Scopus list of publications for November 19, 2023
An investigation of the potential clinical utility of critical slowing down as an early warning sign for recurrence of depression
(2024) Journal of Behavior Therapy and Experimental Psychiatry, 82, art. no. 101922, .
Tonge, N.A.a , Miller, J.P.b , Kharasch, E.D.c , Lenze, E.J.d , Rodebaugh, T.L.a
a Department of Psychology & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
d Department of Psychiatry, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
Abstract
Background and objectives: Much of the burden of depressive illness is due to relapses that occur after treatment into remission. Prediction of an individual’s imminent depressive relapse could lead to just-in-time interventions to prevent relapse, reducing depression’s substantial burden of disability, costs, and suicide risk. Increasingly strong relationships in the form of autocorrelations between depressive symptoms, a signal of a phenomenon described as critical slowing down (CSD), have been proposed as a means of predicting relapse. Methods: In the current study, four participants in remission from depression, one of whom relapsed, responded to daily smartphone surveys with depression symptoms. We used p-technique factor analysis to identify depression factors from over 100 survey responses. We then tested for the presence of CSD using time-varying vector autoregression and detrended fluctuation analysis. Results: We found evidence that CSD provided an early warning sign for depression in the participant who relapsed, but we also detected false positive indications of CSD in participants who did not relapse. Results from time-varying vector autoregression and detrended fluctuation analysis were not in agreement. Limitations: Limitations include use of secondary data and a small number of participants with daily responding to a subset of depression symptoms. Conclusions: CSD provides a compelling framework for predicting depressive relapse and future research should focus on improving detection of early warning signs reliably. Improving early detection methods for depression is clinically significant, as it would allow for the development of just-in-time interventions. © 2023 Elsevier Ltd
Author Keywords
Complex dynamic systems; Critical slowing down; Depression; Early warning signs; Ecological momentary assessment; Relapse
Funding details
National Institutes of HealthNIHU01FD004899
International Colour AssociationAIC
Document Type: Article
Publication Stage: Final
Source: Scopus
Treatment patterns for patients initiating novel acute migraine specific medications (nAMSMs) in the context of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway
(2023) Journal of Headache and Pain, 24 (1), art. no. 153, .
Zhou, Z.a , Urman, R.b , Gill, K.b , Park, A.S.b , Vuvu, F.b , Patel, L.B.b , Lu, J.a , Wade, R.L.a , Frerichs, L.c , Bensink, M.E.d
a IQVIA, Falls Church, VA, United States
b Amgen Inc., Thousand Oaks, CA, United States
c Washington University School of Medicine, St. Louis, MO, United States
d Benofit Consulting, Brisbane, QLD, Australia
Abstract
Background: New acute and preventive migraine medications are available, but data on current treatment patterns are limited. This study describes migraine treatment patterns among patients initiating novel acute migraine specific medications (nAMSMs), overall and by prior use of anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs). Methods: In this retrospective cohort study using IQVIA open-source pharmacy and medical claims data, we identified patients with ≥ 1 claim for a nAMSM (ubrogepant, rimegepant, lasmiditan) between 01/01/2020 and 09/30/2020 (index period). Patients were indexed on their first nAMSM claim and stratified into 2 cohorts: patients with prior mAb use (≥ 1 claim for erenumab, fremanezumab, galcanezumab in the 6-month pre-index period) or patients without prior mAb use. Treatment patterns were assessed during the 6-month post-index period. Results: Overall, 78,574 patients were identified (63% indexed on ubrogepant, 34% on rimegepant, and 3% on lasmiditan) with 26,656 patients (34%) having had prior mAb use. In the pre-index period, 79% of patients used non-mAb preventive medications and 75% of patients used acute medications. Following the index nAMSM claim, 65% of patients had ≥ 1 refill and 21% had ≥ 4 refills of their index nAMSM; 10% of patients switched to another nAMSM. Post-index mAb use was observed in 82% of patients with a prior mAb and 15% of patients without. Among patients with pre- and post-index use of acute medications, 38% discontinued ≥ 1 acute medication class in the post-index period. Among patients with concomitant use of traditional preventive medications at index, 30% discontinued ≥ 1 concomitant preventive anti-migraine medication in the post-index period. Conclusions: Most patients initiating nAMSMs had prior treatment with acute and preventive medications. Approximately one-third of patients had prior treatment with anti-CGRP pathway mAbs. After starting nAMSMs, more than one-third of patients discontinued at least one traditional acute medication and one-third of patients discontinued at least one traditional preventive medication. Despite nAMSM initiation, most patients with prior anti-CGRP pathway mAb use continued mAb use. Around 15% of patients without a prior mAb newly started a mAb. These results provide insight into how nAMSMs and mAbs have been integrated into clinical management of migraine in the real-world. © 2023, The Author(s).
Author Keywords
Acute migraine therapy; CGRP; Migraine; Prophylactic/preventive treatment
Funding details
Amgen
Document Type: Article
Publication Stage: Final
Source: Scopus
Cingulate white matter mediates the effects of fecal Ruminococcus on neuropsychiatric symptoms in patients with amyloid-positive amnestic mild cognitive impairment
(2023) BMC Geriatrics, 23 (1), art. no. 720, .
Hung, C.-C.a b , Chao, Y.-P.c d , Lee, Y.e , Huang, C.-W.f , Huang, S.-H.g , Chang, C.-C.f , Cheng, C.-H.a b h i
a Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, No. 259, Wenhua 1st Road, Taoyuan, 333, Taiwan
b Laboratory of Brain Imaging and Neural Dynamics (BIND Lab), Chang Gung University, Taoyuan, Taiwan
c Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan
d Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan
e Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung university College of Medicine, No. 123 Ta-Pei Rd., Niau-Sung Dist, Kaohsiung, 833, Taiwan
g Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
h Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
i Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan
Abstract
Background: Microbiota-gut-brain axis interacts with one another to regulate brain functions. However, whether the impacts of gut dysbiosis on limbic white matter (WM) tracts contribute to the neuropsychiatric symptoms (NPS) in patients with amyloid-positive amnestic mild cognitive impairment (aMCI+), have not been explored yet. This study aimed to investigate the mediation effects of limbic WM integrity on the association between gut microbiota and NPS in patients with aMCI+. Methods: Twenty patients with aMCI + and 20 healthy controls (HCs) were enrolled. All subjects underwent neuropsychological assessments and their microbial compositions were characterized using 16S rRNA Miseq sequencing technique. Amyloid deposition inspected by positron emission tomography imaging and limbic WM tracts (i.e., fornix, cingulum, and uncinate fasciculus) detected by diffusion tensor imaging were additionally measured in patients with aMCI+. We employed a regression-based mediation analysis using Hayes’s PROCESS macro in this study. Results: The relative abundance of genera Ruminococcus and Lactococcus was significantly decreased in patients with aMCI + versus HCs. The relative abundance of Ruminococcus was negatively correlated with affective symptom cluster in the aMCI + group. Notably, this association was mediated by WM integrity of the left cingulate gyrus. Conclusions: Our findings suggest Ruminococcus as a potential target for the management of affective impairments in patients with aMCI+. © 2023, The Author(s).
Author Keywords
Amnestic mild cognitive impairment; Diffusion tensor imaging; Gut microbiota; Limbic system; Neuropsychiatric symptoms; Ruminococcus
Funding details
Ministry of EducationMOEEMRPD1K0431
Chang Gung Memorial HospitalCGMH
Center for Big Data Analytics and Statistics, Chang Gung Memorial HospitalCBDASCMRPD1K0061, CMRPD1K0581, CMRPG8J0524, CMRPG8J0843, CMRPG8K1533
National Science and Technology CouncilNSTCNSTC-112-2410-H-182-030
Chang Gung UniversityCGUBMRPE25
Ministry of Science and Technology, TaiwanMOSTMOST-108-2628-B-182-002, MOST-109-2628-B-182-012, MOST-110-2628-B-182-010, MOST-111-2314-B-182 A-143
Chang Gung Memorial Hospital, Linkou
Institute for Information Industry, Ministry of Science and Technology, TaiwanIII
Hsinchu Science Park Bureau, Ministry of Science and Technology, TaiwanHSPB, HSP
Document Type: Article
Publication Stage: Final
Source: Scopus
A uniform human multimodal dataset for emotion perception and judgment
(2023) Scientific Data, 10 (1), art. no. 773, .
Sun, S.a b , Cao, R.c , Rutishauser, U.d , Yu, R.e , Wang, S.c
a Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, 980-8578, Japan
b Research Institute of Electrical Communication, Tohoku University, Sendai, 980-8577, Japan
c Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
d Departments of Neurosurgery and Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
e Department of Management, Marketing, and Information Systems, Hong Kong Baptist University, Hong Kong
Abstract
Face perception is a fundamental aspect of human social interaction, yet most research on this topic has focused on single modalities and specific aspects of face perception. Here, we present a comprehensive multimodal dataset for examining facial emotion perception and judgment. This dataset includes EEG data from 97 unique neurotypical participants across 8 experiments, fMRI data from 19 neurotypical participants, single-neuron data from 16 neurosurgical patients (22 sessions), eye tracking data from 24 neurotypical participants, behavioral and eye tracking data from 18 participants with ASD and 15 matched controls, and behavioral data from 3 rare patients with focal bilateral amygdala lesions. Notably, participants from all modalities performed the same task. Overall, this multimodal dataset provides a comprehensive exploration of facial emotion perception, emphasizing the importance of integrating multiple modalities to gain a holistic understanding of this complex cognitive process. This dataset serves as a key missing link between human neuroimaging and neurophysiology literature, and facilitates the study of neuropsychiatric populations. © 2023, The Author(s).
Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
National Institutes of HealthNIHR01MH129426
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088
Dana FoundationDF
Japan Society for the Promotion of ScienceKAKEN22K15626
Document Type: Data Paper
Publication Stage: Final
Source: Scopus
The role of fear of evaluation in group perception
(2023) Journal of Anxiety Disorders, 100, art. no. 102791, .
Shin, J.a , Rodebaugh, T.L.b
a Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
b University of North Carolina at Chapel Hill Department of Psychology and Neuroscience, United States
Abstract
Social anxiety disorder (SAD) is associated with interpersonal impairment. One possible reason for this dysfunction is that people with SAD evaluate others differently on dimensions of warmth and dominance compared to individuals without the disorder. In the current study, we examined whether two core constructs of SAD, fear of negative evaluation and fear of positive evaluation, affect the judgments that people make about groups based on warmth and dominance. We also investigated whether racial similarity (i.e., whether someone is the same race as those they’re interacting with) and ethnic identity (i.e., one’s sense of belonging to a particular social group) played a role in the types of evaluations people made. We created vignettes about groups varying in warmth and dominance, as well as photos varying in racial makeup. We presented photo-vignette pairs to participants and asked them to rate their desire to interact with the groups depicted in the photo-vignette. Participants in general reported greater desire to interact with warmer and less dominant groups. People with higher fear of negative evaluation reported higher desire for interaction with warmer groups, and those with higher fear of positive evaluation reported higher desire to interact with less dominant groups. We did not find any support for our hypothesis that people with stronger ethnic identity would show greater desire to interact with groups that were more similar to their race. Implications for treatment and directions for further research are discussed. © 2023 Elsevier Ltd
Author Keywords
Bivalent fear of evaluation; Dominance; Fear of Negative Evaluation; Fear of positive evaluation; Social Anxiety; Warmth
Document Type: Article
Publication Stage: Final
Source: Scopus
Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits
(2023) Cell Reports, 42 (11), art. no. 113411, .
Beard, D.C.a , Zhang, X.a , Wu, D.Y.a , Martin, J.R.a , Erickson, A.a , Boua, J.V.a , Hamagami, N.a , Swift, R.G.b c , McCullough, K.B.b c , Ge, X.d h , Bell-Hensley, A.e f , Zheng, H.f , Palmer, C.W.b h , Fuhler, N.A.b h , Lawrence, A.B.g , Hill, C.A.g , Papouin, T.a , Noguchi, K.K.b h , McAlinden, A.f , Garbow, J.R.d h h , Dougherty, J.D.b c h , Maloney, S.E.b h , Gabel, H.W.a h
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
f Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, MO 65212, United States
h Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease. © 2023 The Authors
Author Keywords
ASD; CP: Neuroscience; DNA methylation; DNMT3A; enhancer; heterogeneity; mCA; MeCP2; NDD; neurodevelopment; non-CpG
Funding details
F31HD100098, P50HD103525
R01MH117405
National Institute of Neurological Disorders and StrokeNINDSR01NS04102
Simons Foundation Autism Research InitiativeSFARI
Musculoskeletal Research Center, Washington University in St. LouisMRC
Document Type: Article
Publication Stage: Final
Source: Scopus
Testing for Allele-specific Expression from Human Brain Samples
(2023) Bio-protocol, 13 (19), art. no. e4832, .
Diaz-Ortiz, M.E.a , Jain, N.b , Gallagher, M.D.c , Posavi, M.d , Unger, T.L.a , Chen-Plotkin, A.S.a
a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO, United States
c Whitehead Institute for Biomedical Research, Cambridge, MA, United States
d Department of Biology, University of New Mexico, Albuquerque, NM, United States
Abstract
Many single nucleotide polymorphisms (SNPs) identified by genome-wide association studies exert their effects on disease risk as expression quantitative trait loci (eQTL) via allele-specific expression (ASE). While databases for probing eQTLs in tissues from normal individuals exist, one may wish to ascertain eQTLs or ASE in specific tissues or disease-states not characterized in these databases. Here, we present a protocol to assess ASE of two possible target genes (GPNMB and KLHL7) of a known genome-wide association study (GWAS) Parkinson’s disease (PD) risk locus in postmortem human brain tissue from PD and neurologically normal individuals. This was done using a sequence of RNA isolation, cDNA library generation, enrichment for transcripts of interest using customizable cDNA capture probes, paired-end RNA sequencing, and subsequent analysis. This method provides increased sensitivity relative to traditional bulk RNAseq-based and a blueprint that can be extended to the study of other genes, tissues, and disease states. Copyright: © 2023 The Authors; exclusive licensee Bio-protocol LLC.
Author Keywords
Allele-specific expression (ASE); Expression quantitative trait locus (eQTL); Human brain; Neurodegeneration; RNA CaptureSeq
Funding details
National Institutes of HealthNIHF31 NS113481, RO1 NS115139, U19 AG062418
American Heart AssociationAHA
Document Type: Article
Publication Stage: Final
Source: Scopus
Pain-Related Stigma and Its Associations With Clinical and Experimental Pain Severity in Youth With Chronic Musculoskeletal Pain Conditions
(2023) Journal of Pediatric Psychology, 48 (10), pp. 842-851.
Boileau, N.R.a , Thompson-Phillips, K.A.b , Goodin, B.R.a c , Lynch-Milder, M.K.d , Evans, C.T.a , Adetayo, T.a , Rudolph, A.F.a , Stoll, M.L.e , Weiser, P.e , Fobian, A.D.f , Gowey, M.A.g , Wakefield, E.O.h i j
a Department of Psychology, University of Alabama at Birmingham, United States
b Children’s of Alabama, Behavioral Health Ireland Center, United States
c Department of Anesthesiology, Washington University in St. Louis, USA, Japan
d Great Lakes Neurobehavioral Center, USA, Japan
e Department of Pediatrics, Division of Pediatric Rheumatology, University of Alabama at Birmingham, USA, Japan
f Department of Psychiatry & Behavioral Neurobiology, University of Alabama at Birmingham, United States
g Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, & Nutrition, University of Alabama at Birmingham, USA, Japan
h Division of Pain and Palliative Medicine, Connecticut Children’s Medical Center, United States
i Division of Pediatric Psychology, Connecticut Children’s Medical Center, United States
j Department of Pediatrics, University of Connecticut, School of Medicine, United States
Abstract
Objective: Many children with chronic musculoskeletal pain conditions experience stigma which can have negative downstream consequences. This study compares ratings of clinical pain (current pain intensity and pain interference), experimental pain (temporal summation, cold water tolerance, and cold pain intensity), and pain-related stigma among three groups of youth with rheumatic conditions. The relations among ratings of pain-related stigma and pain variables were explored. Methods: Eighty-eight youth aged 8-17 years with a diagnosis of juvenile idiopathic arthritis (JIA = 32), juvenile fibromyalgia (JFM = 31), or non-specific chronic pain (NSCP = 25) completed measures of clinical pain ratings (average 7-day pain intensity, day of assessment pain (DoA), and pain interference), experimental pain (cold pain tolerance, cold pain intensity, and temporal summation of mechanical pain), and pain-related stigma. Data analysis compared pain-related stigma and pain ratings across the three groups and examined the relations among pain-related stigma and pain ratings. Results: Youth with JFM reported higher ratings of clinical pain and pain-related stigma than their counterparts with NSCP or JIA. However, there were no differences in experimental pain. Pain-related stigma was associated with greater ratings of pain interference, particularly for those with JIA and NSCP. Pain-related stigma was also associated with greater average daily pain intensity but not DoA. Conclusion: Youth with medically unexplained pain report greater stigma and worse pain than their peers; thus, robust assessment of pain in this population is necessary. Future work should longitudinally explore the impact of pain-related stigma on pain outcomes and treatment responses. © 2023 The Author(s). Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved.
Author Keywords
chronic and recurrent pain; juvenile arthritis; rheumatology; school age children; social functioning and peers; stress
Funding details
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSK23AR073934
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationship between baseline plasma p-tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults
(2023) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 15 (4), art. no. e12487, .
Pais, M.V.a b , Kuo, C.-L.c , Ances, B.M.d , Wetherell, J.L.e , Lenze, E.J.f , Diniz, B.S.a
a UConn Center on Aging, University of Connecticut Health Center, Farmington, CT, United States
b Laboratory of Neuroscience (LIM-27), Departamento e Instituto de Psiquiatria, Faculdade de Medicina, Universidade de Sao Paulo (FMUSP), Sao Paulo, Brazil
c Department of Public Health Sciences, University of Connecticut Health Center, Farmington, CT, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e VA San Diego Healthcare System and University of California San Diego, San Diego, CA, United States
f Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
INTRODUCTION: Preclinical Alzheimer’s disease (AD) affects a significant proportion of cognitively unimpaired (CU) older adults. Currently, blood-based biomarkers detect very early changes in the AD continuum with great accuracy. METHODS: We measured baseline plasma phosphorylated tau (p-tau)181 using electrochemiluminescence (ECL)-based assay (MesoScale Discovery) in 533 CU older adults. Follow-up lasted up to 18 months. Cognitive performance assessment included memory and cognitive control. Structural brain measures included cortical thickness, which includes the AD magnetic resonance imaging (AD MRI) signature, and hippocampal volume. RESULTS: In this cohort of CU older adults, baseline plasma p-tau181 levels were not associated with short-term changes in cognition and structural brain measures. Also, baseline plasma p-tau levels did not influence the effects of behavioral interventions (exercise or mindfulness) on cognitive and structural brain changes. DISCUSSION: The short follow-up and healthy status of this CU cohort might have limited the sensitivity of plasma p-tau181 in detecting changes associated with AD pathology. © 2023 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; Alzheimer’s disease magnetic resonance imaging signature; cortical thickness; hippocampal volume; plasma phosphorylated tau 181
Funding details
National Institutes of HealthNIHR01AG049689, R01AG072694, R01MH115953
Document Type: Article
Publication Stage: Final
Source: Scopus
Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques
(2023) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 9 (4), art. no. e12431, .
Bathla, S.a , Datta, D.a b , Liang, F.c , Barthelemy, N.d , Wiseman, R.e , Slusher, B.S.e , Asher, J.f , Zeiss, C.f , Ekanayake-Alper, D.f , Holden, D.g , Terwilliger, G.f , Duque, A.b , Arellano, J.b , van Dyck, C.a , Bateman, R.J.g , Xie, Z.f , Nairn, A.C.a , Arnsten, A.F.T.b
a Departments of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b Departments of Neuroscience, Yale University School of Medicine, New Haven, CT, United States
c Department of Anesthesiology, Harvard University School of Medicine, Boston, MA, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Johns Hopkins University Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Departments of Comparative Medicine, Yale University School of Medicine, New Haven, CT, United States
g Departments of Radiology, Yale University School of Medicine, New Haven, CT, United States
Abstract
Introduction: Current approaches for treating sporadic Alzheimer’s disease (sAD) focus on removal of amyloid beta 1-42 (Aβ1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Methods: Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),. Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),. Results: Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. Discussion: These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Highlights: Inflammation is a key driver of sporadic Alzheimer’s disease. GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium. Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys. GCPII inhibition is a novel strategy to help prevent tau pathology at early stages. © 2023 The Authors. Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
calcium; CSF; dorsolateral prefrontal cortex; entorhinal cortex; macaque; mGluR3; plasma; pT217Tau
Funding details
MH113257
National Institutes of HealthNIHAG047270, AG062306, AG066508, DA018343
Connecticut State Department of Mental Health and Addiction ServicesDMHAS
Document Type: Article
Publication Stage: Final
Source: Scopus
Description of the Content and Quality of Publicly Available Information on the Internet About Inhaled Volatile Anesthesia and Total Intravenous Anesthesia: Descriptive Study
(2023) JMIR Perioperative Medicine, 6 (1), art. no. e47714, .
Hu, X.a , Pennington, B.R.T.a , Avidan, M.S.a , Kheterpal, S.b , Debourbon, N.G.c , Politi, M.C.d
a Department of Anesthesiology, Washington University in St Louis, School of Medicine, St Louis, MO, United States
b Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States
c Magnolia Regional Health Center, Corinth, MS, United States
d Department of Surgery, Washington University in St Louis, School of Medicine, St Louis, MO, United States
Abstract
Background: More than 300 million patients undergo surgical procedures requiring anesthesia worldwide annually. There are 2 standard-of-care general anesthesia administration options: inhaled volatile anesthesia (INVA) and total intravenous anesthesia (TIVA). There is limited evidence comparing these methods and their impact on patient experiences and outcomes. Patients often seek this information from sources such as the internet. However, the majority of websites on anesthesia-related topics are not comprehensive, updated, and fully accurate. The quality and availability of web-based patient information about INVA and TIVA have not been sufficiently examined. Objective: This study aimed to (1) assess information on the internet about INVA and TIVA for availability, readability, accuracy, and quality and (2) identify high-quality websites that can be recommended to patients to assist in their anesthesia information-seeking and decision-making. Methods: Web-based searches were conducted using Google from April 2022 to November 2022. Websites were coded using a coding instrument developed based on the International Patient Decision Aids Standards criteria and adapted to be appropriate for assessing websites describing INVA and TIVA. Readability was calculated with the Flesch-Kincaid (F-K) grade level and the simple measure of Gobbledygook (SMOG) readability formula. Results: A total of 67 websites containing 201 individual web pages were included for coding and analysis. Most of the websites provided a basic definition of general anesthesia (unconsciousness, n=57, 85%; analgesia, n=47, 70%). Around half of the websites described common side effects of general anesthesia, while fewer described the rare but serious adverse events, such as intraoperative awareness (n=31, 46%), allergic reactions or anaphylaxis (n=29, 43%), and malignant hyperthermia (n=18, 27%). Of the 67 websites, the median F-K grade level was 11.3 (IQR 9.5-12.8) and the median SMOG score was 13.5 (IQR 12.2-14.4), both far above the American Medical Association (AMA) recommended reading level of sixth grade. A total of 51 (76%) websites distinguished INVA versus TIVA as general anesthesia options. A total of 12 of the 51 (24%) websites explicitly stated that there is a decision to be considered about receiving INVA versus TIVA for general anesthesia. Only 10 (20%) websites made any direct comparisons between INVA and TIVA, discussing their positive and negative features. A total of 12 (24%) websites addressed the concept of shared decision-making in planning anesthesia care, but none specifically asked patients to think about which features of INVA and TIVA matter the most to them. Conclusions: While the majority of websites described INVA and TIVA, few provided comparisons. There is a need for high-quality patient education and decision support about the choice of INVA versus TIVA to provide accurate and more comprehensive information in a format conducive to patient understanding. © 2023, JMIR Publications Inc. All rights reserved.
Author Keywords
anesthesia; anesthesiologist; anesthesiology; decision-making; general anesthesia; information; inhaled volatile anesthesia; internet; patient education; shared decision-making; surgery; total intravenous anesthesia; web-based
Document Type: Article
Publication Stage: Final
Source: Scopus
Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study
(2023) British Journal of Anaesthesia, .
Montana, M.C.a , McLeland, M.b , Fisher, M.a c , Juriga, L.a d , Ercole, P.M.e , Kharasch, E.D.a f
a Department of Anesthesiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
b Sleep Laboratory, Saint Louis Children’s Hospital, St. Louis, MO, United States
c Pediatric Intensive Care Unit, Saint Louis Children’s Hospital, St. Louis, MO, United States
d University of Missouri School of Medicine, Columbia, MO, United States
e Sansom Consulting, Pittsburgh, PA, United States
f Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
Abstract
Background: Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). Methods: This was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml−1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. Results: There were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41–0.61) and subjects without OSA (mean=0.49, 95% CI 0.36–0.62) (mean difference=0.02, 95% CI −0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43–0.68) and subjects without OSA (difference=0.07, 95% CI −0.16 to 0.29); or between untreated OSA and treated OSA (difference=−0.05, 95% CI −0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. Conclusions: Neither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. Clinical trial registration: NCT02898792 (clinicaltrials.gov). © 2023 British Journal of Anaesthesia
Author Keywords
obstructive sleep apnoea; opioid sensitivity; remifentanil; respiratory depression; thermal pain
Funding details
R01 DA042985
National Institutes of HealthNIH
Pharmaceutical Research and Manufacturers of America FoundationPhRMAF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use
(2023) Molecular Psychiatry, .
Fang, F.a , Quach, B.a , Lawrence, K.G.b , van Dongen, J.c d , Marks, J.A.a , Lundgren, S.e , Lin, M.f , Odintsova, V.V.c d g , Costeira, R.h , Xu, Z.b , Zhou, L.a , Mandal, M.a , Xia, Y.h , Vink, J.M.i , Bierut, L.J.j , Ollikainen, M.e k , Taylor, J.A.b , Bell, J.T.h , Kaprio, J.e , Boomsma, D.I.c d , Xu, K.f l , Sandler, D.P.b , Hancock, D.B.a , Johnson, E.O.a m
a GenOmics and Translational Research Center, RTI International, Research Triangle Park, NC, United States
b Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
c Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
d Amsterdam Public Health Research Institute, Amsterdam, Netherlands
e Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
f Department of Psychiatry, Yale School of Medicine, West Haven, CT, United States
g Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
h Department of Twin Research & Genetic Epidemiology, King’s College London, London, United Kingdom
i Behavioural Science Institute, Radboud University, Nijmegen, Netherlands
j Department of Psychiatry, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
k Minerva Foundation Institute for Medical Research, Helsinki, Finland
l VA Connecticut Healthcare System, West Haven, CT, United States
m Fellow Program, RTI International, Research Triangle Park, NC, United States
Abstract
Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9436 participants (7795 European and 1641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 (p< 5.85 × 10 − 7) : cg22572071 near gene ADGRF1, cg15280358 in ADAM12, cg00813162 in ACTN1, and cg01101459 near LINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes. © 2023, The Author(s).
Funding details
National Institute on Drug AbuseNIDAR01DA048824
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A preference to look closer to the eyes is associated with a position-invariant face neural code
(2023) Psychonomic Bulletin and Review, .
Chakravarthula, P.N.a b , Eckstein, M.P.a
a Psychological and Brain Science, University of California, Santa Barbara, CA, United States
b Department of Radiology, Washington University in St. Louis, 4525 Scott Ave, St. Louis, MO 2126 B63110, United States
Abstract
When looking at faces, humans invariably move their eyes to a consistent preferred first fixation location on the face. While most people have the preferred fixation location just below the eyes, a minority have it between the nose-tip and mouth. Not much is known about whether these long-term differences in the preferred fixation location are associated with distinct neural representations of faces. To study this, we used a gaze-contingent face adaptation aftereffect paradigm to test in two groups of observers, one with their mean preferred fixation location closer to the eyes (upper lookers) and the other closer to the mouth (lower lookers). In this task, participants were required to maintain their gaze at either their own group’s mean preferred fixation location or that of the other group during adaptation and testing. The two possible fixation locations were 3.6° apart on the face. We measured the face adaptation aftereffects when the adaptation and testing happened while participants maintained fixation at either the same or different locations on the face. Both groups showed equally strong adaptation effects when the adaptation and testing happened at the same fixation location. Crucially, only the upper lookers showed a partial transfer of the FAE across the two fixation locations, when adaptation occurred at the eyes. Lower lookers showed no spatial transfer of the FAE irrespective of the adaptation position. Given the classic finding that neural tuning is increasingly position invariant as one moves higher in the visual hierarchy, this result suggests that differences in the preferred fixation location are associated with distinct neural representations of faces. © 2023, The Author(s).
Author Keywords
Adaptation aftereffects; Eye movements; Face perception; Individual differences
Document Type: Article
Publication Stage: Article in Press
Source: Scopus