The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile
(2023) Multiple Sclerosis and Related Disorders, 69, art. no. 104426, .
Cardamone, G.a , Paraboschi, E.M.a b , Soldà, G.a b , Liberatore, G.b , Rimoldi, V.a b , Cibella, J.b , Airi, F.b , Tisato, V.c , Cantoni, C.d , Gallia, F.b , Gemmati, D.c e , Piccio, L.d f , Duga, S.a b , Nobile-Orazio, E.b g , Asselta, R.a b
a Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele, 20072, Italy
b IRCCS Humanitas Research Hospital, Via Manzoni 56, Milan, Rozzano, 20089, Italy
c Department of Translational Medicine, University of Ferrara, Italy
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
e Center Haemostasis & Thrombosis, University of Ferrara, Italy
f Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia
g Department of Medical Biotechnology and Translational Medicine, Milan University, Milan, Italy
Abstract
Background: Circular RNAs (circRNAs) are a class of non-coding RNAs increasingly emerging as crucial actors in the pathogenesis of human diseases, including autoimmune and neurological disorders as multiple sclerosis (MS). Despite several efforts, the mechanisms regulating circRNAs expression are still largely unknown and the circRNA profile and regulation in MS-relevant cell models has not been completely investigated. In this work, we aimed at exploring the global landscape of circRNA expression in MS patients, also evaluating a possible correlation with their genetic and epigenetic background. Methods: We performed RNA-seq experiments on circRNA-enriched samples, derived from peripheral blood mononuclear cells (PBMCs) of 10 MS patients and 10 matched controls and performed differential circRNA expression. The genetic background was evaluated using array genotyping, and an expression quantitative trait loci (eQTL) analysis was carried out. Results: Expression analysis revealed 166 differentially expressed circRNAs in MS patients, 125 of which are downregulated. One of the top dysregulated circRNAs, hsa_circ_0007990, derives from the PGAP3 gene, encoding a protein relevant for the control of autoimmune responses. The downregulation of this circRNA was confirmed in two independent replication cohorts, suggesting its implementation as a possible RNA-based biomarker. The eQTL analysis evidenced a significant association between 89 MS-associated loci and the expression of at least one circRNA, suggesting that MS-associated variants could impact on disease pathogenesis by altering circRNA profiles. Finally, we found a significant correlation between exon methylation and circRNA expression levels, supporting the hypothesis that epigenetic features may play an important role in the definition of the cell circRNA pool. Conclusion: We described the circRNA expression profile of PBMCs in MS patients, suggesting that MS-associated variants may tune the expression levels of circRNAs acting as “circ-QTLs”, and proposing a role for exon-based DNA methylation in regulating circRNA expression. © 2022
Author Keywords
Biomarkers; Circular RNAs; DNA methylation; eQTL; Multiple sclerosis
Funding details
Fondazione per la Ricerca BiomedicaFORB1734478
Document Type: Article
Publication Stage: Final
Source: Scopus
Post-acute sensory neurological sequelae in patients with severe acute respiratory syndrome coronavirus 2 infection: The COVID-PN observational cohort study
(2022) Pain, 163 (12), pp. 2398-2410.
Odozor, C.U.a b , Kannampallil, T.a , Ben Abdallah, A.a , Roles, K.a , Burk, C.a , Warner, B.C.b , Alaverdyan, H.a , Clifford, D.B.c , Piccirillo, J.F.d , Haroutounian, S.a e
a Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
b Institute for Informatics, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Otolaryngology-Head & Neck Surgery, Washington University, School of Medicine, St. Louis, MO, United States
e Washington University Pain Center, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause neurological sequelae after the resolution of symptomatic COVID-19 illness, but the occurrence of peripheral neuropathy symptoms and cranial nerve dysfunction is unknown. This study aimed to characterize the occurrence and severity of pain and peripheral neuropathy symptoms in patients with SARS-CoV-2 infection. An observational cohort study included adults tested for a SARS-CoV-2 infection at an academic medical center (assigned as CV+ or control, based on test results). Thirty to 90 days after the index SARS-CoV-2 test, patients completed a web-based questionnaire assessing pain, peripheral neuropathy-related sensory symptoms, and symptoms in the distribution of cranial nerves (current symptoms, symptoms at testing and 2 weeks thereafter). Univariate analyses compared the outcomes between the groups. Multivariable analysis was used to determine the odds for neuropathy symptoms after adjusting for key baseline variables. A total of 1556 participants were included: 542 CV+ patients and 1014 control subjects. CV+ patients reported a higher occurrence of peripheral neuropathy symptoms in the extremities anytime within 90 days postinfection (28.8% vs 12.9%, odds ratio [OR] [95% confidence interval] = 2.72 [2.10-3.54]), as well as such symptoms persisting up to 90 days after infection (6.1% vs 1.9%, OR = 3.39 [1.91-6.03]). The occurrence of pain in the extremities was higher in the CV+ group (24.2% vs 9.8%, OR = 2.95 [2.21-3.91]). SARS-CoV-2 infection was also associated with higher occurrence of peripheral neuropathy symptoms, after adjusting for the history of chronic pain and neuropathy (OR = 3.19 [2.37-4.29]). The results suggest that SARS-CoV-2 infection was independently associated with an increased risk of pain and peripheral neuropathy symptoms. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
Coronavirus; COVID-19; Neuropathic pain; Neuropathy; Pain; Peripheral neuropathy; SARS-CoV-2
Funding details
National Cancer InstituteNCIP30 CA091842
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts
(2022) Brain: A Journal of Neurology, 145 (11), pp. 4065-4079.
Betthauser, T.J.a b , Bilgel, M.c , Koscik, R.L.a b d , Jedynak, B.M.e , An, Y.c , Kellett, K.A.a b , Moghekar, A.c , Jonaitis, E.M.a b d , Stone, C.K.b , Engelman, C.D.a d f , Asthana, S.a b d g , Christian, B.T.a h i , Wong, D.F.j , Albert, M.k , Resnick, S.M.c , Johnson, S.C.a b d g , Alzheimer’s Disease Neuroimaging Initiativel
a Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
b Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
c Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
d Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
e Department of Mathematics and Statistics, Portland State University, Portland, OR, USA
f Department of Population Health Sciences, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
g Geriatric Research Education and Clinical Center, William S. Middleton Veterans Hospital, Madison, WI, United States
h Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, United States
i Department of Medical Physics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
j Department of Radiology, Mallinckrodt Institute of Radiology, Neurology, Psychiatry and Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
k Department of Neurology, Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Abstract
Alzheimer’s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer’s disease continuum. Data were acquired from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer’s disease. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
Author Keywords
Alzheimer’s; amyloid; amyloid onset age; dementia; PET
Document Type: Article
Publication Stage: Final
Source: Scopus
A Deeper Dive Into the Relation Between Psychotic-like Experiences and Suicidal Ideation and Behaviors in Children Across the United States
(2022) Schizophrenia Bulletin, 48 (6), pp. 1241-1251.
Jay, S.Y.a , Schiffman, J.b , Grattan, R.c , O’Hare, K.d , Klaunig, M.b , DeVylder, J.e , Karcher, N.R.f
a Department of Psychology, University of Maryland Baltimore County, Baltimore, MD, United States
b Department of Psychological Science, University of California, Irvine, CA, United States
c School of Psychology, Victoria University of WellingtonWellington, New Zealand
d Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia
e Graduate School of Social Service, Fordham University, New York, NY, USA
f Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
BACKGROUND AND HYPOTHESIS: Children who endorse psychotic-like experiences (PLEs) appear to be at a greater risk for suicidal ideation and behavior (SI/SB) compared to their peers who do not endorse PLEs. Despite evidence of differential relations among subtypes of PLEs and SI/SB, the research on which PLE subtypes produce the strongest associations remains mixed. Further, though there is evidence that general psychological distress may help explain the relation between PLEs and SI/SB, no research has investigated the role of distress specific to PLEs in this association. STUDY DESIGN: The present study sought to assess the associations among individual Prodromal Questionnaire-Brief Child Version (PQ-BC) items and SI/SB, as well as to explore the role of distress associated with PLEs as a mediator and/or moderator in a demographically diverse sample of children across the United States (N = 11 875). STUDY RESULTS: Results revealed that individual items of the PQ-BC may be differentially predictive of lifetime SI (ßs = 0.000-0.098) and SB (ßs=0.002-0.059), even when controlling for sociodemographic variables, internalizing symptoms, and traumatic experiences, with particularly strong associations observed among items indexing thought control, auditory hallucinations, suspiciousness, and nihilistic thinking/dissociative experiences. Item 13, nihilistic thinking/dissociative experiences, displayed the strongest effect sizes. Findings from moderation and mediation models provided evidence consistent with distress as both a partial mediator and moderator of the relation between total PLEs and individual PQ-BC items with SI and SB. CONCLUSIONS: Distress specific to PLEs may be an important modifiable risk factor to target in suicide assessment, prevention, and intervention efforts. © The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Author Keywords
early intervention; prevention; psychosis-spectrum; suicide
Document Type: Article
Publication Stage: Final
Source: Scopus
APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression
(2022) Science Translational Medicine, 14 (671), p. eabl7646.
Dincer, A.a b , Chen, C.D.a b , McKay, N.S.a b , Koenig, L.N.a b , McCullough, A.a b , Flores, S.a b , Keefe, S.J.a b , Schultz, S.A.c , Feldman, R.L.a b , Joseph-Mathurin, N.a b , Hornbeck, R.C.a b , Cruchaga, C.b d , Schindler, S.E.b e , Holtzman, D.M.b e f , Morris, J.C.b e , Fagan, A.M.b e , Benzinger, T.L.S.a b , Gordon, B.A.a b f g
a Mallinckrodt Institute of Radiology, Washington University School of MedicineSaint Louis MO 63110, United States
b Knight Alzheimer Disease Research Center, Washington University School of MedicineSaint Louis MO 63110, United States
c Massachusetts General Hospital, Boston, MA 02114, United States
d Department of Psychiatry, Washington University School of MedicineSaint Louis MO 63110, United States
e Department of Neurology, Washington University School of MedicineSaint Louis MO 63110, United States
f Hope Center for Neurological Disorders, Washington University School of MedicineSaint Louis MO 63110, United States
g Department of Psychological and Brain Sciences, Washington UniversitySaint Louis MO 63110, United States
Abstract
The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.
Document Type: Article
Publication Stage: Final
Source: Scopus
Effect of perioperative sciatic nerve block on chronic pain in patients undergoing below-knee amputation: A randomised controlled trial
(2022) Indian Journal of Anaesthesia, 66, pp. S300-S306.
Makkar, J.K.a , Bandyopadhay, A.a , Jain, K.a , Jafra, A.a , Gopinathan, N.R.b , Singh, P.c
a Department of Anaesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, India
b Department of Orthopaedics, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, India
c Department of Anesthesiology, Washington University in Saint Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States
Abstract
Background and Aims: Many pain syndromes such as chronic phantom limb pain (PLP) and stump pain (SP), involving nociceptive and neuropathic pain, develop after amputation. Recent literature suggests that the use of regional blocks reduces repeated stimulation of transected nerve roots and thus prevents central sensitisation. This randomised, double-blind study was conducted to evaluate the effect of pre-emptive ultrasound-guided single-shot lateral sciatic nerve block on the occurrence of chronic pain at six months after traumatic below-knee amputation. Methods: Thirty patients undergoing traumatic lower limb amputation under general anaesthesia were randomised into two groups: Group B received sciatic nerve block pre-emptively using ultrasound with 20 ml of 0.75% ropivacaine, whereas group C received 20 ml of normal saline. Follow-up of patients was done till six months post-amputation. The primary objective was to assess the occurrence of chronic pain at six months. Pain at 15 days and one month after surgery, post-operative morphine consumption and post-operative nausea and vomiting (PONV) were the secondary outcomes assessed. Results: The occurrence of PLP at six months was comparable in the two groups, group B (46.7%) and C (66.7%). None of the patients developed SP at six months. Median intensities of phantom pain were 1.0 (range, 1-2.0) versus 1.0 (range, 1-2.0) (P = 0.36), and median intensities of SP 2 (range, 2-3.0) versus 3 (range, 2-3.0) (P = 0.39) at 1 month. Conclusion: Pre-emptive sciatic nerve block did not decrease the occurrence or severity of chronic pain after traumatic below-knee amputation. © 2022 Wolters Kluwer Medknow Publications. All rights reserved.
Author Keywords
Amputation; chronic pain; nerve block; phantom limb; pre-emptive; sciatic nerve; stump pain; ultrasound-guided
Document Type: Article
Publication Stage: Final
Source: Scopus
Mindfulness Training for Depressed Older Adults Using Smartphone Technology: Protocol for a Fully Remote Precision Clinical Trial
(2022) JMIR Research Protocols, 11 (10), art. no. e39233, .
Schweiger, A.a b , Rodebaugh, T.L.c , Lenze, E.J.a d , Keenoy, K.d e , Hassenstab, J.c f , Kloeckner, J.a , Gettinger, T.R.a b , Nicol, G.E.a d g
a Healthy Mind Lab, Department of Psychiatry, Washington University, School of Medicine, Saint Louis, MO, United States
b School of Social Work, Saint Louis University, Saint Louis, MO, United States
c Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO, United States
d mHealth Research Core, Washington University, School of Medicine, Saint Louis, MO, United States
e Trial Care Unit, Center for Clinical Studies, Washington University, School of Medicine, Saint Louis, MO, United States
f Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
g Division of Child and Adolescent Psychiatry, Washington University, School of Medicine, Saint Louis, MO, United States
Abstract
Background: Precision medicine, optimized interventions, and access to care are catchphrases for the future of behavioral treatments. Progress has been slow due to the dearth of clinical trials that optimize interventions’ benefits, individually tailor interventions to meet individual needs and preferences, and lead to rapid implementation after effectiveness is demonstrated. Two innovations have emerged to meet these challenges: fully remote trials and precision clinical trials. Objective: This paper provides a detailed description of Mindful MyWay, a study designed to test online mindfulness training in older adults with depression. Consistent with the concept of fully remote trials using a smartphone app, the study requires no in-person contact and can be conducted with participants anywhere in the United States. Based upon the precision medicine framework, the study assesses participants using high-frequency assessments of symptoms, cognitive performance, and patient preferences to both understand the individualized nature of treatment response and help individually tailor the intervention. Methods: Mindful MyWay is an open-label early-phase clinical trial for individuals 65 years and older with current depression. A smartphone app was developed to help coordinate the study, deliver the intervention, and evaluate the acceptability of the intervention, as well as predictors and outcomes of it. The curriculum for the fully remote intervention parallels the mindfulness-based stress reduction curriculum, a protocolized group-based mindfulness training that is typically provided in person. After consent and screening, participants download The Healthy Mind Lab mobile health smartphone app from the Apple App Store, allowing them to complete brief smartphone-based assessments of depressive symptoms and cognitive performance 4 times each day for 4 weeks prior to and after completing the intervention. The intervention consists of an introduction video and 10 weekly mindfulness training sessions, with the expectation to practice mindfulness at home daily. The app collects participant preference data throughout the 10-week intervention period; these high-frequency assessments identify participants’ individually dynamic preferences toward the goal of optimizing the intervention in future iterations. Results: Participant recruitment and data collection began in March 2019. Final end point assessments will be collected in May 2022. The paper describes lessons learned regarding the critical role of early-phase testing prior to moving to a randomized trial. Conclusions: The Mindful MyWay study is an exemplar of innovative clinical trial designs that use smartphone technology in behavioral and neuropsychiatric conditions. These include fully remote studies that can recruit throughout the United States, including hard-to-access areas, and collect high-frequency data, which is ideal for idiographic assessment and individualized intervention optimization. Our findings will be used to modify our methods and inform future randomized controlled trials within a precision medicine framework. © 2022 Abigail Schweiger.
Author Keywords
adult; aging; clinical trial; death; depressed; depression; fully remote trial; intervention; medicine; mHealth; mind; mindfulness; needs; older; online; precision medicine; preferences; remote; session; smartphone; technology; training; treatment
Funding details
National Institutes of HealthNIHP50MH122351
Boehringer IngelheimBI
Merck
Patient-Centered Outcomes Research InstitutePCORI
National Center for Advancing Translational SciencesNCATS
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTSUL1TR002345
McDonnell Center for Systems Neuroscience
Institute for Public Health, Washington University in St. Louis
Skoll Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Automated Quantification of Compartmental Blood Volumes Enables Prediction of Delayed Cerebral Ischemia and Outcomes After Aneurysmal Subarachnoid Hemorrhage
(2022) World Neurosurgery, .
Yuan, J.Y.a , Chen, Y.b , Jayaraman, K.a , Kumar, A.b , Zlepper, Z.a , Allen, M.L.a , Athiraman, U.c , Osbun, J.a , Zipfel, G.a , Dhar, R.b
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Objective: The role of hemorrhage volume in risk of vasospasm, delayed cerebral ischemia (DCI), and poor outcomes after aneurysmal subarachnoid hemorrhage (SAH) is well established. However, the relative contribution of blood within individual compartments is unclear. We present an automated technique for measuring not only total but also volumes of blood in each major compartment after SAH. Methods: We trained convolutional neural networks to identify compartmental blood (cisterns, sulci, and ventricles) from baseline computed tomography scans of patients with SAH. We compared automated blood volumes against traditional markers of bleeding (modified Fisher score [mFS], Hijdra sum score [HSS]) in 190 SAH patients for prediction of vasospasm, DCI, and functional status (modified Rankin Scale) at hospital discharge. Results: Combined cisternal and sulcal volume was better correlated with mFS and HSS than cisternal volume alone (ρ = 0.63 vs. 0.58 and 0.75 vs. 0.70, P < 0.001). Only blood volume in combined cisternal plus sulcal compartments was independently associated with DCI (OR 1.023 per mL, 95% CI 1.002–1.048), after adjusting for clinical factors while ventricular blood volume was not. Total and specifically sulcal blood volume was strongly associated with poor outcome (OR 1.03 per mL, 1.01–1.06, P = 0.006 and OR 1.04, 1.00–1.08 for sulcal) as was HSS (OR 1.06 per point, 1.00–1.12, P = 0.04), while mFS was not (P = 0.24). Conclusions: An automated imaging algorithm can measure the volume of bleeding after SAH within individual compartments, demonstrating cisternal plus sulcal (and not ventricular) blood contributes to risk of DCI/vasospasm. Automated blood volume was independently associated with outcome, while qualitative grading was not. © 2022 Elsevier Inc.
Author Keywords
Cerebral vasospasm; Deep learning; Image segmentation; Intracranial aneurysm; Subarachnoid hemorrhage
Funding details
National Institutes of HealthNIHK23NS099440, R01NS121218
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Osmotic Contribution of Synthesized Betaine by Choline Dehydrogenase Using In Vivo and In Vitro Models of Post-traumatic Syringomyelia
(2022) Cellular and Molecular Bioengineering, .
Pukale, D.D.a , Lazarenko, D.b , Aryal, S.R.c , Khabaz, F.a b , Shriver, L.P.d e f , Leipzig, N.D.a c
a Department of Chemical, Biomolecular, and Corrosion Engineering, University of Akron, Akron, OH 44325, United States
b School of Polymer Science and Polymer Engineering, The University of Akron, Akron, OH 44325, United States
c Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, United States
d Department of Chemistry, Washington University, Saint Louis, MO 63130, United States
e Department of Medicine, Washington University, Saint Louis, MO 63130, United States
f Center for Metabolomics and Isotope Tracing, Washington University, Saint Louis, MO 63130, United States
Abstract
Introduction: Syringomyelia (SM) is a debilitating spinal cord disorder in which a cyst, or syrinx, forms in the spinal cord parenchyma due to congenital and acquired causes. Over time syrinxes expand and elongate, which leads to compressing the neural tissues and a mild to severe range of symptoms. In prior omics studies, significant upregulation of betaine and its synthesis enzyme choline dehydrogenase (CHDH) were reported during syrinx formation/expansion in SM injured spinal cords, but the role of betaine regulation in SM etiology remains unclear. Considering betaine’s known osmoprotectant role in biological systems, along with antioxidant and methyl donor activities, this study aimed to better understand osmotic contributions of synthesized betaine by CHDH in response to SM injuries in the spinal cord. Methods: A post-traumatic SM (PTSM) rat model and in vitro cellular models using rat astrocytes and HepG2 liver cells were utilized to investigate the role of betaine synthesis by CHDH. Additionally, the osmotic contributions of betaine were evaluated using a combination of experimental as well as simulation approaches. Results: In the PTSM injured spinal cord CHDH expression was observed in cells surrounding syrinxes. We next found that rat astrocytes and HepG2 cells were capable of synthesizing betaine via CHDH under osmotic stress in vitro to maintain osmoregulation. Finally, our experimental and simulation approaches showed that betaine was capable of directly increasing meaningful osmotic pressure. Conclusions: The findings from this study demonstrate new evidence that CHDH activity in the spinal cord provides locally synthesized betaine for osmoregulation in SM pathophysiology. © 2022, The Author(s) under exclusive licence to Biomedical Engineering Society.
Author Keywords
Betaine; Choline dehydrogenase (CHDH); Osmoregulation; Osmotic pressure; Post-traumatic syringomyelia; Syrinx
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations of sNfL with clinico-radiological measures in a large MS population
(2022) Annals of Clinical and Translational Neurology, .
Sotirchos, E.S.a , Fitzgerald, K.C.a , Singh, C.M.b , Smith, M.D.a , Reyes-Mantilla, M.a , Hersh, C.M.c , Hyland, M.H.d , Canissario, R.d , Simmons, S.B.e , Arrambide, G.f , Montalban, X.f , Comabella, M.f , Naismith, R.T.g , Qiao, M.g , Krupp, L.B.h , Nicholas, J.A.i , Akgün, K.j , Ziemssen, T.j , Rudick, R.k , Fisher, E.b , Bermel, R.A.e , Mowry, E.M.a , Calabresi, P.A.a
a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Biogen, Cambridge, MA, United States
c Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States
d Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States
e Mellen Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
f Department of Neurology and Centre d’Esclerosi Múltiple de Catalunya, Vall d’Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Neurology, New York University, New York City, NY, United States
i OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, OH, United States
j Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl-Gustav Carus, Dresden, Germany
k (formerly) Biogen, Cambridge, MA, United States
Abstract
Objective: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. Methods: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. Results: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. Interpretation: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIHK01MH121582, K23NS117883, U01NS111678
National Multiple Sclerosis SocietyNMSSRG‐1904‐33800, RG‐1904‐33834
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials
(2022) Annals of Clinical and Translational Neurology, .
Findlay, A.R., Robinson, S.E., Poelker, S., Seiffert, M., Bengoechea, R., Weihl, C.C.
Neuromuscular Division, Department of Neurology, Washington University Saint Louis, Saint Louis, MO, United States
Abstract
Objective: To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). Methods: We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross-sectional observational study using previously validated patient-reported outcome assessments (ACTIVLIM, PROMIS-57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. Results: A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5-1 lb/year). Cross-sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. Interpretation: This study is the largest description of LGMDD1 patients to date and highlights potential genotype-dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIHK08AR075894, K24AR073317, R01AR068797, R03AR081395
St. Louis Children’s HospitalSLCH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Sex-specific hypnotic effects of the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile are mediated by peripheral metabolism into an active hypnotic steroid
(2022) British Journal of Anaesthesia, .
Manzella, F.M.a b , Cabrera, O.H.a , Wilkey, D.a , Fine-Raquet, B.a , Klawitter, J.a , Krishnan, K.c , Covey, D.F.c d , Jevtovic-Todorovic, V.a e , Todorovic, S.M.a b
a Department of Anaesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
b Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
c Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
e Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
Abstract
Background: The novel synthetic neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) blocks T-type calcium channels but does not directly modulate neuronal γ-aminobutyric acid type A (GABAA) currents like other anaesthetic neurosteroids. As 3β-OH has sex-specific hypnotic effects in adult rats, we studied the mechanism contributing to sex differences in its effects. Methods: We used a combination of behavioural loss of righting reflex, neuroendocrine, pharmacokinetic, in vitro patch-clamp electrophysiology, and in vivo electrophysiological approaches in wild-type mice and in genetic knockouts of the CaV3.1 T-type calcium channel isoform to study the mechanisms by which 3β-OH and its metabolite produces sex-specific hypnotic effects. Results: Adult male mice were less sensitive to the hypnotic effects of 3β-OH compared with female mice, and these differences appeared during development. Adult males had higher 3β-OH brain concentrations despite being less sensitive to its hypnotic effects. Females metabolised 3β-OH into the active GABAA receptor positive allosteric modulator (3α,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3α-OH) to a greater extent than males. The 3α-OH metabolite has T-channel blocking properties with sex-specific hypnotic and pharmacokinetic effects. Sex-dependent suppression of the cortical electroencephalogram is more pronounced with 3α-OH compared with 3β-OH. Conclusions: The sex-specific differences in the hypnotic effect of 3β-OH in mice are attributable to differences in its peripheral metabolism into the more potent hypnotic metabolite 3α-OH. © 2022 The Authors
Author Keywords
calcium channels; electroencephalogram; metabolism; neuroactive steroid; pharmacokinetics; sex-specific pharmacology
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Preliminary Evidence for the Sequentially Mediated Effect of Racism-Related Stress on Pain Sensitivity Through Sleep Disturbance and Corticolimbic Opioid Receptor Function
(2022) Journal of Pain, .
Letzen, J.E.a , Hunt, C.a , Kuwabara, H.b , McGill, L.S.c , Reid, M.J.a , Hamilton, K.R.a , Buenaver, L.F.a , Burton, E.a , Sheinberg, R.d , Wong, D.F.e , Smith, M.T.a , Campbell, C.M.a
a Department of Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, United States
b Department of Radiology, Johns Hopkins University, Baltimore, Maryland, United States
c Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, Maryland, United States
d Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
e Departments of Radiology, Psychiatry, Neurology, Neurosciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St, Louis, Missouri, United States
Abstract
Sleep disturbance predicts worse pain outcomes. Because sleep disturbance inequitably impacts Black adults – with racism as the upstream cause – understanding how racism-related stress impacts pain through sleep might help minimize racialized pain inequities. This preliminary study examined sequential mediation of the effect of racism-related stress on experimental pain through sleep disturbance and corticolimbic μOR function in pain-free non-Hispanic Black (NHB) and White (NHW) adults. Participants completed questionnaires, actigraphy, positron emission tomography, and sensory testing. We reproduced findings showing greater sleep disturbance and pain sensitivity among NHB participants; greater sleep disturbance (r = .35) and lower pain tolerance (r=-.37) were significantly associated with greater racism-related stress. In a sequential mediation model, the total effect of racism-related stress on pain tolerance (β=-.38, P = .005) weakened after adding sleep disturbance and ventromedial prefrontal cortex (vmPFC) μOR binding potential (BPND) as mediators (β = -.18, P = .16). The indirect effect was statistically significant [point estimate = -.003, (-.007, -.0003). Findings showed a potential sequentially mediated effect of racism-related stress on pain sensitivity through sleep disturbance and vmPFC μOR BPND. As policy efforts are enacted to eliminate the upstream cause of systemic racism, these results cautiously suggest that sleep interventions within racism-based trauma informed therapy might help prevent downstream effects on pain. Perspective: This preliminary study identified the effect of racism-related stress on pain through sleep disturbance and mu-opioid receptor binding potential in the ventromedial prefrontal cortex. Findings cautiously support the application of sleep interventions within racism-based trauma-informed therapy to prevent pain inequities as policy changes function to eliminate all levels of racism. © 2022 United States Association for the Study of Pain, Inc.
Author Keywords
corticolimbic system; health equity; mu-opioid receptor; pain disparities; Racism; sleep disparities
Funding details
National Institutes of HealthNIHK23NS124935, R01MD009063, T32NS070201
Washington University in St. LouisWUSTL
Catholic Medical CenterCMC5T32HD007414, K24AR081143, UG3DA047699
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Hyperammonaemia disrupts daily rhythms reversibly by elevating glutamate in the central circadian pacemaker
(2022) Liver International, .
Granados-Fuentes, D.a , Cho, K.b , Patti, G.J.b , Costa, R.c d e , Herzog, E.D.a , Montagnese, S.e f
a Biology Department, Washington University in St. Louis, St. Louis, MO, United States
b Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biology, University of Padova, Padova, Italy
d Institute of Neuroscience, National Research Council of Italy (CNR), Padova, Italy
e Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
f Department of Medicine, University of Padova, Padova, Italy
Abstract
Patients with cirrhosis exhibit features of circadian disruption. Hyperammonaemia has been suggested to impair both homeostatic and circadian sleep regulation. Here, we tested if hyperammonaemia directly disrupts circadian rhythm generation in the central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Wheel-running activity was recorded from mice fed with a hyperammonaemic or normal diet for ~35 days in a 12:12 light–dark (LD) cycle followed by ~15 days in constant darkness (DD). The expression of the clock protein PERIOD2 (PER2) was recorded from SCN explants before, during and after ammonia exposure, ±glutamate receptor antagonists. In LD, hyperammonaemic mice advanced their daily activity onset time by ~1 h (16.8 ± 0.3 vs. 18.1 ± 0.04 h, p =.009) and decreased their total activity, concentrating it during the first half of the night. In DD, hyperammonaemia reduced the amplitude of daily activity (551.5 ± 27.7 vs. 724.9 ± 59 counts, p =.007), with no changes in circadian period. Ammonia (≥0.01 mM) rapidly and significantly reduced PER2 amplitude, and slightly increased circadian period. The decrease in PER2 amplitude correlated with decreased synchrony among circadian cells in the SCN and increased extracellular glutamate, which was rescued by AMPA glutamate receptor antagonists. These data suggest that hyperammonaemia affects circadian regulation of rest-activity behaviour by increasing extracellular glutamate in the SCN. © 2022 The Authors. Liver International published by John Wiley & Sons Ltd.
Author Keywords
astrocytes; central circadian clock; cirrhosis; hyperammonaemia; sleep-wake inversion; suprachiasmatic nuclei
Funding details
National Institutes of HealthNIHGM131403, R35ES028365
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparing the functional neuroanatomy of proactive and reactive control between patients with schizophrenia and healthy controls
(2022) Cognitive, Affective and Behavioral Neuroscience, .
Kwashie, A.N.a , Ma, Y.b , Barch, D.M.c , Chafee, M.a , Ragland, J.D.d , Silverstein, S.M.e , Carter, C.S.d , Gold, J.M.b , MacDonald, A.W., IIIa
a Department of Psychology, University of Minnesota, 75 East River Road, N218 Elliott Hall, Minneapolis, MN 55455, United States
b Maryland Psychiatric Research Center, Baltimore, MD, United States
c Washington University of St. Louis, Louis, MO, United States
d University of California, Davis, CA, United States
e University of Rochester, Rochester, NY, United States
Abstract
Cognitive control deficits are associated with impaired executive functioning in schizophrenia. The Dual Mechanisms of Control framework suggests that proactive control requires sustained dorsolateral prefrontal activity, whereas reactive control marshals a larger network. However, primate studies suggest these processes are maintained by dual-encoding regions. To distinguish between these theories, we compared the distinctiveness of proactive and reactive control functional neuroanatomy. In a reanalysis of data from a previous study, 47 adults with schizophrenia and 56 controls completed the Dot Pattern Expectancy task during an fMRI scan examining proactive and reactive control in frontoparietal and medial temporal regions. Areas suggesting specialized control or between-group differences were tested for association with symptoms and task performance. Elastic net models additionally explored these areas’ predictive abilities regarding performance. Most regions were active in both reactive and proactive control. However, evidence of specialized proactive control was found in the left middle and superior frontal gyri. Control participants showed greater proactive control in the left middle and right inferior frontal gyri. Elastic net models moderately predicted task performance and implicated various frontal gyri regions in control participants, with additional involvement of anterior cingulate and posterior parietal regions for reactive control. Elastic nets for patient participants implicated the inferior and superior frontal gyri, and posterior parietal lobe. Specialized cognitive control was unassociated with either performance or schizophrenia symptomatology. Future work is needed to clarify the distinctiveness of proactive and reactive control, and its role in executive deficits in severe psychopathology. © 2022, The Psychonomic Society, Inc.
Author Keywords
Cognitive control; Dot pattern expectancy task; fMRI; Functional neuroanatomy; Psychosis; Schizophrenia
Funding details
National Institutes of HealthNIH5R01MH084821, 5R01MH084826, 5R01MH084828, 5R01MH084840, 5R01MH084861
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
CSF tau microtubule-binding region identifies pathological changes in primary tauopathies
(2022) Nature Medicine, .
Horie, K.a b , Barthélemy, N.R.a b , Spina, S.c , VandeVrede, L.c , He, Y.a b , Paterson, R.W.d , Wright, B.A.e , Day, G.S.f , Davis, A.A.a g , Karch, C.M.g h i , Seeley, W.W.c , Perrin, R.J.a g i j , Koppisetti, R.K.a h , Shaikh, F.a , Lago, A.L.c , Heuer, H.W.c , Ghoshal, N.a h , Gabelle, A.k , Miller, B.L.c , Boxer, A.L.c , Bateman, R.J.a b g i , Sato, C.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b The Tracy Family Stable Isotope Labeling Quantitation Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, University of California San Francisco, San Francisco, CA, United States
d Department of Neurology, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom
e Department of Neurosciences, University of California San Diego School of Medicine, La JollaCA, United States
f Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
g Hope Center for Neurological Disorders, St. Louis, MO, United States
h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
i Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
j Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
k Memory Research and Resources Center, Department of Neurology, University Hospital of Montpellier, Neurosciences Institute of Montpellier, University of Montpellier, Montpellier, France
Abstract
Despite recent advances in fluid biomarker research in Alzheimer’s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau275 and MTBR-tau282) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick’s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau275 and MTBR-tau282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs. © 2022, The Author(s).
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neocortical Lewy Body Pathology Parallels Parkinson’s Dementia, but Not Always
(2022) Annals of Neurology, .
Martin, W.R.W.a , Younce, J.R.b , Campbell, M.C.c d , Racette, B.A.c e f , Norris, S.A.c , Ushe, M.c , Criswell, S.c , Davis, A.A.c , Alfradique-Dunham, I.c , Maiti, B.c , Cairns, N.J.g , Perrin, R.J.c h , Kotzbauer, P.T.c , Perlmutter, J.S.c d i
a Department of Medicine (Neurology), University of Alberta, Edmonton, Canada
b Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, Barrow Neurological Institute, Phoenix, Azerbaijan
f School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
g College of Medicine and Health, University of Exeter, Exeter, United Kingdom
h Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
i Departments of Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objective: The objective of this study was to evaluate the relationship between Parkinson’s disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. Methods: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. Results: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer’s disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. Interpretation: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2022. © 2022 American Neurological Association.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAK23NS125107, NS075321, NS097437, NS097799, U10NS077384
National Institute of Neurological Disorders and StrokeNINDS
American Parkinson Disease AssociationAPDA
Foundation for Barnes-Jewish HospitalFBJH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations Among Loneliness, Purpose in Life and Subjective Cognitive Decline in Ethnoracially Diverse Older Adults Living in the United States
(2022) Journal of Applied Gerontology, .
Pluim, C.F.a b , Anzai, J.A.U.a b , Martinez, J.E.a b , Munera, D.b , Garza-Naveda, A.P.b , Vila-Castelar, C.b , Guzmán-Vélez, E.b , Ramirez-Gomez, L.c , Bustin, J.d , Serrano, C.M.e , Babulal, G.M.f , Okada de Oliveira, M.g h , Quiroz, Y.T.b c
a Department of Psychological and Brain Sciences, Boston University, Boston, MA, United States
b Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
d Favaloro University, INCYT, Buenos Aires, Argentina
e Department of Neurology, Cesar Milstein Hospital, Buenos Aires, Argentina
f Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurology, University of São Paulo, São Paulo, Brazil
h Department of Neurology, Hospital Santa Marcelina, São Paulo, Brazil
Abstract
Subjective cognitive decline (SCD), which precedes Mild Cognitive Impairment and dementia, may be affected by purpose in life (PiL) and loneliness in older adults. We investigated associations among PiL, loneliness, and SCD in US Latino (n = 126), Black (n = 74), Asian (n = 33), and White (n = 637) adults. Higher PiL predicted lower SCD in all groups (p-values <.012), except Black participants. Lower loneliness predicted lower SCD in Latino and White groups (p-values <.05), and PiL moderated this association in White adults. PiL and loneliness may play important roles in cognitive decline. Differential predictors of SCD suggest differential targets for preventing cognitive decline and dementia across ethnoracial groups. © The Author(s) 2022.
Author Keywords
Latinos; loneliness; mild cognitive impairment; purpose in life; social isolation; subjective cognitive decline
Funding details
R01AG056466, R01AG067428, R01AG068183
National Institutes of HealthNIH5T32HL007901-23
Alzheimer’s AssociationAA2019A005859
Massachusetts General HospitalMGH
BrightFocus FoundationBFFA2021142S, K23AG061276
Boston UniversityBUR01AG054671, R01AG066823
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Religiousness and psychotic experiences among young adult college students in the United States
(2022) International Journal of Social Psychiatry, .
Oh, H.Y.a , Davis, E.B.b , Klaunig, M.c , Narita, Z.d , Koyanagi, A.e , Karcher, N.R.f
a Suzanne Dworak Peck School of Social Work, University of Southern California, Los Angeles, CA, United States
b School of Psychology, Wheaton College, Wheaton, IL, United States
c Department of Psychological Science, University of California, Irvine, CA, United States
d Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan
e Research and Development Unit, Parc Sanitari Sant Joan de Déu, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, ICREA, Spain
f School of Medicine, Washington University, Saint Louis, MO, United States
Abstract
Background: Religiousness and psychotic experiences have been related, though findings have been mixed, with little attention paid to specific religious affiliations and religious importance. Methods: We analyzed data from the Healthy Minds Study (2020–2021), which was an online survey administered at 140 college campuses across the United States. We used multivariable logistic regression to examine the associations between religiousness (affiliation and importance) and 12-month psychotic experiences, adjusting for age, gender, and race/ethnicity. Results: Only Christian religious affiliation was associated with lower odds of psychotic experiences (aOR: 0.79; 95% CI: 0.75, 0.84), while Non-Christian religious affiliation (aOR: 1.34; 95% CI: 1.19, 1.50) and Multiple religious affiliation s were associated with greater odds (aOR: 1.28; 95% CI: 1.15, 1.42). Overall, increased religious importance was associated with lower odds of psychotic experiences (aOR: 0.96; 95% CI: 0.94–0.99). After stratifying by affiliation, religious importance was only associated with lower odds of psychotic experiences among people who identified as Other Christian, Mormon, and Other World Religion. Religious importance was associated with greater odds of psychotic experiences among Atheists, Agnostics, Buddhists, Nothing in Particular, and Multiple Religions. Conclusion: Religious affiliation and importance had varying associations with psychotic experiences, depending on type of religious affiliation. More research is needed to explore the modifying effects of religiousness. Responsiveness to religious beliefs and practices may be critical when assessing risk for psychosis. © The Author(s) 2022.
Author Keywords
college; psychosis; psychotic experiences; Religion
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
COVID-19-Related Facilitators and Barriers to In-Person Learning for Children With Intellectual and Development Disabilities
(2022) Journal of School Health, .
Vestal, L.E.a , Schmidt, A.M.a , Dougherty, N.L.b , Sherby, M.R.c , Newland, J.G.d , Mueller, N.B.e , for the COMPASS-T Study Groupf
a Evaluation Center, Brown School at Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130, United States
b Evaluation Center, Brown School at Washington University in St. Louis, MSC 1196-0251-46, One Brookings Drive, St. Louis, MO 63130, United States
c Pediatric and Developmental Neurology Division, Washington University School of Medicine, 620 South Taylor, Northwest Tower 12423, St. Louis, MO 63130, United States
d Pediatric Infectious Diseases, Washington University School of Medicine, 620 South Taylor, Northwest Tower 10113, St. Louis, MO 63130, United States
e Institutional Effectiveness, Office of the Provost, Washington University in St. Louis, Campus Box 1196-0251-46, One Brookings Drive, St. Louis, MO 63130, United States
Abstract
BACKGROUND: Schools provide essential functions for children with intellectual and developmental disabilities (IDD), but their vulnerability to infection with SARS-CoV-2 are a barrier to in-person learning. This qualitative study aimed to understand how weekly SARS-CoV-2 screening testing of students and staff could best facilitate in-school learning during the pandemic. METHODS: Thirty-one focus groups were held with school staff and parents of children with IDD to examine the perceptions of COVID-19 during the 2020-2021 school year. Responses were analyzed using a directed thematic content analysis approach. RESULTS: Five principal themes were identified: risks of returning to in-person learning; facilitators and barriers to participation in SARS-CoV-2 screening testing; messaging strategies; and preferred messengers. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Staff and families agreed that saliva-based SARS-CoV-2 screening testing helps increase comfort with in-person learning. Screening testing increased family and school staff comfort with in-person learning particularly because many students with special needs cannot adhere to public health guidelines. CONCLUSION: To keep children with IDD in school during the pandemic, families found SARS-CoV-2 screening testing important, particularly for students that cannot adhere to mitigation guidelines. © 2022 The Authors. Journal of School Health published by Wiley Periodicals LLC on behalf of American School Health Association.
Author Keywords
children with IDD; COVID-19; COVID-19 school testing; intellectual and developmental disabilities; SARS-CoV-2 testing
Funding details
National Institutes of HealthNIHP50HD103525‐01S1
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
(2022) Nature Genetics, .
Holstege, H.a b c d , Hulsman, M.a b c d , Charbonnier, C.e , Grenier-Boley, B.f , Quenez, O.e , Grozeva, D.g , van Rooij, J.G.J.h i , Sims, R.g , Ahmad, S.j k , Amin, N.j l , Norsworthy, P.J.m , Dols-Icardo, O.n o , Hummerich, H.m , Kawalia, A.p , Amouyel, P.f , Beecham, G.W.q , Berr, C.r , Bis, J.C.s , Boland, A.t , Bossù, P.u , Bouwman, F.b c , Bras, J.v w , Campion, D.e , Cochran, J.N.x , Daniele, A.y , Dartigues, J.-F.z , Debette, S.z aa , Deleuze, J.-F.t , Denning, N.ab , DeStefano, A.L.ac ad ae , Farrer, L.A.ac ae af ag , Fernández, M.V.ah ai aj , Fox, N.C.ak , Galimberti, D.al am , Genin, E.an , Gille, J.J.P.ao , Le Guen, Y.ap , Guerreiro, R.v w , Haines, J.L.aq , Holmes, C.ar , Ikram, M.A.j , Ikram, M.K.j , Jansen, I.E.b c as , Kraaij, R.i , Lathrop, M.at , Lemstra, A.W.b c , Lleó, A.n o , Luckcuck, L.g , Mannens, M.M.A.M.au , Marshall, R.g , Martin, E.R.q av , Masullo, C.aw , Mayeux, R.ax ay , Mecocci, P.az , Meggy, A.ab , Mol, M.O.h , Morgan, K.ba , Myers, R.M.x , Nacmias, B.bb bc , Naj, A.C.bd be , Napolioni, V.ap bf , Pasquier, F.bg , Pastor, P.bh bi , Pericak-Vance, M.A.q av , Raybould, R.ab , Redon, R.bj , Reinders, M.J.T.d , Richard, A.-C.e , Riedel-Heller, S.G.bk , Rivadeneira, F.i , Rousseau, S.e , Ryan, N.S.ak , Saad, S.g , Sanchez-Juan, P.o bl , Schellenberg, G.D.be , Scheltens, P.b c , Schott, J.M.ak , Seripa, D.bm , Seshadri, S.ad ae bn , Sie, D.ao , Sistermans, E.A.ao , Sorbi, S.bb bc , van Spaendonk, R.ao , Spalletta, G.bo , Tesi, N.a b c d , Tijms, B.b , Uitterlinden, A.G.i , van der Lee, S.J.a b c d , Visser, P.J.b , Wagner, M.bp bq , Wallon, D.br , Wang, L.-S.be , Zarea, A.br , Clarimon, J.n o , van Swieten, J.C.h , Greicius, M.D.ap , Yokoyama, J.S.bs , Cruchaga, C.ah ai aj , Hardy, J.bt , Ramirez, A.p bn bp bq bu , Mead, S.m , van der Flier, W.M.b c , van Duijn, C.M.j l , Williams, J.g , Nicolas, G.e , Bellenguez, C.f , Lambert, J.-C.f
a Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
b Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
c Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
d Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands
e Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France
f Université Lille, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France
g Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom
h Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands
i Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, Netherlands
j Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands
k Leiden Academic Centre for Drug Research, Leiden, Netherlands
l Nuffield Department of Population Health Oxford University, Oxford, United Kingdom
m Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases, London, United Kingdom
n Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
o Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
p Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
q The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, United States
r Université Montpellier, INSERM, Institute for Neurosciences of Montpellier, Montpellier, France
s Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
t Université Paris-Saclay, Commissariat à l’Énergie Atomique et aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine Evry, Gif-sur-Yvette, France
u Experimental Neuro-psychobiology Laboratory, Department of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
v Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, United States
w Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, United States
x HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States
y Department of Neuroscience, Catholic University of Sacred Heart, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
z Université Bordeaux, INSERM, Bordeaux Population Health Research Center, Bordeaux, France
aa Department of Neurology, Bordeaux University Hospital, Bordeaux, France
ab UKDRI Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom
ac Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
ad Framingham Heart Study, Framingham, MA, United States
ae Department of Neurology, Boston University School of Medicine, Boston, MA, United States
af Department of Epidemiology, Boston University, Boston, MA, United States
ag Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, United States
ah Neurogenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, United States
ai Psychiatry Department, Washington University School of Medicine, St Louis, MO, United States
aj Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
ak Dementia Research Centre, University College London Queen Square Institute of Neurology, London, United Kingdom
al Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda, Ospedale Policlinico, Milan, Italy
am University of Milan, Milan, Italy
an Université Brest, INSERM, Etablissement Français du Sang, Centre Hospitalier Universitaire Brest, Unité Mixte de Recherche 1078, GGB, Brest, France
ao Genome Diagnostics, Department of Human Genetics, VU University, AmsterdamUMC (location VUmc), Amsterdam, Netherlands
ap Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
aq Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States
ar Clinical and Experimental Science, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
as Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, Netherlands
at McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada
au Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
av Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, United States
aw Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy
ax Taub Institute on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, United States
ay Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
az Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
ba Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
bb Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy
bc IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
bd Penn Neurodegeneration Genomics Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
be Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
bf Genomic and Molecular Epidemiology Laboratory, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
bg Université Lille, INSERM, Centre Hospitalier Universitaire Lille, UMR1172, Resources and Research Memory Center (MRRC) of Distalz, Licend, Lille, France
bh Fundació Docència i Recerca MútuaTerrassa and Movement Disorders Unit, Department of Neurology, University Hospital MútuaTerrassa, Barcelona, Spain
bi Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain
bj Université de Nantes, Centre Hospitalier Universitaire Nantes, Centre National de la Recherche Scientifique, INSERM, l’institut du Thorax, Nantes, France
bk Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany
bl Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain
bm Laboratory for Advanced Hematological Diagnostics, Department of Hematology and Stem Cell Transplant, Lecce, Italy
bn Department of Psychiatry and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, United States
bo Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy
bp Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany
bq German Center for Neurodegenerative Diseases, Bonn, Germany
br Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Neurology and CNRMAJ, Rouen, France
bs Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
bt Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom
bu Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
Abstract
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD. © 2022, The Author(s).
Document Type: Article
Publication Stage: Article in Press
Source: Scopus