Inflammation is associated with pain and fatigue in older adults
(2024) Brain, Behavior, and Immunity – Health, 42, art. no. 100874, .
Norton, S.A.a , Blaydon, L.M.a , Niehaus, M.a b , Miller, A.P.c , Hill, P.L.a , Oltmanns, T.F.a , Bogdan, R.a
a Department of Psychological & Brain Sciences, Washington University in Saint Louis, United States
b University of Missouri Saint Louis, United States
c Department of Psychiatry, Washington University in Saint Louis, United States
Abstract
Introduction: Increasing evidence suggests that inflammation may play a pivotal role in the development of chronic pain and fatigue in aging individuals. This study investigated the relationship between three inflammatory markers (IL-6, CRP, and TNFα) and pain and fatigue, both cross-sectionally and longitudinally, in a sample of older adults from the Saint Louis Personality and Aging (SPAN) study. Methods: SPAN study participants provided blood samples at two in-person sessions approximately 2 years apart for the analysis of the inflammatory biomarkers IL-6, CRP, and TNFα. Pain and fatigue were assessed using the RAND-36 Health Status Inventory. Correlations (with false discovery rate correction for multiple testing) and follow-up linear regressions including potentially confounding demographic (e.g., annual household income) and health (e.g., BMI, medication use) covariates were used to estimate cross sectional and longitudinal associations. Analytic ns ranged from 533 to 815. Results: Cross-sectional analyses revealed that higher IL-6 and CRP were associated with greater reported pain and fatigue, even after accounting for covariates (βs > .098, ps < .05). TNFα was associated with greater fatigue only (β = .100, p = .012). Longitudinally, CRP and IL-6 predicted future pain and fatigue, although only the relationship between CRP and future fatigue survived the inclusion of covariates (β = .104, p = .022). Both pain and fatigue predicted higher levels of IL-6 and CRP approximately 2 years later, although only the associations with IL-6 survived the inclusion of covariates (βs > .12, ps < .01). Discussion: Our study adds to a growing body of literature showing that inflammation is associated with greater pain and fatigue in older adults. Our longitudinal data showing temporal bidirectional associations is consistent with evidence from non-human animal models that heightened inflammation causally contributes to fatigue and also suggests that the experience of pain and fatigue may contribute to inflammation. It will be important for future work to identify how lifestyle factors associated with pain and fatigue (e.g., physical activity) may contribute to these associations. © 2024
Author Keywords
Aging; C-Reactive protein; CRP; Fatigue; IL-6; Inflammation; Pain; TNFα
Document Type: Article
Publication Stage: Final
Source: Scopus
Cardiorespiratory Fitness and Sleep, but not Physical Activity, are Associated with Functional Connectivity in Older Adults
(2024) Sports Medicine – Open, 10 (1), art. no. 113, .
Wing, D.a b , Roelands, B.f j , Wetherell, J.L.d e , Nichols, J.F.a b , Meeusen, R.f j k , Godino, J.G.a b , Shimony, J.S.i , Snyder, A.Z.i , Nishino, T.c , Nicol, G.E.c , Nagels, G.h , Eyler, L.T.e g , Lenze, E.J.c
a Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, United States
b Exercise and Physical Activity Resource Center (EPARC), University of California, San Diego, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Mental Health Service, VA San Diego Healthcare System, San Diego, United States
e Department of Psychiatry, University of California, San Diego, United States
f Human Physiology & amp; Sports Physiotherapy Research Group, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
g Education, and Clinical Center, Desert-Pacific Mental Illness Research, San Diego Veterans Administration Healthcare System, San Diego, United States
h Department of Neurology, Brussels, Belgium/Center for Neurosciences (C4N), UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
i Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
j Vrije Universiteit Brussel, Brussels, Belgium
k Department of Sports, Recreation, Exercise and Sciences, Community and Health Sciences, University of the Western Cape, Cape Town, South Africa
Abstract
Background: Aging results in changes in resting state functional connectivity within key networks associated with cognition. Cardiovascular function, physical activity, sleep, and body composition may influence these age-related changes in the brain. Better understanding these associations may help clarify mechanisms related to brain aging and guide interventional strategies to reduce these changes. Methods: In a large (n = 398) sample of healthy community dwelling older adults that were part of a larger interventional trial, we conducted cross sectional analyses of baseline data to examine the relationships between several modifiable behaviors and resting state functional connectivity within networks associated with cognition and emotional regulation. Additionally, maximal aerobic capacity, physical activity, quality of sleep, and body composition were assessed. Associations were explored both through correlation and best vs. worst group comparisons. Results: Greater cardiovascular fitness, but not larger quantity of daily physical activity, was associated with greater functional connectivity within the Default Mode (p = 0.008 r = 0.142) and Salience Networks (p = 0.005, r = 0.152). Better sleep (greater efficiency and fewer nighttime awakenings) was also associated with greater functional connectivity within multiple networks including the Default Mode, Executive Control, and Salience Networks. When the population was split into quartiles, the highest body fat group displayed higher functional connectivity in the Dorsal Attentional Network compared to the lowest body fat percentage (p = 0.011; 95% CI − 0.0172 to − 0.0023). Conclusion: These findings confirm and expand on previous work indicating that, in older adults, higher levels of cardiovascular fitness and better sleep quality, but not greater quantity of physical activity, total sleep time, or lower body fat percentage are associated with increased functional connectivity within key resting state networks. © The Author(s) 2024.
Author Keywords
Body composition; Brain health; Functional connectivity; Maximal cardiovascular fitness; Physical activity; Sleep quality; Sleep quantity; Successful aging
Document Type: Article
Publication Stage: Final
Source: Scopus
Multimodal investigation of dynamic brain network alterations in autism spectrum disorder: Linking connectivity dynamics to symptoms and developmental trajectories
(2024) NeuroImage, 302, art. no. 120895, .
Wan, L.a b , Li, Y.c d , Zhu, G.a b , Yang, D.e , Li, F.f , Wang, W.a b , Chen, J.a b , Yang, G.a b g , Li, R.c h
a Senior Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing, China
b Department of Pediatrics, The First Medical Center, Chinese PLA General Hospital, Beijing, China
c Center for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Macau S.A.R, Taipa, China
d Department of Psychology, Faculty of Social Sciences, University of Macau, Macau S.A.R, Taipa, China
e Washington University School of Medicine, Mallinckrodt Institute of Radiology, 4515 McKinley Avenue, St. Louis, MO 63110, United States
f School of Life Science and Technology, Center for Information in BioMedicine, University of Electronic Science and Technology of China, Chengdu, China
g The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
h Department of Electrical and Computer Engineering, Faculty of Science and Technology, University of Macau, Macau S.A.R, Taipa, China
Abstract
Background: Autism spectrum disorder (ASD) has been associated with disrupted brain connectivity, yet a comprehensive understanding of the dynamic neural underpinnings remains lacking. This study employed concurrent electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) techniques to investigate dynamic functional connectivity (dFC) patterns and neurovascular characteristics in children with ASD. We also explored associations between neurovascular characteristics and the developmental trajectory of adaptive behavior in individuals with ASD. Methods: Resting-state EEG and fNIRS data were simultaneously recorded from 58 ASD and 63 TD children. We implemented a k-means clustering approach to extract the dFC states for each modality. In addition, a multimodal covariance network (MCN) was constructed from the EEG and fNIRS dFC features to capture the neurovascular characteristics linked to ASD. Results: EEG analyses revealed atypical properties of dFC states in the beta and gamma bands in children with ASD compared to TD children. For fNIRS, the ASD group exhibited atypical properties of dFC states such as duration and transitions relative to the TD group. The MCN analysis revealed significantly suppressed functional covariance between right superior temporal and left Broca’s areas, alongside enhanced right dorsolateral prefrontal-left Broca covariance in ASD. Notably, we found that early neurovascular characteristics can predict the developmental progress of adaptive functioning in ASD. Conclusion: The multimodal investigation revealed distinct dFC patterns and neurovascular characteristics associated with ASD, elucidating potential neural mechanisms underlying core symptoms and their developmental trajectories. Our study highlights that integrating complementary neuroimaging modalities may aid in unraveling the complex neurobiology of ASD. © 2024 The Author(s)
Author Keywords
ASD; Dynamic functional connectivity; EEG; fNIRS; Multimodal covariance network; Neurobiology
Funding details
National Natural Science Foundation of ChinaNSFC82171540, 82301743
National Natural Science Foundation of ChinaNSFC
Universidade de MacauUMSRG2023- 00015-ICI
Universidade de MacauUM
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT0016/2024/RIB1, 0010/2023/ITP1
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT
22JSZ20, qzx-2023-1
National Key Research and Development Program of ChinaNKRDPC2023YFC2706405, 2022YFC2705301
National Key Research and Development Program of ChinaNKRDPC
Natural Science Foundation of Beijing Municipality7222187
Natural Science Foundation of Beijing Municipality
Document Type: Article
Publication Stage: Final
Source: Scopus
Two F-18 radiochemistry methods to synthesize a promising transient receptor potential canonical 5 (TRPC5) radioligand
(2024) Journal of Fluorine Chemistry, 280, art. no. 110367, .
Yu, Y.a , Jadhav, S.B.a , Xing, Z.a , Jiang, H.a , Qiu, L.a , Huang, T.a , Perlmutter, J.S.a b , Li, Z.c , Tu, Z.a
a Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
b Department of Neurology and Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
c Department of Radiology, University of North Carolina at Chapel Hill, ChapelHill, NC 27599, United States
Abstract
TRPC5 is a member of the mammalian transient receptor potential (TRP) channel superfamily and it has been implicated in various physiological and pathological mechanisms of neurological and psychiatric diseases. Fluorine-18 is one of the most widely used radionuclides for PET imaging due to its favorable chemical characteristics and nuclear-physical properties. Herein, we describe two complementary radiosynthetic approaches and preliminary in vivo evaluation for [18F]TZ78141 as a novel and promising fluorine-18 labeled radiotracer for imaging TRPC5. The latter strategy employed a ruthenium-mediated radiofluorination method, facilitating the rapid synthesis of the desired radiotracer with substantial advantages in simplicity and efficiency. © 2024 Elsevier B.V.
Author Keywords
Fluorine -18; PET tracer; Radiolabeling; TRPC5
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDS
National Institute on AgingNIANS075527, NS103988, NS103957, NS134586
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease
(2024) Cell, 187 (22), pp. 6309-6326.e15.
Shen, Y.a b , Timsina, J.a b , Heo, G.a b , Beric, A.a b , Ali, M.a b , Wang, C.a b , Yang, C.a b , Wang, Y.a b , Western, D.a b , Liu, M.a b , Gorijala, P.a b , Budde, J.a b , Do, A.a b , Liu, H.c , Gordon, B.c , Llibre-Guerra, J.J.c , Joseph-Mathurin, N.d , Perrin, R.J.e z , Maschi, D.f , Wyss-Coray, T.g h , Pastor, P.i , Renton, A.E.j k l , Surace, E.I.m , Johnson, E.C.B.n o z , Levey, A.I.o z , Alvarez, I.p , Levin, J.q r z , Ringman, J.M.s , Allegri, R.F.t , Seyfried, N.u , Day, G.S.v , Wu, Q.w , Fernández, M.V.x , Tarawneh, R.y , McDade, E.c z , Morris, J.C.c , Bateman, R.J.c z , Goate, A.j k z , Noble, J.M.z , Day, G.S.z , Graff-Radford, N.R.z , Voglein, J.z , Allegri, R.z , Mendez, P.C.z , Surace, E.z , Berman, S.B.z , Ikonomovic, S.z , Nadkarni, N.z , Lopera, F.z , Ramirez, L.z , Aguillon, D.z , Leon, Y.z , Ramos, C.z , Alzate, D.z , Baena, A.z , Londono, N.z , Mathias Jucker, S.M.z , Laske, C.z , Kuder-Buletta, E.z , Graber-Sultan, S.z , Preische, O.z , Hofmann, A.z , Ikeuchi, T.z , Kasuga, K.z , Niimi, Y.z , Ishii, K.z , Senda, M.z , Sanchez-Valle, R.z , Rosa-Neto, P.z , Fox, N.z , Cash, D.z , Lee, J.-H.z , Roh, J.H.z , Riddle, M.z , Menard, W.z , Bodge, C.z , Surti, M.z , Takada, L.T.z , Farlow, M.z , Chhatwal, J.P.z , Sanchez-Gonzalez, V.J.z , Orozco-Barajas, M.z , Renton, A.z , Esposito, B.z , Karch, C.M.z , Marsh, J.z , Cruchaga, C.a b c z , Fernandez, V.z , Gordon, B.A.z , Fagan, A.M.z , Jerome, G.z , Herries, E.z , Llibre-Guerra, J.z , Seyfried, N.T.z , Schofield, P.R.z , Brooks, W.z , Bechara, J.z , Hassenstab, J.z , Franklin, E.z , Benzinger, T.L.S.z , Chen, A.z , Chen, C.z , Flores, S.z , Friedrichsen, N.z , Hantler, N.z , Hornbeck, R.z , Jarman, S.z , Keefe, S.z , Koudelis, D.z , Massoumzadeh, P.z , McCullough, A.z , McKay, N.z , Nicklaus, J.z , Pulizos, C.z , Wang, Q.z , Mishall, S.z , Sabaredzovic, E.z , Deng, E.z , Candela, M.z , Smith, H.z , Hobbs, D.z , Scott, J.z , Xiong, C.z , Wang, P.z , Xu, X.z , Li, Y.z , Gremminger, E.z , Ma, Y.z , Bui, R.z , Lu, R.z , Martins, R.z , Sosa Ortiz, A.L.z , Daniels, A.z , Courtney, L.z , Mori, H.z , Supnet-Bell, C.z , Xu, J.z , Ringman, J.z , Ibanez, L.a b c , Sung, Y.J.a b c , Dominantly Inherited Alzheimer Networkaa
a Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
b NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Mallinckrodt Institute of Radiology, Washington University St Louis, St Louis, MO 63110, United States
e Department of Pathology and Immunology, Washington University St. Louis, St. Louis, MO 63110, United States
f Department of Cell Biology and Physiology, Washington University St. Louis, St. Louis, MO 63110, United States
g Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, United States
h Department of Neurology & Neurological Sciences, Stanford University, Stanford, CA 94305, United States
i Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, 08916, Spain
j Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
k Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
l Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
m Laboratory of Neurodegenerative Diseases, Institute of Neurosciences (INEU-Fleni-CONICET), Buenos Aires, Argentina
n Goizueta Alzheimer’s Disease Research Center, Emory University School of Medicine, Atlanta, GA 30307, United States
o Department of Neurology, Emory University School of Medicine, Atlanta, GA 30307, United States
p Department of Neurology, University Hospital Mútua de Terrassa and Fundació Docència i Recerca Mútua de Terrassa, Barcelona, Terrassa, 08221, Spain
q Department of Neurology, LMU University Hospital, LMU Munich, Munich, 80336, Germany
r German Center for Neurodegenerative Diseases, site Munich, Munich, 80336, Germany
s Alzheimer’s Disease Research Center, Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA 90033, United States
t Department of Cognitive Neurology, Neuropsychology and Neuropsychiatry, FLENI, Buenos Aires, Argentina
u Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30307, United States
v Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL 32224, United States
w Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
x Fundacio ACE Institut de Neurosciencies Aplicades, Barcelona, 08029, Spain
y The University of New Mexico, Albuquerque, NM 87131, United States
Abstract
In this high-throughput proteomic study of autosomal dominant Alzheimer’s disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers. © 2024 The Author(s)
Author Keywords
autosomal dominant Alzheimer’s disease; microglia; mitochondrial damage; neurodegeneration; neuronal death; proteomics; pseudotrajectory analysis; Somascan
Document Type: Article
Publication Stage: Final
Source: Scopus
The representation of decision variables in orbitofrontal cortex is longitudinally stable
(2024) Cell Reports, 43 (10), art. no. 114772, .
Zhang, M.a b , Livi, A.a , Carter, M.a , Schoknecht, H.a , Burkhalter, A.a , Holy, T.E.a b , Padoa-Schioppa, C.a b c
a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Economics, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
The computation and comparison of subjective values underlying economic choices rely on the orbitofrontal cortex (OFC). In this area, distinct groups of neurons encode the value of individual options, the binary choice outcome, and the chosen value. These variables capture both the choice input and the choice output, suggesting that the cell groups found in the OFC constitute the building blocks of a decision circuit. Here, we show that this neural circuit is longitudinally stable. Using two-photon calcium imaging, we record from the OFC of mice engaged in a juice-choice task. Imaging of individual cells continues for up to 40 weeks. For each cell and each session pair, we compare activity profiles using cosine similarity, and we assess whether the neuron encodes the same variable in both sessions. We find a high degree of stability and a modest representational drift. Quantitative estimates indicate that this drift would not randomize the circuit within the animal’s lifetime. © 2024 The Author(s)
Author Keywords
calcium imaging; decision circuit; decision making; economic choice; longitudinal stability; Neuroscience; orbitofrontal cortex; representational drift; subjective value; two-photon microscopy
Funding details
National Institutes of HealthNIHR01-DA055709, R01-DA032758, R21-DA042882, R01-DC020034
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
The VLDLR entry receptor is required for the pathogenesis of multiple encephalitic alphaviruses
(2024) Cell Reports, 43 (10), art. no. 114809, .
Palakurty, S.a b , Raju, S.a , Sariol, A.b , Chong, Z.b , Wagoner, N.b , Ma, H.b , Zimmerman, O.b , Adams, L.J.a , Carmona, C.b c , Liu, Z.c , Fremont, D.H.a c d , Whelan, S.P.J.c , Klimstra, W.B.e , Diamond, M.S.a b c f g
a Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
e The Center for Vaccine Research and Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15261, United States
f Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, United States
g Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110, United States
Abstract
The very-low-density lipoprotein receptor (VLDLR) has been reported as an entry receptor for Semliki Forest (SFV) and Eastern equine encephalitis (EEEV) alphaviruses in cell cultures. However, the role of VLDLR in alphavirus pathogenesis and the extent to which other alphaviruses can engage VLDLR remains unclear. Here, using a surface protein-targeted CRISPR-Cas9 screen, we identify VLDLR as a receptor for Western equine encephalitis virus (WEEV) and demonstrate that it promotes the infection of multiple viruses in the WEE antigenic complex. In vivo studies show that the pathogenicity of WEEV, EEEV, and SFV, but not the distantly related Venezuelan equine encephalitis virus, is markedly diminished in VLDLR-deficient mice and that mice treated with a soluble VLDLR-Fc decoy molecule are protected against disease. Overall, these results expand our understanding of the role of VLDLR in alphavirus pathogenesis and provide a potential path for developing countermeasures against alphaviruses from different antigenic complexes. © 2024 The Author(s)
Author Keywords
alphavirus; CP: Immunology; CP: Microbiology; decoy; pathogenesis; Receptor; therapy; tropism
Funding details
Defense Threat Reduction AgencyDTRAMCDC2103-01, EQ1090_2023
Defense Threat Reduction AgencyDTRA
National Institutes of HealthNIHR01 AI141436, U19 AI142790, R01 AI163019, T32 AI007172, R01 AI153209, T32 CA009547, AI201800001
National Institutes of HealthNIH
National Institute of Allergy and Infectious DiseasesNIAID75N93022C00035
National Institute of Allergy and Infectious DiseasesNIAID
Document Type: Article
Publication Stage: Final
Source: Scopus
Hepatocyte Period 1 dictates oxidative substrate selection independent of the core circadian clock
(2024) Cell Reports, 43 (10), art. no. 114865, .
Sun, J.a , Zhang, Y.a , Adams, J.A.a , Higgins, C.B.a , Kelly, S.C.a , Zhang, H.b c d , Cho, K.Y.b c d , Johnson, U.G.e f , Swarts, B.M.e f , Wada, S.-I.g , Patti, G.J.b c d , Shriver, L.P.b c d , Finck, B.N.d , Herzog, E.D.h , DeBosch, B.J.a i
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, United States
c Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859, United States
f Biochemistry, Cellular, and Molecular Biology Program, Central Michigan University, Mount Pleasant, MI, United States
g Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Tokyo, Shinagawa-ku, 141-0021, Japan
h Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
i Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Organisms integrate circadian and metabolic signals to optimize substrate selection to survive starvation, yet precisely how this occurs is unclear. Here, we show that hepatocyte Period 1 (Per1) is selectively induced during fasting, and mice lacking hepatocyte Per1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. Transcriptomic analyses show failed induction of the fasting hepatokine Fgf21 in Per1-deficient mice, and single-nucleus multiome sequencing defines a putative responding hepatocyte subpopulation that fails to induce the chromatin accessibility near the Fgf21 locus. In vivo isotopic tracing and indirect calorimetry demonstrate that hepatocyte Per1-deficient mice fail to transit from oxidation of glucose to fat, which is completely reversible by exogenous FGF21 or by inhibiting pyruvate dehydrogenase. Strikingly, disturbing other core circadian genes does not perturb Per1 induction during fasting. We thus describe Per1 as an important mechanism by which hepatocytes integrate internal circadian rhythm and external nutrition signals to facilitate proper fuel utilization. © 2024 The Author(s)
Author Keywords
circadian clock; CP: Metabolism; fasting; glucose oxidation; liver metabolism; metabolite tracing; single-nucleus multiome sequencing
Document Type: Article
Publication Stage: Final
Source: Scopus
Functional Connectivity Relationships to Longitudinal Motor Outcomes Differ in Very Preterm Children with and Without Brain Injury
(2024) Neurology: Clinical Practice, 15 (1), art. no. e200397, .
Cyr, P.E.P.a , Lean, R.E.b , Kenley, J.K.a , Kaplan, S.a , Meyer, D.a , Neil, J.J.a , Alexopoulos, D.a , Brady, R.G.a , Shimony, J.S.c , Rodebaugh, T.L.d , Rogers, C.E.b e , Smyser, C.D.a c e
a Departments of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
Background and ObjectivesChildren born very preterm (VPT) have high rates of motor disability, but mechanisms for early identification remain limited, especially for children who fall behind in early childhood. This study examines the relationship between functional connectivity (FC) measured at term-equivalent age and motor outcomes at 2 and 5 years.MethodsIn this longitudinal observational cohort study, VPT children (gestational age 30 weeks and younger) with and without high-grade brain injury underwent FC MRI at term-equivalent age. Motor development was assessed using the Bayley Scales of Infant Development, Third Edition, at corrected age 2 years and Movement Assessment Battery for Children, Second Edition, at age 5 years. Logistic and negative binomial/Poisson regression models examined relationships between FC measures and 5-year task scores, with and without 2-year scores as covariates. Infants were categorized as “injured”or “uninjured”based on structural MRI findings at term-equivalent age.ResultsIn the injured group (n = 34), each 1 SD decrease in neonatal left-right motor cortex FC was related to approximately 4× increased odds of being unable to complete a fine motor task at age 5 (log odds = -1.34, p < 0.05). In the uninjured group (n = 41), stronger basal ganglia-motor cortex FC was related to poorer fine motor scores (Est = -0.40, p < 0.05) and stronger cerebellum-motor cortex FC was related to poorer balance and fine motor scores (Est = -0.05 to -0.23, p < 0.05), with balance persisting with adjustment for 2-year scores.DiscussionIn VPT children with brain injury, interhemispheric motor cortex FC was related to motor deficits at 5-year assessment, similar to previous findings at 2 years. In uninjured children, FC-measured disruption of the motor system during the neonatal period was associated with motor planning/coordination difficulties that were not apparent on 2-year assessment but emerged at 5 years, suggesting that the neural basis of these deficits was established very early in life. Subsequently, 2-year follow-up may not be sufficient to detect milder motor deficits in VPT children, and they should be monitored for motor difficulties throughout the preschool years. For all VPT children, FC at term-equivalent age has the potential to improve our ability to predict disability before it presents behaviorally. © 2024 American Academy of Neurology.
Funding details
Cerebral Palsy International Research FoundationCPIRF
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
March of Dimes FoundationMDF
Brain and Behavior Research FoundationBBRF
Child Neurology FoundationCNF
National Institutes of HealthNIHR01 HD061619, F30 HD104313, R01 HD057098, GM07200, F30 HD105336, P30 NS098577, K02 NS089852, K23 MH105179, K01 MH122735, R01 MH113570, P50 HD103525
National Institutes of HealthNIH
University of WashingtonUWF30 HD105336, F30 HD104313, R01 MH113570, P30 NS098577, K23 MH105179, R01 HD061619, R01 HD057098, K02 NS089852, GM07200, K01 MH122735
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Modeling human activity comprehension at human scale: prediction, segmentation, and categorization
(2024) PNAS Nexus, 3 (10), art. no. pgae459, .
Nguyen, T.T.a , Bezdek, M.A.a , Gershman, S.J.b , Bobick, A.F.c , Braver, T.S.a , Zacks, J.M.a
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Psychology, Center for Brain Science, Harvard University, Cambridge, MA 02138, United States
c Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Humans form sequences of event models—representations of the current situation—to predict how activity will unfold. Multiple mechanisms have been proposed for how the cognitive system determines when to segment the stream of behavior and switch from one active event model to another. Here, we constructed a computational model that learns knowledge about event classes (event schemas), by combining recurrent neural networks for short-term dynamics with Bayesian inference over event classes for event-to-event transitions. This architecture represents event schemas and uses them to construct a series of event models. This architecture was trained on one pass through 18 h of naturalistic human activities. Another 3.5 h of activities were used to test each variant for agreement with human segmentation and categorization. The architecture was able to learn to predict human activity, and it developed segmentation and categorization approaching human-like performance. We then compared two variants of this architecture designed to better emulate human event segmentation: one transitioned when the active event model produced high uncertainty in its prediction and the other transitioned when the active event model produced a large prediction error. The two variants learned to segment and categorize events, and the prediction uncertainty variant provided a somewhat closer match to human segmentation and categorization—despite being given no feedback about segmentation or categorization. These results suggest that event model transitioning based on prediction uncertainty or prediction error can reproduce two important features of human event comprehension. © The Author(s) 2024.
Author Keywords
action perception; computational modeling; event cognition; segmentation
Funding details
Office of Naval ResearchONRN00014-17-1-2961
Office of Naval ResearchONR
Document Type: Article
Publication Stage: Final
Source: Scopus
The fully activated open state of KCNQ1 controls the cardiac “fight-or-flight” response
(2024) PNAS Nexus, 3 (10), art. no. pgae452, .
Hou, P.a c , Zhao, L.a , Zhong, L.a , Shi, J.a , Wang, H.Z.b , Gao, J.b , Liu, H.b , Zuckerman, J.b , Cohen, I.S.b , Cui, J.a
a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO 63130, United States
b Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Washington University, St. Louis, MO 63130, United States
c Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau
Abstract
The cardiac KCNQ1 + KCNE1 (IKs) channel regulates heart rhythm under both normal and stress conditions. Under stress, the β-Adrenergic stimulation elevates the intracellular cyclic adenosine monophosphate (cAMP) level, leading to KCNQ1 phosphorylation by protein kinase A and increased IKs, which shortens action potentials to adapt to accelerated heart rate. An impaired response to the β-Adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of β-Adrenergic stimulation of IKs remains unclear, impeding the development of new therapeutics. Here, we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1’s fully activated open (AO) state is more sensitive to cAMP than its intermediate open state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of IKs to β-Adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion, the present study not only uncovers the key role of the AO state in IKs channel phosphorylation, but also provides a target for antiarrhythmic strategy. © 2024 The Author(s).
Author Keywords
“fight-or-fight” response; antiarrhythmia; IKschannel; long QT syndrome; phosphorylation
Funding details
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT0074/2022/A2, 0098/2023/RIA2
Fundo para o Desenvolvimento das Ciências e da TecnologiaFDCT
United States-Israel Binational Science FoundationBSFRO1 HL166628, HL166628, 2019159
United States-Israel Binational Science FoundationBSF
American Heart AssociationAHA18POST34030203
American Heart AssociationAHA
National Natural Science Foundation of ChinaNSFC32171221, 0098/2023/RIA2
National Natural Science Foundation of ChinaNSFC
National Institutes of HealthNIHRO1 HL126774, HL155398
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Estrogen predicts multimodal emotion recognition accuracy across the menstrual cycle
(2024) PLoS ONE, 19 (10 October), art. no. e0312404, .
Jang, D.a , Lybeck, M.b , Cortes, D.S.b , Elfenbein, H.A.c , Laukka, P.b d
a Melbourne Business School, University of Melbourne, Carlton, VIC, Australia
b Department of Psychology, Stockholm University, Stockholm, Sweden
c Olin Business School, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, Uppsala University, Uppsala, Sweden
Abstract
Researchers have proposed that variation in sex hormones across the menstrual cycle modulate the ability to recognize emotions in others. Existing research suggests that accuracy is higher during the follicular phase and ovulation compared to the luteal phase, but findings are inconsistent. Using a repeated measures design with a sample of healthy naturally cycling women (N = 63), we investigated whether emotion recognition accuracy varied between the follicular and luteal phases, and whether accuracy related to levels of estrogen (estradiol) and progesterone. Two tasks assessed recognition of a range of positive and negative emotions via brief video recordings presented in visual, auditory, and multimodal blocks, and non-linguistic vocalizations (e.g., laughter, sobs, and sighs). Multilevel models did not show differences in emotion recognition between cycle phases. However, coefficients for estrogen were significant for both emotion recognition tasks. Higher within-person levels of estrogen predicted lower accuracy, whereas higher between-person estrogen levels predicted greater accuracy. This suggests that in general having higher estrogen levels increases accuracy, but that higher-than-usual estrogen at a given time decreases it. Within-person estrogen further interacted with cycle phase for both tasks and showed a quadratic relationship with accuracy for the multimodal task. In particular, women with higher levels of estrogen were more accurate in the follicular phase and middle of the menstrual cycle. We propose that the differing role of within- and between-person hormone levels could explain some of the inconsistency in previous findings. © 2024 Jang 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.
Document Type: Article
Publication Stage: Final
Source: Scopus
The pace of biological aging significantly mediates the relationship between internalized stigma of chronic pain and chronic low back pain severity among non-hispanic black but not non-hispanic white adults
(2024) Neurobiology of Pain, 16, art. no. 100170, .
Freij, K.W.a , Agbor, F.B.A.T.a , Kinnie, K.R.a , Srinivasasainagendra, V.b , Quinn, T.L.c , Tiwari, H.K.b , Sorge, R.E.c , Goodin, B.R.d , Aroke, E.N.a
a Department of Acute, Chronic, & Continuing Care, School of Nursing, The University of Alabama at Birmingham, Birmingham, AL 35294, United States
b Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, United States
c Department of Psychology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, United States
d Department of Anesthesiology, School of Medicine, Washington University, St. Louis, MO 63130, United States
Abstract
This study aimed to determine the nature of the relationship between the internalized stigma of chronic pain (ISCP), the pace of biological aging, and racial disparities in nonspecific chronic low back pain (CLBP). We used Dunedin Pace of Aging from the Epigenome (DunedinPACE), Horvath’s, Hannum’s, and PhenoAge clocks to determine the pace of biological aging in adults, ages 18 to 82 years: 74 no pain, 56 low-impact pain, and 76 high-impact pain. Individuals with high-impact pain reported higher levels of ISCP and DunedinPACE compared to those with low-impact or no pain (p < 0.001). There was no significant relationship between ISCP and epigenetic age acceleration from Horvath, Hannum, and PhenoAge clocks (p > 0.05). Mediation analysis showed that an association between ISCP and pain severity and interference was mediated by the pace of biological aging (p ≤ 0.001). We further found that race moderated the indirect effect of ISCP on pain severity and interference, with ISCP being a stronger positive predictor of the pace of biological aging for non-Hispanic Blacks (NHBs) than for non-Hispanic Whites (NHWs). Future bio-behavioral interventions targeting internalized stigma surrounding chronic pain at various levels are necessary. A deeper understanding of the biological aging process could lead to improvements in managing nonspecific chronic low back pain (CLBP), particularly within underserved minority populations. © 2024 The Author(s)
Author Keywords
DunedinPACE; Epigenetic age; Internalized stigma; Moderated mediation; Nonspecific chronic low back pain; Pace of biological aging; Pain disparities
Document Type: Article
Publication Stage: Final
Source: Scopus
Haves and have-nots: Socioeconomic position improves accuracy of machine learning algorithms for predicting high-impact chronic pain
(2024) Pain, art. no. 10.1097/j.pain.0000000000003451, .
Morris, M.C.a b c , Moradi, H.d , Aslani, M.e , Sun, S.f , Karlson, C.c g , Bartley, E.J.h , Bruehl, S.a b , Archer, K.R.b i j , Bergin, P.F.k , Kinney, K.b l , Watts, A.L.l , Huber, F.A.m , Funches, G.c , Nag, S.a , Goodin, B.R.m
a Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States
b Vanderbilt Center for Musculoskeletal Research, Vanderbilt University Medical Center, Nashville, TN, United States
c Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
d Department of Computer Science, University of North Carolina Agricultural and Technical State University, Greensboro, NC, United States
e Department of Data Analytics, University of North Texas, Denton, TX, United States
f Department of Social Welfare, University of California, Los Angeles, CA, United States
g Department of Hematology and Oncology, University of Mississippi Medical Center, Jackson, MS, United States
h Department of Community Dentistry & Behavioral Science, University of Florida, Gainesville, FL, United States
i Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
j Department of Physical Medicine and Rehabilitation, Osher Center for Integrative Health, Vanderbilt University Medical Center, Nashville, TN, United States
k Department of Orthopaedic Surgery and Rehabilitation, University of Mississippi Medical Center, Jackson, MS, United States
l Department of Psychology, Vanderbilt University, Nashville, TN, United States
m Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Lower socioeconomic position (SEP) is associated with increased risk of developing chronic pain, experiencing more severe pain, and suffering greater pain-related disability. However, SEP is a multidimensional construct; there is a dearth of research on which SEP features are most strongly associated with high-impact chronic pain, the relative importance of SEP predictive features compared to established chronic pain correlates, and whether the relative importance of SEP predictive features differs by race and sex. This study used 3 machine learning algorithms to address these questions among adults in the 2019 National Health Interview Survey. Gradient boosting decision trees achieved the highest accuracy and discriminatory power for high-impact chronic pain. Results suggest that distinct SEP dimensions, including material resources (eg, ratio of family income to poverty threshold) and employment (ie, working in the past week, number of working adults in the family), are highly relevant predictors of high-impact chronic pain. Subgroup analyses compared the relative importance of predictive features of high-impact chronic pain in non-Hispanic Black vs White adults and men vs women. Whereas the relative importance of body mass index and owning/renting a residence was higher for non-Hispanic Black adults, the relative importance of working adults in the family and housing stability was higher for non-Hispanic White adults. Anxiety symptom severity, body mass index, and cigarette smoking had higher relevance for women, while housing stability and frequency of anxiety and depression had higher relevance for men. Results highlight the potential for machine learning algorithms to advance health equity research. © 2024 International Association for the Study of Pain.
Author Keywords
Chronic pain; Machine learning; National Health Interview Survey; Socioeconomic position
Funding details
National Institutes of HealthNIHR01MD016838, R01MD017565, R01DA050334, T32MH018921
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Loneliness, Social Isolation, and Suicidal Ideation and Attempt Among Adolescents Living with HIV: A Cross-Sectional Study in Masaka, Uganda
(2024) Global Social Welfare, .
Atwebembere, R.c , Nakasujja, N.a , Mugisha, J.b , Ssewamala, F.c , Mckay, M.c
a Department of Psychiatry, Makerere University College of Health Sciences, Kampala, Uganda
b Department of Sociology and Social Administration, Faculty of Arts and Social Sciences, Kyambogo University, Kampala, Uganda
c Brown School, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
One in six people are aged 10–19 years. Adolescence is a unique and formative time. Physical, emotional, and social changes, including exposure to poverty, abuse, or violence, can make adolescents vulnerable to mental health problems. Protecting adolescents from adversity, promoting socio-emotional learning and psychological well-being, and ensuring access to mental healthcare are critical for their health and well-being during adolescence and adulthood. Globally, it is estimated that 1 in 7 (14%) 10–19 year-olds experience mental health conditions (1), yet these remain largely unrecognized and untreated. Adolescents with mental health conditions are particularly vulnerable to social exclusion, discrimination, stigma (affecting readiness to seek help), educational difficulties, risk-taking behaviors, physical ill-health, and human rights violations. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.
Funding details
Fogarty International CenterFIC
National Institutes of HealthNIHD43TW011541
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Short-term neurologic outcomes in pediatric extracorporeal membrane oxygenation are proportional to bleeding severity graded by a novel bleeding scale
(2024) Perfusion (United Kingdom), .
Doane, K.a , Guffey, D.b , Loftis, L.L.a , Nguyen, T.C.a c , Musick, M.A.a , Ruth, A.a , Coleman, R.D.a , Teruya, J.d , Allen, C.e , Bembea, M.M.f , Boville, B.g h , Furlong-Dillard, J.i , Kaipa, S.j , Leimanis, M.g h , Malone, M.P.k , Rasmussen, L.K.l , Said, A.m , Steiner, M.E.n , Tzanetos, D.T.i , Viamonte, H.o , Wallenkamp, L.p , Saini, A.a c
a Division of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
b Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
c Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, United States
d Departments of Pathology & Immunology, Pediatrics, and Medicine, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
e Division of Pediatric Critical Care, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
f Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
g Pediatric Critical Care Medicine Division, Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
h Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI, United States
i Division of Pediatric Critical Care Medicine, Department of Pediatrics, Norton Children’s Hospital, University of Louisville School of Medicine, Louisville, KY, United States
j Department of Pediatrics, Children’s Nebraska, University of Nebraska Medical Center, Omaha, NE, United States
k Division of Critical Care Medicine, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR, United States
l Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stanford University, Palo Alto, CA, United States
m Division of Pediatric Critical Care, Department of Pediatrics, Institute of Informatics, Data Science & Biostatistics (I2DB), Washington University in St. Louis School of Medicine, St. Louis, MO, United States
n Divisions of Hematology and Oncology and Critical Care, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
o Divisions of Cardiology and Critical Care, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA, United States
p Children’s Wisconsin and Medical College of Wisconsin, Milwaukee, WI, United States
Abstract
Introduction: This study aimed to characterize the severity of bleeding and its association with short-term neurologic outcomes in pediatric ECMO. Methods: Multicenter retrospective cohort study of pediatric ECMO patients at 10 centers utilizing the Pediatric ECMO Outcomes Registry (PEDECOR) database from December 2013-February 2019. Subjects excluded were post-cardiac surgery patients and those with neonatal pathologies. A novel ECMO bleeding scale was utilized to categorize daily bleeding events. Poor short-term neurologic outcome was defined as an unfavorable Pediatric Cerebral Performance Category (PCPC) or Pediatric Overall Performance Category (POPC) (score of >3) at hospital discharge. Results: This study included 283 pediatric ECMO patients with a median (interquartile range [IQR]) age of 1.3 years [0.1, 9.0], ECMO duration of 5 days [3.0, 9.5], and 44.1% mortality. Unfavorable PCPC and POPC were observed in 48.4% and 51.3% of patients at discharge, respectively. Multivariable logistic regression analysis included patient’s age, cannulation type, duration of ECMO, need for cardiopulmonary resuscitation, acute kidney injury, new infection, and vasoactive-inotropic score. As the severity of bleeding increased, there was a corresponding increase in the likelihood of poor neurologic recovery, shown by increasing odds of unfavorable neurologic outcome (PCPC), with an adjusted odds ratio (aOR) of 0.77 (confidence interval [CI] 0.36–1.62), 1.87 (0.54–6.45), 2.97 (1.32–6.69), and 5.56 (0.59–52.25) for increasing bleeding severity (grade 1 to 4 events, respectively). Similarly, unfavorable POPC aOR (CI) was 1.02 (0.48–2.17), 2.05 (0.63–6.70), 5.29 (2.12–13.23), and 5.11 (0.66–39.64) for bleeding grade 1 to 4 events. Conclusion: Short-term neurologic outcomes in pediatric ECMO are proportional to the severity of bleeding events. Strategies to mitigate bleeding events could improve neurologic recovery in pediatric ECMO. © The Author(s) 2024.
Author Keywords
anticoagulation; child; extracorporeal membrane oxygenation; hemorrhage; mortality; outcome
Funding details
Children’s Discovery InstituteCDI
Medtronic
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long-Term Cognitive Deficits
(2024) Advanced Science, .
Diwan, D.a , Mehla, J.a , Nelson, J.W.a , Quirk, J.D.b , Song, S.-K.b , Cao, S.a , Meron, B.a , Mostofa, A.a , Zipfel, G.J.a
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor’s quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH – especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced significant and trackable long-term cognitive deficits. SAH is induced by performing double blood injections into the prechiasmatic cistern – a simple modification to the well-characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients, including cerebral edema measured by MRI – an indicator of early brain injury (EBI), neuroinflammation, apoptosis, and long-term cognitive impairment. This newly developed SAH mouse model is considered an ideal paradigm for investigating the complex SAH pathophysiology and identifying novel druggable therapeutic targets for treating SAH severity and SAH-associated long-term neurocognitive deficits in patients. © 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH.
Author Keywords
long-term cognitive impairment; prechiasmatic cistern; subarachnoid hemorrhage
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Cognitive Profile of Older Adults With Treatment-Resistant Depression: An Analysis of the OPTIMUM Randomized Controlled Trial
(2024) American Journal of Geriatric Psychiatry, .
Ainsworth, N.J.a b , Oughli, H.c , Lavretsky, H.c , Blumberger, D.M.a b , Brown, P.J.d , Butters, M.A.e , Karp, J.F.f , Lenard, E.g , Lenze, E.J.g , McAndrews, M.P.h , Miller, J.P.i , Pollock, B.G.a b , Reynolds, C.F.e , Mulsant, B.H.a b , OPTIMUM Research Groupj
a Centre for Addiction and Mental Health (NJA. DMB, BGP, BHM), Toronto, ON, Canada
b Department of Psychiatry (NJA, DMB, BGP, BHM), University of Toronto, Toronto, ON, Canada
c Department of Psychiatry and Biobehavioral Sciences (HO, HL), University of California, Los Angeles, CA, United States
d Department of Psychiatry, Columbia University College of Physicians and Surgeons (PJB), New York, NY, United States
e Department of Psychiatry (MAB, CFR), University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
f Department of Psychiatry (JFK), College of Medicine, University of Arizona, Tucson, AZ, United States
g Department of Psychiatry (EL, EJL), Washington University School of Medicine, St. Louis, MO, United States
h Department of Psychology (MPM), University of Toronto, Toronto, ON, Canada
i Institute for Informatics, Data Science and Biostatistics (JPM), Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Major depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy. Design: Secondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD. Setting: Five outpatient academic medical centers (4 US, 1 Canada). Participants: About 369 participants aged 60 and older from the OPTIMUM study. Measurements: Baseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models. Results: Participants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not. Conclusions: Participants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies. © 2024 The Authors
Author Keywords
Aging; clinical trials; cognition; depression; executive function
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Can micro-expressions be used as a biomarker for autism spectrum disorder?
(2024) Frontiers in Neuroinformatics, 18, art. no. 1435091, .
Ruan, M.a , Zhang, N.a , Yu, X.b , Li, W.a , Hu, C.c , Webster, P.J.d , K. Paul, L.e , Wang, S.b , Li, X.c
a Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV, United States
b Department of Radiology, Washington University, St. Louis, MO, United States
c Department of Computer Science, University at Albany, Albany, NY, United States
d Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV, United States
e Division of the Humanities and Social Sciences, California Institute of Technology, Pasadena, CA, United States
Abstract
Introduction: Early and accurate diagnosis of autism spectrum disorder (ASD) is crucial for effective intervention, yet it remains a significant challenge due to its complexity and variability. Micro-expressions are rapid, involuntary facial movements indicative of underlying emotional states. It is unknown whether micro-expression can serve as a valid bio-marker for ASD diagnosis. Methods: This study introduces a novel machine-learning (ML) framework that advances ASD diagnostics by focusing on facial micro-expressions. We applied cutting-edge algorithms to detect and analyze these micro-expressions from video data, aiming to identify distinctive patterns that could differentiate individuals with ASD from typically developing peers. Our computational approach included three key components: (1) micro-expression spotting using Shallow Optical Flow Three-stream CNN (SOFTNet), (2) feature extraction via Micron-BERT, and (3) classification with majority voting of three competing models (MLP, SVM, and ResNet). Results: Despite the sophisticated methodology, the ML framework’s ability to reliably identify ASD-specific patterns was limited by the quality of video data. This limitation raised concerns about the efficacy of using micro-expressions for ASD diagnostics and pointed to the necessity for enhanced video data quality. Discussion: Our research has provided a cautious evaluation of micro-expression diagnostic value, underscoring the need for advancements in behavioral imaging and multimodal AI technology to leverage the full capabilities of ML in an ASD-specific clinical context. Copyright © 2024 Ruan, Zhang, Yu, Li, Hu, Webster, K. Paul, Wang and Li.
Author Keywords
Autism Diagnostic Observation Schedule (ADOS); autism spectrum disorder (ASD); face videos; interpretable machine learning; micro-expressions
Funding details
National Science FoundationNSFHCC-2401748, BCS-2401398
National Science FoundationNSF
Document Type: Article
Publication Stage: Final
Source: Scopus
Preterm birth is associated with dystonic features and reduced cortical parvalbumin immunoreactivity in mice
(2024) Pediatric Research, .
Gemperli, K., Folorunso, F., Norin, B., Joshua, R., Rykowski, R., Hill, C., Galindo, R., Aravamuthan, B.R.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Preterm birth is a common cause of dystonia. Though dystonia is often associated with striatal dysfunction after neonatal brain injury, cortical dysfunction may best predict dystonia following preterm birth. Furthermore, abnormal sensorimotor cortex inhibition is associated with genetic and idiopathic dystonias. To investigate cortical dysfunction and dystonia following preterm birth, we developed a new model of preterm birth in mice. Methods: We induced preterm birth in C57BL/6J mice at embryonic day 18.3, ~24 h early. Leg adduction variability and amplitude, metrics we have shown distinguish between dystonia from spasticity during gait in people with CP, were quantified from gait videos of mice. Parvalbumin-positive interneurons, the largest population of cortical inhibitory interneurons, were quantified in the sensorimotor cortex and striatum. Results: Mice born preterm demonstrate increased leg adduction amplitude and variability during gait, suggestive of clinically observed dystonic gait features. Mice born preterm also demonstrate fewer parvalbumin-positive interneurons and reduced parvalbumin immunoreactivity in the sensorimotor cortex, but not the striatum, suggesting dysfunction of cortical inhibition. Conclusions: These data may suggest an association between cortical dysfunction and dystonic gait features following preterm birth. We propose that our novel mouse model of preterm birth can be used to study this association. Impact: Mouse models of true preterm birth are valuable for studying clinical complications of prematurity. Mice born preterm demonstrate increased leg adduction amplitude and variability during gait, suggestive of clinically observed dystonic gait features. Mice born preterm demonstrate fewer parvalbumin-positive interneurons and reduced parvalbumin immunoreactivity in the sensorimotor cortex, suggesting dysfunction of cortical inhibition. Mice born preterm do not demonstrate changes in parvalbumin immunoreactivity in the striatum. Cortical dysfunction may be associated with dystonic gait features following preterm birth. © The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2024.
Funding details
National Institute of Neurological Disorders and StrokeNINDS1K08NS117850-01A1, 1R01NS112234
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
In Vitro Neuroprotective Effect Evaluation of Donepezil-Loaded PLGA Nanoparticles-Embedded PVA/PEG Nanofibers on SH-SY5Y Cells and AP-APP Plasmid Related Alzheimer Cell Line Model
(2024) Macromolecular Materials and Engineering, .
Guler, E.a b c d , Yekeler, H.B.b c d e , Uner, B.d f g h , Dogan, M.i j , Asghar, A.k , Ikram, F.k , Yazir, Y.l , Gunduz, O.b m , Kalaskar, D.M.c , Cam, M.E.a c d n
a Department of Pharmacology, School of Pharmacy, Istanbul Kent University, Kagithane, Istanbul, 34406, Turkey
b Center for Nanotechnology and Biomaterials Application and Research, Marmara University, Istanbul, 34722, Turkey
c UCL Division of Surgery and Interventional Sciences, Rowland Hill Street, London, NW3 2PF, United Kingdom
d MecNano Technologies, Cube Incubation, Teknopark İstanbul, Istanbul, 34906, Turkey
e Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey
f Department of Pharmaceutical Technology, School of Pharmacy, Istanbul Kent University, Istanbul, 34406, Turkey
g Department of Pharmaceutical and Administrative Science, University of Health Science and Pharmacy in St. Louis, St. Louis, MO 63110, United States
h Department of Anesthesiology, Center for Clinical Pharmacology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
i Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Sivas Cumhuriyet University, Sivas, 58140, Turkey
j Cancer Survivorship Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 625 N. Michigan Ave., Suite 2100, Chicago, IL 60611, United States
k Interdisciplinary Research Centre in Biomedical Materials, COMSATS University Islamabad, Lahore Campus, Pakistan
l Stem Cell and Gene Therapies Research and Applied Center, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey
m Department of Metallurgical and Materials Engineering, Faculty of Technology, Marmara University, Istanbul, 34730, Turkey
n Biomedical Engineering Department, University of Aveiro, Aveiro, 3810-193, Portugal
Abstract
Recently developed nanoparticles and nanofibers present new brain-specific treatment strategies, especially for Alzheimer’s disease treatment. In this study, donepezil (DO)-loaded PLGA nanoparticles (DNP) are embedded in PVA/PEG nanofibers (DNPF) produced by pressurized gyration for sublingual administration. SEM images showed produced drug-loaded and pure nanofibers, which have sizes between 978 and 1123 nm, demonstrated beadless morphology and homogeneous distribution. FT-IR, XRD, and DSC results proved the produced nanoparticles and fibers to consist of the DO and other polymers. The in vitro drug release test presented that the release profile of DO is completed at the end of the 18th day. It is released by the first order kinetic model. DNPF has an ultra-fast release profile via its disintegration within 2 sec, which proved itself to be suitable for the administration sublingually. All samples presented above ≈90% cell viability via their non-toxic natures on SH-SY5Y human neuroblastoma cells by using Alamar blue assay. The anti-Alzheimer effects of DO, DNP, and DNPF are evaluated on the Aβ1−42-induced SH-SY5Y cells at 1, 5, and 10 µM as treatment groups. The 1 µM dosage exhibited the most significant neuroprotective effects, which showed enhanced cellular uptake and superior modulation of Alzheimer’s-related proteins, including tau and Aβ. © 2024 The Author(s). Macromolecular Materials and Engineering published by Wiley-VCH GmbH.
Author Keywords
Alzheimer’s disease; Alzheimer’s disease cell model; AP-APP plasmid transfection; donepezil; drug delivery; nanofiber; nanoparticle
Document Type: Article
Publication Stage: Article in Press
Source: Scopus