Optimal approaches to analyzing functional MRI data in glioma patients
(2024) Journal of Neuroscience Methods, 402, art. no. 110011, .
Park, K.Y.a b k , Shimony, J.S.c , Chakrabarty, S.i , Tanenbaum, A.B.d , Hacker, C.D.a , Donovan, K.M.e k k , Luckett, P.H.a k , Milchenko, M.c , Sotiras, A.c j , Marcus, D.S.c , Leuthardt, E.C.a e f g h k , Snyder, A.Z.c d
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
f Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, United States
g Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO 63110, United States
h Brain Laser Center, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Electrical and Systems Engineering, Washington University, St. Louis, MO 63130, United States
j Institute for Informatics, Data Science & Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
k Division of Neurotechnology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Background: Resting-state fMRI is increasingly used to study the effects of gliomas on the functional organization of the brain. A variety of preprocessing techniques and functional connectivity analyses are represented in the literature. However, there so far has been no systematic comparison of how alternative methods impact observed results. New method: We first surveyed current literature and identified alternative analytical approaches commonly used in the field. Following, we systematically compared alternative approaches to atlas registration, parcellation scheme, and choice of graph-theoretical measure as regards differentiating glioma patients (N = 59) from age-matched reference subjects (N = 163). Results: Our results suggest that non-linear, as opposed to affine registration, improves structural match to an atlas, as well as measures of functional connectivity. Functionally- as opposed to anatomically-derived parcellation schemes maximized the contrast between glioma patients and reference subjects. We also demonstrate that graph-theoretic measures strongly depend on parcellation granularity, parcellation scheme, and graph density. Comparison with existing methods and conclusions: Our current work primarily focuses on technical optimization of rs-fMRI analysis in glioma patients and, therefore, is fundamentally different from the bulk of papers discussing glioma-induced functional network changes. We report that the evaluation of glioma-induced alterations in the functional connectome strongly depends on analytical approaches including atlas registration, choice of parcellation scheme, and graph-theoretical measures. © 2023 The Authors
Author Keywords
Atlas registration; Glioma; Graph-theoretic measures; Parcellation granularity; Parcellation schemes; Resting-state fMRI
Funding details
National Institutes of HealthNIHP41EB018783, R01CA203861, R01EB026439, U24NS109103
McDonnell Center for Systems Neuroscience
Washington University School of Medicine in St. LouisWUSM
Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. LouisIDDRCP50 HD103525
Document Type: Article
Publication Stage: Final
Source: Scopus
Shared and unique heritability of hippocampal subregion volumes in children and adults
(2024) NeuroImage, 285, art. no. 120471, .
Pine, J.G.a , Agrawal, A.b , Bogdan, R.a , Kandala, S.b , Cooper, S.a , Barch, D.M.a b c
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study’s findings suggest that genetic differences in hippocampal longitudinal axis structure can be detected in individual differences in gray matter volume in population-level research designs. © 2023
Author Keywords
Heritability; Hippocampus; Longitudinal axis
Funding details
National Institutes of HealthNIHU01DA041120, U01DA051018, U01DA051037, U01DA051038, U54MH091657
NIH Blueprint for Neuroscience Research
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Associations between age-related differences in occipital alpha power and the broadband parameters of the EEG power spectrum: A cross-sectional cohort study
(2024) International Journal of Psychophysiology, 195, art. no. 112272, .
Clark, M.a , Euler, M.J.b , King, B.R.a , Williams, A.M.c , Lohse, K.R.d
a Department of Health and Kinesiology, University of Utah, United States
b Department of Psychology, University of Utah, United States
c Institute of Human and Machine CognitionFL, United States
d Physical Therapy and Neurology, Washington University School of Medicine in Saint Louis, United States
Abstract
In adulthood, neurological structure and function are often affected by aging, with negative implications for daily life as well as laboratory-based tasks. Some of these changes include decreased efficiency modulating cortical activity and lower signal-to-noise ratios in neural processing (as inferred from surface electroencephalography). To better understand mechanisms influencing age-related changes in cortical activity, we explored the effects of aging on narrow-band alpha power (7.5–12.5 Hz) and broadband/aperiodic components that span a wider range (1.5–30.5 Hz) over the occipital region during eyes-open and eyes-closed wakeful rest in 19 healthy young adults (18–35 years) and 21 community-dwelling older adults (59+ years). Older adults exhibited a smaller change in alpha power across conditions compared to younger adults. Older adults also showed flatter aperiodic slopes in both conditions. These changes in narrow-band alpha are consistent with previous work and suggest that older adults may have a reduced ability to modulate state-specific activity. Differences in the aperiodic slope suggest age-related changes in the signal-noise-ratio in cortical oscillations. However, the relationship between narrow-band alpha modulation and the aperiodic slope was unclear, warranting further investigation into how these variables relate to each other in the aging process. In summary, aging is associated with a broadband flattening of the EEG power spectrum and reduced state-specific modulation of narrow-band alpha power, but these changes appear to be (at least partially) independent of each other. The present findings suggest that separate mechanisms may underlie age-related differences in aperiodic power and narrow-band oscillations. © 2023 Elsevier B.V.
Author Keywords
Aging; Alpha modulation; Electroencephalography (EEG); Neural noise
Document Type: Article
Publication Stage: Final
Source: Scopus
Development of white matter fiber covariance networks supports executive function in youth
(2023) Cell Reports, 42 (12), art. no. 113487, .
Bagautdinova, J.a b c , Bourque, J.a b c , Sydnor, V.J.a b c , Cieslak, M.a b c , Alexander-Bloch, A.F.b c , Bertolero, M.A.a b c , Cook, P.A.d , Gur, R.E.b c d , Gur, R.C.b c d , Hu, F.e f g , Larsen, B.a b c , Moore, T.M.b c , Radhakrishnan, H.a b c , Roalf, D.R.b c , Shinohara, R.T.e f g , Tapera, T.M.a b c , Zhao, C.a b c h , Sotiras, A.i , Davatzikos, C.d f , Satterthwaite, T.D.a b c f
a Penn Lifespan Informatics and Neuroimaging Center (PennLINC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
b Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Lifespan Brain Institute (LiBI) of Penn Medicine and Children’s Hospital of Philadelphia (CHOP), University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, United States
e Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
f Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
g Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
h Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, United States
i Department of Radiology and Institute for Informatics, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63130, United States
Abstract
During adolescence, the brain undergoes extensive changes in white matter structure that support cognition. Data-driven approaches applied to cortical surface properties have led the field to understand brain development as a spatially and temporally coordinated mechanism that follows hierarchically organized gradients of change. Although white matter development also appears asynchronous, previous studies have relied largely on anatomical tract-based atlases, precluding a direct assessment of how white matter structure is spatially and temporally coordinated. Harnessing advances in diffusion modeling and machine learning, we identified 14 data-driven patterns of covarying white matter structure in a large sample of youth. Fiber covariance networks aligned with known major tracts, while also capturing distinct patterns of spatial covariance across distributed white matter locations. Most networks showed age-related increases in fiber network properties, which were also related to developmental changes in executive function. This study delineates data-driven patterns of white matter development that support cognition. © 2023 The Author(s)
Author Keywords
CP: Neuroscience; development; diffusion-weighted imaging; executive function; fixel-based analysis; network; non-negative matrix factorization; youth
Funding details
National Science FoundationNSFDGE-1845298
National Institutes of HealthNIHK99MH127293, R01AG067103, R01EB022573, R01MH112847, R01MH113550, R01MH119185, R01MH119219, R01MH120174, R01MH120482, R01MH123550, R01MH133843, R37MH125829, RF1MH116920
AEG FoundationAEGF
Canadian Institutes of Health ResearchIRSCCIHR-396349
Document Type: Article
Publication Stage: Final
Source: Scopus
Cortico-hippocampal networks carry information about characters and their relationships in an extended narrative
(2023) Neuropsychologia, 191, art. no. 108729, .
Karagoz, A.B., Morse, S.J., Reagh, Z.M.
Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63105, United States
Abstract
Social information is a centerpiece of human experience. Despite a wealth of research into the way we understand social relationships and how aspects of social life might be supported by the brain, relatively little is known about how the brain represents individual people and their relationships with others. How do intrinsic networks in the brain track people and their connections in complex situations? Here, we sought to understand this issue using an open neuroimaging dataset in which people freely viewed “The Grand Budapest Hotel.” Using support vector machine classification of fMRI activity patterns, we found that character identity could be decoded throughout subsystems of the brain’s “Default Mode” Network, especially in regions of an Anterior Temporal and a Medial Prefrontal subsystem, as well as a Medial Temporal Network (MTN). We tested character relationships in two ways – onscreen co-occurrence and shared semantic information from an independent sample of character descriptions – and found evidence for these representations throughout the “Default Mode” Network, and the MTN. The extent to which each variant of character relationships fit neural patterns differed across networks, with abstract semantic relatedness being especially prominent in regions of Anterior Temporal and Medial Prefrontal Networks. These data show that subsystems of the brain’s “Default Mode” Network and MTN carry information about individual people as well as their connections, and highlight a particularly strong role for the Anterior Temporal network in representing this information. © 2023 Elsevier Ltd
Author Keywords
Anterior temporal; Default mode network; Multivariate decoding; Naturalistic neuroimaging; Posterior medial
Funding details
Office of Naval ResearchONRN00014-17-1
National Institute on AgingNIA5R01 – AG062438
National Institute of Neurological Disorders and StrokeNINDST32 – NS115672
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Cell-free RNA signatures predict Alzheimer’s disease
(2023) iScience, 26 (12), art. no. 108534, .
Cisterna-García, A.a b c , Beric, A.a c , Ali, M.a c , Pardo, J.A.b , Chen, H.-H.a c , Fernandez, M.V.a c , Norton, J.a c d , Gentsch, J.a c d , Bergmann, K.a c , Budde, J.a c , Perlmutter, J.S.e f g , Morris, J.C.d e h , Cruchaga, C.a c d e f i , Botia, J.A.b , Ibanez, L.a c e
a Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
b Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain
c NeuroGenomics and Informatics Center, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
d The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in Saint Louis, Saint Louis, MO, United States
e Department of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
f Hope Center for Neurological Disorders, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
g Department of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
h Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
i Department of Genetics, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
Abstract
There is a need for affordable, scalable, and specific blood-based biomarkers for Alzheimer’s disease that can be applied to a population level. We have developed and validated disease-specific cell-free transcriptomic blood-based biomarkers composed by a scalable number of transcripts that capture AD pathobiology even in the presymptomatic stages of the disease. Accuracies are in the range of the current CSF and plasma biomarkers, and specificities are high against other neurodegenerative diseases. © 2023 The Author(s)
Author Keywords
Biochemistry; Clinical finding; Disease; Molecular biology
Funding details
20762/FPI/18
National Institutes of HealthNIHK99/R00-AG062723, P01 AG026276, P01AG003991, P30 AG066444, R01AG044546, R01AG058501, RF1AG053303, RO1 NS075321, U01AG058922
U.S. Department of DefenseDOD
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s Drug Discovery FoundationADDF
Biogen
BrightFocus FoundationBFF
Fundación SénecaFS
Hope Center for Neurological Disorders
Japan Science and Technology AgencyJST
Document Type: Article
Publication Stage: Final
Source: Scopus
The anaphase-promoting complex controls a ubiquitination-phosphoprotein axis in chromatin during neurodevelopment
(2023) Developmental Cell, 58 (23), pp. 2666-2683.e9.
Ledvin, L.a , Gassaway, B.M.b , Tawil, J.a , Urso, O.a , Pizzo, D.a , Welsh, K.A.c d , Bolhuis, D.L.e , Fisher, D.f , Bonni, A.g , Gygi, S.P.b , Brown, N.G.c d , Ferguson, C.J.a
a Pathology Department, University of California, San Diego, La Jolla, CA 92093, United States
b Department of Cell Biology, Harvard Medical School, Boston, MA 02115, United States
c Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
d Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
e Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
f Institute of Genetics, Montpelier, France
g Neuroscience Department, Washington University, St. Louis, MO 63110, United States
Abstract
Mutations in the degradative ubiquitin ligase anaphase-promoting complex (APC) alter neurodevelopment by impairing proteasomal protein clearance, but our understanding of their molecular and cellular pathogenesis remains limited. Here, we employ the proteomic-based discovery of APC substrates in APC mutant mouse brain and human cell lines and identify the chromosome-passenger complex (CPC), topoisomerase 2a (Top2a), and Ki-67 as major chromatin factors targeted by the APC during neuronal differentiation. These substrates accumulate in phosphorylated form, suggesting that they fail to be eliminated after mitosis during terminal differentiation. The accumulation of the CPC kinase Aurora B within constitutive heterochromatin and hyperphosphorylation of its target histone 3 are corrected in the mutant brain by pharmacologic Aurora B inhibition. Surprisingly, the reduction of Ki-67, but not H3S10ph, rescued the function of constitutive heterochromatin in APC mutant neurons. These results expand our understanding of how ubiquitin signaling regulates chromatin during neurodevelopment and identify potential therapeutic targets in APC-related disorders. © 2023 The Author(s)
Author Keywords
anaphase-promoting complex; chromatin; chromosome-passenger complex; H3S10ph; heterochromatin; Ki-67; neurodevelopment; proteomics/phosphoproteomics; topoisomerase; ubiquitin ligase
Funding details
1K08HD099314, GM67945
National Institutes of HealthNIHR35GM128855, T32GM008570, T32GM135095
Document Type: Article
Publication Stage: Final
Source: Scopus
Prevalence, characteristics, and correlates of probable avoidant/restrictive food intake disorder among adult respondents to the National Eating Disorders Association online screen: a cross-sectional study
(2023) Journal of Eating Disorders, 11 (1), art. no. 214, .
D’Adamo, L.a b , Smolar, L.c , Balantekin, K.N.d , Taylor, C.B.e f , Wilfley, D.E.b , Fitzsimmons-Craft, E.E.b
a Department of Psychological and Brain Sciences and Center for Weight, Eating, and Lifestyle Science (WELL Center), Drexel University, 3201 Chestnut St., Philadelphia, PA 19104, United States
b Department of Psychiatry, Washington University School of Medicine, Mailstop 8134-29-2100, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
c National Eating Disorders Association, New York, NY, United States
d Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, United States
e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305, United States
f Center for m2Health, Palo Alto University, 5150 El Camino Real, Los Altos, CA 94022, United States
Abstract
Background: Avoidant/restrictive food intake disorder (ARFID) is a serious, albeit under-researched, feeding or eating disorder. This exploratory study utilized data from adult respondents to the National Eating Disorders Association online eating disorder screen to validate items assessing the presence of ARFID and examine the prevalence, clinical characteristics, and correlates of a positive ARFID screen. Methods: Among 50,082 adult screen respondents between January 2022 and January 2023, the prevalence of a positive ARFID screen was calculated. Chi-square tests and t-tests compared demographics, eating disorder attitudes and behaviors, suicidal ideation, current eating disorder treatment status, and eating disorder treatment-seeking intentions between respondents with possible ARFID and other eating disorder diagnostic and risk categories. Clinical characteristics of respondents with possible ARFID were also examined. Results: 2378 (4.7%) adult respondents screened positive for ARFID. Respondents with possible ARFID tended to be younger, male, and have lower household income, and were less likely to be White and more likely to be Hispanic/Latino than most other diagnostic/risk groups. They had lower weight/shape concerns and eating disorder behaviors than most other diagnoses and higher BMI than those with AN. 35% reported suicidal ideation, 47% reported intentions to seek treatment for an eating disorder, and 2% reported currently being in treatment. The most common clinical feature of ARFID was lack of interest in eating (80%), followed by food sensory avoidance (55%) and avoidance of food due to fear of aversive consequences (31%). Conclusions: Findings from this study indicated that ARFID was prevalent among adult screen respondents and more common among individuals who were younger, male, non-White, Hispanic, and lower income relative to those with other eating disorders, at risk for an eating disorder, or at low risk. Individuals with possible ARFID frequently reported suicidal ideation and were rarely in treatment for an eating disorder. Further research is urgently needed to improve advances in the assessment and treatment of ARFID and improve access to care in order to prevent prolonged illness duration. © 2023, The Author(s).
Author Keywords
Avoidant/restrictive food intake disorder; Dietary restriction; Feeding and eating disorders; Mental health screening
Funding details
National Institutes of HealthNIHK01 DK120778, K08 MH120341, T32 HL130357
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Document Type: Article
Publication Stage: Final
Source: Scopus
Predicting cognitive dysfunction and regional hubs using Braak staging amyloid-beta biomarkers and machine learning
(2023) Brain Informatics, 10 (1), art. no. 33, .
Bhattarai, P.a , Taha, A.a , Soni, B.a , Thakuri, D.S.a b , Ritter, E.a c , Chand, G.B.a d e f
a Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b University of Missouri School of Medicine, Columbia, MO, United States
c Department of Biomedical Engineering, Washington University McKelvey School of Engineering, St. Louis, MO, United States
d Imaging Core, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
e Institute of Clinical and Translational Sciences, Washington University School of Medicine, St. Louis, MO, United States
f NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Mild cognitive impairment (MCI) is a transitional stage between normal aging and early Alzheimer’s disease (AD). The presence of extracellular amyloid-beta (Aβ) in Braak regions suggests a connection with cognitive dysfunction in MCI/AD. Investigating the multivariate predictive relationships between regional Aβ biomarkers and cognitive function can aid in the early detection and prevention of AD. We introduced machine learning approaches to estimate cognitive dysfunction from regional Aβ biomarkers and identify the Aβ-related dominant brain regions involved with cognitive impairment. We employed Aβ biomarkers and cognitive measurements from the same individuals to train support vector regression (SVR) and artificial neural network (ANN) models and predict cognitive performance solely based on Aβ biomarkers on the test set. To identify Aβ-related dominant brain regions involved in cognitive prediction, we built the local interpretable model-agnostic explanations (LIME) model. We found elevated Aβ in MCI compared to controls and a stronger correlation between Aβ and cognition, particularly in Braak stages III–IV and V–VII (p < 0.05) biomarkers. Both SVR and ANN, especially ANN, showed strong predictive relationships between regional Aβ biomarkers and cognitive impairment (p < 0.05). LIME integrated with ANN showed that the parahippocampal gyrus, inferior temporal gyrus, and hippocampus were the most decisive Braak regions for predicting cognitive decline. Consistent with previous findings, this new approach suggests relationships between Aβ biomarkers and cognitive impairment. The proposed analytical framework can estimate cognitive impairment from Braak staging Aβ biomarkers and delineate the dominant brain regions collectively involved in AD pathophysiology. © 2023, The Author(s).
Author Keywords
Amyloid-beta; Braak staging; Feature importance; Machine learning; Mild cognitive impairment; Neuroimaging
Funding details
National Institutes of HealthNIHK01AG083230, P01 AG003991, P01 AG026276, P30 NS09857781, P50 AG00561, R01 AG043434, R01 EB009352, UL1 TR000448
University of WashingtonUW
Institute of Clinical and Translational SciencesICTS
Mallinckrodt Institute of RadiologyMIR
Document Type: Article
Publication Stage: Final
Source: Scopus
Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation
(2023) Genome Biology, 24 (1), art. no. 269, .
Wang, J.a b , Cheng, X.a b , Liang, Q.a b c , Owen, L.A.d , Lu, J.a b c , Zheng, Y.e , Wang, M.a b , Chen, S.e f , DeAngelis, M.M.g , Li, Y.a b , Chen, R.a b
a Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
b Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
c Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, United States
d Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, UT, United States
e Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, MO, United States
f Department of Developmental Biology, Washington University in St Louis, Saint Louis, MO, United States
g Department of Ophthalmology, University at Buffalo the State University of New York, Buffalo, NY, United States
Abstract
Background: Systematic characterization of how genetic variation modulates gene regulation in a cell type-specific context is essential for understanding complex traits. To address this question, we profile gene expression and chromatin accessibility in cells from healthy retinae of 20 human donors through single-cell multiomics and genomic sequencing. Results: We map eQTL, caQTL, allelic-specific expression, and allelic-specific chromatin accessibility in major retinal cell types. By integrating these results, we identify and characterize regulatory elements and genetic variants effective on gene regulation in individual cell types. The majority of identified sc-eQTLs and sc-caQTLs display cell type-specific effects, while the cis-elements containing genetic variants with cell type-specific effects are often accessible in multiple cell types. Furthermore, the transcription factors whose binding sites are perturbed by genetic variants tend to have higher expression levels in the cell types where the variants exert their effects, compared to the cell types where the variants have no impact. We further validate our findings with high-throughput reporter assays. Lastly, we identify the enriched cell types, candidate causal variants and genes, and cell type-specific regulatory mechanism underlying GWAS loci. Conclusions: Overall, genetic effects on gene regulation are highly context dependent. Our results suggest that cell type-dependent genetic effect is driven by precise modulation of both trans-factor expression and chromatin accessibility of cis-elements. Our findings indicate hierarchical collaboration among transcription factors plays a crucial role in mediating cell type-specific effects of genetic variants on gene regulation. © 2023, The Author(s).
Author Keywords
ASCA; ASE; caQTL; Cell type-specific effect; eQTL; Gene regulation; Genetic variants; Single-cell multiomics; The human retina; Transcription factor collaboration
Funding details
National Institutes of HealthNIHP30EY002520, S10OD023469, S10OD025240
National Eye InstituteNEICZF2019-02425, R01EY018571, R01EY020540, R01EY022356
Foundation Fighting BlindnessFFBBR-GE-0613–0618-BCM
Cancer Prevention and Research Institute of TexasCPRITP30 EY002687, RP200504
Baylor College of Medicine
Document Type: Article
Publication Stage: Final
Source: Scopus
Widespread amyloid aggregates formation by Zika virus proteins and peptides
(2023) Protein Science, 32 (12), art. no. e4833, .
Giri, R.a , Bhardwaj, T.a , Kapuganti, S.K.a , Saumya, K.U.a , Sharma, N.b , Bhardwaj, A.a , Joshi, R.a , Verma, D.a , Gadhave, K.c
a School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Himachal Pradesh,Kamand, India
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Abstract
Viral pathogenesis typically involves numerous molecular mechanisms. Protein aggregation is a relatively unknown characteristic of viruses, despite the fact that viral proteins have been shown to form terminally misfolded forms. Zika virus (ZIKV) is a neurotropic one with the potential to cause neurodegeneration. Its protein amyloid aggregation may link the neurodegenerative component to the pathogenicity associated with the viral infection. Therefore, we investigated protein aggregation in the ZIKV proteome as a putative pathogenic route and one of the alternate pathways. We discovered that it contains numerous anticipated aggregation-prone regions in this investigation. To validate our prediction, we used a combination of supporting experimental techniques routinely used for morphological characterization and study of amyloid aggregates. Several ZIKV proteins and peptides, including the full-length envelope protein, its domain III (EDIII) and fusion peptide, Pr N-terminal peptide, NS1 β-roll peptide, membrane-embedded signal peptide 2K, and cytosolic region of NS4B protein, were shown to be highly aggregating in our study. Because our findings show that viral proteins can form amyloids in vitro, we need to do a thorough functional study of these anticipated APRs to understand better the role of amyloids in the pathophysiology of ZIKV infection. © 2023 The Protein Society.
Author Keywords
aggregation-prone regions; anti-amyloid antibody; bacterial cell staining; envelope protein; ThT; viral protein aggregation; Zika pathogenesis
Funding details
SPARC/2018‐2019/P37/SL
Department of Biotechnology, Ministry of Science and Technology, IndiaDBT
Department of Science and Technology, Ministry of Science and Technology, IndiaDSTBT/11/IYBA/2018/06
Indian Council of Medical ResearchICMR
Science and Engineering Research BoardSERB52/04/2020/BIO/BMS, 58/6/2020/PHA/BMS, CRG/2019/005603
Indian Institute of Technology MandiIIT
Document Type: Article
Publication Stage: Final
Source: Scopus
CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors
(2023) Science Advances, 9 (47), p. eadg8876.
Wang, J.a , Calizo, A.a , Zhang, L.a , Pino, J.C.b , Lyu, Y.c , Pollard, K.a , Zhang, X.c , Larsson, A.T.d , Conniff, E.e , Llosa, N.J.a , Wood, D.K.e , Largaespada, D.A.d , Moody, S.E.f , Gosline, S.J.b , Hirbe, A.C.c , Pratilas, C.A.a
a Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Pacific Northwest National Laboratory (PNNL), Seattle, WA, United States
c Division of Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University in St. LouisMO, United States
d Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
e Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States
f Novartis Institutes for Biomedical Research, Cambridge, MA, United States
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.
Document Type: Article
Publication Stage: Final
Source: Scopus
Fine Particulate Matter and Parkinson Disease Risk among Medicare Beneficiaries
(2023) Neurology, 101 (21), pp. E2058-E2067.
Krzyzanowski, B.a , Searles Nielsen, S.b , Turner, J.R.b , Racette, B.A.a
a The Barrow Neurological Institute, Phoenix, AZ, United States
b Washington University in St. LouisMO, United States
Abstract
Background and ObjectivesNumerous studies suggest that environmental exposures play a critical role in Parkinson disease (PD) pathogenesis, and large, population-based studies have the potential to advance substantially the identification of novel PD risk factors. We sought to study the nationwide geographic relationship between PD and air pollution, specifically PM2.5 (particulate matter with a diameter <2.5 micrometers), using population-based US Medicare data.MethodsWe conducted a population-based geographic study of Medicare beneficiaries aged 66-90 years geocoded to US counties and zip+4. We used integrated nested Laplace approximation to create age, sex, race, smoking, and health care utilization-Adjusted relative risk (RR) at the county level for geographic analyses with PM2.5 as the primary exposure of interest. We also performed an individual-level analysis using logistic regression with cases and controls with zip+4 centroid PM2.5. We adjusted a priori for the same covariates and verified no confounding by indicators of socioeconomic status or neurologist density.ResultsAmong 21,639,190 Medicare beneficiaries, 89,390 had incident PD in 2009. There was a nationwide association between average annual PM2.5 and PD risk whereby the RR of PD was 56% (95% CI 47%-66%) greater for those exposed to the median level of PM2.5 compared with those with the lowest level of PM2.5. This association was linear up to 13 g/m3 corresponding to a 4.2% (95% CI 3.7%-4.8%) greater risk of PD for each additional g/m3 of PM2.5 (ptrend < 0.0001). We identified a region with high PD risk in the Mississippi-Ohio River Valley, where the risk of PD was 19% greater compared with the rest of the nation. The strongest association between PM2.5 and PD was found in a region with low PD risk in the Rocky Mountains. PM2.5 was also associated with PD in the Mississippi-Ohio River Valley where the association was relatively weaker, due to a possible ceiling effect at average annual PM2.5 levels of ∼13 g/m3.DiscussionState-of-The-Art geographic analytic techniques revealed an association between PM2.5 and PD that varied in strength by region. A deeper investigation into the specific subfractions of PM2.5 may provide additional insight into regional variability in the PM2.5-PD association. © American Academy of Neurology.
Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODPD190057
National Institute of Environmental Health SciencesNIEHSK01ES028295, R01ES025991-S1, R01ES026891-S1, R01ES029524
Michael J. Fox Foundation for Parkinson’s ResearchMJFF000939, 020718, MJFF000939, R01ES025991-02S1, R01ES030937-S1
Cure Alzheimer’s FundCAF
Hope Center for Neurological Disorders
National Institute of Occupational Safety and Health, JapanJNIOSHR01OH011661
Document Type: Article
Publication Stage: Final
Source: Scopus
Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease
(2023) New England Journal of Medicine, 389 (20), pp. 1862-1876.
Bateman, R.J.a , Smith, J.b , Donohue, M.C.e , Delmar, P.g , Abbas, R.g , Salloway, S.h , Wojtowicz, J.g , Blennow, K.i , Bittner, T.f g , Black, S.E.j , Klein, G.g , Boada, M.k , Grimmer, T.l , Tamaoka, A.m , Perry, R.J.c , Turner, R.S.n , Watson, D.o , Woodward, M.p , Thanasopoulou, A.g , Lane, C.b , Baudler, M.g , Fox, N.C.d , Cummings, J.L.q , Fontoura, P.g , Doody, R.S.f g
a The Department of Neurology, Washington University, School of Medicine, St. Louis, United States
b Roche Products, Welwyn Garden City, United Kingdom
c The Department of Brain Sciences, Faculty of Medicine, Imperial College London, United Kingdom
d The Dementia Research Centre, Department of Neurodegenerative Disease, The U.K. Dementia Research Institute, Queen Square Institute of Neurology, University College London, London, United Kingdom
e The Alzheimer’s Therapeutic Research Institute, Keck School of Medicine, University of Southern California, San Diego, CA, United States
f Genentech, South San Francisco, CA, United States
g F. Hoffmann-La Roche, Basel, Switzerland
h Butler Hospital and Warren Alpert Medical School, Brown University, Providence, RI, United States
i The Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, The Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
j The Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, The L.C. Campbell Cognitive Neurology Research Unit, Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
k The Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, The Networking Research Center on Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain
l The Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
m The Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
n The Department of Neurology, Georgetown University, School of Medicine, Washington, DC, United States
o The Alzheimer’s Research and Treatment Center, Wellington, FL, United States
p The Medical and Cognitive Research Unit, Heidelberg Repatriation Hospital, Austin Health, Melbourne, VIC, Australia
q The Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas, United States
Abstract
Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer’s disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer’s disease. Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer’s disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Conclusions: Among persons with early Alzheimer’s disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. © 2023 Massachussetts Medical Society. All rights reserved.
Funding details
Roche
Document Type: Article
Publication Stage: Final
Source: Scopus
Concurrent and prospective associations between infant frontoparietal and default mode network connectivity and negative affectivity
(2023) Biological Psychology, 184, art. no. 108717, .
Ravi, S.a , Catalina Camacho, M.b , Fleming, B.a , Scudder, M.R.a , Humphreys, K.L.a
a Vanderbilt University, 230 Appleton Place, #552, Nashville, TN 37204, United States
b Washington University in St. Louis, One Brookings Drive, Campus Box 1125, St. Louis, MO 63130, United States
Abstract
Emotion dysregulation is linked to differences in frontoparietal (FPN) and default mode (DMN) brain network functioning. These differences may be identifiable early in development. Temperamental negative affectivity has been identified as a precursor to later emotion dysregulation, though the underlying neurodevelopmental mechanism is unknown. The present study explores concurrent and prospective associations between FPN and DMN connectivity in infants and measures of negative affectivity. 72 infants underwent 5.03–13.28 min of resting state fMRI during natural sleep (M±SD age=4.90 ± 0.84 weeks; 54% male; usable data=9.92 ± 2.15 min). FPN and DMN intra- and internetwork connectivity were computed using adult network assignments. Crying was obtained from both parent-report and day-long audio recordings. Temperamental negative affectivity was obtained from a parent-report questionnaire. In this preregistered study, based on analyses conducted with a subset of this data (N = 32), we hypothesized that greater functional connectivity within and between FPN and DMN would be associated with greater negative affectivity. In the full sample we did not find support for these hypotheses. Instead, greater DMN intranetwork connectivity at age one month was associated with lower concurrent parent-reported crying and temperamental negative affectivity at age six months (ßs>−0.35, ps<.025), but not crying at age six months. DMN intranetwork connectivity was also negatively associated with internalizing symptoms at age eighteen-months (ß=−0.58, p = .012). FPN intra- and internetwork connectivity was not associated with negative affectivity measures after accounting for covariates. This work furthers a neurodevelopmental model of emotion dysregulation by suggesting that infant functional connectivity at rest is associated with later emotional functioning. © 2023
Author Keywords
Crying; Early childhood; Internalizing; Neurodevelopment; Resting-state functional connectivity
Funding details
National Science FoundationNSF2042285
National Institutes of HealthNIHF32 MH132185
Brain and Behavior Research FoundationBBRF29593
Vanderbilt Institute for Clinical and Translational ResearchVICTRVR53419
John and Polly Sparks Foundation
Vanderbilt Kennedy Center, Vanderbilt University Medical CenterVKC
Jacobs Foundation2017-1261-05
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients
(2023) Journal of the Peripheral Nervous System, .
van Doormaal, P.T.C.a b c , Thomas, S.a , Ajroud-Driss, S.d , Cole, R.N.e , DeVine, L.R.e , Dimachkie, M.M.f , Geisler, S.g , Freeman, R.h , Simpson, D.M.i , Singleton, J.R.j , Smith, A.G.k , Stino, A.l , Höke, A.a
a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Department of Neurology, Brain Center Rudolph Magnus, Utrecht Medical Center, Utrecht, Netherlands
c Department of Neurology, Tergooi Medical Center, Hilversum, Netherlands
d Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
e Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, United States
f Department of Neurology, Kansas University Medical Center, Kansas City, MO, United States
g Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
h Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
i Department of Neurology, Icahn School of Medicine at Mount Sinai Medical Center, New York City, NY, United States
j Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, United States
k Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
l Department of Neurology, University of Michigan, Ann Arbor, MI, United States
Abstract
Background and Aims: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. Methods: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein–protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. Results: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini–Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini–Hochberg adjusted p-value =.0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. Interpretation: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN. © 2023 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.
Author Keywords
complement; neuropathy; pain; proteomics
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Spatial and amplitude dynamics of neurostimulation: Insights from the acute intrahippocampal kainate seizure mouse model
(2023) Epilepsia Open, .
Foutz, T.J.a , Rensing, N.a , Han, L.a , Durand, D.M.b , Wong, M.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States
Abstract
Objective: Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. Methods: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. Results: We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. Significance: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. Plain Language Summary: In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode’s placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure-like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy. © 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
Author Keywords
brain stimulation; epilepsy; neuromodulation; seizures; status epilepticus
Funding details
National Institutes of HealthNIHP50HD103525
National Institute of General Medical SciencesNIGMS
American Epilepsy SocietyAES
Washington University in St. LouisWUSTL
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The effects of temporal cues, point-light displays, and faces on speech identification and listening effort
(2023) PloS One, 18 (11), p. e0290826.
Sewell, K.a , Brown, V.A.b , Farwell, G.a , Rogers, M.a , Zhang, X.a , Strand, J.F.a
a Department of Psychology, Carleton College, Northfield, MN, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Among the most robust findings in speech research is that the presence of a talking face improves the intelligibility of spoken language. Talking faces supplement the auditory signal by providing fine phonetic cues based on the placement of the articulators, as well as temporal cues to when speech is occurring. In this study, we varied the amount of information contained in the visual signal, ranging from temporal information alone to a natural talking face. Participants were presented with spoken sentences in energetic or informational masking in four different visual conditions: audio-only, a modulating circle providing temporal cues to salient features of the speech, a digitally rendered point-light display showing lip movement, and a natural talking face. We assessed both sentence identification accuracy and self-reported listening effort. Audiovisual benefit for intelligibility was observed for the natural face in both informational and energetic masking, but the digitally rendered point-light display only provided benefit in energetic masking. Intelligibility for speech accompanied by the modulating circle did not differ from the audio-only conditions in either masker type. Thus, the temporal cues used here were insufficient to improve speech intelligibility in noise, but some types of digital point-light displays may contain enough phonetic detail to produce modest improvements in speech identification in noise. Copyright: © 2023 Sewell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Personality predictors of dementia diagnosis and neuropathological burden: An individual participant data meta-analysis
(2023) Alzheimer’s and Dementia, .
Beck, E.D.a b , Yoneda, T.a b , James, B.D.c , Bennett, D.A.d , Hassenstab, J.e , Katz, M.J.f , Lipton, R.B.f , Morris, J.d , Mroczek, D.K.a g , Graham, E.K.a
a Department of Medical Social Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
b Department of Psychology, University of California, Davis, Davis, CA, United States
c Rush Alzheimer’s Disease Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
d Department of Neurology, Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United States
g Department of Psychology, Northwestern University, Weinberg College of Arts & Sciences, Evanston, IL, United States
Abstract
INTRODUCTION: The extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear. METHODS: Using data from eight independent studies (Ntotal= 44,531; Ndementia= 1703; baseline Mage= 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia. RESULTS: Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology. DISCUSSION: This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy. Highlights: N(+), C(−), E(−), PA(−), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
agreeableness; arteriosclerosis; Braak stage; CERAD; cerebral amyloid angiopathy; cerebral atherosclerosis; extraversion; gross cerebral infarcts; gross cerebral microinfarcts; hippocampal sclerosis; individual participant data meta-analysis; Lewy body disease; openness; positive affect; satisfaction with life; TDP-43
Funding details
National Institutes of HealthNIHP01AG03949, P01AG043362, P30AG010161, P30AG72975, R01AG017917, R01AG018436, R01AG067622, R01AG072559, R01AG15819
National Institute on AgingNIA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Risk of pre-term birth as a function of sleep quality and obesity: prospective analysis in a large Prematurity Research Cohort
(2023) SLEEP Advances, 4 (1), art. no. zpad043, .
Sutcliffe, S.a , Zhao, P.b , Pilz, L.K.c d , Oakes, M.e , Frolova, A.I.f , Herzog, E.D.g , England, S.K.h
a Division of Public Health Sciences, Department of Surgery, Alvin J. Siteman Cancer Center, The Department of Obstetrics and Gynecology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Division of Clinical Research, Department of Obstetrics and Gynecology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Anesthesiology, Intensive Care Medicine, The Experimental and Clinical Research Center, Charite Universitatsmedizin Berlin, Berlin, Germany
d Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin, Germany
e Department of Obstetrics and Gynecology, MemorialCare Miller Children’s and Women’s Hospital, Long Beach, CA, United States
f Division of Maternal-Fetal Medicine and Ultrasound, Department of Obstetrics and Gynecology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
g Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Study Objective: To investigate whether poor sleep quality is associated with pre-term birth (PTB) risk, overall and independent of sleep apnea and habitual snoring. Methods: We used longitudinal data from the Washington University Prematurity Research Cohort to investigate the association between poor sleep quality (defined as a Pittsburgh Sleep Quality Index > 5) and PTB, overall and independent of sleep apnea and snoring (defined by the Berlin questionnaire and prior sleep clinic attendance). Associations were investigated for sleep quality early and throughout pregnancy. Stratified analyses were performed by factors previously shown to modify associations between sleep and PTB (race, pre-pregnancy obesity). Results: Of the 976 eligible participants, 50.1% experienced poor sleep quality early in pregnancy (<20 completed weeks) and 14.2% delivered pre-term (n = 50 without and 89 with poor sleep quality). In multivariable-adjusted analyses, poor sleep quality early in pregnancy was associated with increased PTB risk (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.02–2.14). This association persisted after further adjustment for sleep apnea and snoring (HR = 1.50, 95% CI = 1.02–2.20) and in analyses stratified by race. It varied, however, by pre-pregnancy obesity. Among individuals without obesity, no association was observed between poor sleep and PTB (HR = 1.08, 95% CI = 0.65–1.79), whereas among those with obesity, a positive association was observed (HR = 2.94, 95% CI = 1.52–5.69, p-interaction = .05). This association was limited to individuals with obesity who experienced poor sleep both earlier and later in pregnancy (HR = 3.94, 95% CI = 1.56–9.99). Conclusion: Our findings suggest that improving sleep quality early in pregnancy may be important for PTB prevention, particularly among individuals with obesity. © The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.
Author Keywords
cohort study; obesity; pregnancy; sleep
Funding details
March of Dimes FoundationMDF
University of WashingtonUW
Washington University School of Medicine in St. LouisWUSM
St. Louis Children’s HospitalSLCH
Document Type: Article
Publication Stage: Final
Source: Scopus
Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms
(2023) eLife, 12, art. no. RP87147, .
Zheng, Y.a b , Sun, C.a b , Zhang, X.b , Ruzycki, P.A.b c , Chen, S.a b d
a Molecular Genetic and Genomics Graduate Program, Division of Biological and Biomedical Sciences, Washington University in St Louis, Saint Louis, United States
b Department of Ophthalmology and Visual Sciences, Washington University in St Louis, Saint Louis, United States
c Department of Genetics, Washington University in St Louis, Saint Louis, United States
d Department of Developmental Biology, Washington University in St Louis, Saint Louis, United States
Abstract
Homeodomain transcription factors (HD TFs) are instrumental to vertebrate develop-ment. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we use Cone-Rod Homeobox (CRX) as a model to decipher the disease-causing mechanisms of two HD mutations, p.E80A and p.K88N, that produce severe dominant reti-nopathies. Through integrated analysis of molecular and functional evidence in vitro and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: p.E80A increases CRX-mediated transactivation of canonical CRX target genes in developing photoreceptors; p.K88N alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression. Both mechanisms produce novel retinal morphological defects and hinder photo-receptor maturation distinct from loss-of-function models. This study reveals the distinct roles of E80 and K88 residues in CRX HD regulatory functions and emphasizes the importance of transcriptional precision in normal development. © 2023, eLife Sciences Publications Ltd. All rights reserved.
Funding details
National Institutes of HealthNIHEY002687, EY012543, EY032136
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer’s Disease
(2023) Journal of Alzheimer’s Disease: JAD, 96 (3), pp. 1051-1058.
Chwa, W.J.a b , Raji, C.A.b , Toups, K.c , Hathaway, A.d , Gordon, D.e , Chung, H.f , Boyd, A.g , Hill, B.D.h , Hausman-Cohen, S.i , Attarha, M.j , Jarrett, M.f , Bredesen, D.E.k
a Saint Louis University School of Medicine, Saint Louis, MO, USA
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA
c Bay Area WellnessCA, United States
d Dr. Ann Hathaway, San Rafael, CA, United States
e Northwest Memory Center, Ashland, OR, United States
f Quesgen Systems, Burlingame, CA, United States
g CNS Vital Signs, Morrisville, NC, United States
h Department of Psychology, University of South Alabama, Mobile, AL, United States
i Austin, TX, United States
j Posit Science, San Francisco, CA, United States
k Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
Abstract
BACKGROUND: Alzheimer’s disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.
Document Type: Article
Publication Stage: Final
Source: Scopus
Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods
(2023) Neuropsychopharmacology, .
Yang, J.a , Huggins, A.A.b c , Sun, D.b c d , Baird, C.L.b c , Haswell, C.C.b c , Frijling, J.L.e , Olff, M.e f , van Zuiden, M.e , Koch, S.B.J.e g , Nawijn, L.e , Veltman, D.J.e , Suarez-Jimenez, B.h , Zhu, X.i j , Neria, Y.i j , Hudson, A.R.k , Mueller, S.C.k , Baker, J.T.l m , Lebois, L.A.M.l n , Kaufman, M.L.l o , Qi, R.p , Lu, G.M.p , Říha, P.q r , Rektor, I.r , Dennis, E.L.s t , Ching, C.R.K.u , Thomopoulos, S.I.u , Salminen, L.E.u , Jahanshad, N.u , Thompson, P.M.u , Stein, D.J.v , Koopowitz, S.M.v , Ipser, J.C.v , Seedat, S.w , du Plessis, S.w , van den Heuvel, L.L.w , Wang, L.x y , Zhu, Y.x y , Li, G.x y , Sierk, A.z , Manthey, A.z , Walter, H.z , Daniels, J.K.aa , Schmahl, C.ab , Herzog, J.I.ab , Liberzon, I.ac , King, A.ad , Angstadt, M.ad , Davenport, N.D.ae af , Sponheim, S.R.ae af , Disner, S.G.ae af , Straube, T.ag , Hofmann, D.ag , Grupe, D.W.ah , Nitschke, J.B.ai , Davidson, R.J.ah ai aj , Larson, C.L.ak , deRoon-Cassini, T.A.al am , Blackford, J.U.an ao , Olatunji, B.O.ap , Gordon, E.M.a , May, G.aq ar as at , Nelson, S.M.aq ar as at , Abdallah, C.G.au av , Levy, I.aw ax ay az ba , Harpaz-Rotem, I.au ay ba , Krystal, J.H.au ba , Morey, R.A.b c , Sotiras, A.a bb
a Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
b Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, NC, United States
c Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, United States
d Department of Psychology, The Education University of Hong Kong, Hong Kong
e Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, Netherlands
f ARQ National Psychotrauma Centre, Diemen, Netherlands
g Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, Netherlands
h Del Monte Institute for Neuroscience, University of Rochester Medical Center, Rochester, NY, United States
i Department of Psychiatry, Columbia University Medical Center, New York, NY, United States
j New York State Psychiatric Institute, New York, NY, United States
k Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium
l Department of Psychiatry, Harvard Medical School, Boston, MA, United States
m Institute for Technology in Psychiatry, McLean Hospital, Harvard University, Belmont, MA, United States
n Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, United States
o Division of Women’s Mental Health, McLean Hospital, Belmont, MA, United States
p Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Jiangsu, China
q First Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
r CEITEC-Central European Institute of Technology, Multimodal and Functional Neuroimaging Research Group, Masaryk University, Brno, Czech Republic
s Department of Neurology, University of Utah, Salt Lake City, UT, United States
t George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, United States
u Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, United States
v Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
w Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
x Laboratory for Traumatic Stress Studies, Chinese Academy of Sciences Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
y Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
z University Medical Centre Charité, Berlin, Germany
aa Department of Clinical Psychology, University of Groningen, Groningen, Netherlands
ab Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
ac Department of Psychiatry and Behavioral Science, Texas A&M University, College Station, TX, United States
ad Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
ae Minneapolis VA Health Care System, Minneapolis, MN, United States
af Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
ag Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
ah Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, United States
ai Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States
aj Department of Psychology, University of Wisconsin-Madison, Madison, WI, United States
ak Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
al Division of Trauma and Acute Care Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, United States
am Comprehensive Injury Center, Medical College of Wisconsin, Milwaukee, WI, United States
an Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, United States
ao Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
ap Department of Psychology, Vanderbilt University, Nashville, TN, United States
aq Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
ar Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
as Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
at Department of Psychiatry and Behavioral Science, Texas A&M University Health Science Center, Bryan, TX, United States
au Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
av Department of Psychiatry of Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
aw Department of Comparative Medicine, Yale University, New Haven, CT, United States
ax Department of Neuroscience, Yale University, New Haven, CT, United States
ay Department of Psychology, Yale University, New Haven, CT, United States
az Wu Tsai Institute, Yale University, New Haven, CT, United States
ba Division of Clinical Neuroscience, National Center for PTSD, West Haven, CT, United States
bb Institute for Informatics, Data Science & Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions. © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Funding details
110614, K01 MH118428-01
AZV NV18-7 04-00559, BE2022705
National Science FoundationNSF
National Institutes of HealthNIHMJFF 14848, R01 AG059874, R01 MH111671, R01 MH116147, R01 MH117601, R01 MH129742, U54 EB020403
U.S. Department of DefenseDODP41 EB015922, R56 AG058854, W81XWH-12-2-0012
National Institute of Mental HealthNIMHR01-MH043454, T32-MH018931
National Institute on Alcohol Abuse and AlcoholismNIAAAP50
National Institute of Child Health and Human DevelopmentNICHDP30-HD003352, R01 MH106574, VA CSR&D 1IK2CX001680
Congressionally Directed Medical Research ProgramsCDMRPW81XWH-08–2–0038
U.S. Department of Veterans AffairsVA
Dana FoundationDF
Scoliosis Research SocietySRS1K2RX002922, VA RR&D 1K1RX002325
California Department of Fish and GameDFGC06
Institute for Clinical and Translational Research, University of Wisconsin, MadisonUW ICTR
National Center for Advancing Translational SciencesNCATSR01AG067103
National Alliance for Research on Schizophrenia and DepressionNARSAD01J05415, 27040, R01 MH105355, RO1 MH111671
National Center for PTSD, U.S. Department of Veterans AffairsNCPTSDR01 MH105535, R21 MH102634
National Research FoundationNRF
South African Medical Research CouncilSAMRCMRC-RFA-IFSP-01-2013
Department of Science and Technology, Ministry of Science and Technology, IndiaDST
Deutsche ForschungsgemeinschaftDFGDA 1222/4-1, R01 MH113574, VA RR&D 1IK2RX000709, VA RR&D I01RX000622, WA 1539/8-2
National Natural Science Foundation of ChinaNSFC31971020, U21A20364
ZonMw40-00812-98-10041
Chinese Academy of SciencesCAS
Ministry of EducationMOE16JJD190006
Ministerstvo Zdravotnictví Ceské RepublikyMZCR
Universiteit GentK01 MH118467, R01 MH119227, R21 MH112956
Natural Science Foundation of Jiangsu ProvinceBK20221554
Bijzonder Onderzoeksfonds UGentBOF
National Office for Philosophy and Social SciencesNPOPSS20ZDA079
National Treasury
Document Type: Article
Publication Stage: Article in Press
Source: Scopus