Representations of Complex Contexts: A Role for Hippocampus
(2023) Journal of Cognitive Neuroscience, 35 (1), pp. 90-110. Cited 1 time.
Dimsdale-Zucker, H.R.a , Montchal, M.E.b , Reagh, Z.M.c , Wang, S.-F.d , Libby, L.A.b , Ranganath, C.b
a Columbia University, United States
b University of California, Irvine, United States
c Washington University, St. Louis-Danforth Campus, United States
d Stanford University, United States
Abstract
The hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item–context binding. To address this question, we constructed a task in which items were affiliated with differing types of context—cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval. © 2022 Massachusetts Institute of Technology.
Document Type: Article
Publication Stage: Final
Source: Scopus
Macrophage depletion blocks congenital SARM1-dependent neuropathy
(2022) The Journal of Clinical Investigation, 132 (23), .
Dingwall, C.B.a , Strickland, A.a , Yum, S.W.b , Yim, A.K.a , Zhu, J.a , Wang, P.L.a c , Yamada, Y.a , Schmidt, R.E.c , Sasaki, Y.a , Bloom, A.J.a d , DiAntonio, A.d e , Milbrandt, J.a d
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Division of Neurology, Children’s Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, Philadelphia, PA, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, United States
e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.
Author Keywords
Macrophages; Mouse models; Neurodegeneration; Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model
(2022) The Journal of Clinical Investigation, 132 (23), .
Sato-Yamada, Y.a b , Strickland, A.a , Sasaki, Y.a , Bloom, J.a c , DiAntonio, A.c d , Milbrandt, J.a c e
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Science, Niigata City, Japan
c Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, United States
d Department of Developmental Biology and
e McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities – all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and Mfn2H361Y Sarm1 double-mutant rats and found that deletion of Sarm1 rescued axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 was responsible for much of the neuropathology in this model. Despite the presence of mutant MFN2 protein in these double-mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activated SARM1 and that activated SARM1 fed back on mitochondria to exacerbate the mitochondrial pathology. As such, this work identifies SARM1 inhibition as a therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.
Author Keywords
Neurodegeneration; Neurological disorders; Neuromuscular disease; Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Impact of the COVID-19 Pandemic on the Behavioral Health of People With Intellectual and Developmental Disabilities
(2022) Psychiatric Services (Washington, D.C.), 73 (12), pp. 1389-1392.
Sanders, J.S., Pillai, R.L.I., Sturley, R., Sillau, S., Asato, M.R., Aravamuthan, B.R., Bonuck, K., Cervenka, M.C., Hammond, N., Siegel, J.F., Siasoco, V., Margolis, B.A.
Department of Pediatrics (Sanders) and Department of Neurology (Sanders, Sillau), University of Colorado School of Medicine, Aurora; University of Massachusetts Chan Medical School-Baystate, Springfield (Pillai); Program in Humanistic Studies, Princeton University, Princeton, New Jersey (Sturley); Kennedy Krieger Institute (Asato) and Adult Epilepsy Diet Center (Cervenka), Johns Hopkins School of Medicine, Baltimore; Institute of Clinical and Translational Sciences, Washington University School of Medicine, St. Louis (Aravamuthan); Department of Pediatrics, Albert Einstein College of Medicine, New York City (Bonuck, Siegel, Siasoco); Department of Neurology, University of Kansas Medical Center, Kansas City (Hammond); Access: Supports for Living, Middletown, New York (Margolis)
Abstract
OBJECTIVE: The authors examined how the COVID-19 pandemic affected the behavioral health of people with intellectual and developmental disabilities (IDD). METHODS: A modified version of the Coronavirus Health Impact Survey-Adapted for Autism and Related Neurodevelopmental Conditions was sent to the authors’ clinical networks and IDD-affiliated organizations from March to June 2021. RESULTS: In total, 437 people with IDD or their caregivers responded to the survey. Diagnoses included intellectual disability (51%) and autism spectrum disorder (48%). More than half (52%) of respondents reported worsened mental health. Losing access to services correlated with declining mental health. Interventions suggested to improve behavioral health included more time with friends and family (68%), more time outdoors (61%), and access to community activities (59%). CONCLUSIONS: COVID-19 affected the behavioral health of individuals with IDD. Survey results highlight the opportunity to leverage physical activity and pandemic-safe social supports as accessible means to mitigate gaps in services.
Author Keywords
Autism spectrum disorder; Community mental health services; Developmental disability; Intellectual disability
Document Type: Article
Publication Stage: Final
Source: Scopus
A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis
(2022) Science Translational Medicine, 14 (673), p. eadc9778.
Ostkamp, P.a , Deffner, M.a , Schulte-Mecklenbeck, A.a , Wünsch, C.a , Lu, I.-N.a , Wu, G.F.b c , Goelz, S.d , De Jager, P.L.e , Kuhlmann, T.f , Gross, C.C.a , Klotz, L.a , Meyer Zu Hörste, G.a , Wiendl, H.a , Schneider-Hohendorf, T.a , Schwab, N.a
a Department of Neurology with Institute of Translational Neurology, University Hospital MünsterMünster 48149, Germany
b Department of Pathology and Immunology, Washington University School of MedicineMO 63110, United States
c Department of Neurology, Washington University School of MedicineMO 63110, United States
d Oregon Health and Science UniversityPortland OR 97239, United States
e Center for Translational and Computational Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, Columbia University Irving Medical Center, NY, 10032, United States
f Institute of Neuropathology, University Hospital MünsterMünster 48149, Germany
Abstract
Peripheral central nervous system (CNS)-infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (TRM) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible for diagnostics, we evaluated whether human CSF, apart from infiltrating cells, also contains TRM cells and CNS-resident myeloid cells draining from the parenchyma or border tissues. Using deep generative models, we integrated 41 CSF and 14 CNS parenchyma single-cell RNA sequencing (scRNAseq) samples from eight independent studies, encompassing 120,629 cells. By comparing CSF immune cells collected during multiple sclerosis relapse with cells collected during therapeutic very late antigen-4 blockade, we could identify immune subsets with tissue provenance across multiple lineages, including CNS border-associated macrophages, CD8 and CD4 TRM cells, and tissue-resident natural killer cells. All lymphocytic CNS-resident cells shared expression of CXCR6 but showed differential ITGAE expression (encoding CD103). A common signature defined CD4 and CD8 TRM cells by expression of ZFP36L2, DUSP1, and ID2. We further developed a user interface-driven application based on this analysis framework for atlas-level cell identity transfer onto new CSF scRNAseq data. Together, these results define CNS-resident immune cells involved in multiple sclerosis pathology that can be detected and monitored in CSF. Targeting these cell populations might be promising to modulate immunopathology in progressive multiple sclerosis and other neuroinflammatory diseases.
Document Type: Article
Publication Stage: Final
Source: Scopus
A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication
(2022) PLoS Genetics, 18 (11), art. no. e1010477, .
Shackleford, G.G.a b c , Marziali, L.N.a b , Sasaki, Y.d , Claessens, A.c , Ferri, C.c , Weinstock, N.I.a b , Rossor, A.M.e , Silvestri, N.J.a b , Wilson, E.R.a b , Hurley, E.a b , Kidd, G.J.f , Manohar, S.g , Ding, D.g , Salvi, R.J.g , Laura Feltri, M.a b , D’Antonio, M.c , Wrabetz, L.a b
a Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, United States
b Department of Biochemistry, Institute for Myelin and Glia Exploration, Department Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, United States
c Biology of Myelin Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
d Needleman Center for Neurometabolism and Axonal Therapeutics, Department of Genetics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
e Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
f Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
g Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY, United States
Abstract
Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons. Copyright: © 2022 Shackleford 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
Upper Limb Nerve Transfer Surgery in Patients With Tetraplegia
(2022) JAMA Network Open, 5 (11), p. e2243890.
Javeed, S.a , Dibble, C.F.a , Greenberg, J.K.a , Zhang, J.K.a , Khalifeh, J.M.b , Park, Y.c , Wilson, T.J.d , Zager, E.L.e , Faraji, A.H.f , Mahan, M.A.g , Yang, L.J.h , Midha, R.i , Juknis, N.j , Ray, W.Z.a
a Department of Neurological Surgery, Washington University, St Louis, MO, United States
b Department of Neurological Surgery, Johns Hopkins University, Baltimore, MD, Liberia
c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurosurgery, Stanford University, Stanford, CA, United States
e Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, United States
f Department of Neurological Surgery, Houston Methodist Hospital, Houston, TX, United States
g Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, United States
h Department of Neurological Surgery, University of Michigan School of Medicine, Ann Arbor, United States
i Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
j Physical Medicine and Rehabilitation, Washington University, St Louis, MO, United States
Abstract
Importance: Cervical spinal cord injury (SCI) causes devastating loss of upper extremity function and independence. Nerve transfers are a promising approach to reanimate upper limbs; however, there remains a paucity of high-quality evidence supporting a clinical benefit for patients with tetraplegia. Objective: To evaluate the clinical utility of nerve transfers for reanimation of upper limb function in tetraplegia. Design, Setting, and Participants: In this prospective case series, adults with cervical SCI and upper extremity paralysis whose recovery plateaued were enrolled between September 1, 2015, and January 31, 2019. Data analysis was performed from August 2021 to February 2022. Interventions: Nerve transfers to reanimate upper extremity motor function with target reinnervation of elbow extension and hand grasp, pinch, and/or release. Main Outcomes and Measures: The primary outcome was motor strength measured by Medical Research Council (MRC) grades 0 to 5. Secondary outcomes included Sollerman Hand Function Test (SHFT); Michigan Hand Outcome Questionnaire (MHQ); Disabilities of Arm, Shoulder, and Hand (DASH); and 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores. Outcomes were assessed up to 48 months postoperatively. Results: Twenty-two patients with tetraplegia (median age, 36 years [range, 18-76 years]; 21 male [95%]) underwent 60 nerve transfers on 35 upper limbs at a median time of 21 months (range, 6-142 months) after SCI. At final follow-up, upper limb motor strength improved significantly: median MRC grades were 3 (IQR, 2.5-4; P = .01) for triceps, with 70% of upper limbs gaining an MRC grade of 3 or higher for elbow extension; 4 (IQR, 2-4; P < .001) for finger extensors, with 79% of hands gaining an MRC grade of 3 or higher for finger extension; and 2 (IQR, 1-3; P < .001) for finger flexors, with 52% of hands gaining an MRC grade of 3 or higher for finger flexion. The secondary outcomes of SHFT, MHQ, DASH, and SF36-PCS scores improved beyond the established minimal clinically important difference. Both early (<12 months) and delayed (≥12 months) nerve transfers after SCI achieved comparable motor outcomes. Continual improvement in motor strength was observed in the finger flexors and extensors across the entire duration of follow-up. Conclusions and Relevance: In this prospective case series, nerve transfer surgery was associated with improvement of upper limb motor strength and functional independence in patients with tetraplegia. Nerve transfer is a promising intervention feasible in both subacute and chronic SCI.
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluation of Cisplatin-Induced Pathology in the Larval Zebrafish Lateral Line
(2022) International Journal of Molecular Sciences, 23 (22), art. no. 14302, .
Lee, D.S.a , Schrader, A.a , Bell, E.a , Warchol, M.E.a b , Sheets, L.a c
a Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Cisplatin is an effective anticancer agent, but also causes permanent hearing loss by damaging hair cells—the sensory receptors essential for hearing. There is an urgent clinical need to protect cochlear hair cells in patients undergoing cisplatin chemotherapy. The zebrafish lateral line organ contains hair cells and has been frequently used in studies to screen for otoprotective compounds. However, these studies have employed a wide range of cisplatin dosages and exposure times. We therefore performed a comprehensive evaluation of cisplatin ototoxicity in the zebrafish lateral line with the goal of producing a standardized, clinically relevant protocol for future studies. To define the dose- and time-response patterns of cisplatin-induced hair-cell death, we treated 6-day-old larvae for 2 h in 50 µM–1 mM cisplatin and allowed them to recover. We observed delayed hair cell death, which peaked at 4–8 h post-exposure. Cisplatin also activated a robust inflammatory response, as determined by macrophage recruitment and phagocytosis of hair cells. However, selective depletion of macrophages did not affect hair cell loss. We also examined the effect of cisplatin treatment on fish behavior and found that cisplatin-induced lateral line injury measurably impaired rheotaxis. Finally, we examined the function of remaining hair cells that appeared resistant to cisplatin treatment. We observed significantly reduced uptake of the cationic dye FM1-43 in these cells relative to untreated controls, indicating that surviving hair cells may be functionally impaired. Cumulatively, these results indicate that relatively brief exposures to cisplatin can produce hair cell damage and delayed hair cell death. Our observations provide guidance on standardizing methods for the use of the zebrafish model in studies of cisplatin ototoxicity. © 2022 by the authors.
Author Keywords
cisplatin; lateral line organ; macrophage; ototoxicity; rheotaxis; zebrafish
Funding details
MC-LI-2018-762
National Institutes of HealthNIHT32DC000022
National Institute on Deafness and Other Communication DisordersNIDCD
American Society of Pediatric OtolaryngologyASPO930395
Document Type: Article
Publication Stage: Final
Source: Scopus
Perceptions of Research Burden and Retention among Participants in ADRC Cohorts
(2022) Alzheimer Disease and Associated Disorders, 36 (4), pp. 281-287.
Gabel, M.a , Bollinger, R.M.c , Knox, M.d e , Coble, D.W.c , Grill, J.D.f , Edwards, D.F.g h , Stark, S.L.b , Lingler, J.H.d
a Department of Political Science, Washington University, St. Louis, United States
b Knight Alzheimer Disease Research Center, Washington University, St. Louis, United States
c Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
d University of Pittsburgh, School of Nursing, United States
e University of Pittsburgh, Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States
f Departments of Psychiatry & Human Behavior and Neurobiology & Behavior, Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, CA, United States
g # School of Medicine and Public Health, University of Wisconsin, Madison, United States
h Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
Abstract
Objectives: Alzheimer disease (AD) and related dementias clinical research is associated with significant participant burden. The Perceived Research Burden Assessment (PeRBA) measures participants’ perceptions of logistical, psychological, and physical burdens. The purpose of this study was to assess PeRBA’s psychometric properties, perceptual sources, and behavioral consequences with participants in a multisite study of participant retention in longitudinal cohort studies of Alzheimer disease and related dementias. Design: Multicenter mixed methods. Setting: In-person or phone. Participants: A total of 443 participants at 4 NIA-funded Alzheimer Disease Research Centers (ADRCs) were randomly selected and invited to participate if they were 45 years of age or more, enrolled in longitudinal studies, and had a Clinical Dementia Rating Scale global score ≤1. Measurements: Participants completed a 20-minute survey including the 21-item PeRBA about their research participation. Results: PeRBA demonstrated high-internal consistency and convergent validity. PeRBA scores correlated with expected perceptual factors. Higher PeRBA scores were associated with lower attendance and higher dropout rates. Conclusions: PeRBA can be used by researchers to identify participants who may feel overburdened and tailor approaches and strategies to support participants in longitudinal AD studies, maximizing participation, and reducing dropout. Making efforts to increase participants’ understanding of study procedures, and building and maintaining trust throughout the study, can contribute to reducing perceived burden and potentially increasing retention in longitudinal AD studies. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
Alzheimer disease; dementia; longitudinal studies; psychogeriatrics; research design and methodology
Funding details
National Institutes of HealthNIHU01 AG016976
National Institute on AgingNIA
National Alzheimer’s Coordinating CenterNACC2017-01
Document Type: Article
Publication Stage: Final
Source: Scopus
K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas
(2022) Nature Genetics, . Cited 1 time.
Jessa, S.a b , Mohammadnia, A.c , Harutyunyan, A.S.d , Hulswit, M.c , Varadharajan, S.e , Lakkis, H.b c , Kabir, N.c , Bashardanesh, Z.b , Hébert, S.b c , Faury, D.d , Vladoiu, M.C.f g h , Worme, S.b i , Coutelier, M.b c , Krug, B.c , Faria Andrade, A.c , Pathania, M.j k , Bajic, A.c , Weil, A.G.l , Ellezam, B.m , Atkinson, J.n , Dudley, R.W.R.n , Farmer, J.-P.n , Perreault, S.o , Garcia, B.A.p ab , Larouche, V.q , Blanchette, M.r , Garzia, L.s t , Bhaduri, A.u , Ligon, K.L.v w x , Bandopadhayay, P.x y z , Taylor, M.D.g h , Mack, S.C.aa , Jabado, N.c d i , Kleinman, C.L.b c
a Quantitative Life Sciences, McGill University, Montreal, QC, Canada
b Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
c Department of Human Genetics, McGill University, Montreal, QC, Canada
d Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
e Brain Tumour Program, Children’s Cancer Centre and Department of Paediatrics, Baylor College of Medicine, Houston, TX, United States
f Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
g Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
h The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
i Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
j Department of Oncology and The Milner Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom
k CRUK Children’s Brain Tumour Centre of Excellence, University of Cambridge, Cambridge, United Kingdom
l Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC, Canada
m Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC, Canada
n Department of Pediatric Surgery, Division of Neurosurgery, Montreal Children’s Hospital, McGill University, Montreal, QC, Canada
o Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, QC, Canada
p Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
q Department of Pediatrics, Centre mère-enfant Soleil du CHU de Québec-Université Laval, Quebec City, QC, Canada
r School of Computer Science, McGill University, Montreal, QC, Canada
s Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada
t Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, QC, Canada
u Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, United States
v Department of Pathology, Boston Children’s Hospital and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
w Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, United States
x Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, United States
y Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
z Department of Pediatrics, Harvard Medical School, Boston, MA, United States
aa Department of Developmental Neurobiology, Neural Brain Tumor Program, St Jude Children’s Research Hospital, Memphis, TN, United States
ab Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, whereas H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, whereas other epigenetic changes are mainly contingent on the cell of origin chromatin state and cycling rate. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
WST-164-AB
National Institutes of HealthNIHP01-CA196539, R01CA148699, R01CA159859
Genome CanadaGC
Ontario Institute for Cancer ResearchOICR
Ministère de l’Économie, de la Science et de l’Innovation – QuébecMESI
Government of Ontario
Canadian Cancer Society Research InstituteCCSRI705182
Government of Canada
Canadian Institutes of Health ResearchIRSCFDN-154307, MOP-286756, PJT-156086
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN-2016-04911
Fonds de Recherche du Québec – SantéFRQS
Canada Foundation for InnovationCFI33902
Canadian Cancer Society
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease
(2022) Blood, .
Hulbert, M.L.a , Fields, M.E.a b , Guilliams, K.P.a b c , Bijlani, P.d , Shenoy, S.a , Fellah, S.c , Towerman, A.S.a , Binkley, M.M.e , McKinstry, R.C.c , Shimony, J.S.c , Chen, Y.c , Eldeniz, C.c , Ragan, D.K.f , Vo, K.c , An, H.c , Lee, J.-M.b c , Ford, A.L.b c
a Department, of Pediatrics, Washington University in St. Louis, St. Louis, MO
b Department of Neurology, Washington University in St. Louis, St. Louis, MO
c Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO
d Department of Internal Medicine, University of California San Diego, San Diego, CA
e CNS Consultants, LLC, St. Louis, MO
f Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, United States
Abstract
Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population. © 2022 The American Society of Hematology
Funding details
National Institutes of HealthNIHK23HL136904, K23NS099472, R01HL129241, R01HL157188
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring
(2022) Nature Medicine, .
Ashton, N.J.a b c d , Janelidze, S.e , Mattsson-Carlgren, N.e f g , Binette, A.P.e , Strandberg, O.e , Brum, W.S.a h , Karikari, T.K.a i , González-Ortiz, F.a , Di Molfetta, G.a , Meda, F.J.a , Jonaitis, E.M.j k , Koscik, R.L.j k , Cody, K.j k , Betthauser, T.J.j k , Li, Y.l m , Vanmechelen, E.n , Palmqvist, S.e o , Stomrud, E.e o , Bateman, R.J.l m , Zetterberg, H.a p q r s , Johnson, S.C.j k , Blennow, K.a n , Hansson, O.e o
a Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
b King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, United Kingdom
c NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom
d Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
e Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
f Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
g Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
h Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
i Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
j Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
k Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
l Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
m SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
n ADx NeuroSciences, Technologiepark 94, Ghent, Belgium
o Memory Clinic, Skåne University Hospital, Malmö, Sweden
p Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
q Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
r UK Dementia Research Institute at UCL, London, United Kingdom
s Hong Kong Center for Neurodegenerative Diseases, Hong Kong
Abstract
Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments. © 2022, The Author(s).
Funding details
ALFGBG-715986, ALFGBG-965240
JPND2019-466-236
1280/20
2020-0314
ALFGBG-720931
2018-Projekt0054, 2018-Projekt0279, AG021155, AG027161
2019
National Institutes of HealthNIH2016-00906, 2021-02219
Alzheimer’s AssociationAAADSF-21-831376-C, ADSF-21-831377-C, ADSF-21-831381-C, ZEN-21-848495
Alzheimer’s Drug Discovery FoundationADDF1R01AG068398-01, 201809-2016862, RDAPB-201809-2016615
Familjen Erling-Perssons Stiftelse
Horizon 2020 Framework ProgrammeH2020
H2020 Marie Skłodowska-Curie ActionsMSCA860197
Stiftelsen för Gamla Tjänarinnor2019-00845, ALZ2022-0006, FO2017-0243, FO2019-0228
European Research CouncilERC681712
Brain FoundationFO2020-0271
Lunds UniversitetAF-930655, AF-939932, AF-968453
HjärnfondenFO2019-0029, FO2020-0275, FO2021-0293
Knut och Alice Wallenbergs Stiftelse2017-0383
VetenskapsrådetVR2017-00915, 2018-02052, 2018-02532
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
AlzheimerfondenAF-930351, AF-939721, AF-940046, AF-968270
Region Skåne
Marcus och Amalia Wallenbergs minnesfondMAW2015.0125
UK Dementia Research InstituteUK DRI
University Hospital FoundationUHF2020-O000028
Olav Thon Stiftelsen
Stiftelsen Bundy Academy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Dual-contrast MRI reveals intraplacental oxygenation patterns, detects placental abnormalities and fetal brain oxygenation
(2022) Ultrasound in Obstetrics and Gynecology, .
Sun, Z.a b , Wu, W.a b , Zhao, P.b , Wang, Q.c , Woodard, P.a c , Nelson, D.M.b , Odibo, A.b , Cahill, A.d , Wang, Y.a b c e
a Department of Biomedical Engineering, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Women’s Health, University of Texas at Austin, Dell Medical School, Austin, TX, United States
e Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Objectives: Most human in-vivo placenta imaging techniques are unable to distinguish and separately characterize various placental compartments such as the intervillous space (IVS), placental vessels (PV), and placental tissue (PT). This significantly limits their specificity in imaging the human placenta. Here, we describe a method that employs T2* and diffusion MRI contrasts to automatically distinguish placental compartments, quantify their tissue oxygenation properties, and delineate placental lesions (PL) in vivo. Methods: Dual-contrast clinical MRI includes T2* and diffusion MR scans acquired from 27 patients, including 22 normal and 5 complicated pregnancies at gestational ages between 20 and 38 weeks. We trained a fuzzy clustering method to analyze both T2* and diffusion MRI contrasts and assign all placental voxels to one of four clusters based on their distinct imaging domain features. The fuzzy clustering model was employed to analyze the quantitative imaging metrics of T2* and diffusion MRI to dissect the placenta compartmental heterogeneity. The new method automatically classified the placental tissues into IVS, PV, PT, and PL compartments and characterized their oxygenation changes over pregnancy. Results: Total placental oxygenation level and T2* did not demonstrate a statistically significant temporal correlation with GA (R2=0.060, p=0.27). Strikingly, the oxygenation level indicated by T2* values in the placental IVS (R2=0.51, p=2.1e-5) and PV (R2=0.76, p=1.1e-7) decreased significantly with advancing GA. In contrast, oxygenation levels in the PT did not show any temporal change (R2=0.00044, p=0.93) during pregnancy. Additionally, a strong spatial-dependent correlation between PV oxygenation level and GA was also discovered. The strongest negative correlation between PV oxygenation and GA (R2=0.73, p=4.5e-7) was found at the fetal vessel-dominated region close to the chorionic plate. The location and extent of the placenta abnormality were automatically delineated and quantified in the 5 women with clinically confirmed placental pathologies. Compared to the averaged total placental oxygenation, the placental IVS oxygenation level best reflects the fetal brain oxygenation level during fetal development. Conclusion: Based on the clinically feasible dual-MRI images, our method enables the accurate spatial-temporal quantification of placenta compartment and fetal brain oxygenation across different gestational ages. This information will be essential in improving our knowledge of human placenta development and its relationship to normal and abnormal pregnancy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Author Keywords
Diffusion MRI; fetal brain oxygenation; intervillous space oxygenation; intra-placental segmentation; T2* MRI; tissue-specific
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Association between recent overdose and chronic pain among individuals in treatment for opioid use disorder
(2022) PLoS ONE, 17 (11 November), art. no. e0271379, .
Hartz, S.M.a , Culverhouse, R.C.b , Mintz, C.M.a , Ellis, M.S.a , Kasper, Z.A.a , Cavazos-Rehg, P.a , Grucza, R.A.c , Bierut, L.J.a , Cicero, T.J.a
a Department of Psychiatry, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Medicine, Division of Biostatistics, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Family & Community Medicine, St. Louis University, School of Medicine, St. Louis, MO, United States
Abstract
Chronic pain increases risk for opioid overdose among individuals with opioid use disorder. The purpose of this study is to evaluate the relationship between recent overdose and whether or not chronic pain is active. 3,577 individuals in treatment for opioid use disorder in 2017 or 2018 were surveyed regarding recent overdoses and chronic pain. Demographics from the 2017 Treatment Episode Data Set, which includes all U.S. facilities licensed or certified to provide substance use care, were used to evaluate the generalizability of the sample. χ2 tests and logistic regression models were used to compare associations between recent overdoses and chronic pain. Specifically, active chronic pain was associated with opioid overdose among people in treatment for opioid use disorder. Individuals with active chronic pain were more likely to have had a past month opioid overdose than those with no history chronic pain (adjusted OR = 1.55, 95% CI 1.16–2.08, p = 0.0003). In contrast, individuals with prior chronic pain, but no symptoms in the past 30 days, had a risk of past month opioid overdose similar to those with no history of chronic pain (adjusted OR = 0.88, 95% CI 0.66–1.17, p = 0.38). This suggests that the incorporation of treatment for chronic pain into treatment for opioid use disorder may reduce opioid overdoses. Copyright: © 2022 Hartz 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.
Funding details
National Institutes of HealthNIHR21 AA024888-01, R21 DA044744, UL1 TR002345
Document Type: Article
Publication Stage: Final
Source: Scopus
The relevance of rich club regions for functional outcome post-stroke is enhanced in women
(2022) Human Brain Mapping, .
Bonkhoff, A.K.a , Schirmer, M.D.a , Bretzner, M.a b , Hong, S.a , Regenhardt, R.W.a , Donahue, K.L.a , Nardin, M.J.a , Dalca, A.V.c d , Giese, A.-K.e , Etherton, M.R.a , Hancock, B.L.d , Mocking, S.J.T.d , McIntosh, E.C.f , Attia, J.g h , Cole, J.W.i , Donatti, A.j , Griessenauer, C.J.k l , Heitsch, L.m n , Holmegaard, L.o p , Jood, K.o p , Jimenez-Conde, J.q , Kittner, S.J.i , Lemmens, R.r s , Levi, C.R.h t , McDonough, C.W.u , Meschia, J.F.v , Phuah, C.-L.n , Ropele, S.w , Rosand, J.a d x , Roquer, J.q , Rundek, T.y , Sacco, R.L.y , Schmidt, R.w , Sharma, P.z aa , Slowik, A.ab , Sousa, A.j , Stanne, T.M.ac , Strbian, D.ad , Tatlisumak, T.o p , Thijs, V.ae af , Vagal, A.ag , Wasselius, J.ah ai , Woo, D.aj , Zand, R.ak , McArdle, P.F.al , Worrall, B.B.am , Jern, C.ab an , Lindgren, A.G.ao ap , Maguire, J.aq , Wu, O.d , Rost, N.S.a , the MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortiumar
a J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
b Univ. Lille, Inserm, CHU Lille, U1171 – LilNCog (JPARC) – Lille Neurosciences & Cognition, Lille, France
c Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Boston, MA, United States
d Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States
e Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
f Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, United States
g Hunter Medical Research Institute, Newcastle, NSW, Australia
h School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
i Department of Neurology, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore, MD, United States
j School of Medical Sciences, University of Campinas (UNICAMP) and the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), São Paulo, Campinas, Brazil
k Department of Neurosurgery, Geisinger, Danville, PA, United States
l Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria
m Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
n Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St Louis, MO, United States
o Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
p Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
q Department of Neurology, Neurovascular Research Group (NEUVAS), IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mèdiques). Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
r Department of Neurosciences, KU Leuven – University of Leuven, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium
s Department of Neurology, VIB, Vesalius Research Center, Laboratory of Neurobiology, University Hospitals Leuven, Leuven, Belgium
t Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia
u Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL, United States
v Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
w Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
x Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States
y Department of Neurology and Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
z Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL), Egham, United Kingdom
aa St Peter’s and Ashford Hospitals, Ashford, United Kingdom
ab Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
ac Department of Laboratory Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
ad Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
ae Stroke Division, Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia
af Department of Neurology, Austin Health, Heidelberg, Australia
ag Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
ah Department of Clinical Sciences Lund, Radiology, Lund University, Lund, Sweden
ai Department of Radiology, Neuroradiology, Skåne University Hospital, Lund, Sweden
aj Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
ak Department of Neurology, Pennsylvania State University, Hershey, PA, United States
al Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
am Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, VA, United States
an Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
ao Department of Neurology, Skåne University Hospital, Lund, Sweden
ap Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
aq University of Technology Sydney, Sydney, Australia
Abstract
This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into “rich club” and “non-rich club” regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women. © 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.
Author Keywords
Bayesian hierarchical modeling; functional outcome; lesion-symptom mapping; rich club; sex differences
Funding details
ALFGBG‐965328
R01 NS100417, R01 NS103824, R01NS082285, R01NS086905, RF1 NS117643, U01NS100699, U01NS110772, U19NS115388
Medtronic
Hjärt-Lungfonden20190203, 2019‐01757
VetenskapsrådetVR2021‐01114
STROKE-Riksförbundet
Société Française de RadiologieSFR
Skånes universitetssjukhusSUS
Forschungsfabrik Mikroelektronik DeutschlandFMD
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterization of the Targeting Accuracy of a Neuronavigation-guided Transcranial FUS system in vitro, in vivo, and in silico
(2022) IEEE Transactions on Biomedical Engineering, pp. 1-11.
Xu, L.a , Pacia, C.P.a , Gong, Y.a , Hu, Z.a , Chien, C.a , Yang, L.a , Gach, H.M.b , Hao, Y.c , Comron, H.c , Huang, J.c , Leuthardt, E.C.d , Chen, H.e
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
b Department of Radiation Oncology, Department of Radiology, and the Department of Biomedical Engineering, Washington University in St. Louis, MO, USA
c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
d Department of Neurosurgery, Department of Biomedical Engineering, Department of Neuroscience, Center for Innovation in Neuroscience and Technology, Washington University in St. Louis, MO, USA
e Department of Biomedical Engineering and the Department of Radiation Oncology, Washington University in St. Louis, MO, USA
Abstract
Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized <italic>in vitro</italic>, <italic>in vivo</italic>, and <italic>in silico</italic>. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized <italic>in vitro</italic> in a water tank using a hydrophone. The performance of the device in BBB disruption was verified <italic>in vivo</italic> using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated <italic>in silico</italic> using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 ± 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 ± 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 ± 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in glioblastoma patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic. IEEE
Author Keywords
Biomarkers; blood-brain barrier; Computed tomography; Focused ultrasound; glioblastoma; Magnetic resonance imaging; neuronavigation; Storage tanks; Target tracking; targeting accuracy; Transducers; Tumors
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
ICAM-reg: Interpretable Classification and Regression with Feature Attribution for Mapping Neurological Phenotypes in Individual Scans
(2022) IEEE Transactions on Medical Imaging, pp. 1-1.
Bass, C.a , Da Silva, M.a , Sudre, C.a , Williams, L.Z.J.a , Sousa, H.S.a , Tudosiu, P.a , Alfaro-Almagro, F.b , Fitzgibbon, S.P.c , Glasser, M.F.d , Smith, S.M.b , Robinson, E.C.a
a School of Biomedical Engineering and Imaging Sciences, King’s College London, UK
b FMRIB, Clinical Neurology, UK
c The University of Oxford, Wellcome Centre for Integrative Neuroimaging, UK
d Department of Anatomy and Neurobiology, Washington University in St Louis, USA
Abstract
An important goal of medical imaging is to be able to precisely detect patterns of disease specific to individual scans; however, this is challenged in brain imaging by the degree of heterogeneity of shape and appearance. Traditional methods, based on image registration, historically fail to detect variable features of disease, as they utilise population-based analyses, suited primarily to studying group-average effects. In this paper we therefore take advantage of recent developments in generative deep learning to develop a method for simultaneous classification, or regression, and feature attribution (FA). Specifically, we explore the use of a VAE-GAN (variational autoencoder – general adversarial network) for translation called ICAM, to explicitly disentangle class relevant features, from background confounds, for improved interpretability and regression of neurological phenotypes. We validate our method on the tasks of Mini-Mental State Examination (MMSE) cognitive test score prediction for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, as well as brain age prediction, for both neurodevelopment and neurodegeneration, using the developing Human Connectome Project (dHCP) and UK Biobank datasets. We show that the generated FA maps can be used to explain outlier predictions and demonstrate that the inclusion of a regression module improves the disentanglement of the latent space. Our code is freely available on GitHub https://github.com/CherBass/ICAM. Author
Author Keywords
Alzheimer’s disease; Biomedical imaging; Brain Imaging; Deep generative models; Diseases; Feature Attribution; Feature extraction; Image-to-image translation; Imaging; Neuroimaging; Training
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
ACES: Analysis of Conservation with an Extensive list of Species
(2021) Bioinformatics, 37 (21), pp. 3920-3922.
Padhi, E.M., Ng, J.K., Mehinovic, E., Sams, E.I., Turner, T.N.
Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
Motivation: An abundance of new reference genomes is becoming available through large-scale sequencing efforts. While the reference FASTA for each genome is available, there is currently no automated mechanism to query a specific sequence across all new reference genomes. Results: We developed ACES (Analysis of Conservation with an Extensive list of Species) as a computational workflow to query specific sequences of interest (e.g. enhancers, promoters, exons) against reference genomes with an available reference FASTA. This automated workflow generates BLAST hits against each of the reference genomes, a multiple sequence alignment file, a graphical fragment assembly file and a phylogenetic tree file. These data files can then be used by the researcher in several ways to provide key insights into conservation of the query sequence. © 2021 The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus