Scopus list of publications for September 3, 2023
Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
(2023) Nature Communications, 14 (1), art. no. 5197, .
Lee, J.a , Dimitry, J.M.a , Song, J.H.b , Son, M.b , Sheehan, P.W.a , King, M.W.a , Travis Tabor, G.c , Goo, Y.A.b , Lazar, M.A.d , Petrucelli, L.e , Musiek, E.S.a
a Department of Neurology and Center On Biological Rhythms And Sleep, Washington University School of Medicine, St. Louis, MO, United States
b Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
Abstract
Alzheimer’s disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy. © 2023, Springer Nature Limited.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAU19AG060909
National Cancer InstituteNCI30 CA91842
National Center for Research ResourcesNCRR
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
University of WashingtonUW
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis586 R35NS097273, P01NS084974-01, R01DK45586, R35NS097273, RF1AG062077, RF1AG062171
Document Type: Article
Publication Stage: Final
Source: Scopus
Enhanced in vivo blood brain barrier transcytosis of macromolecular cargo using an engineered pH-sensitive mouse transferrin receptor binding nanobody
(2023) Fluids and Barriers of the CNS, 20 (1), art. no. 64, .
Esparza, T.J.a b , Su, S.a c , Francescutti, C.M.a , Rodionova, E.a , Kim, J.H.a b , Brody, D.L.a d e
a National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
b Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Center for Neuroscience and Regenerative Medicine, Bethesda, MD, United States
e Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
Abstract
Background: The blood brain barrier limits entry of macromolecular diagnostic and therapeutic cargos. Blood brain barrier transcytosis via receptor mediated transport systems, such as the transferrin receptor, can be used to carry macromolecular cargos with variable efficiency. Transcytosis involves trafficking through acidified intracellular vesicles, but it is not known whether pH-dependent unbinding of transport shuttles can be used to improve blood brain barrier transport efficiency. Methods: A mouse transferrin receptor binding nanobody, NIH-mTfR-M1, was engineered to confer greater unbinding at pH 5.5 vs 7.4 by introducing multiple histidine mutations. The histidine mutant nanobodies were coupled to neurotensin for in vivo functional blood brain barrier transcytosis testing via central neurotensin-mediated hypothermia in wild-type mice. Multi-nanobody constructs including the mutant M1R56H, P96H, Y102H and two copies of the P2X7 receptor-binding 13A7 nanobody were produced to test proof-of-concept macromolecular cargo transport in vivo using quantitatively verified capillary depleted brain lysates and in situ histology. Results: The most effective histidine mutant, M1R56H, P96H, Y102H-neurotensin, caused > 8 °C hypothermia after 25 nmol/kg intravenous injection. Levels of the heterotrimeric construct M1R56H, P96H, Y102H-13A7-13A7 in capillary depleted brain lysates peaked at 1 h and were 60% retained at 8 h. A control construct with no brain targets was only 15% retained at 8 h. Addition of the albumin-binding Nb80 nanobody to make M1R56H, P96H, Y102H-13A7-13A7-Nb80 extended blood half-life from 21 min to 2.6 h. At 30–60 min, biotinylated M1R56H, P96H, Y102H-13A7-13A7-Nb80 was visualized in capillaries using in situ histochemistry, whereas at 2–16 h it was detected in diffuse hippocampal and cortical cellular structures. Levels of M1R56H, P96H, Y102H-13A7-13A7-Nb80 reached more than 3.5 percent injected dose/gram of brain tissue after 30 nmol/kg intravenous injection. However, higher injected concentrations did not result in higher brain levels, compatible with saturation and an apparent substrate inhibitory effect. Conclusion: The pH-sensitive mouse transferrin receptor binding nanobody M1R56H, P96H, Y102H may be a useful tool for rapid and efficient modular transport of diagnostic and therapeutic macromolecular cargos across the blood brain barrier in mouse models. Additional development will be required to determine whether this nanobody-based shuttle system will be useful for imaging and fast-acting therapeutic applications. © 2023, BioMed Central Ltd., part of Springer Nature.
Author Keywords
Blood brain barrier; Capillary depletion; Histidine; Mouse; Nanobody; Neurotensin; P2X7 receptor; Transferrin receptor
Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS
Henry M. Jackson FoundationHJF
Uniformed Services University of the Health SciencesUSUHS
Document Type: Article
Publication Stage: Final
Source: Scopus
The association between maternal urinary Bisphenol A levels and neurodevelopment at age 2 years in Chinese boys and girls: A prospective cohort study
(2023) Ecotoxicology and Environmental Safety, 264, art. no. 115413, .
Wang, X.a b , Luo, Z.-C.a c , Du, O.a d , Zhang, H.-J.e , Fan, P.a , Ma, R.a , Chen, Y.a , Wang, W.a , Zhang, J.a , Ouyang, F.a
a Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
b Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
c Department of Obstetrics and Gynecology, Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
d Department of Electrical and Systems Engineering, McKelvey School of Engineering at Washington University in St. Louis, United States
e Department of Pathology, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
Abstract
The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 μg/g. creatinine) and 99.8% children (GM: 3.4 μg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: −8.3, −1.2) in gross motor and 3.7 points lower (95% CI: −7.4, −0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free “in utero” environment. © 2023 The Authors
Author Keywords
Bisphenol A (BPA); Child neurodevelopment; Cognitive ability; Maternal exposure; The Ages & Stages Questionnaires; Third Edition (ASQ-3)
Funding details
Shanghai Municipal Health Commission2020CXJQ01
National Natural Science Foundation of ChinaNSFC81961128023
Shanghai Municipal Education Commission20152518
National Key Research and Development Program of ChinaNKRDPC2017YFE0124700, 81102139, 81673178, 81803256
Document Type: Article
Publication Stage: Final
Source: Scopus
Neural basis of sound-symbolic pseudoword-shape correspondences
(2023) Neuropsychologia, 188, art. no. 108657, .
Barany, D.A.a , Lacey, S.b c d , Matthews, K.L.e f , Nygaard, L.C.e , Sathian, K.b c d
a Department of Kinesiology, University of Georgia and Augusta University/University of Georgia Medical Partnership, Athens, GA 30602, United States
b Department of Neurology, Penn State College of Medicine, Hershey, PA 17033-0859, United States
c Department of Neural & Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033-0859, United States
d Department of Psychology, Penn State College of Liberal Arts, University ParkPA 16802, United States
e Department of Psychology, Emory University, Atlanta, GA 30322, United States
f Present address: Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Non-arbitrary mapping between the sound of a word and its meaning, termed sound symbolism, is commonly studied through crossmodal correspondences between sounds and visual shapes, e.g., auditory pseudowords, like ‘mohloh’ and ‘kehteh’, are matched to rounded and pointed visual shapes, respectively. Here, we used functional magnetic resonance imaging (fMRI) during a crossmodal matching task to investigate the hypotheses that sound symbolism (1) involves language processing; (2) depends on multisensory integration; (3) reflects embodiment of speech in hand movements. These hypotheses lead to corresponding neuroanatomical predictions of crossmodal congruency effects in (1) the language network; (2) areas mediating multisensory processing, including visual and auditory cortex; (3) regions responsible for sensorimotor control of the hand and mouth. Right-handed participants (n = 22) encountered audiovisual stimuli comprising a simultaneously presented visual shape (rounded or pointed) and an auditory pseudoword (‘mohloh’ or ‘kehteh’) and indicated via a right-hand keypress whether the stimuli matched or not. Reaction times were faster for congruent than incongruent stimuli. Univariate analysis showed that activity was greater for the congruent compared to the incongruent condition in the left primary and association auditory cortex, and left anterior fusiform/parahippocampal gyri. Multivoxel pattern analysis revealed higher classification accuracy for the audiovisual stimuli when congruent than when incongruent, in the pars opercularis of the left inferior frontal (Broca’s area), the left supramarginal, and the right mid-occipital gyri. These findings, considered in relation to the neuroanatomical predictions, support the first two hypotheses and suggest that sound symbolism involves both language processing and multisensory integration. © 2023 Elsevier Ltd
Author Keywords
fMRI; Language; Multisensory; Multivoxel pattern analysis; Sound symbolism
Funding details
National Institutes of HealthNIHR01 EY025978
National Eye InstituteNEI
U.S. Department of Veterans AffairsVA
Document Type: Article
Publication Stage: Final
Source: Scopus
Awake Hippocampal–Cortical Co-reactivation Is Associated with Forgetting
(2023) Journal of Cognitive Neuroscience, 35 (9), pp. 1446-1462.
Tanrıverdi, B.a , Cowan, E.T.a , Metoki, A.b , Jobson, K.R.a , Murty, V.P.a , Chein, J.a , Olson, I.R.a
a Temple University, Philadelphia, PA, United States
b Washington University, St. Louis, MO, United States
Abstract
Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex [Moscovitch, M., & Gilboa, A. Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. PsyArXiv, 2021; Kumaran, D., Hassabis, D., & McClelland,J.L.Whatlearningsystemsdointelligentagents need? Complementary learning systems theory updated. Trends in Cognitive Sciences, 20, 512–534, 2016; McClelland, J. L., & O’Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419–457, 1995]. Recent sleep studies in rodents have shown that hippocam-pus and visual cortex replay the same information at temporal proximity (“co-replay”; Lansink,C.S.,Goltstein,P.M., Lankelma, J. V., McNaughton, B. L., & Pennartz, C. M. A. Hip-pocampus leads ventral striatum in replay of place-reward information. PLoS Biology, 7, e1000173, 2009; Peyrache, A., Khamassi,M.,Benchenane,K.,Wiener,S.I.,&Battaglia,F. P. Replay of rule-learning related neural patterns in the pre-frontal cortex during sleep. Nature Neuroscience, 12, 919– 926,2009;Wierzynski,C.M.,Lubenov,E.V.,Gu,M.,&Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron, 61, 587–596, 2009; Ji, D., & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100–107, 2007). We developed a novel repetition time (TR)-based co-reactivation analysis method to study hippocampal–cortical co-replays in humans using fMRI. Thirty-six young adults completed an image (face or scene) and location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (± 1) that showed neural reactivation of each image–location trials in both hippo-campus (HPC) and category-selective cortex (fusiform face area [FFA]). This allowed us to characterize temporally proxi-mal coordinated reactivations (“co-reactivations”) between HPC and FFA. Moreover, we found that increased HPC–FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p =.004). Finally, we found that these HPC–FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p =.043) and 1-week delay period (p =.031). We discuss these results from a trace transformation perspective [Sekeres, M. J., Winocur, G., & Moscovitch, M. The hippocampus and related neocortical structures in memory transformation. Neuroscience Letters, 680, 39–53, 2018; Winocur, G., & Moscovitch, M. Memory transformation and systems consolidation. Journal of the International Neuropsychological Society, 17, 766–780, 2011] and speculate that HPC–FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting. © 2023 Massachusetts Institute of Technology.
Funding details
National Science FoundationNSF1625061
National Institutes of HealthNIHR01DA055259, R01HD098097, R01HD099165, R01MH091113, R21DA043568, R21HD098509
Army Research LaboratoryARLW911NF-16-2-0189
Document Type: Article
Publication Stage: Final
Source: Scopus
A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders
(2023) Addiction Biology, 28 (9), art. no. e13319, .
Poore, H.E.a , Hatoum, A.b , Mallard, T.T.c , Sanchez-Roige, S.d e , Waldman, I.D.f , Palmer, A.A.d g , Harden, K.P.h i , Barr, P.B.j k , Dick, D.M.a
a Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
d Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
e Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
f Department of Psychology, Emory University, Atlanta, GA, United States
g Institute for Genomic Medicine, University of California, San Diego, San Diego, CA, United States
h Department of Psychology, University of Texas at Austin, Austin, TX, United States
i Population Research Center, University of Texas at Austin, Austin, TX, United States
j Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
k VA New York Harbor Healthcare System, Brooklyn, NY, United States
Abstract
Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under-control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate genome-wide association studies of an externalizing and an addiction risk factor, respectively. We first evaluated five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures and a bifactor model. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. Finally, we quantified the degree of polygenic overlap between externalizing and addiction risk using MiXeR. We found that the common and two-factor structures provided the best fit to the data, evidenced by high factor loadings, good factor reliability and no evidence of concerning model characteristics. The two-factor models yielded high genetic correlations between factors (rgs ≥ 0.87), and between the effect sizes of genetic correlations with external traits (rg ≥ 0.95). Nevertheless, 21 of the 84 correlations with external criteria showed small, significant differences between externalizing and addiction risk factors. MiXer results showed that approximately 81% of influential externalizing variants were shared with addiction risk, whereas addiction risk shared 56% of its influential variants with externalizing. These results suggest that externalizing and addiction genetic risk are largely shared, though both constructs also retain meaningful unshared genetic variance. These results can inform future efforts to identify specific genetic influences on externalizing and SUDs. © 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
Author Keywords
externalizing; genomic structural equation modelling; substance use disorders
Funding details
National Institute on Drug AbuseNIDAR01DA050721
National Institute on Alcohol Abuse and AlcoholismNIAAAK01AA030083, P50AA022537, P50DA037844, T32AA028254
Document Type: Article
Publication Stage: Final
Source: Scopus
Aicardi Syndrome Is a Genetically Heterogeneous Disorder
(2023) Genes, 14 (8), art. no. 1565, .
Ha, T.T.a b , Burgess, R.c , Newman, M.d , Moey, C.e , Mandelstam, S.A.f g , Gardner, A.E.h , Ivancevic, A.M.i , Pham, D.h , Kumar, R.h , Smith, N.h j , Patel, C.k , Malone, S.l , Ryan, M.M.f m n , Calvert, S.o , van Eyk, C.L.h , Lardelli, M.d , Berkovic, S.F.c , Leventer, R.J.f m n , Richards, L.J.e p , Scheffer, I.E.c f m n q , Gecz, J.a h r , Corbett, M.A.h
a School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia
b Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance between SA Pathology, University of South Australia, Adelaide, SA 5000, Australia
c Epilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia
d Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia
e The Queensland Brain Institute, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
f Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
g Department of Medical Imaging, The Royal Children’s Hospital, Melbourne, VIC 3052, Australia
h Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
i Department of Molecular, Cellular, and Developmental Biology, College of Arts and Sciences, University of Colorado, Boulder, CO 80309, United States
j Department of Neurology, Women’s and Children’s Hospital, North AdelaideSA 5006, Australia
k Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia
l Queensland Children’s Hospital, South BrisbaneQLD 4101, Australia
m Department of Neurology, The Royal Children’s Hospital, Parkville, VIC 3052, Australia
n Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
o Department of Neurosciences, Queensland Children’s Hospital, South BrisbaneQLD 4101, Australia
p Department of Neuroscience, School of Medicine, Washington University, St Louis, MO 63110, United States
q Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
r South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
Abstract
Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development. © 2023 by the authors.
Author Keywords
developmental epileptic encephalopathy; DNA repair; DNA sequencing; sex bias; wnt signalling; X-linked
Funding details
Australian Research CouncilARCDP200102363
National Health and Medical Research CouncilNHMRC1091593, 1104831, 1120615, 1155224, 1159783, 1172897, 2010562
Channel 7 Children’s Research FoundationCRF
Cerebral Palsy AllianceCPACDG9416
Women’s and Children’s Hospital Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
A Comprehensive Report of Intrinsically Disordered Regions in Inherited Retinal Diseases
(2023) Genes, 14 (8), art. no. 1601, .
Lee, K.E.a , Pulido, J.S.b , da Palma, M.M.c , Procopio, R.a , Hufnagel, R.B.d , Reynolds, M.e
a Department of Pediatric Ophthalmology and Strabismus, Wills Eye Hospital, Philadelphia, PA 19107, United States
b Retina Service, Wills Eye Hospital, Philadelphia, PA 19107, United States
c Department of Ophthalmology, Federal University of São Paulo, UNIFESP, SP, São Paulo, 04023-062, Brazil
d Medical Genetics and Ophthalmic Genetics Unit, National Eye Institute, Bethesda, MD 20892, United States
e Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Background/purpose: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated. Methods: IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder. Main outcome measures: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation. Results: We included 287 RetNet genes with relevant data available from gnomAD. Mean percent disorder was 26.3% ± 26.0%, mean percent pathogenicity was 5.2% ± 11.0%, mean number of total missense variants was 424.4 ± 450.0, and mean percent total missense was 50.0% ± 13.4%. The percent disorder followed a bimodal distribution with the highest number of occurrences in the 0 to 10th disorder decile. The five outlier proteins in the first disorder decile with a higher-than-expected number of total missense variation were identified (HMCN1, ADGRV, USH2A, DYNC2H1, LAMA1, and SLC38A8). When excluded, % total missense was significantly associated with percent disorder (R = 0.238 and p = 0.0240). Conclusions: This novel study examining all genes implicated in IRDs found that the majority genes had a disorder in the 0 to 10th decile and were relatively intolerant to missense variation. This may have future utility when interpreting variants of undetermined significance and missense variants. © 2023 by the authors.
Author Keywords
genetics; IDR; inherited eye diseases; intrinsically disordered regions; IRD; proteins; RetNet
Document Type: Article
Publication Stage: Final
Source: Scopus
PROMIS Physical Function and Pain Interference Scores Correlate with the Lower Extremity Toronto Extremity Salvage Score
(2023) JBJS Open Access, 8 (3), art. no. 00011, .
Jin, J.a , Hong, Z.a , Rhea, L.b , McDonald, D.J.a , O’Keefe, R.J.a , Cipriano, C.A.c
a Division of Musculoskeletal Oncology, Department of Orthopaedic Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Division of Orthopaedic Oncology, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Background:The Toronto Extremity Salvage Score (TESS) and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) are both utilized to measure patient-reported outcomes in adults with musculoskeletal oncologic conditions. However, the relationship between them has not been studied. We sought to describe a link between Lower Extremity (LE) TESS and PROMIS Physical Function (PF) scores, as well as between LE TESS and Pain Interference (PI) scores, to develop a method for converting scores between TESS and PROMIS and to examine whether TESS and PROMIS captured differences in pain and function between clinically relevant subgroups in our population.Methods:Our study population consisted of 125 adult patients who underwent surgical treatment of a lower-extremity musculoskeletal tumor at a single sarcoma center between December 2015 and October 2018. The LE TESS questionnaire was administered to patients via paper and the PROMIS PF and PI were administered via iPad at a preoperative appointment. The relationship between LE TESS and PROMIS measures was analyzed with use of generalized linear modeling. Subgroup analyses were performed with a 2-tailed t test or 1-way analysis of variance.Results:PROMIS PF had a very strong positive correlation with LE TESS (r = 0.83) and was related through the following equation: PROMIS PF = 0.00294 × (LE TESS)2 + 22.6. PROMIS PI had a strong negative correlation with LE TESS (r = -0.77) and was related through the following equation: PROMIS PI = -0.00259 × (LE TESS)2 + 73.8. PROMIS PF and PI performed similarly to LE TESS across multiple patient subgroups and captured the expected differences between subgroups.Conclusions:LE TESS and PROMIS PF appeared to measure similar information in patients with an orthopaedic oncologic condition. Moreover, PROMIS PI scores were strongly correlated with functional disability as measured with the LE TESS. Understanding the relationship between TESS and PROMIS will allow the comparison and combination of data for both clinical and research purposes.Level of Evidence:Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
AT(N) biomarker profiles and Alzheimer’s disease symptomology in Down syndrome
(2023) Alzheimer’s and Dementia, .
Hartley, S.L.a b , Handen, B.c , Tudorascu, D.c , Lee, L.c , Cohen, A.c , Schworer, E.K.a , Peven, J.C.c , Zammit, M.a d , Klunk, W.c , Laymon, C.e f , Minhas, D.e , Luo, W.e , Zaman, S.g , Ances, B.h , Preboske, G.i , Christian, B.T.a d
a Waisman Center, University of Wisconsin–Madison, Madison, WI, United States
b School of Human Ecology, University of Wisconsin–Madison, Madison, WI, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Medical Physics, University of Wisconsin–Madison, Madison, WI, United States
e Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
g Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
h Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
i Mayo Clinic, Rochester, MN, United States
Abstract
INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer’s disease (AD). The National Institute on Aging–Alzheimer’s Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer’s Biomarker Consortium–Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11C]Pittsburgh compound B) and tau (10 mCi of [18F]AV-1451) were used to classify amyloid (A) –/+ and tau (T) +/–. Hippocampal volume classified neurodegeneration (N) –/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A–/T–/(N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A–T–(N)– and A+T–(N)–. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)–/tau (T)–/neurodegeneration (N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer’s disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
adults; Alzheimer’s; amyloid; ATN; biomarker; cognitive; dementia; Down syndrome; hippocampal; imaging; magnetic resonance imaging; memory; positron emission tomography; tau
Funding details
National Institute on AgingNIA
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD105353, R01AG031110, UO1 AG051406, UO1 AG051412
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterizing the emergence of amyloid and tau burden in Down syndrome
(2023) Alzheimer’s and Dementia, .
Zammit, M.D.a , Betthauser, T.J.b c , McVea, A.K.a , Laymon, C.M.d , Tudorascu, D.L.e , Johnson, S.C.b c , Hartley, S.L.a , Converse, A.K.a , Minhas, D.S.d , Zaman, S.H.f , Ances, B.M.g , Stone, C.K.c , Mathis, C.A.e , Cohen, A.D.e , Klunk, W.E.e , Handen, B.L.e , Christian, B.T.a h
a University of Wisconsin-Madison Waisman Center, Madison, WI, United States
b University of Wisconsin-Madison Alzheimer’s Disease Research Center, Madison, WI, United States
c Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
d Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
f Cambridge Intellectual Disability Research Group, University of Cambridge, Cambridge, United Kingdom
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
Abstract
INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer’s disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aβ) trajectories were modeled to provide individual-level estimates of Aβ-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0–2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. Highlights: Longitudinal amyloid trajectories reveal rapid Aβ accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5–5 years after reaching A+. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; amyloid chronicity; Down syndrome; longitudinal; PET; Tau; trajectory modeling
Funding details
P50 HD105353, U54 HD087011, U54 HD090256
U24 AG21886
National Institutes of HealthNIHP30 AG062421, P30 AG062715, P30 AG066519, P50 AG005133, P50 AG005681, P50 AG008702, P50 AG16537
National Institute on AgingNIA
National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, U01 AG051412, U19 AG068054
National Center for Advancing Translational SciencesNCATSUL1 TR001414, UL1 TR001857, UL1 TR001873, UL1 TR002345, UL1 TR002373
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
NIHR Cambridge Biomedical Research Centre
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
(2023) European Journal of Human Genetics, .
Oppermann, H.a , Marcos-Grañeda, E.b , Weiss, L.A.b , Gurnett, C.A.c , Jelsig, A.M.d , Vineke, S.H.d , Isidor, B.e , Mercier, S.e f , Magnussen, K.g , Zacher, P.h , Hashim, M.i , Pagnamenta, A.T.i , Race, S.j , Srivastava, S.k , Frazier, Z.k , Maiwald, R.l , Pergande, M.m , Milani, D.n , Rinelli, M.o p , Levy, J.q , Krey, I.a , Fontana, P.r , Lonardo, F.r , Riley, S.s , Kretzer, J.s , Rankin, J.t , Reis, L.M.u , Semina, E.V.u , Reuter, M.S.v w , Scherer, S.W.v w , Iascone, M.x , Weis, D.y , Fagerberg, C.R.z , Brasch-Andersen, C.z , Hansen, L.K.aa , Kuechler, A.ab , Noble, N.ac , Gardham, A.ad , Tenney, J.ae , Rathore, G.af , Beck-Woedl, S.ag , Haack, T.B.ag , Pavlidou, D.C.ah , Atallah, I.ah , Vodopiutz, J.ai aj , Janecke, A.R.ak al , Hsieh, T.-C.am , Lesmann, H.am an , Klinkhammer, H.am ao , Krawitz, P.M.am , Lemke, J.R.a ap , Jamra, R.A.a , Nieto, M.b , Tümer, Z.aq ar , Platzer, K.a
a Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
b Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Dpt. of Clinical Genetics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
e Service de Génétique Médicale, CHU de Nantes, Nantes, France
f L’institut du thorax, Inserm, Cnrs, Univ Nantes, Nantes, France
g Randall Children’s Hospital at Legacy Emanuel, Portland, OR, United States
h Epilepsy Center Kleinwachau, Radeberg, Germany
i NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
j BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
k Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
l MVZ for Coagulation Diagnostics and Medical Genetics Cologne, ÜBAG Zotz/Klimas, Cologne, Germany
m MVZ Düsseldorf Zentrum, ÜBAG Zotz/Klimas, Düsseldorf, Germany
n Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy
o Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
p Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
q Genetics Department, CHU Robert-Debré, AP-HP, Paris, France
r Medical Genetics Unit, A.O.R.N. San Pio, Benevento, Italy
s Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
t Department of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, United Kingdom
u Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee, WI, United States
v The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
w Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
x Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, Bergamo, Italy
y Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria
z Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
aa HC Andersen Childrens Hospital, Odense University Hospital, Odense, Denmark
ab Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
ac Blank Children’s Developmental Center, Unity Point Health, Des Moines, IA, United States
ad North West Thames Regional Genetic Service, North West London Hospitals, London, United Kingdom
ae Division of Medical Genetics, University of California, San Francisco, CA, United States
af Dvision of Pediatric Neurology, University of Nebraska Medical Center, Omaha, NE, United States
ag Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
ah Division of Genetic Medicine, Lausanne Universitary Hospital and University of Lausanne, Lausanne, Switzerland
ai Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
aj Vienna Bone and Growth Center, Vienna, Austria
ak Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria
al Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
am Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
an Institut für Humangenetik, Universitätsklinikum Bonn, Universität Bonn, Bonn, Germany
ao Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
ap Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
aq Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
ar Department of Clinical Medicin, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1 +/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1 +/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course. © 2023, The Author(s).
Funding details
National Institutes of HealthNIHP50 HD103525, PID2020-112831GB-I00 AEI /10.13039/501100011033
National Institute of Neurological Disorders and StrokeNINDSK23NS119666
Autism SpeaksAS
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Ministerio de Ciencia, Innovación y UniversidadesMCIUEY025718, FPU18/06240
Sick Kids Foundation
McLaughlin Centre, University of Toronto
Region Syddanmark
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial
(2023) CJC Open, .
Spence, J.a , Belley-Côté, E.b , Jacobsohn, E.c , Lee, S.F.d , D’Aragon, F.e , Avidan, M.f , Mazer, C.D.g , Rousseau-Saine, N.h , Rajamohan, R.i , Pryor, K.j , Klein, R.i , Tan, E.C.-H.k , Cameron, M.l , Di Sante, E.m , DeBorba, E.m , Mustard, M.n , Couture, E.o , Zamper, R.p , Law, M.i , Djaiani, G.q , Saha, T.r , Choi, S.q , Hedlin, P.s , Pikaluk, R.s , Lam, W.Y.t , Deschamps, A.h , Whitlock, R.u , Dulong, B.k , Devereaux, P.J.b , Beaver, C.v , Kloppenburg, S.w , Oczkowski, S.x , McIntyre, W.F.y , McFarling, M.z , Lamy, A.aa , Vincent, J.m , Connolly, S.ab , B-Free Investigatorsac
a Departments of Anesthesia and Critical Care and Health Research Methods, Evaluation, and Impact, McMaster University; and Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada
b Departments of Medicine (Cardiology and Critical Care), and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada
c Departments of Anesthesia and Perioperative Medicine and Medicine (Critical Care), University of Manitoba, Winnipeg, MB, Canada
d Department of Health Research Methods, Evaluation, and Impact, McMaster University, and Population Health Research Institute, Hamilton, ON, Canada
e Département d’anesthésiologie, Université de Sherbrooke, Sherbrooke, QC, Canada
f Department of Anesthesia, Washington University at St. Louis, St. Louis, MO, United States
g Department of Anesthesia and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada
h Département d’anesthésiologie, Université de Montréal, Montréal, QC, Canada
i Department of Anesthesia, University of British Columbia, Vancouver, BC, Canada
j Department of Anesthesiology, Weill Cornell Medical College, New York, NY, United States
k Department of Anesthesia, Dalhousie University, Halifax, NS, Canada
l Department of Anesthesia, McGill University, Montreal, QC, Canada
m Population Health Research Institute, McMaster University, Hamilton, ON, Canada
n St. Michael’s Hospital, Toronto, ON, Canada
o Département d’anesthésiologie, Université Laval, Quebec City, QC, Canada
p Department of Anesthesia, University of Western Ontario, London, ON, Canada
q Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada
r Department of Anesthesia, Queen’s University, Kingston, ON, Canada
s Department of Anesthesia, University of Saskatchewan, Saskatoon, SK, Canada
t Department of Anesthesia, University of Alberta, Edmonton, AB, Canada
u Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada
v Sheridan College, Brampton, ON, Canada
w Population Health Research Institute, Hamilton, ON, Canada
x Department of Medicine (Critical Care), McMaster University, Hamilton, ON, Canada
y Department of Medicine (Cardiology), McMaster University, and Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada
z Department of Anesthesia, McMaster University, Hamilton, ON, Canada
aa Departments of Surgery (Cardiac Surgery) and Health Research Methods, Evaluation, and Impact, McMaster University, Perioperative Research Division, Population Health Research Institute, Hamilton, ON, Canada
ab Department of Medicine (Cardiology), McMaster University, and Population Health Research Institute, Hamilton, ON, Canada
Abstract
Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group agrees to apply both benzodiazepine policies per their randomization, and patients are assessed for postoperative delirium every 12 hours in routine clinical care. Hospitals apply the restricted or liberal benzodiazepine policy during 12 to 18 crossover periods of 4 weeks each. Randomization for all periods takes place in advance of site startup; sites are notified of their allocated policy during the last week of each crossover period. Policies are applied to all patients undergoing cardiac surgery during the trial period. The primary outcome is the incidence of delirium at up to 72 hours after surgery. The B-Free trial will enroll ≥ 18,000 patients undergoing cardiac surgery at 20 hospitals across North America. Delirium is common after cardiac surgery, and benzodiazepines are associated with the occurrence of delirium. The B-Free trial will determine whether an institutional policy restricting the administration of benzodiazepines during cardiac surgery reduces the incidence of delirium after cardiac surgery. Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019). © 2023 The Authors
Funding details
Canadian Institutes of Health ResearchIRSC
Heart and Stroke Foundation of CanadaHSF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum
(2023) Annals of Neurology, .
Zhang, L.a , Flagan, T.M.a , Häkkinen, S.a , Chu, S.A.a , Brown, J.A.a , Lee, A.J.a , Pasquini, L.a , Mandelli, M.L.a , Gorno-Tempini, M.L.a , Sturm, V.E.a , Yokoyama, J.S.a , Appleby, B.S.b , Cobigo, Y.a , Dickerson, B.C.c , Domoto-Reilly, K.d , Geschwind, D.H.e , Ghoshal, N.f , Graff-Radford, N.R.g , Grossman, M.h , Hsiung, G.-Y.R.i , Huey, E.D.j , Kantarci, K.k , Lario Lago, A.a , Litvan, I.l , Mackenzie, I.R.i , Mendez, M.F.e , Onyike, C.U.m , Ramos, E.M.e , Roberson, E.D.n , Tartaglia, M.C.o , Toga, A.W.p , Weintraub, S.q , Wszolek, Z.K.g , Forsberg, L.K.k , Heuer, H.W.a , Boeve, B.F.k , Boxer, A.L.a , Rosen, H.J.a , Miller, B.L.a , Seeley, W.W.a , Lee, S.E.a
a Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
b Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
c Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
d Department of Neurology, University of Washington, Seattle, WA, United States
e Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
f Departments of Neurology and Psychiatry, Washington University School of Medicine, St Louis, MO, United States
g Mayo Clinic, Jacksonville, FL, United States
h Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
i University of British Columbia, Vancouver, BC, Canada
j Departments of Psychiatry and Neurology, Columbia University, New York, NY, United States
k Department of Neurology, Mayo Clinic, Rochester, MN, United States
l Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
m Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
n Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
o Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, University of Toronto, Toronto, ON, Canada
p University of Southern California, Laboratory of Neuroimaging (LONI), Los Angeles, CA, United States
q Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern Feinberg School of Medicine, Chicago, IL, United States
Abstract
Objective: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. Methods: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. Results: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. Interpretation: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers’ baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023. © 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
U24AG021886
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSU54 NS092089
National Center for Advancing Translational SciencesNCATSU01 AG045390
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A high-performance speech neuroprosthesis
(2023) Nature, 620 (7976), pp. 1031-1036. Cited 1 time.
Willett, F.R.a , Kunz, E.M.b c , Fan, C.d , Avansino, D.T.a , Wilson, G.H.e , Choi, E.Y.f , Kamdar, F.f , Glasser, M.F.g h , Hochberg, L.R.i j k , Druckmann, S.l , Shenoy, K.V.a b c l m n , Henderson, J.M.c f
a Howard Hughes Medical Institute at Stanford University, Stanford, CA, United States
b Department of Electrical Engineering, Stanford University, Stanford, CA, United States
c Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
d Department of Computer Science, Stanford University, Stanford, CA, United States
e Department of Neuroscience, Stanford University, Stanford, CA, United States
f Department of Neurosurgery, Stanford University, Stanford, CA, United States
g Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
h Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
i VA RR&D Center for Neurorestoration and Neurotechnology, Rehabilitation R&D Service, Providence VA Medical Center, Providence, RI, United States
j School of Engineering and Carney Institute for Brain Science, Brown University, Providence, RI, United States
k Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
l Department of Neurobiology, Stanford University, Stanford, CA, United States
m Department of Bioengineering, Stanford University, Stanford, CA, United States
n Bio-X Program, Stanford University, Stanford, CA, United States
Abstract
Speech brain–computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text1,2 or sound3,4. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary1–7. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant—who can no longer speak intelligibly owing to amyotrophic lateral sclerosis—achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI2) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant’s attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record8 and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak. © 2023, The Author(s).
Funding details
Howard Hughes Medical InstituteHHMI
National Institute on Deafness and Other Communication DisordersNIDCDU01-DC017844, U01-DC019430
U.S. Department of Veterans AffairsVAA2295R, N2864C
Wu Tsai Neurosciences Institute, Stanford University
Document Type: Article
Publication Stage: Final
Source: Scopus
Psychotic-like experiences and adverse life events in young people. Does gender matter?
(2023) Child and Adolescent Mental Health, .
Adjorlolo, S.a b , Awortwe, V.c , Anum, A.d , Huang, K.-Y.e f , Mamah, D.g
a Department of Mental Health, School of Nursing and Midwifery, College of Health Sciences, University of Ghana, Accra, Ghana
b Research and Grant Institute of Ghana, Accra, Ghana
c Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
d Department of Psychology, School of Social Sciences, College of Humanities, University of Ghana, Accra, Ghana
e Department of Population Health, New York University School of Medicine, New York, NY, United States
f Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, United States
g Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
Abstract
Background: Psychotic-like experiences (PLEs) and adverse life events (ALEs) are highly prevalent in sub-Saharan Africa where gendered practices are also common. There is, however, a paucity of data on how the relationship between PLEs and life adversities is influenced by gender. The current study addressed this gap. Method: Data were collected from 1886 school-based young people (1174 females) in Ghana, West Africa using a cross-sectional survey methodology and analyzed using Chi-square, independent t-test, Pearson correlation, and multivariate regression. Results: The results showed that victimization experiences, school stress and having a family member with mental illness were significantly associated with PLEs in both males and females. In contrast, substance misuse and experiences of head trauma correlated significantly with PLEs in females only. Conclusion: Life adversities constitute major risk factors for PLEs among school-based young people in Ghana, who could benefit from gender neutral and gender-sensitive intervention programming to remediate the effects of life adversities on PLEs. © 2023 Association for Child and Adolescent Mental Health.
Author Keywords
Adolescents; adverse life experiences; Africa; Ghana; psychosis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-Type glioblastoma
(2023) Neuro-Oncology Advances, 5 (1), art. no. vdad088, .
Ghosh, S.a b , Johanns, T.M.b d , Chheda, M.G.b d , Liu, E.a , Butt, O.b d , Abraham, C.a d d , Badiyan, S.a d d , Huang, Y.a d d , Denardo, D.b , Kim, A.H.b d c d , Hallahan, D.d , Thotala, D.a b , Huang, J.a d d
a Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, 4921 Parkview Place, Campus Box 8224, St. Louis, MI 63110, United States
b Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
c Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MI, United States
d Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, 4511 Forest Park Ave, St. Louis, MO 63108, United States
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-Target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-Type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P=0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P=0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P<0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1β was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation. © 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Author Keywords
glioblastoma; immunosuppression; MDSC; radiotherapy; tadalafil
Funding details
National Cancer InstituteNCI30 CA091842
Document Type: Article
Publication Stage: Final
Source: Scopus
Mapping sleep’s oscillatory events as a biomarker of Alzheimer’s disease
(2023) Alzheimer’s and Dementia, .
Pulver, R.L.a b , Kronberg, E.a , Medenblik, L.M.a b , Kheyfets, V.O.c , Ramos, A.R.d , Holtzman, D.M.e f g , Morris, J.C.e f g , Toedebusch, C.D.e , Sillau, S.H.a b , Bettcher, B.M.a b , Lucey, B.P.e f g , McConnell, B.V.a b
a Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
b University of Colorado Alzheimer’s and Cognition Center, University of Colorado School of Medicine, Aurora, CO, United States
c Department of Pediatric Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, United States
d Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
f Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
Abstract
INTRODUCTION: Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the “coupling” of these events may indicate early Alzheimer’s disease (AD) pathogenesis. METHODS: We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers. RESULTS: Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aβ42/Aβ40, phosphorylated- tau181, and total-tau. DISCUSSION: Sleep-dependent memory processing integrity in neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdown associates with amyloid positivity, increased AD pathology, and cognitive impairment. Highlights: At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; EEG; memory; mild cognitive impairment; slow wave; tau
Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30 AG066444, R01AG058772, R03AG080427, U19 AG032438
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Behavioral and psychiatric correlates of brain responses to social feedback
(2023) Psychophysiology, .
Rappaport, B.I.a , Kujawa, A.b , Arfer, K.B.c , Pegg, S.b , Kelly, D.d , Jackson, J.J.a , Luby, J.L.d , Barch, D.M.a d e
a Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychology & Human Development, Vanderbilt University, Nashville, TN, United States
c Icahn School of Medicine, Mount Sinai Hospital, New York, NY, United States
d Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
e Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Maladaptive responses to peer acceptance and rejection arise in numerous psychiatric disorders in adolescence; yet, homogeneity and heterogeneity across disorders suggest common and unique mechanisms of impaired social function. We tested the hypothesis that social feedback is processed similarly to other forms of feedback (e.g., monetary) by examining the correspondence between the brain’s response to social acceptance and rejection and behavioral performance on a separate reward and loss task. We also examined the relationship between these brain responses and depression and social anxiety severity. The sample consisted of one hundred and thirteen 16–21-year olds who received virtual peer acceptance/rejection feedback in an event-related potential (ERP) task. We used temporospatial principal component analysis and identified a component consistent with the reward positivity (RewP) or feedback negativity (FN). RewP to social acceptance was not significantly related to reward bias or the FN to social rejection related to loss avoidance. The relationship between RewP and depression severity, while nonsignificant, was of a similar magnitude to prior studies. Exploratory analyses yielded a significant relationship between lower socioeconomic status (SES) and blunted RewP and between lower SES and heightened loss avoidance and blunted reward bias. These findings build on prior work to improve our understanding of the function of the brain’s response to social feedback, while also suggesting a pathway for further study, whereby poverty leads to depression via social and reward learning mechanisms. © 2023 Society for Psychophysiological Research.
Author Keywords
adolescents < groups studied; ERPs < methods; RewP; social factors < content/topics; socioeconomic status; young adults < groups studied
Document Type: Article
Publication Stage: Article in Press
Source: Scopus