Scopus list of publications for July 2, 2023
Brain hubs defined in the group do not overlap with regions of high inter-individual variability
(2023) NeuroImage, 277, art. no. 120195, .
Smith, D.M.a b , Kraus, B.T.a , Dworetsky, A.a c , Gordon, E.M.d , Gratton, C.a c e
a Department of Psychology, Northwestern University, Evanston, IL, United States
b Department of Neurology, Division of Cognitive Neurology/Neuropsychology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Department of Psychology, Florida State University, Tallahassee, FL, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Northwestern University, Evanston, IL, United States
Abstract
Connector ‘hubs’ are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability. To answer this question, we examined inter-individual variation at group-level hubs in both the Midnight Scan Club and Human Connectome Project datasets. The top group hubs defined based on the participation coefficient did not overlap strongly with the most prominent regions of inter-individual variation (termed ‘variants’ in prior work). These hubs have relatively strong similarity across participants and consistent cross-network profiles, similar to what was seen for many other areas of cortex. Consistency across participants was further improved when these hubs were allowed to shift slightly in local position. Thus, our results demonstrate that the top group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density (which are based on spatial proximity to network borders) and intermediate hub regions which show higher correspondence to locations of individual variability. © 2023
Funding details
National Science FoundationNSF2048066
National Institutes of HealthNIHMH121276, MH124567, NS129521, R01MH118370, T32NS047987
Northwestern UniversityNU
University of WashingtonUW
Office of the Provost, University of South Carolina
Dysphonia InternationalNSDA
Office of Research, University of Georgia
Document Type: Article
Publication Stage: Final
Source: Scopus
Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials
(2023) eBioMedicine, 93, art. no. 104662, .
Bar-Or, A.a , Thanei, G.-A.b , Harp, C.c , Bernasconi, C.b , Bonati, U.b , Cross, A.H.d , Fischer, S.c , Gaetano, L.b , Hauser, S.L.e , Hendricks, R.c , Kappos, L.f g , Kuhle, J.f g , Leppert, D.f g , Model, F.b , Sauter, A.b , Koendgen, H.b , Jia, X.c , Herman, A.E.c
a Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b F. Hoffmann-La Roche Ltd., Basel, Switzerland
c Genentech, Inc., South San Francisco, CA, United States
d Washington University School of Medicine, St Louis, MO, United States
e University of California, San Francisco, San Francisco, CA, United States
f Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
g Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel and University of Basel, Switzerland
Abstract
Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. Funding: F. Hoffmann-La Roche Ltd. © 2023 The Author(s)
Author Keywords
Biomarker; Disease progression; Multiple sclerosis; NfL; Ocrelizumab
Funding details
F. Hoffmann-La Roche
Document Type: Article
Publication Stage: Final
Source: Scopus
Measurement of relative motion of the brain and skull in the mini-pig in-vivo
(2023) Journal of Biomechanics, 156, art. no. 111676, .
Kailash, K.A.a , Guertler, C.A.b , Johnson, C.L.c , Okamoto, R.J.b , Bayly, P.V.a b
a Washington University in St. Louis, Biomedical Engineering, United States
b Washington University in St. Louis, Mechanical Engineering and Material Science, United States
c University of Delaware, Biomedical Engineering, United States
Abstract
The mechanical role of the skull-brain interface is critical to the pathology of concussion and traumatic brain injury (TBI) and may evolve with age. Here we characterize the skull-brain interface in juvenile, female Yucatan mini-pigs from 3 to 6 months old using techniques from magnetic resonance elastography (MRE). The displacements of the skull and brain were measured by a motion-sensitive MR imaging sequence during low-amplitude harmonic motion of the head. Each animal was scanned four times at 1-month intervals. Harmonic motion at 100 Hz was excited by three different configurations of a jaw actuator in order to vary the direction of loading. Rigid-body linear motions of the brain and skull were similar, although brain rotations were consistently smaller than corresponding skull rotations. Relative displacements between the brain and skull were estimated for voxels on the surface of the brain. Amplitudes of relative displacements between skull and brain were 1–3 μm, approximately 25–50% of corresponding skull displacements. Maps of relative displacement showed variations by anatomical region, and the normal component of relative displacement was consistently 25–50% of the tangential component. These results illuminate the mechanics of the skull-brain interface in a gyrencephalic animal model relevant to human brain injury and development. © 2023 Elsevier Ltd
Author Keywords
Brain biomechanics; Brain-skull interface; Magnetic resonance elastography; MRI
Funding details
R01EB027577, U01 NS112120
N00014-22-1-2198
Document Type: Article
Publication Stage: Final
Source: Scopus
Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E
(2023) The Journal of Clinical Investigation, 133 (12), .
Li, C.a , Wilborn, J.b , Pittman, S.a , Daw, J.a , Alonso-Pérez, J.c , Díaz-Manera, J.d , Weihl, C.C.a , Haller, G.a b e
a Department of Neurology and
b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
c Neuromuscular Disease Unit, Neurology Department, Hospital Universitario Nuestra Señora de Candelaria, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Tenerife, Spain
d John Walton Muscular Dystrophy Research Center, Newcastle University, Newcastle Upon Tyne, United Kingdom
e Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy.
Author Keywords
Genetic variation; Genetics; Muscle Biology; Neuromuscular disease
Document Type: Article
Publication Stage: Final
Source: Scopus
Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease
(2023) Science Translational Medicine, 15 (700), p. eabo2984.
Ferreiro, A.L.a b c , Choi, J.a , Ryou, J.a , Newcomer, E.P.a b , Thompson, R.d , Bollinger, R.M.e , Hall-Moore, C.f , Ndao, I.M.f , Sax, L.f , Benzinger, T.L.S.g h , Stark, S.L.d e h , Holtzman, D.M.d h i , Fagan, A.M.d h i , Schindler, S.E.d h , Cruchaga, C.d i j k , Butt, O.H.d , Morris, J.C.d h , Tarr, P.I.f l , Ances, B.M.b d g h i l , Dantas, G.a b c l m
a Edison Family Center for Genome Sciences and Systems Biology, Washington University School of MedicineMO 63110, United States
b Department of Biomedical Engineering, Washington University in St. LouisMO 63130, United States
c Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of MedicineMO 63110, United States
d Department of Neurology, Washington University School of MedicineMO 63110, United States
e Program in Occupational Therapy, Washington University School of MedicineMO 63110, United States
f Division of Gastroenterology, Hepatology, Nutrition, Department of Pediatrics, Washington University School of MedicineMO 63110, United States
g Department of Radiology, Washington University School of MedicineMO 63110, United States
h Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of MedicineMO 63110, United States
i Hope Center for Neurological Disorders, Washington University School of MedicineMO 63110, United States
j Washington University School of MedicineMO 63110, United States
k Department of Psychiatry, Washington University School of MedicineMO 63110, United States
l Department of Molecular Microbiology, Washington University School of MedicineMO 63110, United States
m Department of Pediatrics, Washington University School of MedicineMO 63110, United States
Abstract
Alzheimer’s disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.
Document Type: Article
Publication Stage: Final
Source: Scopus
Oxidation Driven Reversal of PIP2-dependent Gating in GIRK2 Channels
(2023) Function, 4 (3), art. no. zqad016, .
Lee, S.-J.a , Maeda, S.b , Gao, J.a , Nichols, C.G.a
a Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, United States
Abstract
Physiological activity of G protein gated inward rectifier K+ (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP2), G, and Na+, underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP2 and Na+-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP2. Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP2 and Na+-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels. © Function. All Rights Reserved.
Author Keywords
GIRK2; kir3; oxidation; oxidative stress; PIP2; reversed gating
Funding details
National Institutes of HealthNIHHL140024, TR003670
Document Type: Article
Publication Stage: Final
Source: Scopus