Neonatal Seizures and Associated Neurobehavioral Profiles in Preschool Age Children
(2025) Pediatric Neurology, 163, pp. 76-81.
Mattes, A.M.a b , Shellhaas, R.A.c , Glass, H.C.d e , Sturza, J.f , Rau, S.a , Lemmon, M.g , Rogers, E.E.e , Numis, A.d e , Soul, J.S.h , Berl, M.i , Wusthoff, C.J.j , Chu, C.J.h , Massey, S.L.k , Thomas, C.l , Franck, L.S.e , McCulloch, C.E.m , Benedetti, G.M.f , Means, J.n , Means, K.n , Anwar, T.i , Gidley Larson, J.C.a
a Division of Rehabilitation Psychology Neuropsychology, Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, United States
b New Day Neuropsychology LLC, Noblesville, IN, United States
c Department of Neurology, Washington University in St Louis School of Medicine, St. Louis, MO, United States
d Department of Neurology and Weill Institute for Neuroscience, University of California, San Francisco, CA, United States
e Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California, San Francisco, CA, United States
f Department of Pediatrics, University of Michigan, Michigan Medicine, Ann Arbor, MI, United States
g Departments of Pediatrics and Population Health Sciences, Duke University, School of Medicine, DUMC 3710, Durham, NC, United States
h Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
i Division of Neuropsychology, Children’s National Hospital, Washington, DC, United States
j Department of Neurology, University of California Davis, Davis, CA, United States
k Department of Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
l Division of Neurology, Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
m Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States
n NSR Parent Partner, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Abstract
Background: Neonatal seizures are common with acute brain injury. Up to 25% of survivors develop postneonatal epilepsy. We hypothesized postneonatal epilepsy diagnosed by age 24 months would increase risk for early markers of neurobehavioral disorders than acute provoked neonatal seizures alone. Methods: Neonates with acute provoked seizures born from July 2015 to March 2018 were enrolled at nine Neonatal Seizure Registry sites. Composite scores from parent-completed standardized ratings assessed Adaptive, Social, Externalizing, Internalizing, Self-Regulation, and Sensory Seeking domains. Linear regression demonstrated relationships between composite scores for children who developed postneonatal epilepsy compared with those who did not. Results were adjusted for seizure etiology, sex, gestational age, and cerebral palsy (CP) severity. Results: A total of 151 children (n = 20, 13% with postneonatal epilepsy), 4.1 years median age, participated. Children with epilepsy had impaired adaptive (Cohen d = 1.62, P < 0.0001), social (Cohen d = 0.86, P = 0.004), and executive functioning (Cohen d = 0.56, P = 0.06) compared with children without epilepsy. Mean scores for children without epilepsy were within average range. Risk for impairment among children with epilepsy persisted after adjusting for neonatal seizure etiology, sex, and gestational age, but not when adjusting for CP severity. Conclusions: There was higher incidence of adverse neurobehavioral outcomes among preschool children diagnosed with postneonatal epilepsy compared with those without epilepsy. CP severity was associated with greater impairment; results also suggest that epilepsy is an independent predictor of adaptive functioning. Children with postneonatal epilepsy should be screened for neurobehavioral problems to facilitate early identification and developmental support. © 2024 Elsevier Inc.
Author Keywords
Adaptive functioning; Behavior; Development; Epilepsy; Neonatal seizure; Neurobehavioral profiles; Social skills
Funding details
Pediatric Epilepsy Research FoundationPERF
Patient-Centered Outcomes Research InstitutePCORI1507-31187, R01NS111166
Patient-Centered Outcomes Research InstitutePCORI
Document Type: Article
Publication Stage: Final
Source: Scopus
Intrinsic adaptive plasticity in mouse and human sensory neurons
(2025) The Journal of General Physiology, 157 (1), .
McIlvried, L.A.a , Del Rosario, J.S.a , Pullen, M.Y.a , Wangzhou, A.b , Sheahan, T.D.a , Shepherd, A.J.a , Slivicki, R.A.a , Lemen, J.A.c , Price, T.J.b , Copits, B.A.a , Gereau, R.W., 4tha d
a Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Dallas, TX, United States
c Mid-America Transplant, St. Louis, MO, United States
d Department of Neuroscience and Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
Abstract
In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory changes that decrease the excitability of mouse and human sensory neurons without directly opposing membrane depolarization. Voltage-clamp recordings show that sustained depolarization produces no significant alteration in voltage-gated potassium currents, but a robust reduction in voltage-gated sodium currents, likely contributing to the overall decrease in neuronal excitability. The compensatory decrease in neuronal excitability and reduction in voltage-gated sodium currents reversed completely following a 24-h recovery period in a normal medium. Similar adaptive changes were not observed in response to 24 h of sustained action potential firing induced by optogenetic stimulation at 1 Hz, indicating the need for prolonged depolarization to drive engagement of this adaptive mechanism in sensory neurons. Our findings show that mouse and human sensory neurons are capable of engaging adaptive mechanisms to regulate intrinsic excitability in response to sustained depolarization in a manner similar to that described in neurons in the central nervous system. © 2024 McIlvried et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations between prenatal caffeine exposure and child development: Longitudinal results from the Adolescent Brain Cognitive Development (ABCD) Study
(2025) Neurotoxicology and Teratology, 107, art. no. 107404, .
Modi, H.a b , Baranger, D.A.A.a , Paul, S.E.a , Gorelik, A.J.a , Hornstein, A.a , Balbona, J.V.b , Agrawal, A.b , Bijsterbosch, J.D.c , Bogdan, R.a
a Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University in Saint Louis, United States
c Department of Radiology, Washington University in Saint Louis, United States
Abstract
Objective: Though caffeine use during pregnancy is common, its longitudinal associations with child behavioral and physical health outcomes remain poorly understood. Here, we estimated associations between prenatal caffeine exposure, body mass index (BMI), and behavior as children enter adolescence. Method: Longitudinal data and caregiver-reported prenatal caffeine exposure were obtained from the ongoing Adolescent Brain and Cognitive Development (ABCD)SM Study, which recruited 11,875 children aged 9–11 years at baseline from 21 sites across the United States starting June 1, 2016. Prenatal caffeine exposure was analyzed as a 4-level categorical variable, and further group contrasts were used to characterize “any exposure” and “daily exposure” groups. Outcomes included psychopathology characteristics in children, sleep problems, and BMI. Potentially confounding covariates included familial (e.g., income, familial psychopathology), pregnancy (e.g., prenatal substance exposure), and child (e.g., caffeine use) variables. Results: Among 10,873 children (5686 boys [52.3 %]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal caffeine exposure data, 6560 (60 %) were exposed to caffeine prenatally. Relative to no exposure, daily caffeine exposure was associated with higher child BMI (β = 0.08; FDR-corrected p = 0.02), but was not associated with child behavior following correction for multiple testing. Those exposed to two or more cups of caffeine daily (n = 1028) had greater sleep problems than those with lower/no exposure (β > 0.92; FDR-corrected p < 0.04). Conclusion: Daily prenatal caffeine exposure is associated with heightened childhood BMI, and when used multiple times a day greater sleep problems even after accounting for potential confounds. Whether this relationship is a consequence of prenatal caffeine exposure or its correlated factors remains unknown. © 2024 The Authors
Author Keywords
Child development; Longitudinal; Mental health; Prenatal caffeine exposure; Psychopathology
Funding details
National Institute of Mental HealthNIMH
National Institutes of HealthNIH
Secretaría de Educación PúblicaSEPF31AA029934
Secretaría de Educación PúblicaSEP
R01MH132962, U01DA055367S, R01MH128286, R01HD113188, R01AG061162, U01DA055367, R21AA027827, K99AA030808
National Science FoundationNSFDGE-213989
National Science FoundationNSF
Document Type: Article
Publication Stage: Final
Source: Scopus
Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study
(2024) The Journal of Clinical Investigation, 134 (24), .
Wang, W.X.a , Spiegelman, D.a , Rao, P.K.a , Rhee, R.L.b , Ford, A.L.c , Miner, J.J.d , Apte, R.S.a e
a John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medicine and RVCL Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Departments of Medicine and Microbiology, Colton Center for Autoimmunity, RVCL Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
e Department of Medicine, Washington University, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Examining Clinical Features and Severe Neurologic Disease of Parechovirus Infection in Young Infants: A Multistate Cohort Study
(2024) Clinical Infectious Diseases, 79 (6), pp. 1479-1486.
Evans, A.S.a b , Singh, S.b c , Joshi, C.b d , Filkins, L.b , Akkoyun, E.a b , Custodio, H.e , Daniels, E.A.f , Kao, C.M.f , Richardson, K.g , Carrillo-Marquez, M.h , Borré, C.I.i , Oliveira, C.R.j , Espinosa, C.k , Mandelia, Y.l , Mazade, M.m , Kimberlin, D.W.n
a Department of Pediatrics, Division of Infectious Diseases, University of Texas, Southwestern Medical Center, Dallas, TX, United States
b Children’s Health, Dallas, TX, United States
c Department of Radiology, University of Texas, Southwestern Medical Center, Dallas, TX, United States
d Department of Pediatrics, Division of Neurology, University of Texas, Southwestern Medical Center, Dallas, TX, United States
e Department of Pediatrics, Division of Infectious Diseases, University of South Alabama, Mobile, AL, United States
f Department of Pediatrics, Washington University, School of Medicine, St Louis, MO, United States
g Department of Pediatrics, Division of Infectious Diseases, Prisma Health Children’s Hospital-Upstate, Greenville, SC, United States
h Department of Pediatrics, Division of Infectious Diseases, University of Tennessee, Health Science Center, Memphis, TN, United States
i Department of Epidemiology of Microbial Diseases, Yale University, School of Public Health, New Haven, CT, United States
j Department of Pediatrics, Section of Infectious Diseases, Yale University, School of Medicine, New Haven, CT, United States
k Department of Pediatrics, Division of Infectious Diseases, University of South Florida, Tampa, FL, United States
l Department of Pediatrics, Division of Infectious Diseases, East Carolina University, Greenville, NC, United States
m Department of Infectious Diseases, Cook Children’s Hospital, Fort Worth, TX, United States
n Department of Pediatrics, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, United States
Abstract
Background: Human parechovirus (HPeV) infection can result in severe disease in infants, including sepsis, seizures, brain injury, and death. In 2022, a resurgence of HPeV was noted in young infants. The spectrum of illness and outcomes remain to be fully described. Methods: A multistate retrospective cohort study was conducted to evaluate hospitalizations and outcomes of infants aged ≤6 months admitted in 2022 with laboratory-confirmed HPeV infection. Infants with severe disease were defined as having clinical seizures, or abnormalities on magnetic resonance imaging or electroencephalogram during admission. Infants with severe versus nonsevere disease were compared using descriptive statistics. Results: A total of 124 U.S. infants were identified with HPeV in 11 states. Cases of HPeV peaked in May and presented at a median of 25.8 days of life (0-194 d) with fever, fussiness, and poor feeding. Bacterial and other viral co-infections were rare. Thirty-three (27%) of infants had severe neurologic disease, were more likely to present at an earlier age (13.9 vs 30 days of life, P <. 01), have preterm gestation (12% vs 1%, P =. 02), and present with respiratory symptoms (26% vs 8%, P =. 01) or apnea (41% vs 1%, P <. 001). Subcortical white matter cytoxic cerebral edema was common in severe cases. Two infants with HPeV died during admission with severe neurologic HPeV disease; no infant with mild HPeV disease died. Conclusions: This is the largest, geographically diverse U.S. study to describe the 2022 HPeV outbreak among infants. Longitudinal follow up of infants is needed to define predictors and outcomes of severe HPeV disease. © 2024 The Author(s).
Author Keywords
cohort; neonate; parechovirus; severity; United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Maternal obesogenic diet operates at the tumor cell of origin to increase incidence and decrease latency of neurofibromatosis type 1 optic pathway glioma
(2024) Neuro-oncology, 26 (12), pp. 2339-2351.
Chan, A.a , Zhang, K.a , Martin, G.a , Bano, S.a , Chatterjee, J.b , Mahto, S.a , Wang, A.a , Gutmann, D.H.b , Brossier, N.M.a
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
BACKGROUND: Pediatric low-grade glioma incidence has been rising in the United States, mirroring the rising rates of pediatric and maternal obesity. Recently, children of obese mothers were demonstrated to develop brain tumors at higher rates. Importantly, obesity in the United States is largely driven by diet, given the prevalence of high-fat and high-sugar (HFHS) food choices. Since high-fat diet exposure can increase embryonic neuroglial progenitor cell (NPC) proliferation, the potential cells of origin for a low-grade glioma, we hypothesized that in utero exposure to an obesogenic diet would modify pediatric brain penetrance and latency by affecting the tumor cell of origin. METHODS: We employed several murine models of the neurofibromatosis type 1 (NF1) pediatric brain tumor predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from neuroglial progenitor cells in the embryonic third ventricular zone (TVZ). We exposed dams and offspring to an obesogenic HFHS diet or control chow and analyzed fetal neurodevelopment at E19.5 and tumor formation at 6 weeks-3 months. RESULTS: Progeny from HFHS diet-exposed dams demonstrated increased TVZ NPC proliferation and glial differentiation. Dietary switch cohorts confirmed that these effects were dependent upon maternal diet, rather than maternal weight. Obesogenic diet (Ob) similarly accelerated glioma formation in a high-penetrance Nf1-OPG strain and increased glioma penetrance in 2 low-penetrance Nf1-OPG strains. In contrast, Ob exposure in the postnatal period alone did not recapitulate these effects. CONCLUSIONS: These findings establish maternal obesogenic diet as a risk factor for murine Nf1-OPG formation, acting in part through in utero effects on the tumor cell of origin. © The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact jou
Author Keywords
maternal high-fat diet; neurofibromatosis; obesity; optic pathway glioma; pediatric brain tumor
Document Type: Article
Publication Stage: Final
Source: Scopus
Cannabis Use and Trajectories of Depression and Stress Across the Prenatal Period
(2024) JAMA Network Open, 7 (12), p. e2451597.
Constantino-Pettit, A.a , Tillman, R.a , Wilson, J.a , Lashley-Simms, N.a , Vatan, N.b , Atkinson, A.c , Leverett, S.D.a d , Lenze, S.a , Smyser, C.D.e , Bogdan, R.f , Rogers, C.a , Agrawal, A.a
a Department of Psychiatry, Washington University in St Louis, School of Medicine, St Louis, MO, United States
b Washington University in St Louis School of Medicine, St Louis, MO, United States
c Meharry Medical College School of Medicine, Nashville, TN, United States
d Division of Biology & Biomedical Sciences, Neurosciences Program, Washington University in St Louis, St Louis, MO, United States
e Department of Neurology, Washington University in St Louis, St Louis, MO, United States
f Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
Abstract
Importance: Cannabis use among pregnant individuals has increased. Depression and stress are frequently reported motives for cannabis use that may prolong using cannabis during pregnancy. Objective: To examine associations between changes in depression, stress, and self-reported prenatal cannabis use (PCU), to examine motives for PCU, and to examine whether trajectories of depression and stress vary across individuals who report using cannabis to cope with mental health symptoms and/or stress, those who use cannabis for other reasons, and those who do not report PCU. Design, Setting, and Participants: This cohort study recruited pregnant individuals at an obstetric clinic at an academic hospital between July 2019 and January 2024 and followed them during pregnancy. Pregnant individuals with a history of lifetime cannabis use were included. Individuals reporting heavy episodic alcohol use or with other illicit drug use were excluded. Exposure: Self-reported PCU. Main Outcomes and Measures: The primary outcomes were self-reported depression (Edinburgh Postnatal Depression Scale), stress (Cohen Perceived Stress Scale), and cannabis use at each trimester during pregnancy, as well as motives for cannabis use during the first trimester (T1). Stability and changes in depression and stress scores and categorical self-reported prenatal cannabis use from T1 to the third trimester (T3) were estimated using individual linear growth curve models. Results: In this sample of 504 patients (all identified as women; median [IQR] age, 26 [18-40] years), 236 individuals (46.8%) reported PCU after pregnancy knowledge. Depression, stress, and PCU decreased from T1 to T3 (all slope estimates less than -0.29; SEs, 0.23-0.7; all P < .001). There were positive associations between depression and PCU at T1 (r = 0.17; P = .004) and in their rate of change (r = 0.18; P = .01). Only T1 stress and PCU were correlated (r = 0.14; P = .004). Participants reporting PCU for mental health reasons (137 participants [58.1%]) had the highest depression scores at each trimester; however, their rate of change in depression was statistically equivalent to those who did not use cannabis. Conclusions and Relevance: In this cohort study of PCU, participants who used cannabis did not experience a more significant decline in stress or depression symptoms compared with those who did not use cannabis. Individuals who used cannabis for mental health reasons did not hasten a decrease in their symptoms. Health care professionals are encouraged to enhance prenatal individuals’ access to empirically supported treatments for depression and stress.
Document Type: Article
Publication Stage: Final
Source: Scopus
Dura immunity configures leptomeningeal metastasis immunosuppression for cerebrospinal fluid barrier invasion
(2024) Nature Cancer, 5 (12), art. no. e20212121, pp. 1940-1961. Cited 1 time.
Zhao, J.a b c d e , Zeng, R.a b c d e , Li, X.a b c d e , Lu, Y.f g , Wang, Z.h i , Peng, H.a b c d e , Chen, H.b c d e , Fu, M.a , Zhang, Y.a b c d e , Huang, Y.a b c d e , Chen, W.b c d e , Wang, X.j k l m , Guan, Y.j k l m , Han, W.a , Huang, R.n , Yao, C.a , Qin, Z.a , Chen, L.a , Chen, L.a , Feng, X.o , Yang, H.b p , Pereira, P.M.R.q , Tong, X.r s t , Li, B.u v , Zhang, Q.w x , Chi, Y.a b c d e
a Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
b Institute for Translational Brain Research, Fudan University, Shanghai, China
c State Key Laboratory of Medical Neurobiology, Shanghai, China
d MOE Frontiers Center for Brain Science, Shanghai, China
e MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai, China
f Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Shanghai, China
g Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
h Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
i Department of Gastroenterology, Shanghai Xuhui Center Hospital, Shanghai Medical College, Fudan University, Shanghai, China
j CyberKnife Center, Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
k Neurosurgical Institute, Fudan University, Shanghai, China
l National Center for Neurological Disorders, Shanghai, China
m Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, China
n Department of Oncology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
o Laboratory Animal Center, Fudan University, Shanghai, China
p Department of Neurology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
q Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
r Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
s Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai, China
t Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai, China
u Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
v Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
w Advanced Model Animal Research Center, Department of Biotechnology and Biomedicine, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, China
x Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, China
Abstract
The cerebrospinal fluid (CSF) border accommodates diverse immune cells that permit peripheral cell immunosurveillance. However, the intricate interactions between CSF immune cells and infiltrating cancer cells remain poorly understood. Here we use fate mapping, longitudinal time-lapse imaging and multiomics technologies to investigate the precise origin, cellular crosstalk and molecular landscape of macrophages that contribute to leptomeningeal metastasis (LM) progression. Mechanically, we find that dura-derived LM-associated macrophages (dLAMs) migrate into the CSF in a matrix metalloproteinase 14 (MMP14)-dependent manner. Furthermore, we identify that dLAMs critically require the presence of secreted phosphoprotein 1 (SPP1) in cancer cells for their recruitment, fostering an immunosuppressed microenvironment characterized by T cell exhaustion and inactivation. Conversely, inhibition of the SPP1–MMP14 axis can impede macrophages from bypassing the border barrier, prevent cancer cell growth and improve survival in LM mouse models. Our findings reveal an unexpectedly private source of innate immunity within the meningeal space, shed light on CSF barrier dysfunction dynamics and supply potential targets of clinical immunotherapy. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Funding details
Fudan UniversityFDU
Chinese Academy of SciencesCAS
American Association for Cancer ResearchAACR20-40-49-CHI
American Association for Cancer ResearchAACR
Natural Science Foundation of Shanghai Municipality21ZR1403400
Natural Science Foundation of Shanghai Municipality
20JC1419500
National Natural Science Foundation of ChinaNSFC82303437, 82273304/32200640
National Natural Science Foundation of ChinaNSFC
Ministry of Science and Technology of the People’s Republic of ChinaMOST2022YFA1106400
Ministry of Science and Technology of the People’s Republic of ChinaMOST
Document Type: Article
Publication Stage: Final
Source: Scopus
Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression(2024) Genome Medicine, 16 (1), art. no. 146, .
Pehlivan, D.a b c d , Bengtsson, J.D.e , Bajikar, S.S.b d , Grochowski, C.M.b f , Lun, M.Y.e , Gandhi, M.e , Jolly, A.b , Trostle, A.J.c d , Harris, H.K.c g , Suter, B.a c , Aras, S.d , Ramocki, M.B.a h , Du, H.b , Mehaffey, M.G.e , Park, K.e , Wilkey, E.e , Karakas, C.i , Eisfeldt, J.J.j , Pettersson, M.j , Liu, L.k , Shinawi, M.S.l , Kimonis, V.E.m , Wiszniewski, W.n , Mckenzie, K.o , Roser, T.p , Vianna-Morgante, A.M.q , Cornier, A.S.r , Abdelmoity, A.s , Hwang, J.P.f , Jhangiani, S.N.f , Muzny, D.M.f , Mitani, T.t , Muramatsu, K.t , Nabatame, S.u , Glaze, D.G.a c , Fatih, J.M.b , Gibbs, R.A.b f , Liu, Z.c d , Lindstrand, A.j , Sedlazeck, F.J.f , Lupski, J.R.b c f v , Zoghbi, H.Y.a b c d w , Carvalho, C.M.B.b e
a Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States
b Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
c Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States
d Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, United States
e Pacific Northwest Research Institute, Seattle, WA 98122, United States
f Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, United States
g The Meyer Center for Developmental Pediatrics and Autism, 8080 North Stadium Drive, Houston, TX 77054, United States
h University Otolaryngology, East Greenwich, RI 02818, United States
i Department of Pediatrics, Division of Neurology, University of Louisville, Louisville, KY 40202, United States
j Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
k Department of Neurology, Division of Epilepsy, University of North Carolina, Chapel Hill, NC 27599, United States
l Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
m Department of Pediatrics, Division of Genetics and Genomic Medicine, University of California, Irvine, CA 92697, United States
n Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, United States
o Department of Pediatrics, Division of General and Community Pediatrics, University of Alberta, Edmonton, AB T6G 2R7, Canada
p Department of Pediatrics, Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Dr. Von Haunersches Children’s Hospital, Ludwig Maximilian University of Munich, Munich, 80337, Germany
q Department of Genetics and Evolutionary Biology, Institute of Biosciences, São Paulo – SP, 05508-090, Brazil
r Department of Genetics, San Jorge Children’s Hospital, San Juan, 00771, Puerto Rico
s Division of Neurology, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, United States
t Department of Pediatrics, Jichi Medical University, Shimotsuke-City, Tochigi, 329-0498, Japan
u Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
v Texas Children’s Hospital, Houston, TX 77030, United States
w Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, United States
Abstract
Background: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. Methods: To study the role of the genomic rearrangement structures on an individual’s clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. Results: Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype–phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. Conclusion: In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches. © The Author(s) 2024.
Author Keywords
Clinical severity; MECP2 duplication syndrome; MRXSL; Survival; Tandem duplication; Terminal duplication
Funding details
Doris Duke Charitable FoundationDDCF
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Human Genome Research InstituteNHGRI
Rett Syndrome Research TrustRSRT
Baylor-Hopkins Center for Mendelian GenomicsBHCMG
R01 GM152556, R01 GM132589
National Institute of Neurological Disorders and StrokeNINDSP50HD103555, 1K23 NS125126-01A1, R35 NS105078, R01NS057819
National Institute of Neurological Disorders and StrokeNINDS
Intellectual and Developmental Disabilities Research CenterIDDRC1U54 HD083092
Intellectual and Developmental Disabilities Research CenterIDDRC
National Heart, Lung, and Blood InstituteNHLBIUM1HG006542
National Heart, Lung, and Blood InstituteNHLBI
HjärnfondenFO2020-0351
Hjärnfonden
International Rett Syndrome FoundationIRSF3701–1
International Rett Syndrome FoundationIRSF
Document Type: Article
Publication Stage: Final
Source: Scopus
Brain volumes, cognitive, and adaptive skills in school-age children with Down syndrome
(2024) Journal of Neurodevelopmental Disorders, 16 (1), art. no. 70, .
Grzadzinski, R.a b , Mata, K.a , Bhatt, A.S.a , Jatkar, A.c , Garic, D.a b , Shen, M.D.a b , Girault, J.B.a b , St. John, T.d e , Pandey, J.f , Zwaigenbaum, L.g , Estes, A.d e , Shen, A.M.h , Dager, S.i , Schultz, R.f , Botteron, K.j , Marrus, N.j , Styner, M.b , Evans, A.k , Kim, S.H.b , McKinstry, R.l , Gerig, G.m , Piven, J.a b , Hazlett, H.a b , Fallin, D.n , Volk, H.n , Truong, K.n , Das, S.n , MacIntyre, L.n , Fonov, V.n , Collins, D.L.n , Pruett, J.n , Wolff, J.n , Elison, J.n , Constantino, J.n , Shaw, D.n , Chappell, C.n , for the IBIS Networkn
a Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, 101, Renee Lynne Court, Carrboro, NC 27510, United States
b Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c New England College of Optometry, Boston, MA, United States
d University of Washington Autism Research Center, Seattle, WA, United States
e Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
f Center for Autism Research at the Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g Autism Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Canada
h Easter Seals, UCP, Raleigh, NC, United States
i Center On Human Development and Disability, University of Washington, Seattle, WA, United States
j Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
k Montreal Neurological Institute, McGill University, Montreal, Canada
l Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
m Department of Computer Science and Engineering, New York University, New York, NY, United States
Abstract
Background: Down syndrome (DS) is the most common congenital neurodevelopmental disorder, present in about 1 in every 700 live births. Despite its prevalence, literature exploring the neurobiology underlying DS and how this neurobiology is related to behavior is limited. This study fills this gap by examining cortical volumes and behavioral correlates in school-age children with DS. Methods: School-age children (mean = 9.7 years ± 1.1) underwent comprehensive assessments, including cognitive and adaptive assessments, as well as an MRI scan without the use of sedation. Children with DS (n = 35) were compared to available samples of typically developing (TD; n = 80) and ASD children (n = 29). ANOVAs were conducted to compare groups on cognitive and adaptive assessments. ANCOVAs (covarying for age, sex, and total cerebral volume; TCV) compared cortical brain volumes between groups. Correlations between behavioral metrics and cortical and cerebellar volumes (separately for gray (GM) and white matter (WM)) were conducted separately by group. Results: As expected, children with DS had significantly lower cognitive skills compared to ASD and TD children. Daily Living adaptive skills were comparable between ASD children and children with DS, and both groups scored lower than TD children. Children with DS exhibited a smaller TCV compared to ASD and TD children. Additionally, when controlling for TCV, age, and sex, children with DS had significantly smaller total GM and tissue volumes. Cerebellum volumes were significantly correlated with Daily Living adaptive behaviors in the DS group only. Conclusions: Despite children with DS exhibiting lower cognitive skills and smaller brain volume overall than children with ASD, their deficits in Socialization and Daily Living adaptive skills are comparable. Differences in lobar volumes (e.g., Right Frontal GM/WM, Left Frontal WM, and Left and Right Temporal WM) were observed above and beyond overall differences in total volume. The correlation between cerebellum volumes and Daily Living adaptive behaviors in the DS group provides a novel area to explore in future research. © The Author(s) 2024.
Author Keywords
Adaptive; Autism spectrum disorder; Brain volumes; Cognitive; Cortical volumes; Down syndrome; Intellectual disability; MRI; Neurobehavioral/behavioral profiles; Neurodevelopmental disorder; Neuroimaging; School-age children
Funding details
Washington University in St. LouisWUSTL
University of MinnesotaUMN
National Institutes of HealthNIH
University of North Carolina WilmingtonUNCW
Johns Hopkins University PressJHUP
University of AlbertaU of A
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis
(2024) Molecular Neurodegeneration, 19 (1), art. no. 95, .
Zhang, L.a , Huang, L.a , Zhou, Y.a , Meng, J.a , Zhang, L.a , Zhou, Y.a , Zheng, N.a , Guo, T.a , Zhao, S.a , Wang, Z.a , Huo, Y.a , Zhao, Y.a , Chen, X.-F.a , Zheng, H.a , Holtzman, D.M.b , Zhang, Y.-W.a
a Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Fujian, Xiamen, 361102, China
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: The CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer’s disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive. Methods: CD2AP protein levels in cultured primary cells and in 5xFAD mice was studied. Microglial CD2AP-deficient mice were crossed with 5xFAD mice and the offspring were subjected to neuropathological assessment, behavioral tests, electrophysiology, RNA-seq, Golgi staining, and biochemistry analysis. Primary microglia were also isolated for assessing their uptake and morphology changes. Results: We find that CD2AP is abundantly expressed in microglia and its levels are elevated in the brain of AD patients and the 5xFAD model mice at pathological stages. We demonstrate that CD2AP haploinsufficiency in microglia significantly attenuates cognitive and synaptic deficits, weakens the response of microglia to Aβ and the formation of disease-associated microglia (DAM), and alleviates synapse loss in 5xFAD mice. We show that CD2AP-deficient microglia exhibit compromised uptake ability. In addition, we find that CD2AP expression is positively correlated with the expression of the complement C1q that is important for synapse phagocytosis and the formation of DAM in response to Aβ deposition. Moreover, we reveal that CD2AP interacts with colony stimulating factor 1 receptor (CSF1R) and regulates CSF1R cell surface levels, which may further affect C1q expression. Conclusions: Our results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against Aβ deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD. © The Author(s) 2024.
Author Keywords
Alzheimer’s disease; C1q; CD2AP; CSF1R; Disease-associated microglia; Microglia; β-amyloid
Funding details
National Natural Science Foundation of ChinaNSFCU21A20361, 82130039
National Natural Science Foundation of ChinaNSFC
Fundamental Research Funds for the Central Universities20720220133
Fundamental Research Funds for the Central Universities
Document Type: Article
Publication Stage: Final
Source: Scopus
Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial
(2024) Brain Stimulation, .
Conway, C.R.a , Aaronson, S.T.b , Sackeim, H.A.c , George, M.S.c d , Zajecka, J.e f , Bunker, M.T.g , Duffy, W.h , Stedman, M.i , Riva-Posse, P.j , Allen, R.M.k , Quevedo, J.l , Berger, M.m , Alva, G.n , Malik, M.A.o , Dunner, D.L.p , Cichowicz, I.q , Banov, M.r , Manu, L.s , Nahas, Z.t , Macaluso, M.u , Mickey, B.J.v , Sheline, Y.w , Kriedt, C.L.a , Lee, Y.-C.L.g , Gordon, C.g , Shy, O.g , Tran, Q.g , Yates, L.g , Rush, A.J.x
a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
b Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, Baltimore, MD, United States
c Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
d Ralph H. Johnson VA Health Care System, Charleston, SC, United States
e Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
f Psychiatric Medicine Associates, LLC, Skokie, IL, United States
g LivaNova PLC (or a Subsidiary), Great Britain, London, United Kingdom
h Alivation Research, Lincoln, NE, United States
i Stedman Clinical Trials, Tampa, FL, United States
j Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
k Seattle Neuropsychiatric Treatment Center, Seattle, WA, United States
l Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
m Offices of Psychiatry & Counseling Services, Moosic, PA, United States
n ATP Clinical Research, Costa Mesa, CA, United States
o PsychCare Consultants Research, St Louis, MO, United States
p Center for Anxiety and Depression, Mercer Island, WA, United States
q Mindful Behavioral Health, Boca Raton, FL, United States
r PsychAtlanta Research Center, Marietta, GA, United States
s Department of Psychiatry and Behavioral Health, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States
t University of Minnesota, Minneapolis, MN, United States
u University of Alabama, Birmingham, AL, United States
v Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, United States
w Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Duke–NUS Medical School, Singapore
Abstract
Background: Few treatments are available for individuals with marked treatment-resistant depression (TRD). Objective: Evaluate the safety and effectiveness of FDA-approved adjunctive vagus nerve stimulation (VNS) in patients with marked TRD. Methods: This 12-month, multicenter, double-blind, sham-controlled trial included 493 adults with marked treatment-resistant major depression who were randomized to active or no-stimulation sham VNS for 12 months. The primary outcome was percent time in response across months 3–12, with response defined as a ≥50 % change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS). Several secondary endpoints were evaluated. Results: Overall, 88.4 % of participants completed the trial. Percent time in MADRS response did not distinguish active from sham VNS. However, ratings from on-site clinicians (Clinical Global Inventory–Impression [CGI-I]), patients (Quick Inventory of Depressive Symptomology–Self Report [QIDS-SR]), and offsite masked raters (Quick Inventory of Depressive Symptomology–Clinician [QIDS-C]) revealed antidepressant benefits significantly favoring active VNS. Active VNS demonstrated significantly more percent time in response on the CGI-I (P = 0.004) and QIDS-SR (P = 0.049), and significantly more percent time in partial response (PR; symptom improvement ≥30 %) on the CGI-I (P < 0.001) and QIDS-C (P = 0.006) versus sham VNS. Active VNS exceeded sham VNS in rate of dyspnea (P = 0.035), a known side effect of VNS. No new adverse events were identified. Conclusions: Percent time in MADRS response did not distinguish the treatment groups, but on multiple instruments time in response and PR showed a positive treatment effect. VNS was found safe and effective in participants with marked TRD. © 2024
Author Keywords
Adjunctive therapy; Efficacy; Partial response; Randomized trial; Response; Treatment-resistant depression; Vagus nerve stimulation
Funding details
University of MinnesotaUMN
Texas Tech University Health Sciences CenterTTUHSC
University of AlabamaUA
Medical University of South CarolinaMUSC
Carilion Clinic
University of Wisconsin-MadisonUW
Ohio State UniversityOSU
McGovern Medical School
University of California, San DiegoUCSD
Massachusetts General HospitalMGH
Centers for Medicare and Medicaid ServicesCMS
University of UtahUU
University of MissouriMU
School of Medicine, Southern Illinois University
Icahn School of Medicine at Mount SinaiISMMS
Emory UniversityEU
Dell Medical School, University of Texas at Austin
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Increased White Matter Aerobic Glycolysis in Multiple Sclerosis
(2024) Annals of Neurology, .
Brier, M.R.a b , Judge, B.a , Ying, C.b , Salter, A.c , An, H.b , Patel, A.d , Wang, Q.b , Wang, Y.b e , Cross, A.H.a , Naismith, R.T.a , Benzinger, T.L.S.b , Goyal, M.S.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Despite treatments which reduce relapses in multiple sclerosis (MS), many patients continue to experience progressive disability accumulation. MS is associated with metabolic disruptions and cerebral metabolic stress predisposes to tissue injury and possibly impaired remyelination. Additionally, myelin homeostasis is metabolically expensive and reliant on glycolysis. We investigated cerebral metabolic changes in MS and when in the disease course they occurred, and assessed their relationship with microstructural changes. Methods: This study used combined fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) to measure cerebral metabolic rate of glucose and oxygen, thereby quantifying glycolysis. Twelve healthy controls, 20 patients with relapsing MS, and 13 patients with non-relapsing MS were studied. Relapsing patients with MS were treatment naïve and scanned pre- and post-initiation of high efficacy disease modifying therapy. Results: In normal appearing white matter, we observed increased glucose utilization and reduced oxygen utilization in newly diagnosed MS, consistent with increased glycolysis. Increased glycolysis was greater in patients with a longer disease duration course and higher disability. Among newly diagnosed patients, different treatments had differential impacts on glucose utilization. Last, whereas hypermetabolism within lesions was clearly associated with inflammation, no such relationship was found within normal appearing white matter. Interpretation: Increased white matter glycolysis is a prominent feature of cerebral metabolism in MS. It begins early in the disease course, increases with disease duration and is independent of microstructural evidence of inflammation in normal appearing white matter. Optimization of the metabolic environment may be an important component of therapies designed to reduce progressive disability. ANN NEUROL 2024. © 2024 American Neurological Association.
Funding details
School of Medicine, Washington University in St. LouisWUSM
National Multiple Sclerosis SocietyNMSS
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthNIHBI‐2105‐37656, R21MH131962
National Institutes of HealthNIH
Institute of Clinical and Translational SciencesICTSUL1TR002345
Institute of Clinical and Translational SciencesICTS
Foundation for Barnes-Jewish HospitalFBJHRF1AG073210
Foundation for Barnes-Jewish HospitalFBJH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Individual and prescription level factors associated with overdose in opioid naïve older people
(2024) Journal of the American Geriatrics Society, .
Little, K.a , El Ibrahimi, S.a b , Yoo, J.a , Flores, D.a , Hendricks, M.c , Hildebran, C.a , Ritter, G.d , Wright, D.e , Loy, B.e , Weiner, S.G.f
a Division of Research and Evaluation, Comagine Health, Portland, OR, United States
b School of Public Health, Department of Epidemiology and Biostatistics, University of Nevada, Las Vegas, NV, United States
c General Medical Sciences Division, Washington University School of Medicine, St. Louis, MO, United States
d Schneider Institutes for Health Policy, Heller School for Social Policy and Management, Brandeis University, Waltham, MA, United States
e Injury and Violence Prevention Program—Public Health Division, Oregon Health Authority, Oregon, United States
f Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
Abstract
Background: Opioid naïve older adults may be at risk of overdose after receiving an initial opioid prescription. Methods: This population-based cohort study from a linked dataset of patients in Oregon, linking all payer claims data to other administrative datasets, aimed to assess the prescription- and patient-level characteristics associated with increased odds of opioid overdose after an initial opioid prescription. Included patients were ≥65 years old and received an index pain-formulation opioid prescription between 2016 and 2019. The primary outcome was an index nonfatal or fatal overdose within 6- or 12-months following index prescription. Patient characteristics included age, sex, insurance plan, number of medical comorbidities, and presence of psychiatric comorbidities. Prescription characteristics included opioid type, duration of action, and days’ supply. A logistic regression model was used to determine the association with opioid overdose. Results: There were 223,799 individuals included for analysis (58.6% 65–74 years old, 53.9% female). There were 183 fatal or nonfatal opioid overdoses in 6 months and 232 in 12 months following the index prescription. Adults aged ≥85 years were less likely to experience an overdose versus those 65–74 years (6-month adjusted odds ratio (aOR) 0.35, [95% confidence interval, 0.20–0.59]; 12-month aOR 0.38 [0.24–0.60]). Multiple factors were associated with increased odds, including dually enrolled in Medicare/Medicaid compared to commercial insurance (6-month aOR 5.99, [1.93–19.65]; 12-month aOR 3.53, [1.58–7.90]), three or more comorbidities compared to none: (6-month aOR 3.69, [1.91–8.13]; 12-month aOR 4.24, [2.32–7.74]), history of depression: (6-month aOR 1.94, [1.34–2.81]; 12-month aOR 2.20, [1.60–3.04]), received long-acting opioids (6-month aOR 5.76, [1.56–21.22]; 12-month aOR 4.0, [1.39–11.55]) compared to short-acting. Conclusions: For older adults, there is an association between opioid overdose risk and factors including patient insurance type, patient comorbidities, and receiving a long-acting opioid prescription. Providers should be aware of the risks of opioids in this population. © 2024 The American Geriatrics Society.
Author Keywords
older adults; opioid naïve; opioid overdose; opioids
Funding details
National Institute on Drug AbuseNIDA
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Differences in baseline cognitive performance between participants with early-onset and late-onset Alzheimer’s disease: Comparison of LEADS and ADNI
(2024) Alzheimer’s and Dementia, . Cited 1 time.
Hammers, D.B.a , Eloyan, A.b , Thangarajah, M.b , Taurone, A.b , Beckett, L.c , Gao, S.d , Polsinelli, A.J.a , Kirby, K.a , Dage, J.L.a , Nudelman, K.e , Aisen, P.f , Reman, R.f , La Joie, R.g , Lagarde, J.g , Atri, A.h , Clark, D.a , Day, G.S.i , Duara, R.j , Graff-Radford, N.R.i , Honig, L.S.k , Jones, D.T.l , Masdeu, J.C.m , Mendez, M.F.n , Womack, K.o , Musiek, E.o , Onyike, C.U.p , Riddle, M.q , Grant, I.r , Rogalski, E.s , Johnson, E.C.B.t , Salloway, S.q , Sha, S.J.u , Turner, R.S.v , Wingo, T.S.w , Wolk, D.A.x , Carrillo, M.C.y , Dickerson, B.C.z , Rabinovici, G.D.g aa , Apostolova, L.G.a e ab , the LEADS Consortium 1 for the Alzheimer’s Disease Neuroimaging Initiativeac
a Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
c Department of Public Health Sciences, University of California—Davis, Davis, CA, United States
d Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
f Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
g Department of Neurology, University of California—San Francisco, San Francisco, CA, United States
h Banner Sun Health Research Institute, Sun City, AZ, United States
i Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
j Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
k Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
l Department of Neurology, Mayo Clinic, Rochester, MN, United States
m Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
n Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
o Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
p Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
q Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
r Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
s Healthy Aging & Alzheimer’s Research Care Center, Department of Neurology, University of Chicago, Chicago, IL, United States
t Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
u Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
v Department of Neurology, Georgetown University, Washington, DC, United States
w Department of Neurology, UC Davis Alzheimer’s Disease Research Center, University of California—Davis, Davis, CA, United States
x Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
y Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
z Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
aa Department of Radiology & Biomedical Imaging, University of California—San Francisco, San Francisco, CA, United States
ab Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
Abstract
INTRODUCTION: Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) share similar amyloid etiology, but evidence from smaller-scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS: Z-score cognitive-domain composites for 311 amyloid-positive sporadic EOAD and 314 amyloid-positive LOAD participants were calculated from baseline data from age-appropriate control cohorts. Z-score composites were compared between AD groups for each domain. RESULTS: After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION: Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non-amnestic impairments in younger patients to ensure proper identification and intervention using disease-modifying treatments. Highlights: Both early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) participants displayed widespread cognitive impairments relative to their same-aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv-PPA), and frontal-variant AD. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amnestic; early-onset; late-onset; non-amnestic
Funding details
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Biogen
Alzheimer’s Disease Neuroimaging InitiativeADNI
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
Alzheimer’s AssociationAAP30AG066506, P30 AG010124, U01 AG016976, P50AG047366, P30 AG013854, P30 AG062422, P30 AG010133, LEADS GENETICS‐19‐639372, P30 AG062421, P50 AG005681, P50 AG008702, P50 AG005146, P50 AG025688, P50 AG023501
Alzheimer’s AssociationAA
Fondation pour la Recherche sur AlzheimerU24AG021886, R56 AG057195, U01AG6057195
Fondation pour la Recherche sur Alzheimer
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institutes of HealthNIHU01 AG024904
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring individual differences in amygdala-mediated memory modulation
(2024) Cognitive, Affective and Behavioral Neuroscience, art. no. 107860, .
Hollearn, M.K.a , Manns, J.R.f , Blanpain, L.T.c , Hamann, S.B.f , Bijanki, K.g , Gross, R.E.e , Drane, D.L.d , Campbell, J.M.b , Wahlstrom, K.L.a , Light, G.F.a , Tasevac, A.a , Demarest, P.i , Brunner, P.h i , Willie, J.T.h j , Inman, C.S.a b
a Department of Psychology, University of Utah, 380 S 1530 E BEH S 502, Salt Lake City, UT 84112, United States
b Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, United States
c Neuroscience, Emory School of Medicine, Atlanta, GA, United States
d Neurology, Emory School of Medicine, Atlanta, GA, United States
e Neurosurgery, Emory School of Medicine, Atlanta, GA, United States
f Psychology, Emory University, Atlanta, GA, United States
g Neurosurgery, Baylor College of Medicine, Huston, TX, United States
h Neurosurgery, Washington University School of Medicine, Saint Louis, MO, United States
i Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO, United States
j Barnes-Jewish Hospital, Saint Louis, MO, United States
Abstract
Amygdala activation by emotional arousal during memory formation can prioritize events for long-term memory. Building upon our prior demonstration that brief electrical stimulation to the human amygdala reliably improved long-term recognition memory for images of neutral objects without eliciting an emotional response, our study aims to explore and describe individual differences and stimulation-related factors in amygdala-mediated memory modulation. Thirty-one patients undergoing intracranial monitoring for intractable epilepsy were shown neutral object images paired with direct amygdala stimulation during encoding with recognition memory tested immediately and one day later. Adding to our prior sample, we found an overall memory enhancement effect without subjective emotional arousal at the one-day delay, but not at the immediate delay, for previously stimulated objects compared to not stimulated objects. Importantly, we observed a larger variation in performance across this larger sample than our initial sample, including some participants who showed a memory impairment for stimulated objects. Of the explored individual differences, the factor that most accounted for variability in memory modulation was each participant’s pre-operative memory performance. Worse memory performance on standardized neuropsychological tests was associated with a stronger susceptibility to memory modulation in a positive or negative direction. Sex differences and the frequency of interictal epileptiform discharges (IEDs) during testing also accounted for some variance in amygdala-mediated memory modulation. Given the potential and challenges of this memory modulation approach, we discuss additional individual and stimulation factors that we hope will differentiate between memory enhancement and impairment to further optimize the potential of amygdala-mediated memory enhancement for therapeutic interventions. © The Psychonomic Society, Inc. 2024.
Author Keywords
Basolateral amygdala; Direct brain stimulation; Epilepsy; Episodic memory; Hippocampus
Funding details
National Science FoundationNSF1747505
National Science FoundationNSF
National Institutes of HealthNIH2124252, R01-MH120194, T32-NS115723, P41-EB018783
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Effects of vagus nerve stimulation on daily function and quality of life in markedly treatment-resistant major depression: Findings from a one-year, randomized, sham-controlled trial
(2024) Brain Stimulation, . Cited 1 time.
Rush, A.J.a b , Conway, C.R.c , Aaronson, S.T.d , George, M.S.e f , Riva-Posse, P.g , Dunner, D.L.h , Zajecka, J.i j , Bunker, M.T.k , Quevedo, J.l , Allen, R.M.m , Alva, G.n , Luing, H.o , Nahas, Z.p , Manu, L.q , Bennett, J.I.r , Mickey, B.J.s , Becker, J.t , Sheline, Y.u , Cusin, C.v , Murrough, J.W.w , Reeves, K.x , Rosenquist, P.B.y , Lee, Y.-C.L.k , Majewski, S.k , Way, J.k , Olin, B.k , Sackeim, H.A.f
a Duke-NUS Medical School, Singapore
b CEO, Curbstone Consultant LLC, Dallas, TX, United States
c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
d Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, Baltimore, MD, United States
e Ralph H. Johnson VA Health Care System (VAHCS), Charleston, SC, United States
f Medical University of South Carolina, Department of Psychiatry, Charleston, SC, United States
g Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Emory University, Atlanta, GA, United States
h Center for Anxiety and Depression, Mercer Island, WA, United States
i Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
j Psychiatric Medicine Associates, LLC, SkokieIL, United States
k LivaNova PLC (or a Subsidiary), Great Britain, London, United Kingdom
l Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, United States
m Seattle Neuropsychiatric Treatment Center, Seattle, WA, United States
n ATP Clinical Research, Costa Mesa, CA, United States
o Florida Center for TMS, St Augustine, FL, United States
p University of Minnesota, Minneapolis, MN, United States
q Department of Psychiatry and Behavioral Health, Renaissance School of Medicine at Stony Brook University, Stony BrookNY, United States
r SIU Neuroscience Institute, Springfield, IL, United States
s Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, United States
t NeuroScience & TMS Treatment Centers, Brentwood, TN, United States
u UPenn Perelman School of Medicine, Philadelphia, PA, United States
v Mass General Psychiatry: Depression Clinical & Research Program, Boston, MA, United States
w Icahn School of Medicine at Mount Sinai, New York, NY, United States
x The Ohio State University Wexner Medical Center, Columbus, OH, United States
y Medical College of Georgia at Augusta University, Augusta, GA, United States
Abstract
Background: Depression treatments aim to minimize symptom burden and optimize quality of life (QoL) and psychosocial function. Objective: Compare the effects of adjunctive versus sham vagus nerve stimulation (VNS) on QoL and function in markedly treatment-resistant depression (TRD). Methods: In this multicenter, double-blind, sham-controlled trial, 493 adults with TRD and ≥4 adequate but unsuccessful antidepressant treatment trials (current episode) were randomized to active (n = 249) or sham (n = 244) VNS (plus treatment as usual) over a 12-month observation period. Quarterly outcomes included QoL with the Q-LES-Q, Mini-Q-LES-Q, and EQ-5D-5L, and function with the WHODAS 2.0 and Work Productivity and Activity Impairment Questionnaire (WPAI) item 6. Differences between treatment groups in change in scores from baseline and percentage of time with a meaningful response in Q-LES-Q, Mini-Q-LES-Q, and WPAI item 6 scores were analyzed. Results: Active VNS was superior to sham in mean change in scores from baseline in the Mini-Q-LES-Q (P = 0.050) and WPAI item 6 (health condition’s effect on regular activities [P = 0.050]) used as continuous variables, with a similar trend for Q-LES-Q (P = 0.061). Active VNS was superior to sham in time spent in clinically meaningful benefit (categorical analyses) using the Q-LES-Q (P = 0.029), Mini-Q-LES-Q (P = 0.011), and WPAI item 6 (P = 0.039). The WHODAS 2.0 (P = 0.304) and EQ-5D visual analog scale (P = 0.125) failed to reveal between-group differences. Conclusion: Active VNS was superior to sham VNS in improving QoL and psychosocial function in patients with TRD. VNS has a broader therapeutic impact than symptom improvement alone in patients with marked psychosocial impairment. © 2024
Author Keywords
Efficacy; Function; Quality of life; RECOVER trial; Treatment-resistant depression; Vagus nerve stimulation
Funding details
LivaNova
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Full-field, frequency-domain comparison of simulated and measured human brain deformation
(2024) Biomechanics and Modeling in Mechanobiology, art. no. 081006, .
Arani, A.H.G.a , Okamoto, R.J.a , Escarcega, J.D.a , Jerusalem, A.b , Alshareef, A.A.c , Bayly, P.V.a
a Mechanical Engineering and Materials Science, Washington University, St. Louis, MO, United States
b Department of Engineering Science, University of Oxford, Oxford, OX1 3PJ, United Kingdom
c Department of Mechanical Engineering, University of South Carolina, Columbia, SC, United States
Abstract
We propose a robust framework for quantitatively comparing model-predicted and experimentally measured strain fields in the human brain during harmonic skull motion. Traumatic brain injuries (TBIs) are typically caused by skull impact or acceleration, but how skull motion leads to brain deformation and consequent neural injury remains unclear and comparison of model predictions to experimental data remains limited. Magnetic resonance elastography (MRE) provides high-resolution, full-field measurements of dynamic brain deformation induced by harmonic skull motion. In the proposed framework, full-field strain measurements from human brain MRE in vivo are compared to simulated strain fields from models with similar harmonic loading. To enable comparison, the model geometry and subject anatomy, and subsequently, the predicted and measured strain fields are nonlinearly registered to the same standard brain atlas. Strain field correlations (Cv), both global (over the brain volume) and local (over smaller sub-volumes), are then computed from the inner product of the complex-valued strain tensors from model and experiment at each voxel. To demonstrate our approach, we compare strain fields from MRE in six human subjects to predictions from two previously developed models. Notably, global Cv values are higher when comparing strain fields from different subjects (Cv~0.6–0.7) than when comparing strain fields from either of the two models to strain fields in any subject. The proposed framework provides a quantitative method to assess similarity (and to identify discrepancies) between model predictions and experimental measurements of brain deformation and thus can aid in the development and evaluation of improved models of brain biomechanics. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Author Keywords
Brain simulation; Frequency-domain comparison; Magnetic resonance elastography; Nonlinear registration; Strain fields; Traumatic brain injury
Funding details
National Institutes of HealthNIHU01 NS112120
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus