECTIVE: The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls. METHODS: Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls. RESULTS: There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives. DISCUSSION: The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS. Copyright © 2021 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
“Alterations of the gut mycobiome in patients with MS” (2021) EBioMedicine
Alterations of the gut mycobiome in patients with MS
(2021) EBioMedicine, 71, art. no. 103557, .
Shah, S.a , Locca, A.b , Dorsett, Y.c , Cantoni, C.b , Ghezzi, L.b d , Lin, Q.a , Bokoliya, S.c , Panier, H.c , Suther, C.c e , Gormley, M.f , Liu, Y.f , Evans, E.b , Mikesell, R.b , Obert, K.b , Salter, A.g , Cross, A.H.b h , Tarr, P.I.i , Lovett-Racke, A.f , Piccio, L.b h j , Zhou, Y.c
a Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medicine, UConn Health, Farmington, CT, United States
d University of Milan, Dino Ferrari Centre, Milan, Italy
e Department of Food Science, University of Massachusetts, Amherst, MA, United States
f Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, United States
g Division of Biostatistics, School of Medicine, Washington University, St. Louis, MO, United States
h Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
j Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW 2050, Australia
Abstract
Background: The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied. Methods: In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months. Findings: The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16+ dendritic cells in pwMS. Different mycobiome profiles, defined as mycotypes, were associated with different bacterial microbiome and immune cell subsets in the blood. Initial treatment with dimethyl fumarate, a common immunomodulatory therapy which also has fungicidal activity, did not cause uniform gut mycobiome changes across all pwMS. Interpretation: There is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS102633-04 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-1805-31003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG- 1907-34474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. © 2021
Author Keywords
fungi; gut microbiome; immune system; multiple sclerosis; mycobiome
Funding details
National Institutes of HealthNIH
National Multiple Sclerosis SocietyFG-1907-34474, TA-1805-31003
Biogen
National Center for Advancing Translational SciencesNCATSR01 NS102633-04
Foundation for Barnes-Jewish Hospital
Associazione Italiana Sclerosi MultiplaAISMFISM 2018/B/1
University of MassachusettsUMASS
Institute of Clinical and Translational SciencesICTSUL1 TR000448
Document Type: Article
Publication Stage: Final
Source: Scopus
“Stroke imaging utilization according to age and severity during the covid-19 pandemic” (2021) Radiology
Stroke imaging utilization according to age and severity during the covid-19 pandemic
(2021) Radiology, 300 (3), pp. E342-E344.
Kansagra, A.P.a b c , Goyal, M.S.a c d , Hamilton, S.e , Albers, G.W.e f
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd , Campus Box 8131, St Louis, MO 63110, United States
b Department of Neurologic Surgery, Washington University School of Medicine, 510 S Kingshighway Blvd. Campus Box 8131, St Louis, MO 63110, United States
c Department of Neurology, Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8131, St Louis, MO 63110, United States
d Department of Neuroscience, Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8131, St Louis, MO 63110, United States
e Department of Neurology and Neurologic Sciences, Stanford University, Stanford, CA, United States
f Department of Neurosurgery, Stanford University, Stanford, CA, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
“Static magnetic fields dampen focused ultrasound- mediated blood-brain barrier opening” (2021) Radiology
Static magnetic fields dampen focused ultrasound- mediated blood-brain barrier opening
(2021) Radiology, 300 (3), p. 681.
Yang, Y.a , Pacia, C.P.a , Ye, D.a , Yue, Y.a , Chien, C.-Y.a , Chen, H.a b
a Departments of Biomedical Engineering, Washington University in St Louis, 4511 Forest Park Ave, St Louis, MO 63108, United States
b Departments of Radiation Oncology, Washington University in St Louis, 4511 Forest Park Ave, St Louis, MO 63108, United States
Abstract
Background: Focused ultrasound combined with microbubbles has been used in clinical studies for blood-brain barrier (BBB) opening in conjunction with MRI. However, the impact of the static magnetic field generated by an MRI scanner on the BBB opening outcome has not been evaluated. Purpose: To determine the relationship of the static magnetic field of an MRI scanner on focused ultrasound combined with microbubble- induced BBB opening. Materials and Methods: Thirty wild-type mice were divided into four groups. Mice from different groups were sonicated with focused ultrasound in different static magnetic fields (approximately 0, 1.5, 3.0, and 4.7 T), with all other experimental parameters kept the same. Focused ultrasound sonication was performed after intravenous injection of microbubbles. Microbubble cavitation activity, the fundamental physical mechanism underlying focused ultrasound BBB opening, was monitored with passive cavitation detection. After sonication, contrast-enhanced T1-weighted MRI was performed to assess BBB opening outcome. Intravenously injected Evans blue was used as a model agent to evaluate trans-BBB delivery efficiency. Results: The microbubble cavitation dose decreased by an average of 2.1 dB at 1.5 T (P = .05), 2.9 dB at 3.0 T (P = .01), and 3.0 dB at 4.7 T (P = .01) compared with that outside the magnetic field (approximately 0 T). The static magnetic field of an MRI scanner decreased BBB opening volume in mice by 3.2-fold at 1.5 T (P <001), 4.5-fold at 3.0 T (P <.001), and 11.6-fold at 4.7 T (P <.001) compared with mice treated outside the magnetic field. It also decreased Evans blue trans-BBB delivery 1.4-fold at 1.5 T (P = .009), 1.6-fold at 3.0 T (P <.001), and 1.9-fold at 4.7 T (P <.001). Conclusion: Static magnetic fields dampened microbubble cavitation activity and decreased trans-blood-brain barrier (BBB) delivery by focused ultrasound combined with microbubble-induced BBB opening. © 2021 Radiological Society of North America Inc.. All rights reserved.
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981
Document Type: Article
Publication Stage: Final
Source: Scopus
“Uncoupling in intrinsic brain activity” (2021) Proceedings of the National Academy of Sciences of the United States of America
Uncoupling in intrinsic brain activity
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (34), art. no. e2110556118, .
Goyal, M.S., Snyder, A.Z.
Mallinckrodt Institute of Radiology, Neuroimaging Laboratories, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
Document Type: Note
Publication Stage: Final
Source: Scopus
“Parallel hippocampal-parietal circuits for self- And goal-oriented processing” (2021) Proceedings of the National Academy of Sciences of the United States of America
Parallel hippocampal-parietal circuits for self- And goal-oriented processing
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (34), art. no. e2101743118, .
Zheng, A.a , Montez, D.F.a , Marek, S.b , Gilmore, A.W.c , Newbold, D.J.a , Laumann, T.O.b , Kay, B.P.a , Seider, N.A.a , Van, A.N.a , Hampton, J.M.a b , Alexopoulos, D.a , Schlaggar, B.L.d e f , Sylvester, C.M.b , Greene, D.J.g , Shimony, J.S.h , Nelson, S.M.i j , Wig, G.S.k l , Gratton, C.m n , McDermott, K.B.c h , Raichle, M.E.a h , Gordon, E.M.h , Dosenbach, N.U.F.a h o p q
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
d Kennedy Krieger Institute, Baltimore, MD 21205, United States
e Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
f Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
g Department of Cognitive Science, University of California, San Diego, CA 92093, United States
h Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, United States
j Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55414, United States
k Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75235, United States
l Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
m Department of Psychology, Northwestern University, Evanston, IL 60208, United States
n Department of Neurology, Northwestern University, Evanston, IL 60208, United States
o Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
p Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
q Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior–posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Brain networks; Functional connectivity; Hippocampus; Individual variability; Resting state
Funding details
HD087011, MH109983, MH121518, MH122389, NS110332, P30AG13854
National Institutes of HealthNIHMH096773, MH118370, MH121276, MH122066, MH123091, MH124567, NS088590, NS115672
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience
Jacobs Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
“Prevalence of Kratom Use and Co-Occurring Substance Use Disorders in the United States” (2021) The Primary Care Companion for CNS Disorders
Prevalence of Kratom Use and Co-Occurring Substance Use Disorders in the United States
(2021) The Primary Care Companion for CNS Disorders, 23 (4), .
Xu, K.Y.a b , Mintz, C.M.a , Borodovsky, J.T.a c , Glaser, P.E.A.d , Bierut, L.J.a e , Grucza, R.A.a f
a Health and Behavior Research Center, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Corresponding author: Kevin Y. Xu, MD, MPH, Department of Psychiatry, Washington University School of Medicine, 420 South Euclid Ave, Campus Box 8134, St Louis, MO 63110 ()
c Center for Technology and Behavioral Health, Department of Biomedical Data Science, Geisel School of Medicine at DartmouthNH, Lebanon
d William Greenleaf Eliot Division of Child Psychiatry, Washington University School of Medicine, St Louis, MO, United States
e Alvin J Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St Louis, MO, United States
f Departments of Family and Community Medicine and Health and Outcomes Research, St Louis University, St Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
“Quality Improvement in Neurology: 2020 Parkinson Disease Quality Measurement Set Update” (2021) Neurology
Quality Improvement in Neurology: 2020 Parkinson Disease Quality Measurement Set Update
(2021) Neurology, 97 (5), pp. 239-245.
Chou, K.L.a , Martello, J.a , Atem, J.a , Elrod, M.a , Foster, E.R.a , Freshwater, K.a , Gunzler, S.A.a , Kim, H.a , Mahajan, A.a , Sarva, H.a , Stebbins, G.T.a , Lee, E.b , Yang, L.a
a From the University of Michigan Medical School (K.L.C.), Ann Arbor; Christiana Care (J.M.), Wilmington, DE; UT Southwestern Medical Center (J.A.), Dallas, TX; MaxMD (M.E.), Fort Lee, NJ; Washington University School of Medicine (E.R.F.), St. Louis, MO; Bronson Neuroscience Center (K.F.), Kalamazoo, MI; University Hospitals Cleveland Medical Center and Case Western Reserve University (S.A.G.), OH; Veterans Affairs Puget Sound Health Care System (H.K.), Seattle, WA; Rush University Medical Center (A.M.), Chicago, IL; Weill Cornell Medicine (H.S.), New York, NY; Rush University (G.T.S.), Chicago, IL; American Academy of Neurology (E.L.), Minneapolis, MN; and Stanford Health Care (L.Y.), Palo Alto, CA
b From the University of Michigan Medical School (K.L.C.), Ann Arbor; Christiana Care (J.M.), Wilmington, DE; UT Southwestern Medical Center (J.A.), Dallas, TX; MaxMD (M.E.), Fort Lee, NJ; Washington University School of Medicine (E.R.F.), St. Louis, MO; Bronson Neuroscience Center (K.F.), Kalamazoo, MI; University Hospitals Cleveland Medical Center and Case Western Reserve University (S.A.G.), OH; Veterans Affairs Puget Sound Health Care System (H.K.), Seattle, WA; Rush University Medical Center (A.M.), Chicago, IL; Weill Cornell Medicine (H.S.), New York, NY; Rush University (G.T.S.), Chicago, IL; American Academy of Neurology (E.L.), Minneapolis, MN; and Stanford Health Care (L.Y.), Palo Alto, CA. quality@aan.com
Document Type: Article
Publication Stage: Final
Source: Scopus
“Population health impact of extended window thrombectomy in acute ischemic stroke” (2021) Interventional Neuroradiology
Population health impact of extended window thrombectomy in acute ischemic stroke
(2021) Interventional Neuroradiology, 27 (4), pp. 516-522.
Zhou, M.H.a , Kansagra, A.P.b c d
a School of Medicine, Washington University, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
c Department of Neurological Surgery, Washington University, St. Louis, MO, United States
d Department of Neurology, Washington University, St. Louis, MO, United States
Abstract
Background: Recent trials support endovascular thrombectomy (EVT) in select patients beyond the conventional 6-hour window. Objective: In this work, we estimate the impact of extended window EVT on procedural volumes and population-level clinical outcomes using Monte Carlo simulation. Methods: We simulated extending EVT eligibility in a system comprising an EVT-incapable primary stroke center (PSC) and EVT-capable comprehensive stroke center (CSC) using routing paradigms that initially direct patients to (1) the nearest center, (2) the CSC, or (3) either CSC or nearest center based on stroke severity. EVT eligibility and outcomes are based on HERMES, DEFUSE-3, and DAWN studies in the 0-6, 6-16, and 16-24 hour windows, respectively. Probability of good clinical outcome is determined by type and timing of treatment using clinical trial data. Results: Relative increase in EVT volume in the three tested routing paradigms was 15.7-15.8%. The absolute increase in the rate of good clinical outcome 0.4% in all routing paradigms. NNT for extended window EVT was 239.9-246.4 among the entire stroke population. Conclusion: Extended window EVT with DEFUSE-3 and DAWN criteria increases EVT volume and modestly improves population-level clinical outcomes. © The Author(s) 2020.
Author Keywords
computer simulation; Stroke; thrombectomy
Document Type: Article
Publication Stage: Final
Source: Scopus
“Enhanced Multiplexing of Immunofluorescence Microscopy Using a Long-Stokes-Shift Fluorophore” (2021) Current Protocols
Enhanced Multiplexing of Immunofluorescence Microscopy Using a Long-Stokes-Shift Fluorophore
(2021) Current Protocols, 1 (8), art. no. e214, .
Reitz, S.J., Sauerbeck, A.D., Kummer, T.T.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Immunofluorescence labeling and microscopy offer a highly specific means to visualize proteins or other molecular species in a sample by labeling target antigens with fluorescent probes. These fluorescent probes can then be visualized using a fluorescence microscope, allowing their relative spatial relationships to be determined. Due to spectral overlap of common fluorophores, however, it can be challenging to analyze more than three antigens in a single sample with standard imaging approaches. This article describes multiplexed labeling and imaging of four target antigens through the use of a long-Stokes-shift fluorophore—a fluorophore with an unusually large gap between its excitation and emission maxima—in tandem with three conventional fluorophores. This combination allows for multiplexed imaging of four antigens in a single sample with excellent spectral discrimination suitable for sensitive analyses using standard imaging hardware. Particular advantages of this approach are its flexibility in terms of target antigens and the lack of any specialized procedures, reagents, or equipment beyond the commercially available labeling reagent coupled to the long-Stokes-shift fluorophore. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Four-probe immunofluorescence labeling. Basic Protocol 2: Four-probe immunofluorescence imaging. © 2021 Wiley Periodicals LLC
Author Keywords
fluorophore; immunofluorescence microscopy; immunolabeling; microglia; multiplex imaging; neuroscience; Stokes shift
Funding details
CDI‐CORE‐2015‐505
National Institutes of HealthNIHI01BX005204, OD021629, S10 OD025029
Foundation for Barnes-Jewish Hospital3770
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
“Identification of structures for ion channel kinetic models” (2021) PLoS Computational Biology
Identification of structures for ion channel kinetic models
(2021) PLoS Computational Biology, 17 (8), art. no. e1008932, .
Mangold, K.E.a , Wang, W.b , Johnson, E.K.b , Bhagavan, D.a , Moreno, J.D.a b , Nerbonne, J.M.b c , Silva, J.R.a
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Medicine, Cardiovascular Division, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori. Copyright: © 2021 Mangold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding details
National Institutes of HealthNIHR01HL136553, R01HL142520, R01HL150637, T32-HL134635
Amazon Web ServicesAWS
Document Type: Article
Publication Stage: Final
Source: Scopus
“Redesigning a web-based stakeholder consensus meeting about core outcomes for clinical trials: Formative feedback study” (2021) JMIR Formative Research
Redesigning a web-based stakeholder consensus meeting about core outcomes for clinical trials: Formative feedback study
(2021) JMIR Formative Research, 5 (8), art. no. e28878, .
Katiri, R.a b j , Hall, D.A.a c j , Hoare, D.J.a d j , Fackrell, K.a e j , Horobin, A.a d , Buggy, N.j , Hogan, N.j , Kitterick, P.T.a j d j , Snik, A.i , Sygrove, C.i , Campbell-Bell, C.i , Parker, C.i , Zeitler, D.M.i , Williams, L.i , Oxford, M.i , Boyle, P.i , James, P.K.i , Hill-Feltham, P.R.i , Toth, P.i , Bowles, R.i , Nicholson, R.i , Bayston, R.i , Rosenbom, T.i , van de Heyning, P.f , Firszt, J.B.g , Bruce, I.A.h , Core Rehabilitation Outcome Set For Single-Sided Deafness (CROSSSD) Initiativej
a Hearing Sciences, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, United Kingdom
b Audiology Department, Mater Misericordiae University Hospital, Dublin, Ireland
c Department of Psychology, School of Social Sciences, Heriot-Watt University Malaysia, Putrajaya, Malaysia
d Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Nottingham, United Kingdom
e Wessex Institute, University of Southampton, University Road, Southampton, United Kingdom
f Department of Otorhinolaryngology, Head and Neck Surgery, Antwerp University Hospital, Antwerp, Belgium
g School of Medicine, Washington University in St Louis, St Louis, MO, United States
h Manchester University Hospitals, National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
j National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), Ropewalk House, Nottingham, United Kingdom
Abstract
Background: Clinical trials that assess the benefits and harms of an intervention do so by measuring and reporting outcomes. Inconsistent selection and diversity in the choice of outcomes make it challenging to directly compare interventions. To achieve an agreed core set of outcomes, a consensus methodology is recommended, comprising a web-based Delphi survey and a face-to-face consensus meeting. However, UK government regulations to control the pandemic prohibited plans for a face-to-face consensus meeting as part of the Core Rehabilitation Outcome Set for Single-Sided Deafness (CROSSSD) study. Objective: This study aims to evaluate the modifications made by the CROSSSD study team to achieve consensus using web-based methods, but with minimal deviation from the original study protocol. Methods: The study team worked with health care users and professionals to translate the planned face-to-face consensus meeting in a web-based format, preserving the key elements of the nominal group technique. A follow-up survey gathered evaluation feedback on the experiences of the 22 participating members. Feedback covered premeeting preparation, the process of facilitated discussions and voting, ability to contribute, and perceived fairness of the outcome. Results: Overall, 98% (53/54) of feedback responses agreed or strongly agreed with the statements given, indicating that the web-based meeting achieved its original goals of open discussion, debate, and voting to agree with a core outcome set for single-sided deafness. Hearing-impaired participants were fully engaged, but there were some methodological challenges. For the participants, challenges included building rapport, understanding, and delivering the tasks in hand. For the study team, challenges included the need for thorough preparation and management of the unpredictability of tasks on the day. Conclusions: Sharing our experiences and lessons learned can benefit future core outcome set developers. Overcoming the challenges of delivering a web-based consensus exercise in the face of the pandemic can be applied more generally to maximize inclusiveness, enhance geographical access, and reduce research costs. © Roulla Katiri, Deborah A Hall, Derek J Hoare, Kathryn Fackrell, Adele Horobin, Nóra Buggy, Nicholas Hogan, Pádraig T Kitterick, Core Rehabilitation Outcome Set For Single-Sided Deafness (CROSSSD) Initiative. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.08.2021. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Formative Research, is properly cited. The complete bibliographic information, a link to the original publication on https://formative.jmir.org, as well as this copyright and license information must be included.
Author Keywords
COVID-19; Formative research; Mobile phone; Nominal group technique; Patient participation; Persons with hearing impairments
Funding details
Cochlear
National Institute for Health ResearchNIHR
Document Type: Article
Publication Stage: Final
Source: Scopus
“Structural and functional connectivity in premature neonates” (2021) Seminars in Perinatology
Structural and functional connectivity in premature neonates
(2021) Seminars in Perinatology, art. no. 151473, .
Brady, R.G.a , Wheelock, M.D.b , Neil, J.J.a c , Smyser, C.D.a b c
a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8111, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Advances in neuroimaging have increasingly enabled researchers to investigate whether alterations in brain development commonly identified in preterm infants underlie their high risk of long-term neurodevelopmental impairment, including sensory, motor, cognitive, and psychiatric deficits. This review begins by examining the growing body of literature utilizing advanced magnetic resonance imaging (MRI) techniques to probe structural (via diffusion MRI) and functional (via resting state-functional MRI) connectivity development in the preterm brain during the neonatal period, both in the presence and absence of brain injury. It then details the recent work linking neonatal brain connectivity measures to neurodevelopmental and psychiatric outcomes in prematurely-born cohorts. Finally, building upon the recent substantive growth in the utilization of these neuroimaging modalities, it concludes by highlighting areas in which continued optimization of age-specific acquisition and analysis techniques for these data remains necessary, efforts fundamental to advancing the field toward establishing individual-level predictive capabilities in this high-risk population. © 2021 Elsevier Inc.
Author Keywords
Brain Development; Functional and Structural Connectivity; MRI; Neurodevelopmental Outcomes; Prematurity
Funding details
National Institutes of HealthNIHK99 EB029343, R01 MH113570, R01 MH113883, T32 EB014855
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Ascaris suum Informs Extrasynaptic Volume Transmission in Nematodes” (2021) ACS Chemical Neuroscience
Ascaris suum Informs Extrasynaptic Volume Transmission in Nematodes
(2021) ACS Chemical Neuroscience, .
Atkinson, L.E.a , Liu, Y.b , McKay, F.a , Vandewyer, E.c , Viau, C.a , Irvine, A.a , Rosa, B.A.d , Li, Z.b , Liang, Q.a , Marks, N.J.a , Maule, A.G.a , Mitreva, M.d , Beets, I.c , Li, L.b , Mousley, A.a
a Parasitology and Pathogen Biology, Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, BT9 5DL, United Kingdom
b School of Pharmacy, Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, United States
c Department of Biology, KU Leuven, Naamsestraat 59, Leuven, 3000, Belgium
d McDonnell Genome Institute, Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, United States
Abstract
Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other nonsynaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of Caenorhabditis elegans neurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematode Ascaris suum, FMRFamide-like peptides encoded on flp-18 potently stimulate female reproductive organs but are expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we investigate nonsynaptic neuropeptide signaling in nematodes mediated by the body cavity fluid. Our data show that (i) A. suum PCF (As-PCF) contains a catalog of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins, (ii) the A. suum FMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome, (iii) As-PCF potently modulates nematode reproductive muscle function ex vivo, mirroring the effects of synthetic FLP-18 peptides, (iv) As-PCF activates the C. elegans FLP-18 receptors NPR-4 and -5, (v) As-PCF alters C. elegans behavior, and (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. This study provides the first direct experimental evidence to support an extrasynaptic volume route for neuropeptide transmission in nematodes. These data indicate nonsynaptic signaling within the nematode functional connectome and are particularly pertinent to receptor deorphanization approaches underpinning drug discovery programs for nematode pathogens. © 2021 The Authors. Published by American Chemical Society.
Author Keywords
Ascaris; Extrasynaptic volume transmission; nematode; neuronal signaling; neuropeptide; parasite; pseudocoelomic fluid
Funding details
BB/MO10392/1, BB/TO16396/1
National Institutes of HealthNIHGM097435, R01DK071801, S10RR029531
Biotechnology and Biological Sciences Research CouncilBBSRCBB/H019472/1
Fonds Wetenschappelijk OnderzoekFWOG0C0618N
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“The feasibility, acceptability, and preliminary efficacy of an mHealth mindfulness therapy for caregivers of adults with cognitive impairment” (2021) Aging and Mental Health
The feasibility, acceptability, and preliminary efficacy of an mHealth mindfulness therapy for caregivers of adults with cognitive impairment
(2021) Aging and Mental Health, .
Kozlov, E.a , McDarby, M.b , Pagano, I.c , Llaneza, D.a , Owen, J.d , Duberstein, P.a
a School of Public Health, Rutgers University, Piscataway, NJ, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, St Louis, MO, United States
c University of Hawaii Cancer Center, Honolulu, HI, United States
d National Center for PTSD, VA Palo Alto Health Care System, Menlo Park, CA, United States
Abstract
Objectives: To examine the feasibility, acceptability, and preliminary efficacy of Mindfulness Coach, an mHealth Mindfulness Therapy intervention. Methods: We recruited 58 informal caregivers of older adults with cognitive impairment for this pilot feasibility trial. Participants completed measures of caregiver burden, stress, anxiety, and depression at baseline, 2 weeks, 4 weeks, and 8 weeks as well as acceptability and usability data at 8-weeks. The mobile app collected in-app use data including minutes spent using the app and number of unique visits to the app. Results: Users found the app acceptable to use and were satisfied with its design and usability. Over the course of the study period, depression, anxiety, caregiver burden and perceived stress improved. These outcome variables also improved more as caregivers spent more time using the Mindfulness Therapy mHealth intervention. Conclusions: Our results suggest that mHealth mindfulness therapy with caregivers of older adults with cognitive impairment is both feasible and acceptable to users, and that it successfully reduces psychological symptoms. Future work should focus on determining the appropriate doses of the mHealth therapy for particular outcomes and strategies to integrate it into routine care. Mindfulness Therapy delivered in an mHealth format may increase access to psychological treatment for caregivers. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
Caregiving; dementia caregiving; mHealth interventions; mindfulness therapy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Intrahepatic Cholestasis, Refractory Epilepsy, Skeletal Dysplasia, Endocrine Failure, and Dysmorphic Features in a Child With a Monoallelic 2q24-32.2 Deletion Encompassing ABCB11” (2021) Pediatric and Developmental Pathology
Intrahepatic Cholestasis, Refractory Epilepsy, Skeletal Dysplasia, Endocrine Failure, and Dysmorphic Features in a Child With a Monoallelic 2q24-32.2 Deletion Encompassing ABCB11
(2021) Pediatric and Developmental Pathology, .
Starosta, R.T.a b , Granadillo, J.L.a , Patel, K.R.c , Finegold, M.J.d , Stoll, J.b , Kulkarni, S.b
a Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in Saint Louis, Saint Louis Children’s Hospital, Washington University in Saint Louis, Saint Louis, MO, United States
b Department of Pediatrics, Washington University in Saint Louis, Washington University in Saint Louis, St. Louis Children’s Hospital, Saint Louis, MO, United States
c Department of Pathology and Immunology, Texas Children’s Hospital, Houston, TX, United States
d Baylor College of Medicine, Houston, TX, United States
Abstract
We report a newborn who presented with multiple limb and facial anomalies, endocrine disorders, and progressively worsening low-GGT cholestasis. A liver biopsy revealed hepatocellular cholestasis with giant cell transformation. Immunohistochemical staining revealed complete absence of BSEP protein compared to control liver. A large 2q24-32.2 deletion leading to loss of 78 OMIM genes. Multiple structural anomalies, epilepsy and endocrine anomalies have been described with hemizygous loss of these genes. This deletion also resulted in complete heterozygous deletion of ABCB11, which encodes the bile salt export pump (BSEP). Genetic analysis did not reveal any pathogenic variants, deletions, or duplications in the other ABCB11 allele. A heterozygous variant in NR1H4, which causes the autosomal recessive progressive familial intrahepatic cholestasis type 5, was also detected. The possible explanations for the PFIC type 2 phenotype in heterozygous loss of ABCB11 include genetic modifiers or di-genic disease with a compound ABCB11 deletion and an NR1H4 missense variant; or undetected pathogenic variants in the other ABCB11 or NR1H4 alleles. © 2021, Society for Pediatric Pathology All rights reserved.
Author Keywords
congenital heart disease; congenital hypothyroidism; dysmorphology; farnesoid X-activated receptor; metabolic liver; neonatal cholestasis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants” (2021) Alzheimer’s and Dementia
Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants
(2021) Alzheimer’s and Dementia, .
Damotte, V.a , van der Lee, S.J.b c , Chouraki, V.a d , Grenier-Boley, B.a , Simino, J.e , Adams, H.f , Tosto, G.g h , White, C.i j , Terzikhan, N.c k , Cruchaga, C.l , Knol, M.J.c , Li, S.m n , Schraen, S.o , Grove, M.L.p , Satizabal, C.d n , Amin, N.c , Berr, C.q , Younkin, S.r , Gottesman, R.F.s t , Buée, L.a u , Beiser, A.d m n , Knopman, D.S.v , Uitterlinden, A.w , DeCarli, C.x , Bressler, J.p , DeStefano, A.d m n , Dartigues, J.-F.y , Yang, Q.m n , Boerwinkle, E.p z , Tzourio, C.y , Fornage, M.p aa , Ikram, M.A.f , Amouyel, P.a , de Jager, P.i j ab , Reitz, C.g h ac ad , Mosley, T.H.ae , Lambert, J.-C.a , Seshadri, S.d n af , van Duijn, C.M.c ag , Alzheimer’s Disease Neuroimaging Initiativeah
a Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France
b Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
c Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
d Department of Neurology, Boston University School of Medicine, Boston, MA, United States
e Gertrude C. Ford MIND Center, Department of Data Science, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, United States
f Departments of Epidemiology, Neurology, and Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, Netherlands
g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
h Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
i Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, MA, United States
j Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
k Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
l Department of Psychiatry, Washington University in St. Louis, Saint Louis, MO, United States
m Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
n The Framingham Heart Study, Framingham, MA, United States
o Université Lille, CHU-Lille, Inserm, UF de Neurobiologie, CBPG, Lille, France
p Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
q INSERM U1061, University of Montpellier, Montpellier, France
r Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
s Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
t Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
u Institut National de la Santé et de la Recherche Medicale (INSERM, Université de Lille, Lille, France
v Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, United States
w Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
x Department of Neurology, University of California at Davis, Davis, CA, United States
y Bordeaux Population Health Research Center, INSERM, UMR1219, Bordeaux University, Bordeaux, France
z Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
aa Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
ab Center for Translational & Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, NY, United States
ac Department of Neurology, Columbia University, New York, NY, United States
ad Department of Epidemiology, Columbia University, New York, NY, United States
ae Department of Medicine, Gertrude C. Ford MIND Center, University of Mississippi Medical Center, Jackson, MS, United States
af Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, United States
ag Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Abstract
Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer’s disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association
Author Keywords
Alzheimer’s disease; APOE; APP; BACE1; endophenotype; genetic epidemiology; genome‑wide association study; plasma amyloid beta levels; plasma biomarkers; preclinical biomarkers; PSEN2
Funding details
115975
018947, LSHG‐CT‐2006‐01947
733051021
602633, QLG2‐CT‐2002‐01254
PO1AG007232, R01AG037212, RF1AG054023
National Institutes of HealthNIHAG034189, AG042483, AG045334, HHSN268200625226C, HL096814, HL096899, HL096902, HL096917, U01 AG024904, U01 HL096812, UL1TR001873
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDA
National Institute on AgingNIAAG008122, AG033040, AG033193, AG054076, R01AG049607, U01‐AG049505
National Heart, Lung, and Blood InstituteNHLBIHHSN268201100010C, N01‐HC‐25195, R01HL086694, R01HL087641, R01HL59367
National Human Genome Research InstituteNHGRIU01HG004402
National Cancer InstituteNCI
National Institute on Deafness and Other Communication DisordersNIDCDR01HL70825, UL1RR025005
National Institute of Neurological Disorders and StrokeNINDSR01‐NS017950, R01‐NS087541
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Biogen
National Center for Advancing Translational SciencesNCATS
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
BioClinica
European CommissionEC
Agence Nationale de la RechercheANR
Institut National de la Santé et de la Recherche MédicaleInserm
ZonMw
Erasmus Universiteit RotterdamEUR
Ministerie van Volksgezondheid, Welzijn en SportVWS
Erasmus Medisch CentrumErasmus MC
Ministerie van Onderwijs, Cultuur en WetenschapOCW
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
Labex
Seventh Framework ProgrammeFP7FP7/2007‐2013, HEALTH‐F4‐2007‐201413
Agence Française de Sécurité Sanitaire des Produits de SantéAFSSAPS
Horizon 2020667375
Hersenstichting
Internationale Stichting Alzheimer OnderzoekISAO
European Regional Development FundERDF
Institute Pasteur De Lille
Centre for Medical Systems BiologyCMSB
Document Type: Article
Publication Stage: Article in Press
Source: Scopus