Protocol to study inter-tissue communication between the hypothalamus and white adipose tissue and lifespan using a chemogenetic approach in aged mice
(2025) STAR Protocols, 6 (1), art. no. 103551, .
Tokizane, K.a , Imai, S.-I.a b
a Department of Developmental Biology, 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
Abstract
Here, we present a protocol for assessing the impact of a chemogenetic manipulation in a subpopulation of the hypothalamic neurons on aging and lifespan control using a mouse model developed specifically for this purpose. We describe steps for stereotaxic viral injection and assess inter-tissue communication between protein phosphatase 1 regulatory subunit 17 (Ppp1r17)-expressing neurons in the dorsomedial hypothalamus and white adipose tissue. We then detail procedures for lifespan measurements following chemogenetic manipulation in aged mice. For complete details on the use and execution of this protocol, please refer to Tokizane et al.1 © 2024 The Author(s)
Author Keywords
Metabolism; Model Organisms; Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Active learning of enhancers and silencers in the developing neural retina
(2025) Cell Systems, 16 (1), art. no. 101163, .
Friedman, R.Z.a b , Ramu, A.a b , Lichtarge, S.a b , Wu, Y.a b , Tripp, L.a b , Lyon, D.a b , Myers, C.A.c , Granas, D.M.a b , Gause, M.c , Corbo, J.C.c , Cohen, B.A.a b , White, M.A.a b
a The Edison Family Center for Genome Sciences & Systems Biology, Saint Louis, MO 63110, United States
b Department of Genetics, Saint Louis, MO 63110, United States
c Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States
Abstract
Deep learning is a promising strategy for modeling cis-regulatory elements. However, models trained on genomic sequences often fail to explain why the same transcription factor can activate or repress transcription in different contexts. To address this limitation, we developed an active learning approach to train models that distinguish between enhancers and silencers composed of binding sites for the photoreceptor transcription factor cone-rod homeobox (CRX). After training the model on nearly all bound CRX sites from the genome, we coupled synthetic biology with uncertainty sampling to generate additional rounds of informative training data. This allowed us to iteratively train models on data from multiple rounds of massively parallel reporter assays. The ability of the resulting models to discriminate between CRX sites with identical sequence but opposite functions establishes active learning as an effective strategy to train models of regulatory DNA. A record of this paper’s transparent peer review process is included in the supplemental information. © 2024 The Author(s)
Author Keywords
active learning; cis-regulatory elements; enhancers; gene regulation; machine learning; retina; silencers; transcription factors
Document Type: Article
Publication Stage: Final
Source: Scopus
A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity
(2025) Science Advances, 11 (1), p. eadr7427.
Burtscher, V.a b , Wang, L.a c d , Cowgill, J.e , Chen, Z.-W.a , Edge, C.f , Smith, E.g , Chang, Y.a b , Delemotte, L.h , Evers, A.S.a i , Chanda, B.a b j k
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Center for Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
d Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, 430022, China
e Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University, Solna, 17121, Sweden
f Department of Life Sciences, Imperial College, London, SW7 2AZ, United Kingdom
g Department of Biophysics, Imperial College of Science, Medicine and Technology, London, SW7 2AZ, United Kingdom
h Department of Applied Physics, SciLifeLab, KTH Royal Institute of Technology, Solna, 17121, Sweden
i Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
j Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
k Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels are members of the cyclic nucleotide-binding family and are crucial for regulating cellular automaticity in many excitable cells. HCN channel activation contributes to pain perception, and propofol, a widely used anesthetic, acts as an analgesic by inhibiting the voltage-dependent activity of HCN channels. However, the molecular determinants of propofol action on HCN channels remain unknown. Here, we use a propofol-analog photoaffinity labeling reagent to identify propofol binding sites in the human HCN1 isoform. Mass spectrometry analyses combined with molecular dynamics simulations show that a binding pocket is formed by extracellularly facing residues in the S3 and S4 transmembrane segments in the resting voltage-sensor conformation. Mutations of residues within the putative binding pocket mitigate or eliminate voltage-dependent modulation of HCN1 currents by propofol. Together, these findings reveal a conformation-specific propofol binding site that underlies voltage-dependent inhibition of HCN currents and provides a framework for identifying highly specific modulators of HCN channel gating.
Document Type: Article
Publication Stage: Final
Source: Scopus
A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations
(2025) Journal of Clinical Investigation, 135 (1), art. no. e177793, .
Cantoni, C.a , Smirnov, R.A.b , Firulyova, M.b , Andhey, P.S.b , Bradstreet, T.R.b , Esaulova, E.b , Terekhova, M.b , Schwarzkopf, E.A.b , Abdalla, N.M.b , Kleverov, M.b , Sabatino, J.J., Jr.c , Liu, K.d , Schwab, N.e , Meyer Zu Hörste, G.e , Cross, A.H.f , Artyomov, M.N.b , Edelson, B.T.b , Wu, G.F.b f g
a Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Weill Institute for Neurosciences, UCSF, San Francisco, CA, United States
d Regeneron Pharmaceuticals, Tarrytown, NY, United States
e Department of Neurology, Institute of Translational Neurology, University Hospital Münster, Münster, Germany
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Neurology Service, Veterans Affairs St. Louis Health Care System, St. Louis, MO, United States
Abstract
Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization of CSF immune cells. CSF derives from and borders central nervous system (CNS) tissue, allowing for comprehensive accounting of cell types along with their relative abundance and immunologic profiles relevant to CNS diseases. Using integration techniques applied to publicly available datasets in combination with our own studies, we generated a compendium with 139 subjects encompassing 135 CSF and 58 blood samples. Healthy subjects and individuals across a wide range of diseases, such as multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, COVID-19, and autoimmune encephalitis, were included. We found differences in lymphocyte and myeloid subset frequencies across different diseases as well as in their distribution between blood and CSF. We identified what we believe to be a new subset of AREG+ dendritic cells exclusive to the CSF that was more abundant in subjects with MS compared with healthy controls. Finally, transcriptional cell states in CSF microglia-like cells and lymphoid subsets were elucidated. Altogether, we have created a reference compendium for single-cell transcriptional profiling encompassing CSF immune cells useful to the scientific community for future studies on neurologic diseases. Copyright: © 2025, Cantoni et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Satisfaction, user experiences, and initial efficacy of a technology-supported self-management intervention (iSMART) to improve post-stroke functioning: a remoted randomized controlled trial
(2025) Topics in Stroke Rehabilitation, .
Lei, Y.a , Li, Z.b , Bui, Q.c , DePaul, O.d , Nicol, G.E.e , Mohr, D.C.f , Fong, M.W.M.g , Metts, C.L.h , Lee, S.I.i , Tomazin, S.E.j , Wong, A.W.K.j k
a Department of Occupational Therapy, New York University, New York, NY, United States
b Division of Occupational Science and Occupational Therapy, University of North Carolina School of Medicine, Chapel Hill, NC, United States
c Internal Medicine Residency Program, South Texas Health System, GME Consortium, Edinburg, TX, United States
d Memorial Hospital Belleville, BJC HealthCare, Belleville, IL, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Center for Behavioral Intervention Technologies and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
g Michigan Avenue Neuropsychologists, Chicago, IL, United States
h Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
i Manning College of Information and Computer Sciences, University of Massachusetts Amherst, Amherst, MA, United States
j Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL, United States
k Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Abstract
Background: Self-management interventions empower individuals to manage their chronic conditions and daily life after stroke. However, traditional in-person self-management interventions often face transportation and geographical barriers. Digital interventions may offer a solution to address this gap. Objectives: This pilot randomized controlled trial (RCT) aimed to examine treatment satisfaction, user experiences, and the initial effect of the interactive Self-Management Augmented by Rehabilitation Technologies (iSMART) intervention in stroke survivors to improve post-stroke functioning. Methods: Participants (N = 24) with mild-to-moderate chronic stroke completed a parallel, 2-arm, nonblinded, remote RCT. They were randomly assigned to either a 12-week iSMART or a control intervention (post-stroke information). iSMART was a technology-based self-management intervention involving skill-building education, human coaching, and text messaging. Participants completed a battery measuring treatment satisfaction, use experiences, and function and participation outcomes at baseline and post-intervention. Results: iSMART participants expressed greater satisfaction with their treatment (r = 0.387), healthcare environment (r = 0.454), relationships with providers (r = 0.374), and higher expectations for positive treatment outcomes (r = 0.328) than control participants, with medium effect sizes. The iSMART group rated the overall program and its coaching, skill-building, and text messaging components as helpful. iSMART participants showed a medium effect in improving overall post-stroke functioning, but control participants showed a small effect. Moreover, iSMART participants showed moderate-to-large effects in improving hand function (r = 0.699), mobility (r = 0.499), memory and thinking (r = 0.436), communication (r = 0.416), social participation (r = 0.307), community reintegration (r = 0.652), and perceived recovery (r = 0.545). Conclusions: Our results provide initial evidence that iSMART supports stroke survivors in managing chronic conditions and enhancing post-stroke functioning. © 2025 Taylor & Francis Group, LLC.
Author Keywords
health and function; Mobile health; participation; self-management; stroke rehabilitation; technology; user experiences
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
FK506 Enhancement of Neuromuscular Junction Recovery After Nerve Injury Is Macrophage-Dependent
(2025) Muscle and Nerve, .
Jablonka-Shariff, A.a , Broberg, C.b , Snyder-Warwick, A.K.a
a Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: Motor recovery following nerve injury is dependent on time required for muscle reinnervation. This process is imperfect, however, and recovery is often incomplete. At the neuromuscular junction (NMJ), macrophage signaling aids muscle reinnervation. Tacrolimus (FK506) treatment speeds functional recovery through unknown mechanisms. This study investigated whether macrophages were required for FK506 neuroenhancing effects. Methods: Wildtype (WT) mice and mice with impaired macrophage recruitment to injury sites (Ccr2−/−) were injected subcutaneously with either saline or FK506 for 3 days prior to sciatic nerve transection and immediate repair and then daily for 4 weeks. Functional recovery was assessed by grid walk and muscle force. Morphometric NMJ and macrophage analyses were conducted in extensor digitorum longus muscles. Results: FK506-injected WT mice showed increased proportions of fully reinnervated NMJs and terminal Schwann cells/NMJ (p < 0.05), improved recovery of tetanic muscle force (p < 0.05), and improved grid walking (p < 0.05) relative to controls. Ccr2−/− mice showed no enhancements in recovery; Ccr2−/− mice treated with FK506 did not differ from controls on any tested metric. We also observed at the NMJ of WT mice increased macrophage numbers with FK506 treatment and increased macrophages expressing FK506 binding protein, FKBP52, after nerve injury. Discussion: These results show that macrophages are required for FK506-mediated improvements in NMJ reinnervation and muscle function. These data implicate macrophages in the mechanism underlying FK506-mediated enhancement of motor recovery after nerve injury. Enhanced knowledge of the neuroenhancing mechanism of FK506 may identify new clinically relevant therapeutic targets. © 2025 Wiley Periodicals LLC.
Author Keywords
FK506; functional muscle recovery; macrophages; neuromuscular junction; regeneration
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a “real-world” setting
(2025) Annals of Clinical and Translational Neurology, .
Smith, S.E., McCoy-Gross, K., Malcolm, A., Oranski, J., Markway, J.W., Miller, T.M., Bucelli, R.C.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures. Methods: This was a single-center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes. Results: Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: −57.9%; mean change CSF pNFH: −67.6%). There was apparent disease stabilization as assessed by the ALSFRS-R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85). Interpretation: This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers. © 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Sleep as a possible mediator in the association of mental health parameters with cardiovascular health indices in women: Exploratory analyses from the Heart SCORE Study
(2025) Menopause, .
Fonkoue, I.T.a , Silva, M.b , Racette, S.B.c , Safo, S.E.b , De Las Fuentes, L.d e , Lowe, D.a , Ebong, I.A.f , Buysse, D.g , Reis, S.E.h , Saeed, A.h
a Divisions of Physical Therapy and Rehabilitation Science, Department of Family Medicine and Community Health, University of Minnesota Medical School, Minneapolis, MN, United States
b Division of Biostatistics and Health Data Science, University of Minnesota, Minneapolis, MN, United States
c College of Health Solutions, Arizona State University, Phoenix, AZ, United States
d Cardiovascular Division, Department of Medicine, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
e Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
f Department of Internal Medicine, Division of Cardiovascular Medicine, University of California Davis, Sacramento, CA, United States
g Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
h Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
Abstract
Objective This exploratory study aimed to determine the possible role of sleep in the relationships of depression and anxiety, with early surrogate markers of subclinical atherosclerosis, such as brachial artery (BA) diameter and carotid intima media thickness (CIMT) in women. Methods We included 1,075 self-reported postmenopausal women, 45 to 75 years from the Heart Strategies Concentrating on Risk Evaluation Study. Exposure variables were depression and anxiety assessed using the Center for Epidemiologic Studies Depression Scale and the State-Trait Anxiety Inventory, respectively. Outcome variables were BA diameter and CIMT measured using ultrasonography. The mediator, sleep, was assessed with the Pittsburgh Sleep Symptom Questionnaire-Insomnia. Ordinary least squares regression was used for mediation analyses. Results Of the 1,075 participants, 56.3% were White and 43.7% were Black. Our analyses revealed significant associations of depression and anxiety with sleep (P < 0.001 for all). After adjusting for confounders, depression was associated with max CIMT (R2 = 0.15, P = 0.004), but not BA diameter (R2 = 0.09, P = 0.083). Although the mediating role of sleep in the association between anxiety and BA diameter was not statistically significant [proportion mediated (CI); 0.41 (-2.77, 4.06); P = 0.219], we observed differential results within each racial group. Sleep appeared to partially mediate the association of anxiety with BA diameter in White [0.21 (0.54, 0.80); P = 0.044] women only. Conclusions We found preliminary indications that sleep might mediate the association of anxiety with BA diameter in White women but does not appear to serve as a mediator in all the other relationships we examined. © 2024 The Author(s). Published byWolters Kluwer Health, Inc.
Author Keywords
Anxiety; Brachial artery diameter; Depression; Intima media thickness; Sleep
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Higher amplitudes of visual networks are associated with trait- but not state-depression
(2025) Psychological Medicine, .
Zhang, W.a , Dutt, R.a b , Lew, D.c , Barch, D.M.a d e , Bijsterbosch, J.D.a
a Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
b Biological Sciences Collegiate Division, University of Chicago, Chicago, IL, United States
c Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Despite depression being a leading cause of global disability, neuroimaging studies have struggled to identify replicable neural correlates of depression or explain limited variance. This challenge may, in part, stem from the intertwined state (current symptoms; variable) and trait (general propensity; stable) experiences of depression. Here, we sought to disentangle state from trait experiences of depression by leveraging a longitudinal cohort and stratifying individuals into four groups: those in remission (‘trait depression group’), those with large longitudinal severity changes in depression symptomatology (‘state depression group’), and their respective matched control groups (total analytic n = 1030). We hypothesized that spatial network organization would be linked to trait depression due to its temporal stability, whereas functional connectivity between networks would be more sensitive to state-dependent depression symptoms due to its capacity to fluctuate. We identified 15 large-scale probabilistic functional networks from resting-state fMRI data and performed group comparisons on the amplitude, connectivity, and spatial overlap between these networks, using matched control participants as reference. Our findings revealed higher amplitude in visual networks for the trait depression group at the time of remission, in contrast to controls. This observation may suggest altered visual processing in individuals predisposed to developing depression over time. No significant group differences were observed in any other network measures for the trait-control comparison, nor in any measures for the state-control comparison. These results underscore the overlooked contribution of visual networks to the psychopathology of depression and provide evidence for distinct neural correlates between state and trait experiences of depression. Copyright © The Author(s), 2025. Published by Cambridge University Press.
Author Keywords
brain network; depression; neuroimaging; PROFUMO; resting-state fMRI; state depression; trait depression; UK Biobank
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Patient stratification by genetic risk in Alzheimer’s disease is only effective in the presence of phenotypic heterogeneity
(2025) PLoS ONE, 20 (1 January), art. no. e0310977, .
Euesden, J.a , Ali, M.b , Robins, C.c , Surendran, P.d , Gormley, P.e , Pulford, D.d , Cruchaga, C.b , Alzheimer’s Disease Neuroimaging Initiative (ADNI)f
a GSK Pharma R&D, Stevenage, Hertfordshire, United Kingdom
b Washington University School of Medicine, NeuroGenomics and Informatics Center, St. Louis, MO, United States
c GSK Pharma R&D, Collegeville, PA, United States
d GSK Pharma R&D, Stevenage, Hertfordshire, United Kingdom
e GSK Pharma R&D, Cambridge, MA, United States
Abstract
Case-only designs in longitudinal cohorts are a valuable resource for identifying disease-relevant genes, pathways, and novel targets influencing disease progression. This is particularly relevant in Alzheimer’s disease (AD), where longitudinal cohorts measure disease “progression,” defined by rate of cognitive decline. Few of the identified drug targets for AD have been clinically tractable, and phenotypic heterogeneity is an obstacle to both clinical research and basic science. In four cohorts (n = 7241), we performed genome-wide association studies (GWAS) and Mendelian randomization (MR) to discover novel targets associated with progression and assess causal relationships. We tested opportunities for patient stratification by deriving polygenic risk scores (PRS) for AD risk and severity and tested the value of these scores in predicting progression. Genome-wide association studies identified no loci associated with progression at genome-wide significance (α = 5×10−8); MR analyses provided no significant evidence of an association between cognitive decline in AD patients and protein levels in brain, cerebrospinal fluid (CSF), and plasma. Polygenic risk scores for AD risk did not reliably stratify fast from slow progressors; however, a deeper investigation found that APOE ε4 status predicts amyloid-β and tau positive versus negative patients (odds ratio for an additional APOE ε4 allele = 5.78 [95% confidence interval: 3.76–8.89], P<0.001) when restricting to a subset of patients with available CSF biomarker data. These results provided no evidence for large-effect, common-variant loci involved in the rate of memory decline, suggesting that patient stratification based on common genetic risk factors for progression may have limited utility. Where clinically relevant biomarkers suggest diagnostic heterogeneity, there is evidence that a priori identified genetic risk factors may have value in patient stratification. Mendelian randomization was less tractable due to the lack of large-effect loci, and future analyses with increased samples sizes are needed to replicate and validate our results. Copyright: © 2025 Euesden et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
A Comparison of Automatically Extracted Quantitative EEG Features for Seizure Risk Stratification in Neonatal Encephalopathy
(2025) Journal of Clinical Neurophysiology : Official publication of the American Electroencephalographic Society, 42 (1), pp. 57-63.
Keene, J.C.a , Loe, M.E.b c , Fulton, T.d , Keene, M.a b c d e , Morrissey, M.J.a , Tomko, S.R.a , Vesoulis, Z.A.e , Zempel, J.M.a , Ching, S.b , Guerriero, R.M.a
a Division of Pediatric & Developmental Neurology, Department of Neurology. Washington University in St. Louis, St. Louis, United States
b Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
d Washington University in St. Louis, St. Louis, Missouri, U.S.A.; and
e Division of Newborn Medicine, Department of Pediatrics. Washington University in St. Louis, St. Louis, MO, United States
Abstract
PURPOSE: Seizures occur in up to 40% of neonates with neonatal encephalopathy. Earlier identification of seizures leads to more successful seizure treatment, but is often delayed because of limited availability of continuous EEG monitoring. Clinical variables poorly stratify seizure risk, and EEG use to stratify seizure risk has previously been limited by need for manual review and artifact exclusion. The goal of this study is to compare the utility of automatically extracted quantitative EEG (qEEG) features for seizure risk stratification. METHODS: We conducted a retrospective analysis of neonates with moderate-to-severe neonatal encephalopathy who underwent therapeutic hypothermia at a single center. The first 24 hours of EEG underwent automated artifact removal and qEEG analysis, comparing qEEG features for seizure risk stratification. RESULTS: The study included 150 neonates and compared the 36 (23%) with seizures with those without. Absolute spectral power best stratified seizure risk with area under the curve ranging from 63% to 71%, followed by range EEG lower and upper margin, median and SD of the range EEG lower margin. No features were significantly more predictive in the hour before seizure onset. Clinical examination was not associated with seizure risk. CONCLUSIONS: Automatically extracted qEEG features were more predictive than clinical examination in stratifying neonatal seizure risk during therapeutic hypothermia. qEEG represents a potential practical bedside tool to individualize intensity and duration of EEG monitoring and decrease time to seizure recognition. Future work is needed to refine and combine qEEG features to improve risk stratification. Copyright © 2024 by the American Clinical Neurophysiology Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
Cochlear Mechanics Are Preserved After Inner Ear Delivery of Gold Nanoparticles
(2025) International Journal of Molecular Sciences, 26 (1), art. no. 126, .
Pan, D.W.a , Kim, J.b c , Quiñones, P.M.a , Ricci, A.J.b , Applegate, B.E.a d , Oghalai, J.S.a d
a Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033, United States
b Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94304, United States
c Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Alfred Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, United States
Abstract
Novel therapeutic delivery systems and delivery methods to the inner ear are necessary to treat hearing loss and inner ear disorders. However, numerous barriers exist to therapeutic delivery into the bone-encased and immune-privileged environment of the inner ear and cochlea, which makes treating inner ear disorders challenging. Nanoparticles (NPs) are a type of therapeutic delivery system that can be engineered for multiple purposes, and posterior semicircular canal (PSCC) infusion is a method to directly deposit them into the cochlea. We sought to assess PSCC infusion of gold NPs into the cochlea, including the NPs’ distribution and effect on cochlear mechanics. We performed optical coherence tomography (OCT) imaging to monitor PSCC infusion of gold NPs into the cochlear chambers. OCT imaging demonstrated that the infusion specifically targeted the perilymphatic spaces within the cochlea. We assessed cochlear mechanics by using OCT vibrometry to measure sound-evoked movements of the basilar membrane. We found no changes in cochlear mechanics between measurements at baseline, after the PSCC canalostomy, immediately after the infusion, and 1 h after the infusion of gold NPs (p > 0.05, paired t-test). These findings validate the PSCC infusion approach for perfusing the cochlear perilymphatic space with a nanoparticle delivery system. Thus, PSCC infusion of nanoparticles is a feasible therapeutic delivery technique for treating inner ear disorders while preserving residual cochlear function. © 2024 by the authors.
Author Keywords
cochlear mechanics; inner ear drug delivery; nanoparticles; optical coherence tomography
Document Type: Article
Publication Stage: Final
Source: Scopus
Head-to-Head Comparison of Aptamer- and Antibody-Based Proteomic Platforms in Human Cerebrospinal Fluid Samples from a Real-World Memory Clinic Cohort
(2025) International Journal of Molecular Sciences, 26 (1), art. no. 286, .
Puerta, R.a b , Cano, A.a c , García-González, P.a c , García-Gutiérrez, F.a , Capdevila, M.a d , de Rojas, I.a c , Olivé, C.a , Blázquez-Folch, J.a , Sotolongo-Grau, O.a , Miguel, A.a , Montrreal, L.a , Martino-Adami, P.e , Khan, A.f , Orellana, A.a c , Sung, Y.J.g h , Frikke-Schmidt, R.i j , Marchant, N.k , Lambert, J.C.l m , Rosende-Roca, M.a , Alegret, M.a c , Fernández, M.V.a c , Marquié, M.a c , Valero, S.a c , Tárraga, L.a c , Cruchaga, C.g h , Ramírez, A.e n o p q , Boada, M.a c , Smets, B.f , Cabrera-Socorro, A.f , Ruiz, A.a c r
a Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, 08029, Spain
b PhD Program in Biotecnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, Spain
c Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, Madrid, 28029, Spain
d Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, 08007, Spain
e Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany
f Janssen Pharmaceutica NV, a Johnson & Johnson Company, Beerse, 2340, Belgium
g NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO 63108, United States
h Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, United States
i Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark
j Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark
k Division of Psychiatry, University College London, London, W1T 7NK, United Kingdom
l Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Université de Lille, Lille, F-59000, France
m Institut Pasteur de Lille, Inserm U1167, CHU de Lille, LabEx DISTALZ, Université de Lille, Lille, F-59000, France
n Department of Neurodegenerative Diseases and Geriatric Psychiatry, Medical Faculty, University Hospital Bonn, Bonn, 53127, Germany
o German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany
p Department of Psychiatry and Glenn, Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX 78229, United States
q Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, 50931, Germany
r Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX 77204, United States
Abstract
High-throughput proteomic platforms are crucial to identify novel Alzheimer’s disease (AD) biomarkers and pathways. In this study, we evaluated the reproducibility and reliability of aptamer-based (SomaScan® 7k) and antibody-based (Olink® Explore 3k) proteomic platforms in cerebrospinal fluid (CSF) samples from the Ace Alzheimer Center Barcelona real-world cohort. Intra- and inter-platform reproducibility were evaluated through correlations between two independent SomaScan® assays analyzing the same samples, and between SomaScan® and Olink® results. Association analyses were performed between proteomic measures, CSF biological traits, sample demographics, and AD endophenotypes. Our 12-category metric of reproducibility combining correlation analyses identified 2428 highly reproducible SomaScan CSF measures, with over 600 proteins well reproduced on another proteomic platform. The association analyses among AD clinical phenotypes revealed that the significant associations mainly involved reproducible proteins. The validation of reproducibility in these novel proteomics platforms, measured using this scarce biomaterial, is essential for accurate analysis and proper interpretation of innovative results. This classification metric could enhance confidence in multiplexed proteomic platforms and improve the design of future panels. © 2024 by the authors.
Author Keywords
Alzheimer’s disease; biomarkers; cerebrospinal fluid; mild cognitive impairment; Olink; proteomics; SomaScan
Document Type: Article
Publication Stage: Final
Source: Scopus
Refinement of an Algorithm to Detect and Predict Freezing of Gait in Parkinson Disease Using Wearable Sensors
(2025) Sensors, 25 (1), art. no. 124, .
Haussler, A.M.a , Tueth, L.E.a , May, D.S.a , Earhart, G.M.a b c , Mazzoni, P.d
a Program in Physical Therapy, School of Medicine, Washington University in St. Louis, St. Louis, MO 63108, United States
b Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63108, United States
c Department of Neuroscience, School of Medicine, Washington University in St. Louis, St. Louis, MO 63108, United States
d Department of Neurology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
Abstract
Freezing of gait (FOG) is a debilitating symptom of Parkinson disease (PD). It is episodic and variable in nature, making assessment difficult. Wearable sensors used in conjunction with specialized algorithms, such as our group’s pFOG algorithm, provide objective data to better understand this phenomenon. While these methods are effective at detecting FOG retrospectively, more work is needed. The purpose of this paper is to explore how the existing pFOG algorithm can be refined to improve the detection and prediction of FOG. To accomplish this goal, previously collected data were utilized to assess the prediction ability of the current algorithm, the potency of each FOG assessment task(s) for eliciting FOG, and the maintenance of detection accuracy when modifying the sampling rate. Results illustrate that the algorithm was able to predict upcoming FOG episodes, but false positive rates were high. The Go Out and Turn-Dual Task was most potent for eliciting FOG, and the 360-Dual Task elicited the longest duration of FOG. The detection accuracy of the pFOG algorithm was maintained at a sampling rate of 60 Hz but significantly worse at 30 Hz. This work is an important step in refining the pFOG algorithm for improved clinical utility. © 2024 by the authors.
Author Keywords
freezing of gait; gait assessment; Parkinson disease; rehabilitation; wearable sensors
Document Type: Article
Publication Stage: Final
Source: Scopus
Activation of δ-opioid receptors blocks allodynia in a model of headache induced by PACAP
(2025) British Journal of Pharmacology, .
Mangutov, E.a b , Dripps, I.b , Siegersma, K.b , Zhang, Y.a , Bocian, R.b , Asif, S.b , Halbesma, T.b , Witkowski, W.b , Pradhan, A.A.a b b
a Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
Abstract
Background and purpose: Pituitary adenylate cyclase activating polypeptide (PACAP) is a human migraine trigger that is being targeted for migraine. The δ-opioid receptor (δ-receptor) is a novel target for the treatment of migraine, but its mechanism remains unclear. The goals of this study were to develop a mouse PACAP-headache model using clinically significant doses of PACAP; determine the effects of δ-receptor activation in this model; and investigate the co-expression of δ-receptors, PACAP and PACAP-PAC1 receptor. Experimental approach: Cephalic allodynia to low doses of acute and chronic PACAP were tested. A triptan (sumatriptan) and a CGRP receptor antagonist (olcegepant) were tested in this model. The δ-receptor agonist SNC80 was tested in PACAP and CGRP-induced headache models. Expression of PACAP, PAC1, CRLR and δ-receptors was determined using in situ hybridisation. Key results: Low doses of PACAP produced dose-dependent acute and chronic cephalic allodynia, blocked by sumatriptan but not by olcegepant. The PAC1 antagonist (M65) did not inhibit CGRP-induced allodynia. There was moderate co-expression of PAC1 and CRLR transcripts in migraine-related regions. SNC80 blocked PACAP- and CGRP-induced allodynia. There was low co-expression of PACAP and δ-receptors in brain regions measured. However, there was high co-expression of PAC1 and δ-receptors in somatosensory cortex, hippocampus and trigeminal nucleus caudalis. Conclusion and implications: We developed a translationally significant model of PACAP-induced headache, which was mechanistically distinct from CGRP. Activation of δ-receptors blocked PACAP- and CGRP-induced allodynia, and δ-receptors were highly co-expressed with the PACAP-ergic system. Future studies will examine the functional relationship between δ-receptors and PAC1. © 2025 British Pharmacological Society.
Author Keywords
headache; opioid; RNAScope; trigeminovascular pain
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Elevated p16Ink4a Expression Enhances Tau Phosphorylation in Neurons Differentiated From Human-Induced Pluripotent Stem Cells
(2025) Aging Cell, .
Holloway, K.a , Neherin, K.a , Song, Y.b , Sato, K.b , Houston, A.b , Chen, F.b , Ding, L.b , Zhang, H.a
a Department of Pediatrics, 3 NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, United States
b Department of Medicine, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer’s disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, and up-regulates genes involved in focal adhesion, interferon α response and PI3K-Akt signaling. Our approach enables temporal control of p16 induction upon differentiation from iPSCs to neurons. In differentiated cortical neurons, we found that up-regulation of p16 increases tau phosphorylation at Ser202/Thr205 and Thr231 in a cell-autonomous manner, while amyloid beta secretion is not affected. These data suggest a critical role of p16 in regulating tau phosphorylation in neurons, and thereby contributing to pathological progression of AD. As pathological tau tangles have been shown to induce p16 expression, our studies suggest a positive feedback loop between p16 and tau to exacerbate tau pathologies. © 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Author Keywords
aging; Alzheimer’s disease; cellular senescence; disease modeling; p16Ink4a; tau
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Molecular mechanisms of inverse agonism via κ-opioid receptor–G protein complexes
(2025) Nature Chemical Biology, art. no. 743, .
Tyson, A.S.a b , Khan, S.a c , Motiwala, Z.a c h , Han, G.W.a , Zhang, Z.a d , Ranjbar, M.a b , Styrpejko, D.a c , Ramos-Gonzalez, N.e , Woo, S.f , Villers, K.a , Landaker, D.a , Kenakin, T.g , Shenvi, R.f , Majumdar, S.e , Gati, C.a b c
a The Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, United States
b Department of Chemistry, University of Southern California, Los Angeles, CA, United States
c Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States
d Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
e Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, MO, United States
f Department of Chemistry, Scripps Research, La JollaCA, United States
g Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States
h Amgen Inc., Thousand Oaks, CA, United States
Abstract
Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor–G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor–G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR–Gi protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR–Gi protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR–G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free ‘inactive’ receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonical model of receptor antagonism and offers crucial insights into GPCR pharmacology. (Figure presented.) © The Author(s) 2025.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring the Experience of Loneliness among People Living with Schizophrenia: A Qualitative Study
(2025) Issues in Mental Health Nursing, 46 (1), pp. 12-19.
Randolph, S.B.a , Ratner, A.M.a , Kersey, J.a , Moran, E.b , Barch, D.M.b c , Rousso, B.a , Connor, L.T.a
a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: People living with schizophrenia or schizoaffective disorder are at heightened risk for experiencing loneliness, which is associated with negative health, quality of life, and symptom-specific outcomes. Aims: This study aimed to better understand the experience of loneliness among adults living with schizophrenia or schizoaffective disorder. Methods: Using a semi-structured interview guide, researchers interviewed twelve participants living with schizophrenia or schizoaffective disorder. Interview topics included the contexts of loneliness, hopes related to living a life less impacted by loneliness, and coping strategies. Researchers used conventional content analysis to analyze interview data and generate themes. Results: The research team identified four themes from the interview data: emotional disconnection, social anxiety leading to loneliness, unmet needs within social networks, and lacking companionship. Participants had a variety of hopes for the future, including increasing the quality of their relationships and improving their sense of self-efficacy. Participants described a variety of coping strategies, ranging from individual (e.g. leveraging technology, using cognitive reframing techniques) to systems-level (e.g. local clubhouses and walkable neighborhoods). Conclusions: Participants have identified several priorities and coping strategies to reduce loneliness that can be integrated with current models of loneliness to develop interventions that are meaningful and effective for this population. © 2025 Taylor & Francis Group, LLC.
Document Type: Article
Publication Stage: Final
Source: Scopus
Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) associated retinal degeneration: an international study
(2025) Ophthalmic Genetics, .
Uner, O.E.a , Elsharawi, R.a , Reynolds, M.b , Bacci, G.M.c , Bargiacchi, S.d , Birch, D.G.e , Chen, F.K.f g , Jain, N.h , Heath Jeffery, R.C.f g , Lamey, T.M.i , Mustafi, D.j , da Palma, M.M.k , Sallum, J.M.F.k , Torres Soto, M.h , Jones, K.e , Yang, P.a , Pennesi, M.E.a e , Everett, L.A.a
a Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, United States
b Department of Ophthalmology, St. Louis Children’s Hospital, Washington University in St. Louis, St. Louis, MO, United States
c Pediatric Ophthalmology Unit, Meyer Children’s Hospital IRCCS, Toscana, Firenze, Italy
d Medical Genetics Unit, Meyer Children’s Hospital IRCCS, Toscana, Firenze, Italy
e Ophthalmology, Retina Foundation of the Southwest, Dallas, TX, United States
f Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia
g Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia
h Department of Ophthalmology, Emory School of Medicine, Atlanta, GA, United States
i Australian Inherited Retinal Diseases Registry, Medical Technology and Physics Department, Sir Charles Gairdner Hospital, Nedlands, Australia
j Department of Ophthalmology, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, United States
k Instituto de Genetica Ocular, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
Abstract
Introduction: Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an X-linked gene critical for nucleotide metabolism. Pathogenic PRPS1 variants cause three overlapping phenotypes: Arts syndrome (severe neurological disease), Charcot-Marie-Tooth type 5 [CMTX5] (peripheral neuropathy), and non-syndromic sensorineural hearing loss (SNHL). Each may be associated with retinal dystrophy. Multicenter phenotypic studies are limited. Methods: A multicenter retrospective clinical case series of 15 patients from 12 pedigrees with PRPS1-associated retinal degeneration is presented. Results: Of 15 patients, 11 (73.3%) were female. Mean age of ocular disease onset was 8.5 years (range, 0.5-35 years). Many were diagnosed with Leber congenital amaurosis prior to genetic testing (n = 5). Five patients had clinical diagnoses of CMTX5 and Arts syndrome, two had isolated ocular disease, and one was asymptomatic. Mean initial VA (LogMAR) was 0.74, 0.74, 0.83, and 0.85 for isolated ocular disease, CMTX5, Arts, and SNHL, respectively. Ten patients were hyperopic and eight had asymmetric VA. Macular atrophy (n = 13), optic atrophy (n = 13), bone spicules (n = 10), and parafoveal outer retinal atrophy (n = 12) were common findings. Electroretinogram showed delayed and attenuated photopic and scotopic responses (n = 10). Median follow-up of 2.9 years (range, 1.5–11.6 years) in six patients showed retinal disease progression in two patients. Discussion: PRPS1-associated retinal degeneration predominantly manifests as a bilateral asymmetric cone and rod dystrophy, commonly associated with hyperopia and optic atrophy. © 2025 Taylor & Francis Group, LLC.
Author Keywords
Arts syndrome; Charcot-Marie-Tooth; cone-rod dystrophy; hearing loss; hyperopia; PRPS1
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Impact of a Multi-Component Home-Based Physical Therapy Intervention on Cognitive Outcomes: Results From the CAP Randomized Controlled Trial
(2025) Journal of Aging and Health, .
Gruber-Baldini, A.L.a , Fortinsky, R.H.b , Resnick, B.c , Magder, L.S.a , Beamer, B.A.d e , Mangione, K.f , Orwig, D.a , Binder, E.F.g , Terrin, M.a , Magaziner, J.a
a Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States
b UConn Center on Aging, University of Connecticut, Farmington, CT, United States
c University of Maryland School of Nursing, Baltimore, MD, United States
d Gerontology Research, Education and Clinical Center (GRECC), Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States
e Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
f Department of Physical Therapy, College of Health Sciences, Arcadia University, Glenside, PA, United States
g Division of Geriatrics and Nutritional Science, School of Medicine, Washington University in St Louis, St Louis, MO, United States
Abstract
Objective: Differences in cognitive outcomes for two home-based 16-week interventions after usual rehabilitative care post-hip fracture were examined. Methods: Community Ambulation Project randomized controlled trial included 210 hip fracture participants. Interventions: Specific multi-component (PUSH) included strength-, balance-, function-, and endurance-based exercises; non-specific active control (PULSE) included seated range-of-motion exercises and sensory transcutaneous electrical neurostimulation. Cognitive measures: Modified Mini-Mental State Examination, plus Hooper Visual Organization Test and Trails A/B in an ancillary study (CAP-MP, n = 40), assessed pre-randomization and 16 and 40 weeks post-randomization. Results: Over 16 weeks, PUSH-assigned participants became faster on Trails A (Δ = −6.3, 95% CI: −16.7, 4.2); those in PULSE became slower (Δ = 9.3, 95% CI: −1.7, 20.3, p =.04). At 40 weeks, PUSH-assigned participants became faster on Trails B (Δ = −21.5, 95% CI: −46.2, 3.3) while those in PULSE became slower (Δ = 15.2, 95% CI: −11.9, 42.3, p =.04). No other significant differences were found. Discussion: Results suggest that multi-component exercise interventions like PUSH may prevent/delay decline or improve attention and psychomotor speed in patients with recent hip fracture. © The Author(s) 2025.
Author Keywords
cognition; exercise; hip fracture; RCT
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Alcohol Use Disorder Polygenic Score Compared with Family History and ADH1B
(2024) JAMA Network Open, 7 (12), p. e2452705.
Lai, D.a , Zhang, M.a , Abreu, M.a , Schwantes-An, T.-H.a , Chan, G.b c , Dick, D.M.d , Kamarajan, C.e , Kuang, W.e , Nurnberger, J.I.a f , Plawecki, M.H.f , Rice, J.g , Schuckit, M.h , Porjesz, B.e , Liu, Y.a , Foroud, T.a
a Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States
b Department of Psychiatry, University of Connecticut School of Medicine, Farmington, United States
c Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, United States
d Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
e Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry, SUNY Downstate Health Science University, New York, NY, United States
f Department of Psychiatry, Indiana University School of Medicine, Indianapolis, United States
g Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, United States
h Department of Psychiatry, University of California San Diego Medical School, San Diego, United States
Abstract
Importance: Identification of individuals at high risk of alcohol use disorder (AUD) and subsequent application of prevention and intervention programs has been reported to decrease the incidence of AUD. The polygenic score (PGS), which measures an individual’s genetic liability to a disease, can potentially be used to evaluate AUD risk. Objective: To assess the estimability and generalizability of the PGS, compared with family history and ADH1B, in evaluating the risk of AUD among populations of European ancestry. Design, Setting, and Participants: This genetic association study was conducted between October 1, 2023, and May 21, 2024. A 2-stage design was used. First, the pruning and thresholding method was used to calculate PGSs in the screening stage. Second, the estimability and generalizability of the best PGS was determined using 2 independent samples in the testing stage. Three cohorts ascertained to study AUD were used in the screening stage: the Collaborative Study on the Genetics of Alcoholism (COGA), the Study of Addiction: Genetics and Environment (SAGE), and the Australian Twin-Family Study of Alcohol Use Disorder (OZALC). The All of Us Research Program (AOU), which comprises participants with diverse backgrounds and conditions, and the Indiana Biobank (IB), consisting of Indiana University Health system patients, were used to test the best PGS. For the COGA, SAGE, and OZALC cohorts, cases with AUD were determined using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or Fifth Edition (DSM-5) criteria; controls did not meet any criteria or did not have any other substance use disorders. For the AOU and IB cohorts, cases with AUD were identified using International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, Tenth Revision (ICD-10) codes; controls were aged 21 years or older and did not have AUD. Exposure: The PGS was calculated using single-nucleotide variants with concordant effects in 3 large-scale genome-wide association studies of AUD-related phenotypes. Main Outcomes and Measures: The main outcome was AUD determined with DSM-IV or DSM-5 criteria and ICD-9 or ICD-10 codes. Generalized linear mixed models and logistic regression models were used to analyze related and unrelated samples, respectively. Results: The COGA, SAGE, and OZALC cohorts included a total of 8799 samples (6323 cases and 2476 controls; 50.6% were men). The AOU cohort had a total of 116 064 samples (5660 cases and 110404 controls; 60.4% were women). The IB cohort had 6373 samples (936 cases and 5437 controls; 54.9% were women). The 5% of samples with the highest PGS in the AOU and IB cohorts were approximately 2 times more likely to develop AUD (odds ratio [OR], 1.96 [95% CI, 1.78-2.16]; P = 4.10 × 10-43; and OR, 2.07 [95% CI, 1.59-2.71]; P = 9.15 × 10-8, respectively) compared with the remaining 95% of samples; these ORs were comparable to family history of AUD. For the 5% of samples with the lowest PGS in the AOU and IB cohorts, the risk of AUD development was approximately half (OR, 0.53 [95% CI, 0.45-0.62]; P = 6.98 × 10-15; and OR, 0.57 [95% CI, 0.39-0.84]; P = 4.88 × 10-3) compared with the remaining 95% of samples; these ORs were comparable to the protective effect of ADH1B. PGS had similar estimabilities in male and female individuals. Conclusions and Relevance: In this study of AUD risk among populations of European ancestry, PGSs were calculated using concordant single-nucleotide variants and the best PGS was tested in targeted datasets. The findings suggest that the PGS may potentially be used to evaluate AUD risk. More datasets with similar AUD prevalence as in general populations are needed to further test the generalizability of PGS.. © 2024 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence
(2024) JAMA Network Open, 7 (12), p. e2452027. Cited 1 time.
Miller, A.P.a , Baranger, D.A.A.b , Paul, S.E.b , Garavan, H.c , MacKey, S.c , Tapert, S.F.d , Leblanc, K.H.e , Agrawal, A.f , Bogdan, R.b
a Department of Psychiatry, Indiana University, School of Medicine, Indianapolis, United States
b Department of Psychological and Brain Sciences, Washington University, St Louis, MO, United States
c Department of Psychiatry, University of Vermont, Larner College of Medicine, Burlington, United States
d Department of Psychiatry, University of California, San Diego, United States
e Division of Extramural Research, National Institute on Drug Abuse, Bethesda, MD, United States
f Department of Psychiatry, Washington University, St Louis School of Medicine, St Louis, MO, United States
Abstract
Importance: The extent to which neuroanatomical variability associated with early substance involvement, which is associated with subsequent risk for substance use disorder development, reflects preexisting risk and/or consequences of substance exposure remains poorly understood. Objective: To examine neuroanatomical features associated with early substance use initiation and to what extent associations may reflect preexisting vulnerability. Design, Setting, and Participants: Cohort study using data from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study. Children aged 9 to 11 years at baseline were recruited from 22 sites across the US between June 1, 2016, and October 15, 2018. Data were analyzed from February to September 2024. Exposures: Substance use initiation through 3-year follow-up (ie, age <15 years). Main Outcomes and Measures: Self-reported alcohol, nicotine, cannabis, and other substance use initiation and baseline magnetic resonance imaging (MRI)-derived estimates of brain structure (ie, global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume). Covariates included family (eg, familial relationships), pregnancy (eg, prenatal exposure to substances), child (eg, sex and pubertal status), and MRI (eg, scanner model) variables. Results: Among 9804 children (mean [SD] baseline age, 9.9 [0.6] years; 5160 boys [52.6%]; 213 Asian [2.2%], 1474 Black [15.0%], 514 Hispanic/Latino [5.2%], 29 American Indian [0.3%], 10 Pacific Islander [0.1%], 7463 White [76.1%], and 75 other [0.7%]) with nonmissing baseline neuroimaging and covariate data, 3460 (35.3%) reported substance use initiation before age 15. Initiation of any substance or alcohol use was associated with thinner cortex in prefrontal regions (eg, rostral middle frontal gyrus, β = -0.03; 95% CI, -0.02 to -0.05; P = 6.99 × 10-6) but thicker cortex in all other lobes, larger globus pallidus and hippocampal volumes, as well as greater global indices of brain structure (eg, larger whole brain volume, β = 0.05; 95% CI, 0.03 to 0.06; P = 2.80 × 10-8) following Bonferroni or false discovery rate multiple testing correction. Cannabis use initiation was associated with lower right caudate volume (β = -0.03; 95% CI, -0.01 to -0.05; P =.002). Post hoc examinations restricting to postbaseline initiation suggested that the majority of associations, including thinner prefrontal cortex and greater whole brain volume, preceded initiation. Conclusions and Relevance: In this cohort study of children, preexisting neuroanatomical variability was associated with substance use initiation. In addition to putative neurotoxic effects of substance exposure, brain structure variability may reflect predispositional risk for initiating substance use earlier in life with potential cascading implications for development of later problems. © 2024 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Major Depressive Disorder and Driving Behavior among Older Adults
(2024) JAMA Network Open, p. e2452038.
Babulal, G.M.a b c , Chen, L.d , Trani, J.-F.b c e f , Brown, D.C.a , Carr, D.B.g , Ances, B.M.a , Lenze, E.J.h
a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
b Institute of Public Health, Washington University in St Louis, St Louis, MO, United States
c Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
d Division of Biostatistics, Washington University in St Louis, St Louis, MO, United States
e Brown School of Social Work, Washington University in St Louis, St Louis, MO, United States
f National Conservatory of Arts and Crafts, Paris, France
g Department of Medicine, Washington University in St Louis, St Louis, MO, United States
h Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
Abstract
Importance: Depression and antidepressant use are independently associated with crash risk among older drivers. However, it is unclear what factors impact daily driving that increase safety risk for drivers with depression. Objective: To examine differences in naturalistic driving behavior and safety between older adults with and without major depressive disorder (MDD). Design, Setting, and Participants: A prospective longitudinal cohort study was conducted among older adults (≥65 years) from the Driving Real-World In-Vehicle Evaluation System Project collected from July 1, 2021, to December 30, 2023. The sample included 85 participants with MDD and 310 participants without. Neurological, clinical, mood, and neuropsychological tests were collected annually. Daily driving behavior was recorded using a commercial data logger. Statistical analysis was performed from January 31 to June 24, 2024. Exposure: MDD and antidepressant usage. Main outcomes and measures: Linear mixed models with propensity score weighting compared slopes of driving behaviors over time (trips taken at night, speeding, hard braking, entropy, and radius of gyration) between groups. Results: In a sample of 395 participants, 85 were classified as individuals with MDD (mean [SD] age, 69.6 [6.1] years; 60 [70.6%] female; 8 [9.4%] non-Hispanic Black and 77 [90.6%] non-Hispanic White) and 310 as individuals in the control group without depression (mean [SD] age, 70.1 [5.1] years; 153 [49.4%] female; 40 [12.9%] non-Hispanic Black and 270 [87.1%] non-Hispanic White). Adults with MDD had greater depressive symptoms (mean [SD], 8.35 [5.35] vs 2.33 [2.72]; difference, 6.02; 95% CI for difference, 5.17 to 6.85; P <.001), comorbidities (mean [SD], 4.08 [2.07] vs 2.79 [1.67]; difference, 1.29; 95% CI for difference, 0.87 to 1.70; P <.001), used more antidepressants (mean [SD], 0.94 [0.81] vs 0.27 [0.54]; χ21= 65.8; P <.001), and had a higher number of medications (mean [SD], 3.80 [3.27] vs 1.98 [2.21]; χ21= 21.0; P <.001) compared with controls at baseline. Longitudinal analysis demonstrated an association between adults with MDD and hard braking (mean [SE], 3.17 × 10-4[7.30 × 10-5] vs 6.70 × 10-5[4.00 × 10-5]; difference, 2.50 × 10-4; 95% CI for difference, 1.74 × 10-4to 4.61 × 10-4; P <.001) and hard cornering events per trip (mean [SE], 0.80 [0.64] vs 0.57 [0.25]; difference, 0.23; 95% CI for difference, 0.08 to 1.06; P =.04), greater distances driven from home (mean [SE], 31.19 [7.35] vs 7.76 [3.80] km; difference, 23.43; 95% CI for difference, 0.28 to 15.2; P <.001), more unique destinations visited (mean [SE], 0.34 [0.10] vs -0.27 [0.03]; difference, 0.61; 95% CI for difference, 0.14 to 0.54; P <.001), and higher random entropy (mean [SE], 0.01 [0.01] vs -0.02 [0.00]; difference, 0.03; 95% CI for difference, -0.03 to -0.01; P <.001) over time. Conclusions and relevance: In this longitudinal cohort study of older drivers, adcauults with MDD demonstrated distinct and riskier driving behaviors than those in the control group without depression, with higher rates of hard braking, cornering, and unpredictability in driving patterns over time. Routine depression screening and tailored interventions are essential for enhancing driving safety and maintaining independence among older adults with MDD. Comprehensive care approaches addressing both mental and physical health are crucial for this vulnerable population.. © 2024 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus