Cis-regulatory interfaces reveal the molecular mechanisms underlying the notochord gene regulatory network of Ciona
(2024) Nature Communications, 15 (1), art. no. 3025, .
Negrón-Piñeiro, L.J.a , Wu, Y.a , Popsuj, S.b , José-Edwards, D.S.c , Stolfi, A.b , Di Gregorio, A.a
a Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, United States
b School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, United States
c Post-Baccalaureate Premedical Program, Washington University, St. Louis, MO 63130, United States
Abstract
Tissue-specific gene expression is fundamental in development and evolution, and is mediated by transcription factors and by the cis-regulatory regions (enhancers) that they control. Transcription factors and their respective tissue-specific enhancers are essential components of gene regulatory networks responsible for the development of tissues and organs. Although numerous transcription factors have been characterized from different organisms, the knowledge of the enhancers responsible for their tissue-specific expression remains fragmentary. Here we use Ciona to study the enhancers associated with ten transcription factors expressed in the notochord, an evolutionary hallmark of the chordate phylum. Our results illustrate how two evolutionarily conserved transcription factors, Brachyury and Foxa2, coordinate the deployment of other notochord transcription factors. The results of these detailed cis-regulatory analyses delineate a high-resolution view of the essential notochord gene regulatory network of Ciona, and provide a reference for studies of transcription factors, enhancers, and their roles in development, disease, and evolution. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Subcellular pathways through VGluT3-expressing mouse amacrine cells provide locally tuned object-motion-selective signals in the retina
(2024) Nature Communications, 15 (1), art. no. 2965, .
Friedrichsen, K.a b c d , Hsiang, J.-C.a b c d , Lin, C.-I.a b c d , McCoy, L.a b c , Valkova, K.a b c , Kerschensteiner, D.a b c , Morgan, J.L.a b c
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Graduate Program in Neuroscience, Washington University in St. Louis, St. Louis, United States
Abstract
VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing input distributions to VG3 dendrite responses, we show that VG3 dendrites have a short functional length constant that likely depends on inhibitory shunting. This model predicts that RGCs that extend dendrites into the middle layers of the inner plexiform encounter VG3 dendrites whose responses vary according to the local bipolar cell response type. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures
(2024) Neuropharmacology, 251, art. no. 109918, .
Hobson, B.A.a b , Rowland, D.J.b , Dou, Y.a , Saito, N.c , Harmany, Z.T.b , Bruun, D.A.a , Harvey, D.J.c , Chaudhari, A.J.b d , Garbow, J.R.e , Lein, P.J.a
a Department of Molecular Biosciences, University of California, School of Veterinary Medicine, Davis, Davis, CA 95616, United States
b Center for Molecular and Genomic Imaging, University of California, College of Engineering, Davis, Davis, CA 95616, United States
c Department of Public Health Sciences, University of California, School of Medicine, Davis, CA 95616, United States
d Department of Radiology, University of California, School of Medicine, Davis, CA 95817, United States
e Biomedical Magnetic Resonance Center, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling. © 2024 The Authors
Author Keywords
Benzodiazepines; Diisopropylfluorophosphate; In vivo imaging; Neuroinflammation; Rat; Status epilepticus
Document Type: Article
Publication Stage: Final
Source: Scopus
Retrospective Multicenter Cohort Study on Safety and Electroencephalographic Response to Lacosamide for Neonatal Seizures
(2024) Pediatric Neurology, 155, pp. 18-25.
Kaur, M.a b , Utidjian, L.c , Abend, N.S.d , Dickinson, K.c , Roebling, R.e , McDonald, J.c , Maltenfort, M.G.c , Foskett, N.a , Elmoufti, S.f , Guerriero, R.M.g , Jain, B.G.h , Pajor, N.M.i , Rao, S.j , Shellhaas, R.A.g , Slaughter, L.k , Forrest, C.B.c
a RWE Neurology, UCB Pharma Ltd, Slough, United Kingdom
b Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
c The Applied Clinical Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
d Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
e Epilepsy and Rare Syndrome Organisation, UCB Pharma, Monheim am Rhein, Germany
f Biometric & Quantitative Services-Launch Statistics, UCB Pharma, Morrisville, NC, United States
g Division of Pediatric Neurology, Department of Neurology, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
h Division of Neurology, Department of Pediatrics, Nemours Children’s Health, Wilmington, Delaware, United States
i Divisions of Pulmonary Medicine and Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
j Department of Pediatrics (Infectious Diseases, Epidemiology and Hospital Medicine), University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, United States
k Division of Child Neurology, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH, United States
Abstract
Background: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates. Methods: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days. Results: Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates. Conclusions: The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results. © 2024 The Author(s)
Author Keywords
Electroencephalographic (EEG) response; Lacosamide; Neonate; Safety
Document Type: Article
Publication Stage: Final
Source: Scopus
Functional organization of posterior parietal cortex circuitry based on inferred information flow
(2024) Cell Reports, 43 (4), art. no. 114028, .
Kang, J.U., Mooshagian, E., Snyder, L.H.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Many studies infer the role of neurons by asking what information can be decoded from their activity or by observing the consequences of perturbing their activity. An alternative approach is to consider information flow between neurons. We applied this approach to the parietal reach region (PRR) and the lateral intraparietal area (LIP) in posterior parietal cortex. Two complementary methods imply that across a range of reaching tasks, information flows primarily from PRR to LIP. This indicates that during a coordinated reach task, LIP has minimal influence on PRR and rules out the idea that LIP forms a general purpose spatial processing hub for action and cognition. Instead, we conclude that PRR and LIP operate in parallel to plan arm and eye movements, respectively, with asymmetric interactions that likely support eye-hand coordination. Similar methods can be applied to other areas to infer their functional relationships based on inferred information flow. © 2024 The Authors
Author Keywords
CP: Neuroscience; eye-hand coordination; functional connectivity; motor planning; parietal cortex
Document Type: Article
Publication Stage: Final
Source: Scopus
Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient
(2024) Cell, 187 (8), pp. 1889-1906.e24.
King, M.R.a b , Ruff, K.M.a b , Lin, A.Z.a b , Pant, A.a b , Farag, M.a b , Lalmansingh, J.M.a b , Wu, T.b c , Fossat, M.J.a b , Ouyang, W.d e f , Lew, M.D.b c , Lundberg, E.d e f , Vahey, M.D.a b , Pappu, R.V.a b
a Department of Biomedical Engineering, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Center for Biomolecular Condensates, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Electrical and Systems Engineering, James F. McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, CA, United States
e Department of Pathology, School of Medicine, Stanford University, Stanford, CA, United States
f Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH—Royal Institute of Technology, Stockholm, Sweden
Abstract
Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates. © 2024 The Author(s)
Author Keywords
biomolecular condensates; Cajal bodies; condensation; emergent property; evolution; interphase; nuclear speckles; nucleolus; pH; phase separation; proton motive force; reconstitution
Document Type: Article
Publication Stage: Final
Source: Scopus
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly
(2024) Science Advances, 10 (14), art. no. eadk3674, .
Shue, F.a , White, L.J.b , Hendrix, R.D.c , Ulrich, J.c , Henson, R.L.c , Knight, W.c , Martens, Y.A.a , Wang, N.a , Roy, B.a , Starling, S.C.a , Ren, Y.b , Xiong, C.d , Asmann, Y.W.b , Syrjanen, J.A.e , Vassilaki, M.e , Mielke, M.M.e , Timsina, J.f , Sung, Y.J.f , Cruchaga, C.f , Holtzman, D.M.c , Bu, G.a , Petersen, R.C.g , Heckman, M.G.b , Kanekiyo, T.a
a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
b Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 93110, United States
e Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 93110, United States
g Departments of neurology, Mayo Clinic, Rochester, MN 55905, United States
Abstract
The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly. © 2024 American Association for the Advancement of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Health Factors Associated With Development and Severity of Poststroke Dysphagia: An Epidemiological Investigation
(2024) Journal of the American Heart Association, 13 (7), p. e033922.
Krekeler, B.N.a b , Schieve, H.J.P.c , Khoury, J.d , Ding, L.d , Haverbusch, M.b , Alwell, K.b , Adeoye, O.e , Ferioloi, S.b , Mackey, J.f , Woo, D.b , Flaherty, M.b , La Rosa, F.L.R.b g , Demel, S.b , Star, M.h , Coleman, E.i , Walsh, K.b , Slavin, S.j , Jasne, A.k , Mistry, E.b , Kleindorfer, D.b l , Kissela, B.b
a Department of Otolaryngology-Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati OH USA
b Department of Neurology and Rehabilitation Medicine University of Cincinnati College of Medicine Cincinnati OH USA
c Wake Forest School of Medicine Winston-Salem NC USA
d Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH USA
e Department of Emergency Medicine Washington University School of Medicine St. Louis MO USA
f Department of Neurology Indiana University School of Medicine Indianapolis IN USA
g Baptist Health South Florida Miami Neuroscience Institute Miami FL USA
h Sorkoa Medical Center Beersheva Israel, Israel
i Department of Neurology University of Chicago Medicine Chicago IL USA
j Department of Neurology University of Kansas Medical Center Kansas City KS USA
k Department of Neurology Yale School of Medicine New Haven CT USA
l Department of Neurology University of Michigan Ann Arbor MI USA
Abstract
BACKGROUND: Dysphagia after stroke is common and can impact morbidity and death. The purpose of this population-based study was to determine specific epidemiological and health risk factors that impact development of dysphagia after acute stroke. METHODS AND RESULTS: Ischemic and hemorrhagic stroke cases from 2010 and 2015 were identified via chart review from the GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study), a representative sample of ≈1.3 million adults from southwestern Ohio and northern Kentucky. Dysphagia status was determined on the basis of clinical assessments and necessity for alternative access to nutrition via nasogastric or percutaneous endoscopic gastrostomy tube placement. Comparisons between patients with and without dysphagia were made to determine differences in baseline characteristics and premorbid conditions. Multivariable logistic regression determined factors associated with increased risk of dysphagia. Dysphagia status was ascertained from 4139 cases (1709 with dysphagia). Logistic regression showed that increased age, Black race, higher National Institutes of Health Stroke Scale score at admission, having a hemorrhagic stroke (versus infarct), and right hemispheric stroke increased the risk of developing dysphagia after stroke. Factors associated with reduced risk included history of high cholesterol, lower prestroke modified Rankin Scale score, and white matter disease. CONCLUSIONS: This study replicated previous findings of variables associated with dysphagia (older age, worse stroke, right-sided hemorrhagic lesions), whereas other variables identified were without clear biological rationale (eg, Black race, history of high cholesterol, and presence of white matter disease) and should be investigated in future studies to determine biological relevance and potential influence in stroke recovery.
Author Keywords
dysphagia; feeding; stroke; swallowing
Document Type: Article
Publication Stage: Final
Source: Scopus
Visual feedback improves propulsive force generation during treadmill walking in people with Parkinson disease
(2024) Journal of Biomechanics, 167, art. no. 112073, .
Baudendistel, S.T.a b , Franz, J.R.c , Schmitt, A.C.d , Wade, F.E.e , Pappas, M.C.b , Au, K.L.K.f , Hass, C.J.b g
a Program in Physical Therapy, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, United States
c Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC, United States
d Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, United States
e School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, United States
f University of Kansas Medical Center, Kansas City, KS, United States
g Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
Abstract
Persons with Parkinson’s disease experience gait alterations, such as reduced step length. Gait dysfunction is a significant research priority as the current treatments targeting gait impairment are limited. This study aimed to investigate the effects of visual biofeedback on propulsive force during treadmill walking in persons with Parkinson’s. Sixteen ambulatory persons with Parkinson’s participated in the study. They received real-time biofeedback of anterior ground reaction force during treadmill walking at a constant speed. Peak propulsive force values were measured and normalized to body weight. Spatiotemporal parameters were also assessed, including stride length and double support percent. Persons with Parkinson’s significantly increased peak propulsive force during biofeedback compared to baseline (p <.0001, Cohen’s dz = 1.69). Variability in peak anterior ground reaction force decreased across repeated trials (p <.0001, dz = 1.51). While spatiotemporal parameters did not show significant changes individually, stride length and double support percent improved marginally during biofeedback trials. Persons with Parkinson’s can increase propulsive force with visual biofeedback, suggesting the presence of a propulsive reserve. Though stride length did not significantly change, clinically meaningful improvements were observed. Targeting push-off force through visual biofeedback may offer a potential rehabilitation technique to enhance gait performance in Persons with Parkinson’s. Future studies could explore the long-term efficacy of this intervention and investigate additional strategies to improve gait in Parkinson’s disease. © 2024 Elsevier Ltd
Author Keywords
Biofeedback; Parkinson disease; Propulsive force; Push-off
Document Type: Article
Publication Stage: Final
Source: Scopus
Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon
(2024) Journal of Clinical Sleep Medicine (JCSM): Official Publication of the American Academy of Sleep Medicine, 20 (4), pp. 657-662.
Dominguez, D.a , Rudock, R.a , Tomko, S.a , Pathak, S.a , Mignot, E.b , Licis, A.a c
a Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri
b Stanford Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, United States
c Center on Biological Rhythms and Sleep, Washington University School of Medicine, Saint Louis, Missouri
Abstract
Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic bouts of severe hypersomnia associated with cognitive and behavioral abnormalities and normal alertness and functioning in between episodes. The pathophysiology is unclear but may involve neurotransmitter abnormalities, hypothalamic/thalamic dysfunction, viral/autoimmune etiology, or circadian abnormalities. No single treatment has been shown to be reliably efficacious; lithium has demonstrated the most consistent efficacy, although many do not respond and its use is limited by side effects. Due to the evidence of circadian involvement, we hypothesized that strengthening circadian signals may ameliorate symptoms. Ramelteon is a potent melatonin receptor agonist. In this report, two patients with KLS are described with apparent resolution of hypersomnia episodes following ramelteon initiation. CITATION: Dominguez D, Rudock R, Tomko S, Pathak S, Mignot E, Licis A. Apparent resolution of hypersomnia episodes in two patients with Kleine-Levin syndrome following treatment with the melatonin receptor agonist ramelteon. J Clin Sleep Med. 2024;20(4):657-662. © 2024 American Academy of Sleep Medicine.
Author Keywords
hypersomnia; Kleine–Levin syndrome; melatonin; pharmacology; ramelteon
Document Type: Article
Publication Stage: Final
Source: Scopus
Patient and caregiver perceptions of Chiari malformation: a qualitative analysis of online discussion boards
(2024) Journal of Neurosurgery: Pediatrics, 33 (4), pp. 382-389.
Koller, G.M., Kann, M.R., Pugazenthi, S., Koneru, S., Bhavsar, S., Strahle, J.M.
Department of Neurosurgery, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
OBJECTIVE Patients and their caregivers utilize online discussion board forums as a means to seek and exchange information about their or a loved one’s condition. It is important for providers to be aware of such concerns and experiences. The goal of this study was to identify the primary concerns expressed on these discussion boards regarding Chiari malformation type I (CM) and to help guide clinicians in understanding patient challenges in the treatment of CM. METHODS The authors performed thematic analysis of anonymous online discussion board posts as identified through internet search engines. They then adopted a previously developed grounded theory method that utilizes a three-tiered coding and grouping process of posts based on commonly discovered content themes. RESULTS Analysis of 400 discussion board posts identified four distinct themes raised by CM patients and their caregivers: the path to diagnosis, symptoms experienced, surgical intervention, and high emotional burden. Although each individual experience was unique, the path toward a CM diagnosis was expressed as a journey involving multiple physicians, alternative diagnoses, and feelings of dismissal from providers. The most common reported symptoms included dizziness, headaches, neck and back pain, sensory issues, weakness and paresthesias of the extremities, speech issues, and general fatigue. Additionally, there was an overall sense of uncertainty from patients seeking advice regarding surgical intervention, with users expressing diverse sentiments that included both positive and negative outcomes regarding surgical treatment. Lastly, a wide range of emotions was expressed related to a CM diagnosis, including concern, worry, anxiety, depression, stress, fear, and frustration. CONCLUSIONS CM is a frequent imaging diagnosis identified in patients presenting with a wide range of symptoms, and as a result this leads to a diverse set of patient experiences. Analysis of CM patient and caregiver discussion boards revealed key themes that clinicians may address when counseling for CM. © 2024 American Association of Neurological Surgeons. All rights reserved.
Author Keywords
Chiari malformation; congenital; discussion boards; patient experience; thematic analysis
Document Type: Article
Publication Stage: Final
Source: Scopus
Neurologic Statistical Prognostication and Risk Assessment for Kids on Extracorporeal Membrane Oxygenation – Neuro SPARK
(2024) ASAIO Journal, 70 (4), pp. 305-312.
Shah, N.a , Mathur, S.b , Shanmugham, P.c , Li, X.d , Thiagarajan, R.R.e , Natarajan, S.b , Raman, L.f
a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
b Department of Computer Science, University of Texas at Dallas, Richardson, TX, United States
c Department of Pediatrics, Joe DiMaggio Children’s Hospital, Hollywood, FL, United States
d Department of Population and Data Science, University of Texas Southwestern Medical Center, Dallas, TX, United States
e Department of Cardiology, Boston Children’s Hospital, Boston, MA, United States
f Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
Abstract
This study presents Neuro-SPARK, the first scoring system developed to assess the risk of neurologic injury in pediatric and neonatal patients on extracorporeal membrane oxygenation (ECMO). Using the extracorporeal life support organization (ELSO) registry, we applied robust machine learning methodologies and clinical expertise to a 10 years dataset. We produced separate models for veno-venous (V-V ECMO) and veno-arterial (V-A ECMO) configurations due to their different risk factors and prevalence of neurologic injury. Our models identified 14 predictor variables for V-V ECMO and 20 for V-A ECMO, which demonstrated moderate accuracy in predicting neurologic injury as defined by the area under the receiver operating characteristic (AUROC) (V-V = 0.63, V-A = 0.64) and good calibration as measured by the Brier score (V-V = 0.1, V-A = 0.15). Furthermore, our post-hoc analysis identified high- and low-risk groups that may aid clinicians in targeted neuromonitoring and guide future research on ECMO-associated neurologic injury. Despite the inherent limitations, Neuro-SPARK lays the foundation for a risk-assessment tool for neurologic injury in ECMO patients, with potential implications for improved patient outcomes. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
extracorporeal life support; machine learning; neurologic injury; pediatrics; prediction
Funding details
Extracorporeal Life Support OrganizationELSO
Document Type: Article
Publication Stage: Final
Source: Scopus
The response of Dual-leucine zipper kinase (DLK) to nocodazole: Evidence for a homeostatic cytoskeletal repair mechanism
(2024) PLoS ONE, 19 (4 April), art. no. e0300539, .
DeVault, L.a , Mateusiak, C.b c , Palucki, J.a , Brent, M.b c , Milbrandt, J.b d , DiAntonio, A.a d
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MI, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MI, United States
c Department of Computer Science & Engineering, Washington University, St. Louis, MO, United States
d Needleman Center for Neurometabolism and AxonalTherapeutics, Washington University School of Medicine, St. Louis, MI, United States
Abstract
Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNAseq. This signature includes genes likely to attenuate DLK signaling while simultaneously inducing actin regulating genes. We identify alterations to the cytoskeleton including actinbased morphological changes to the axon. These results are consistent with the model that cytoskeletal disruption in the neuron induces a DLK-dependent homeostatic mechanism, which we term the Cytoskeletal Stress Response (CSR) pathway. © 2024 Public Library of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study
(2024) Neurology, 102 (3), p. e208077.
Madsen, T.E., Ding, L., Khoury, J.C., Haverbusch, M., Woo, D., Ferioli, S., De Los Rios La Rosa, F., Martini, S.R., Adeoye, O., Khatri, P., Flaherty, M.L., Mackey, J., Mistry, E.A., Demel, S., Coleman, E., Jasne, A., Slavin, S., Walsh, K.B., Star, M., Broderick, J.P., Kissela, B., Kleindorfer, D.O.
From the Department of Emergency Medicine (T.E.M.), Alpert Medical School of Brown University; Department of Epidemiology (T.E.M.), Brown University School of Public Health, Providence, RI; Division of Biostatistics and Epidemiology (L.D., J.C.K.), Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati; Department of Neurology and Rehabilitation Medicine (M.H., D.W., S.F., F.D.L.R.L.R., P.K., M.L.F., E.A.M., S.D., K.B.W., J.P.B., B.K., D.O.K.), University of Cincinnati College of Medicine; UC Gardner Neuroscience Institute (S.F., P.K., M.L.F., E.A.M., S.D., K.B.W., J.P.B., B.K., D.O.K.), Cincinnati, OH; Miami Neuroscience Institute (F.D.L.R.L.R.), Baptist Health South Florida, FL; Neurology Program (S.R.M.), Veterans Health Administration and Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Emergency Medicine (O.A.), Washington University, St. Louis, MO; Department of Neurology (J.M.), Indiana University School of Medicine, Indianapolis; Department of Neurology (E.C.), University of Chicago, IL; Department of Neurology (A.J.), Yale School of Medicine, New Haven, CT; University of Kansas Medical Center (S.S.), Kansas City; Soroka Medical Center (M.S.), Beersheba, Israel; and Department of Neurology (D.O.K.), University of Michigan, Ann Arbor
Abstract
BACKGROUND AND OBJECTIVES: Understanding the current status of and temporal trends of stroke epidemiology by age, race, and stroke subtype is critical to evaluate past prevention efforts and to plan future interventions to eliminate existing inequities. We investigated trends in stroke incidence and case fatality over a 22-year time period. METHODS: In this population-based stroke surveillance study, all cases of stroke in acute care hospitals within a 5-county population of southern Ohio/northern Kentucky in adults aged ≥20 years were ascertained during a full year every 5 years from 1993 to 2015. Temporal trends in stroke epidemiology were evaluated by age, race (Black or White), and subtype (ischemic stroke [IS], intracranial hemorrhage [ICH], or subarachnoid hemorrhage [SAH]). Stroke incidence rates per 100,000 individuals from 1993 to 2015 were calculated using US Census data and age-standardized, race-standardized, and sex-standardized as appropriate. Thirty-day case fatality rates were also reported. RESULTS: Incidence rates for stroke of any type and IS decreased in the combined population and among White individuals (any type, per 100,000, 215 [95% CI 204-226] in 1993/4 to 170 [95% CI 161-179] in 2015, p = 0.015). Among Black individuals, incidence rates for stroke of any type decreased over the study period (per 100,000, 349 [95% CI 311-386] in 1993/4 to 311 [95% CI 282-340] in 2015, p = 0.015). Incidence of ICH was stable over time in the combined population and in race-specific subgroups, and SAH decreased in the combined groups and in White adults. Incidence rates among Black adults were higher than those of White adults in all time periods, and Black:White risk ratios were highest in adults in young and middle age groups. Case fatality rates were similar by race and by time period with the exception of SAH in which 30-day case fatality rates decreased in the combined population and White adults over time. DISCUSSION: Stroke incidence is decreasing over time in both Black and White adults, an encouraging trend in the burden of cerebrovascular disease in the US population. Unfortunately, however, Black:White disparities have not decreased over a 22-year period, especially among younger and middle-aged adults, suggesting the need for more effective interventions to eliminate inequities by race.
Document Type: Article
Publication Stage: Final
Source: Scopus
Melatonin-mediated corrective changes in gut microbiota of experimentally chronodisrupted C57BL/6J mice
(2024) Chronobiology International, .
Vohra, A.a b , Karnik, R.a c , Desai, M.d , Vyas, H.e , Kulshrestha, S.a , Upadhyay, K.K.e , Koringa, P.d , Devkar, R.a
a Division of Chronobiology and Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
b Department of Neurology, School of Medicine, Washington University, St. Louis, MO, United States
c Dr Vikram Sarabhai Institute of Cell and Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
d Department of Animal Biotechnology, College of Veterinary Sciences & A.H, Anand Agricultural University, Anand, India
e Department of Internal Medicine, Division of Gastroenterology & Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States
Abstract
Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny. © 2024 Taylor & Francis Group, LLC.
Author Keywords
chronodisruption; gut microbiota; high fat-high fructose diet; inflammation; Melatonin; photoperiod
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Blood-Based Proteomics for Adult-Onset Focal Dystonias
(2024) Annals of Neurology, .
Timsina, J.a b , Dinasarapu, A.c , Kilic-Berkmen, G.c , Budde, J.a b , Sung, Y.J.a b d , Klein, A.M.e , Cruchaga, C.a b f , Jinnah, H.A.c g
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, United States
f Hope Center for Neurologic Diseases, Washington University in St. Louis, St. Louis, MO, United States
g Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Objectives: The adult-onset focal dystonias are characterized by over-active muscles leading to abnormal movements. For most cases, the etiology and pathogenesis remain unknown. In the current study, unbiased proteomics methods were used to identify potential changes in blood plasma proteins. Methods: A large-scale unbiased proteomics screen was used to compare proteins (N = 6,345) in blood plasma of normal healthy controls (N = 49) with adult-onset focal dystonia (N = 143) consisting of specific subpopulations of cervical dystonia (N = 45), laryngeal dystonia (N = 49), and blepharospasm (N = 49). Pathway analyses were conducted to identify relevant biological pathways. Finally, protein changes were used to build a prediction model for dystonia. Results: After correction for multiple comparisons, 15 proteins were associated with adult-onset focal dystonia. Subgroup analyses revealed some proteins were shared across the dystonia subgroups while others were unique to 1 subgroup. The top biological pathways involved changes in the immune system, metal ion transport, and reactive oxygen species. A 4-protein model showed high accuracy in discriminating control individuals from dystonia cases [average area under the curve (AUC) = 0.89]. Interpretation: These studies provide novel insights into the etiopathogenesis of dystonia, as well as novel potential biomarkers. ANN NEUROL 2024. © 2024 American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration
(2024) JAMA Network Open, p. E244266.
Staffaroni, A.M.a , Clark, A.L.a , Taylor, J.C.a , Heuer, H.W.a , Sanderson-Cimino, M.a , Wise, A.B.a , Dhanam, S.a , Cobigo, Y.a , Wolf, A.a , Manoochehri, M.b , Forsberg, L.c , Mester, C.d , Rankin, K.P.a , Appleby, B.S.e , Bayram, E.f , Bozoki, A.g , Clark, D.h , Darby, R.R.i , Domoto-Reilly, K.j , Fields, J.A.k , Galasko, D.f , Geschwind, D.l , Ghoshal, N.m n , Graff-Radford, N.o , Grossman, M.p , Hsiung, G.-Y.q , Huey, E.D.b , Jones, D.T.d , Lapid, M.I.k , Litvan, I.f , Masdeu, J.C.r , Massimo, L.p , Mendez, M.F.s , Miyagawa, T.c , Pascual, B.r , Pressman, P.t , Ramanan, V.K.c , Ramos, E.M.u , Rascovsky, K.p , Roberson, E.D.v , Tartaglia, M.C.w , Wong, B.x , Miller, B.L.a , Kornak, J.y , Kremers, W.d , Hassenstab, J.m z , Kramer, J.H.a , Boeve, B.F.c , Rosen, H.J.a , Boxer, A.L.a
a Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, United States
b Department of Neurology, Columbia University, New York, NY, United States
c Department of Neurology, Mayo Clinic, Rochester, MN, United States
d Department of Quantitative Health Sciences, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
e Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
f Department of Neurosciences, University of California, San Diego, San Diego, United States
g Department of Radiology, University of North Carolina, Chapel Hill, United States
h Department of Neurology, Indiana University, Indianapolis, United States
i Department of Neurology, Vanderbilt University, Nashville, TN, United States
j Department of Neurology, University of Washington, Seattle, United States
k Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
l Department of Neurology, Institute for Precision Health, University of California, Los Angeles, United States
m Department of Neurology, Knight Alzheimer Disease Research Center, Washington University, Saint Louis, MO, United States
n Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University, Saint Louis, MO, United States
o Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
p Department of Neurology, University of Pennsylvania Perelman, School of Medicine, Philadelphia, United States
q Division of Neurology, University of British Columbia, Musqueam, Squamish & Tsleil-Waututh Traditional Territory, Vancouver, Canada
r Department of Neurology, Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston Methodist, Houston, TX, United States
s Department of Neurology, UCLA (University of California, Los Angeles), United States
t Department of Neurology, University of Colorado, Aurora, United States
u Department of Neurology, David Geffen School of Medicine, UCLA, United States
v Department of Neurology, University of Alabama, Birmingham, United States
w Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, ON, Canada
x Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, United States
y Department of Epidemiology and Biostatistics, University of California, San Francisco, United States
z Department of Psychological & Brain Sciences, Washington University, Saint Louis, MO, United States
Abstract
Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P =.01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = -0.49 [95% CI, -0.72 to -0.25]; P <.001) but not a composite of traditional neuropsychological measures (β = -0.14 [95% CI, -0.42 to 0.14]; P =.32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.. © 2024 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals
(2024) eBioMedicine, art. no. 105086, .
Jennings, M.V.a , Martínez-Magaña, J.J.b , Courchesne-Krak, N.S.a , Cupertino, R.B.a , Vilar-Ribó, L.c i j , Bianchi, S.B.a , Hatoum, A.S.d , Atkinson, E.G.e , Giusti-Rodriguez, P.g , Montalvo-Ortiz, J.L.b f , Gelernter, J.h p , Artigas, M.S.c i j k , Aslibekyan, S.q , Auton, A.q , Babalola, E.q , Bell, R.K.q , Bielenberg, J.q , Bryc, K.q , Bullis, E.q , Coker, D.q , Partida, G.C.q , Dhamija, D.q , Das, S.q , Elson, S.L.l q , Eriksson, N.q , Filshtein, T.q , Fitch, A.q , Fletez-Brant, K.q , Fontanillas, P.l q , Freyman, W.q , Granka, J.M.q , Heilbron, K.q , Hernandez, A.q , Hicks, B.q , Hinds, D.A.q , Jewett, E.M.q , Jiang, Y.q , Kukar, K.q , Kwong, A.q , Lin, K.-H.q , Llamas, B.A.q , Lowe, M.q , McCreight, J.C.q , McIntyre, M.H.q , Micheletti, S.J.q , Moreno, M.E.q , Nandakumar, P.q , Nguyen, D.T.q , Noblin, E.S.q , O’Connell, J.q , Petrakovitz, A.A.q , Poznik, G.D.q , Reynoso, A.q , Schumacher, M.q , Shastri, A.J.q , Shelton, J.F.q , Shi, J.q , Shringarpure, S.q , Su, Q.J.q , Tat, S.A.q , Tchakouté, C.T.q , Tran, V.q , Tung, J.Y.q , Wang, X.q , Wang, W.q , Weldon, C.H.q , Wilton, P.q , Wong, C.D.q , Edenberg, H.J.m , Palmer, A.A.a n , Sanchez-Roige, S.a n o , 23andMe, Inc. Research Teamr
a Department of Psychiatry, University of California San Diego, La JollaCA, United States
b Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, Orange, West Haven, CT, United States
c Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
d Department of Psychology & Brain Sciences, Washington University in St. Louis, St Louis, MO, United States
e Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
f National Center of Posttraumatic Stress Disorder, VA CT Healthcare Center, West Haven, CT, United States
g Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States
h VA CT Healthcare Center, Department Psychiatry, West Haven, CT, United States
i Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona, Spain
j Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain
k Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
l 23andMe, Inc., Sunnyvale, CA, United States
m Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
n Institute for Genomic Medicine, University of California San Diego, La JollaCA, United States
o Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, United States
p Departments Psychiatry, Genetics, and Neuroscience, Yale Univ. School of Medicine, New Haven, CT, United States
Abstract
Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. Findings: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. Interpretation: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. Funding: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128). © 2024 The Authors
Author Keywords
ADH1B; ADH1C; Alcohol; Metabolising enzyme genes; PheWAS; rs1229984
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database
(2024) Therapeutic Advances in Neurological Disorders, 17, .
Shirani, A.a , Cross, A.H.b , Stuve, O.c
a Department of Neurological Sciences, University of Nebraska Medical Center, Nebraska Medical Center, 988440, Omaha, NE 68198-8440, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurology, University of Texas Southwestern Medical Center, Dallas VA Medical Center, Dallas, TX, United States
Abstract
Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132–0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109–0.248), liraglutide (ROR: 0.161; 95% CI: 0.091–0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146–0.377), and metformin (ROR: 0.387; 95% CI: 0.340–0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384–0.806). Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies. © The Author(s), 2024.
Author Keywords
disproportionality analysis; FDA Adverse Event Reporting System database; glucagon-like peptide-1 receptor agonists; multiple sclerosis; weight loss-inducing drugs
Document Type: Article
Publication Stage: Final
Source: Scopus
Children with non-central nervous system tumors treated with platinum-based chemotherapy are at risk for hearing loss and cognitive impairments
(2024) Frontiers in Pediatrics, 12, art. no. 1341762, .
L’Hotta, A.J.a , Spence, A.b , Varughese, T.E.b , Felts, K.b , Hayashi, S.S.b , Jones-White, M.b , LaFentres, E.b , Lieu, J.E.C.c , Hayashi, R.J.b , King, A.A.b
a Brown School, Prevention Research Center, Washington University in St. Louis, St. Louis, MO, United States
b Department of Pediatrics, Division of Pediatric Hematology Oncology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Otolaryngology, Division of Pediatric Otolaryngology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Childhood cancer survivors (CCS) with chemotherapy induced sensorineural hearing loss (SNHL) are at risk for neurocognitive impairments. The purpose of this study was to determine the relationship between SNHL and cognitive function among CCS. Procedure: Inclusion: non-CNS solid tumor diagnosis; history of platinum chemotherapy (cisplatin and/or carboplatin); 8–17 years of age; off anti-cancer treatment for ≥6 months; and English speaking. Exclusion: history of intrathecal chemotherapy, cranial radiation, or baseline neurocognitive disorder. Participants completed the NIH Toolbox Cognition Battery at enrollment. T-tests were used to compare participants with normal hearing to those with hearing loss and the total sample with established Toolbox normative data (mean: 50; SD: 10). Results: Fifty-seven individuals enrolled; 52 completed full cognitive testing. Participants were on average 12.2 years of age and 7.0 years since treatment completion. Twenty-one participants (40%) received cisplatin, 27 (52%) carboplatin, and 4 (8%) received both. Fifteen participants (29%) demonstrated SNHL based on the better ear. CCS, regardless of the presence or absence of SNHL, demonstrated significantly lower mean cognitive skills compared to the normative sample in attention, executive function, language- vocabulary and oral reading, processing speed, and fluid, crystallized and total composite scores (all p < 0.01). Participants with SNHL had significantly lower crystallized composite (vocabulary, oral reading) than those with normal hearing (41.9 vs. 47.2, p < 0.05, Cohen’s d = 0.62). Conclusions: CCS at risk for platinum induced hearing loss but without cranial radiation or intrathecal chemotherapy exposure demonstrate impaired cognitive skills and those with SNHL demonstrate lower crystallized composite scores. 2024 L’Hotta, Spence, Varughese, Felts, Hayashi, Jones-White, LaFentres, Lieu, Hayashi and King.
Author Keywords
cancer survivor child; chemotherapy-related cognitive impairment; cognition; hearing loss; solid tumor
Document Type: Article
Publication Stage: Final
Source: Scopus
Assessment of COVID-19 Messaging Strategies to Increase Testing for Students With Intellectual and Developmental Disabilities
(2024) Journal of School Health, .
Walsh, T.J.a , Kalb, L.G.b , Gemmell, M.a , Liu, J.c , Caburnay, C.A.d , Gurnett, C.A.e , Newland, J.G.a
a Department of Pediatrics, Division of Pediatric Infectious Diseases, Washington University in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
b Kennedy Krieger Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 3901 Greenspring Ave, Baltimore, MD 21211, United States
c Department of Surgery, Washington University in St. Louis, 4921 Parkview Pl, St. Louis, MO 63110, United States
d Brown School of Social Work, Washington University in St. Louis, 6350 Forsyth Blvd, St. Louis, MO 63105, United States
e Department of Neurology, Division of Pediatric and Developmental Neurology, Washington University in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
Abstract
Background: Students with intellectual and developmental disabilities (IDD) were disproportionately impacted by the COVID-19 pandemic. This study’s goal was to assess the effectiveness of 2 messaging strategies on participation in SARS-CoV-2 weekly testing. Methods: Cluster randomized trials were conducted at 2 school systems, the special school district (SSD) and Kennedy Krieger Institute (Kennedy) to assess messaging strategies, general versus enhanced, to increase weekly screening for SARS-CoV-2. Testing was offered to staff and students from November 23, 2020 to May 26, 2022. The primary outcomes were percentage of students and staff consented weekly and percentage of study participants who had a test performed weekly. Generalized estimating equation models were utilized to evaluate the primary outcomes. Results: Increases in enrollment and testing occurred during study start up, the beginning of school years, and following surges in both systems. No statistical difference was observed in the primary outcomes between schools receiving standard versus enhanced messaging. Implications for School Health Policy, Practice, and Equity: Frequent and consistent communication is vital for families and staff. Weekly screening testing within schools is possible and highlighted the importance of utilizing equitable protocols to provide important testing to students with IDD. Conclusion: Enhanced messaging strategies did not increase the number of participants enrolled or the percentage of enrolled participants being tested on a weekly basis. © 2024 The Authors. Journal of School Health published by Wiley Periodicals LLC on behalf of American School Health Association.
Author Keywords
communication strategies; COVID-19; infectious diseases; intellectual and developmental disabilities; public health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Theoretical relationships between axoneme distortion and internal forces and torques in ciliary beating
(2024) Cytoskeleton, .
Woodhams, L.G., Bayly, P.V.
Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
Abstract
The axoneme is an intricate nanomachine responsible for generating the propulsive oscillations of cilia and flagella in an astonishing variety of organisms. New imaging techniques based on cryoelectron-tomography (cryo-ET) and subtomogram averaging have revealed the detailed structures of the axoneme and its components with sub-nm resolution, but the mechanical function of each component and how the assembly generates oscillations remains stubbornly unclear. Most explanations of oscillatory behavior rely on the dynamic regulation of dynein by some signal, but this may not be necessary if the system of dynein-driven slender filaments is dynamically unstable. Understanding the possibility of instability-driven oscillations requires a multifilament model of the axoneme that accounts for distortions of the axoneme as it bends. Active bending requires forces and bending moments that will tend to change the spacing and alignment of doublets. We hypothesize that components of the axoneme resist and respond to these loads in ways that are critical to beating. Specifically, we propose (i) that radial spokes provide torsional stiffness by resisting misalignment (as well as spacing) between the central pair and outer doublets, and (ii) that the kinematics of dynein arms affect the relationships between active forces and bending moments on deforming doublets. These proposed relationships enhance the ability of theoretical, multifilament models of axonemal beating to generate propulsive oscillatory waveforms via dynamic mechanical instability. © 2024 Wiley Periodicals LLC.
Author Keywords
axoneme; cilia; mathematical modeling; waveform
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Contribution of Nutritional, Lifestyle, and Metabolic Risk Factors to Parkinson’s Disease
(2024) Movement Disorders, .
Veronese, N.a , Nova, A.b , Fazia, T.b , Riggi, E.b , Yang, L.c d , Piccio, L.e f g , Huang, B.-H.e h , Ahmadi, M.e , Barbagallo, M.a , Notarnicola, M.i , Giannelli, G.i , De Pergola, G.i , Stamatakis, E.e , Cereda, E.j k , Bernardinelli, L.b , Fontana, L.e l
a Geriatric Unit, Department of Internal Medicine and Geriatrics, University of Palermo, Palermo, Italy
b Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
c Cancer Epidemiology and Prevention Research Alberta Health Services–Cancer Care Alberta, Calgary, AB, Canada
d Departments of Oncology and Community Health Sciences, University of Calgary, Calgary, AB, Canada
e Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
f Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
g Department of Neurology, Washington University, St. Louis, MO, United States
h School of Public Health, Faculty of Health, University of Technology Sydney, Sydney, New South Wales, Australia
i National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Castellana Grotte, Italy
j Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
k Fondazione Grigioni per il Morbo di Parkinson, Milan, Italy
l Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Abstract
Background: Modifiable risk factors for Parkinson’s disease (PD) are poorly known. Objectives: The aim is to evaluate independent associations of different nutritional components, physical activity, and sedentary behavior and metabolic factors with the risk of PD. Methods: In this population-based prospective cohort study using the data of the United Kingdom Biobank (from 2006–2010), 502,017 men and women who were free from PD (International Classification of Diseases 10th edition; “G20”) at baseline were included. We implemented a Cox proportion hazard’s model to evaluate the associations of different levels of physical activity, sitting time, sleep habits, diet quality, alcohol and coffee consumption, smoking, and body mass index with PD risk, adjusting for several confounding variables. Results: During a median follow-up of 12.8 years, lifestyle factors including vigorous physical activity (hazard ration [HR] = 0.84; 95% confidence interval [CI], 0.75–0.94), low-to-moderate sitting time (HR = 0.89; 95% CI, 0.81–0.97), and high sleep quality (HR = 0.89; 95% CI, 0.80–0.99) were associated with a reduced risk of PD. Small amounts of coffee (HR = 0.88; 95% CI, 0.82–0.95), red meat (HR = 0.86; 95% CI, 0.76–0.97), and current smoking (HR = 0.65; 95% CI, 0.56–0.75) were also associated with a lower risk of PD, whereas alcohol intake (HR = 1.29; 95% CI, 1.06–1.56) with higher PD risk. Secondary analysis, including metabolic risk factors, confirmed these findings and highlighted the potential protective effect of plasma vitamin D and uric acid, but of low-density lipoprotein-cholesterol, triglycerides, and C-reactive protein as well. Conclusions: Vigorous physical activity, reduced sitting time, good sleep quality together with small coffee intake and vitamin D supplementation are potentially neuroprotective lifestyle interventions for the prevention of PD. © 2024 International Parkinson and Movement Disorder Society. © 2024 International Parkinson and Movement Disorder Society.
Author Keywords
Parkinson’s disease; UKBB
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A qualitative analysis of patient and caregiver experiences with myelomeningocele through online discussion boards
(2024) Child’s Nervous System, .
Koneru, S.a , Bhavsar, S.a , Pugazenthi, S.a , Koller, G.M.a , Karuparti, S.a , Kann, M.R.b , Strahle, J.M.a
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Abstract
Purpose: Patients and caregivers impacted by myelomeningocele (MMC) use online discussion board forums to create community and share information and concerns about this complex medical condition. We aim to identify the primary concerns expressed on these forums with the goal of understanding gaps in care that may merit investment of resources to improve care received by this population. Methods: Anonymous posts from online MMC discussion boards were compiled using internet search engines. Posts were then analyzed using an adaptation of the Grounded Theory Method, a three-step system involving open, axial, and selective coding of the data by two independent researchers to identify common themes. Results: Analysis of 400 posts written primarily by parents (n = 342, 85.5%) and patients (n = 45, 11.25%) yielded three overarching themes: questions surrounding quality of life, a lack of support for mothers of children with MMC, and confusion with a complex healthcare system. Many posts revealed concerns about management and well-being with MMC, including posts discussing symptoms and related conditions (n = 299, 75.75%), treatments (n = 259, 65.75%), and emotional aspects of MMC (n = 146, 36.5%). Additionally, families, especially mothers, felt a lack of support in their roles as caregivers. Finally, in 118 posts (29.5%), patients and families expressed frustration with navigating a complex healthcare system and finding specialists whose opinions they trusted. Conclusions: MMC is a complex medical condition that impacts patients and families in unique ways. Analysis of online discussion board posts identified key themes to be addressed in order to improve the healthcare experiences of those impacted by MMC. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Author Keywords
Caregiver experience; Discussion boards; Myelomeningocele; Patient experience; Thematic analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Use and Co-Use of Alcohol and Cannabis Following Physical Pain in the Daily Life of Community Adults Engaged in Regular Substance Use
(2024) Psychology of Addictive Behaviors, .
Carpenter, R.W.a , Nance, M.a , Frumkin, M.R.b , Boissoneault, J.c , Ellingson, J.M.d
a Department of Psychological Sciences, University of Missouri—St. Louis, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
c Department of Anesthesiology, University of Minnesota, United States
d Department of Psychiatry, University of Colorado School of Medicine, United States
Abstract
Objective: Alcohol and cannabis are often perceived as pain-relieving. However, minimal work has examined whether people use and co-use these substances following pain in daily life. Method: Forty-six adults reporting weekly use of alcohol and/or cannabis completed a 60-day ecological momentary assessment protocol, answering at least four daily reports on their alcohol and cannabis use and pain (nassessments = 10,769 over 2,656 days). We examined whether self-reported pain so far that day (cumulativeaverage pain) was associated with subsequent alcohol and cannabis use and same-occasion co-use. Models also addressed whether associations differed for initiating versus continuing a use episode. Hypotheses were preregistered. Results: A multinomial multilevel model found that cumulative-average pain was associated with a greater likelihood of same-occasion co-use in the continuation phase but not the initiation phase, compared to no use (OR = 1.48,95% CI [1.06, 2.06], p =.023) and alcohol use (OR = 1.52, CI [1.03, 2.26], p =.037). Cumulative-average pain was largely not associated with alcohol-only and cannabis-only use. After alcohol use, greater pain was associated with cannabis use (OR = 1.37, CI [1.11, 1.70], p =.004), but not the reverse. Secondary analyses found greater previous-occasion (not cumulative) pain was associated with initiation of alcohol use and number of drinks, and initiation and continuation of cannabis use, but not number of cannabis hits. Conclusions: Although not all hypotheses were supported, pain was associated with subsequent substance use in this sample engaged in regular substance use and not recruited for chronic pain. Cumulative pain may be particularly related to alcohol–cannabis same-occasion co-use, which may increase the risk of substance use-related problems over time. © 2024 American Psychological Association
Author Keywords
alcohol use; alcohol–cannabis co-use; cannabis use; ecological momentary assessment; physical pain
Funding details
National Institute on Alcohol Abuse and AlcoholismNIAAAK23 AA026635, K23 AA029729
1100101
National Institute of Mental HealthNIMHF31 MH124291, R01 AA025337
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Disparities in Mental Health Symptoms Among Sexual and Gender Diverse Subgroups in a National Sample of College Students
(2024) Psychology of Sexual Orientation and Gender Diversity, .
Vázquez, M.M.a , Fowler, L.A.a , Zhu, Y.b , Grammer, A.C.a , Fitzsimmons-Craft, E.E.a , Lipson, S.K.c , Shah, J.a , Eisenberg, D.d , Newman, M.G.e , Taylor, C.B.f g , Wilfley, D.E.a
a Department of Psychiatry, Washington University School of Medicine in St. Louis, United States
b Department of Psychology, Washington University in St. Louis, United States
c Department of Health Law Policy and Management, Boston University School of Public Health, United States
d Department of Health Policy and Management, University of California, Los Angeles Fielding School of Public Health, United States
e Department of Psychology, The Pennsylvania State University, United States
f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
g Center for m2Health, Palo Alto University, United States
Abstract
Mental health disparities experienced by sexual and gender diverse (SGD) young adults are well documented. Yet, few studies have examined mental health disparities between SGD subgroups. Even fewer have investigated disparities that may exist for individuals whose SGD identities are nonmonosexual (i.e., diverse sexual orientations besides gay/lesbian) or gender nonbinary, who may experience exacerbated marginalization and disparities. The present study examines differences in weight and shape concerns and symptoms of depression, anxiety (general, panic, social, and posttraumatic stress), alcohol use disorder, and insomnia among sexually diverse (SD) subgroups (lesbian or gay, bisexual, queer, asexual, pansexual, multiple identities, and questioning), and gender diverse (GD) subgroups (trans man, trans woman, and nonbinary) of college students. We hypothesized that nonmonosexual students would have a greater mental health symptom burden than their monosexual peers and we explored additional subgroup differences among SD and GD subgroups separately. Kruskal–Wallis tests with Mann–Whitney U post hoc tests were conducted to examine associations between mental health symptoms and sexual orientation and gender identity separately. Results show high mental health symptom levels among most subgroups. Some nonmonosexual SD subgroups were at particularly high risk; namely, pansexual students. Questioning and asexual SD subgroups had similar and lower symptom levels than their monosexual peers, respectively. SD subgroup disparities varied by mental health symptom type. No significant differences by GD subgroups were found. Clinicians and institutions should consider these disparities and future research should aim to better understand them. © 2024 American Psychological Association
Author Keywords
gender identity; mental health; nonbinary; nonmonosexual; sexual orientation
Funding details
National Institute on Minority Health and Health DisparitiesNIMHD
National Institutes of HealthNIHK01MD017630
National Institute of Mental HealthNIMHR01MH115128-02S1, K08MH120341
National Heart, Lung, and Blood InstituteNHLBIK01MH121515, F31HL158000
William T. Grant FoundationWTGFNCT04162847
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex
(2024) Journal of Neurology, .
Makhani, N.a b , Lebrun-Frenay, C.c , Siva, A.d , Shabanova, V.a , Wassmer, E.e , Santoro, J.D.f g , Narula, S.h , Brenton, J.N.i , Mar, S.j , Durand-Dubief, F.k , Zephir, H.l , Mathey, G.m , Rojas, J.I.n , de Seze, J.o , Tenembaum, S.p , Stone, R.T.q , Casez, O.r s , Carra-Dallière, C.t u , Neuteboom, R.F.v , Ahsan, N.f g , Arroyo, H.A.w , Cabre, P.x , Gombolay, G.y , Inglese, M.z aa , Louapre, C.ab , Margoni, M.ac , Palavra, F.ad , Pohl, D.ae , Reich, D.S.af , Ruet, A.ag ah , Thouvenot, E.ai aj , Timby, N.ak , Tintore, M.al , Uygunoglu, U.d , Vargas, W.am , Venkateswaran, S.ae , Verhelst, H.an , Wickstrom, R.ao , Azevedo, C.J.f , Kantarci, O.ap , Shapiro, E.D.a , Okuda, D.T.aq , Pelletier, D.f
a Department of Pediatrics, Yale University, LMP 3088, 333 Cedar Street, New Haven, CT 06520, United States
b Department of Neurology, Yale University, New Haven, CT, United States
c CRCSEP Neurologie Pasteur 2, CHU de Nice, Université Cote d’Azur, UMR2CA (URRIS), Nice, France
d Neuroimmunology Unit, Neurology Department, Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
e Neurology Department, Birmingham Children’s Hospital, Aston University, Birmingham, United Kingdom
f Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, United States
g Division of Neurology, Department of Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, United States
h Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, United States
i Department of Neurology, University of Virginia, Charlottesville, United States
j Department of Neurology, Washington University School of Medicine, St. Louis, United States
k Service de sclérose en plaques, Pathologies de la myéline et Neuro-Inflammation, Hôpital Neurologique, Groupement Hospitalier Est, 59 Bd Pinel, BRON Cedex, 69677, France
l Inserm UMR-S 1172 LilNcog, Lille University Hospital FHU Precise, Lille University, Lille, France
m Department of Neurology, Nancy University Hospital, Nancy, 54035, France
n Hospital Universitario de CEMIC, Buenos Aires, Argentina
o Department of Neurology, Hospital Hautepierre, CHU de Strasbourg and Clinical Investigation Center (CIC) INSERM 1434, Strasbourg, France
p Department of Neurology, National Pediatric Hospital Dr. Juan P Garrahan, Buenos Aires, Argentina
q Department of Neurology, University of Rochester Medical Center, Rochester, United States
r Neurology MS Clinic Grenoble, Grenoble Alpes University Hospital, Grenoble, France
s T-RAIG, TIMC-IMAG, Grenoble Alpes University, Grenoble, France
t Neurology MS Clinic, Montpellier University Hospital, Montpellier, 34295, France
u University of Montpellier (MUSE), Montpellier, 34295, France
v Department of Neurology, Erasmus MC Rotterdam, Sophia’s Children’s Hospital, Rotterdam, Netherlands
w Department of Neurology, Hospital de Pediatría SAMIC. Prof. Dr. J.P. Garrahan, Buenos Aires, Argentina
x Centre Hospitalo Universitaire, Fort-de-France, Martinique
y Division of Neurology, Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, United States
z Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health Department of Neuroscience (DINOGMI), University of Genova, Genoa, Italy
aa IRCCS Ospedale Policlinico San Martino, Genoa, Italy
ab Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, CIC Neurosciences, Sorbonne Université, Paris Brain Institute – ICM, Paris, France
ac Department of Neurosciences, Multiple Sclerosis Center of the Veneto Region, University Hospital-School of Medicine, Padua, Italy
ad Center for Child Development – Neuropaediatrics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
ae Division of Neurology, Children’s Hospital of Eastern Ontario, Ottawa, Canada
af Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
ag Department of Neurology, CHU Bordeaux, Bordeaux, France
ah INSERM, Neurocentre Magendie, University of Bordeaux, Bordeaux, U1215, France
ai Department of Neurology, Nîmes University Hospital, Nîmes, France
aj IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
ak Department of Clinical Sciences/Pediatrics, Umeå University, Umeå, Sweden
al Neurology Department, MS Center of Catalunya Cemcat, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona (UAB), UVIC-Universitat Central de Catalunya, Barcelona, Spain
am Department of Neurology, Columbia University Medical Center, New York, United States
an Division of Pediatric Neurology, Department of Pediatrics, University Hospital Ghent, Ghent, Belgium
ao Neuropaediatric Unit, Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
ap Department of Neurology, Mayo Clinic, Rochester, MN, United States
aq Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States
Abstract
Background: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. Objective: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. Methods: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher’s exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). Results: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). Conclusions: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2024.
Author Keywords
Children; MRI; Multiple sclerosis; Pediatric; Radiologically isolated syndrome
Funding details
National Multiple Sclerosis SocietyNMSS
Multiple Sclerosis SocietyMS Society
Charles H. Hood FoundationCHF
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthNIHTL1-TR001864, KL2TR002381, UL1TR002378, UL1-TR0001863, KL2-TR001862
National Institute of Neurological Disorders and StrokeNINDSK23NS101099
1K23NS116225
Document Type: Article
Publication Stage: Article in Press
Source: Scopus