List of publications for October 13, 2022
Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination
(2022) Genome Medicine, 14 (1), art. no. 108, .
Rosen, S.F.a b , Soung, A.L.a b , Yang, W.c , Ai, S.a b , Kanmogne, M.a b , Davé, V.A.a b , Artyomov, M.d , Magee, J.A.b c d e , Klein, R.S.a b d f
a Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. Methods: Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. Results: Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 not only is required for the maintenance of WNV-specific CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. Conclusions: We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 in mice during recovery may reduce CNS CD8+ TRM cells. © 2022, The Author(s).
Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHR012052632, R01NS104471, R01NS116788, T32AI007172
Document Type: Article
Publication Stage: Final
Source: Scopus
Aqp4 stop codon readthrough facilitates amyloid-β clearance from the brain
(2022) Brain: A Journal of Neurology, 145 (9), pp. 2982-2990.
Sapkota, D.a b c , Florian, C.a b , Doherty, B.M.d , White, K.M.a b , Reardon, K.M.d , Ge, X.e f , Garbow, J.R.e f g , Yuede, C.M.a , Cirrito, J.R.d , Dougherty, J.D.a b
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
g Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Alzheimer’s disease is initiated by the toxic aggregation of amyloid-β. Immunotherapeutics aimed at reducing amyloid beta are in clinical trials but with very limited success to date. Identification of orthogonal approaches for clearing amyloid beta may complement these approaches for treating Alzheimer’s disease. In the brain, the astrocytic water channel Aquaporin 4 is involved in clearance of amyloid beta, and the fraction of Aquaporin 4 found perivascularly is decreased in Alzheimer’s disease. Further, an unusual stop codon readthrough event generates a conserved C-terminally elongated variant of Aquaporin 4 (AQP4X), which is exclusively perivascular. However, it is unclear whether the AQP4X variant specifically mediates amyloid beta clearance. Here, using Aquaporin 4 readthrough-specific knockout mice that still express normal Aquaporin 4, we determine that this isoform indeed mediates amyloid beta clearance. Further, with high-throughput screening and counterscreening, we identify small molecule compounds that enhance readthrough of the Aquaporin 4 sequence and validate a subset on endogenous astrocyte Aquaporin 4. Finally, we demonstrate these compounds enhance brain amyloid-β clearance in vivo, which depends on AQP4X. This suggests derivatives of these compounds may provide a viable pharmaceutical approach to enhance clearance of amyloid beta and potentially other aggregating proteins in neurodegenerative disease. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Alzheimer’s disease; amyloid beta; Aqp4; glymphatic; readthrough
Document Type: Article
Publication Stage: Final
Source: Scopus
Late-Life Depression is Associated With Increased Levels of GDF-15, a Pro-Aging Mitokine
(2022) American Journal of Geriatric Psychiatry, .
Mastrobattista, E.a , Lenze, E.J.b , Reynolds, C.F.c , Mulsant, B.H.d , Wetherell, J.e , Wu, G.F.f , Blumberger, D.M.d , Karp, J.F.g , Butters, M.A.c , Mendes-Silva, A.P.d , Vieira, E.L.d , Tseng, G.h , Diniz, B.S.a i
a UConn Center on Aging (EM, BSD), University of Connecticut, Farmington, CT, United States
b Department of Psychiatry (EJL), Washington University School of Medicine, St Louis, MO, United States
c Department of Psychiatry (CFR, MAB), University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
d Department of Psychiatry (BHM, DMB, APMS, ELV), Temerty Faculty of Medicine, University of Toronto, Centre for Addiction and Mental Health, Toronto, ON, Canada
e VA San Diego Healthcare System (JW), Mental Health Impact Unit 3, University of California, San Diego Department of Psychiatry, United States
f Department of Neurology (GFW), Washington University, St Louis, MO, United States
g Department of Psychiatry (JFK), The University of Arizona College of Medicine, Tucson, AZ, United States
h Department of Biostatistics (GT), University of Pittsburgh School of Public HealthPA, United States
i Department of Psychiatry (BSD), UConn School of Medicine, Farmington, CT, United States
Abstract
Objective: In older adults, major depressive disorder (MDD) is associated with accelerated physiological and cognitive aging, generating interest in uncovering biological pathways that may be targetable by interventions. Growth differentiation factor-15 (GDF-15) plays a significant role in biological aging via multiple biological pathways relevant to age and age-related diseases. Elevated levels of GDF-15 correlate with increasing chronological age, decreased telomerase activity, and increased mortality risk in older adults. We sought to evaluate the circulating levels of GDF-15 in older adults with MDD and its association with depression severity, physical comorbidity burden, age of onset of first depressive episode, and cognitive performance. Design: This study assayed circulating levels of GDF-15 in 393 older adults (mean ± SD age 70 ± 6.6 years, male:female ratio 1:1.54), 308 with MDD and 85 non-depressed comparison individuals. Results: After adjusting for confounding variables, depressed older adults had significantly higher GDF-15 serum levels (640.1 ± 501.5 ng/mL) than comparison individuals (431.90 ± 223.35 ng/mL) (t=3.75, d.f.= 391, p=0.0002). Among depressed individuals, those with high GDF-15 had higher levels of comorbid physical illness, lower executive cognitive functioning, and higher likelihood of having late-onset depression. Conclusion: Our results suggest that depression in late life is associated with GDF-15, a marker of amplified age-related biological changes. GDF-15 is a novel and potentially targetable biological pathway between depression and accelerated aging, including cognitive aging. © 2022 American Association for Geriatric Psychiatry
Author Keywords
Aging; biological markers; GDF-15; Geroscience; Late life depression
Funding details
R01 MH083660, R01AG049369, R01MH118311
National Institutes of HealthNIH
U.S. Department of JusticeDOJ
Novartis
Roche
Patient-Centered Outcomes Research InstitutePCORI
Fondation Brain Canada
Centre for Addiction and Mental HealthCAMH
Centre for Addiction and Mental Health FoundationCAMH
BrainsWay
Canadian Institutes of Health ResearchIRSC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Confounding factors of Alzheimer’s disease plasma biomarkers and their impact on clinical performance
(2022) Alzheimer’s and Dementia, .
Pichet Binette, A.a , Janelidze, S.a , Cullen, N.a , Dage, J.L.b , Bateman, R.J.c , Zetterberg, H.d e f g h , Blennow, K.d e , Stomrud, E.a i , Mattsson-Carlgren, N.a j k , Hansson, O.a i
a Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
b Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
d Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
e Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
f Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
g UK Dementia Research Institute at UCL, London, United Kingdom
h Hong Kong Center for Neurodegenerative Diseases, Hong Kong
i Memory Clinic, Skåne University Hospital, Malmö, Sweden
j Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
k Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
Abstract
Introduction: Plasma biomarkers will likely revolutionize the diagnostic work-up of Alzheimer’s disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. Methods: Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER-1: n = 748, BioFINDER-2: n = 421). We measured beta-amyloid (Aβ42, Aβ40), phosphorylated tau (p-tau217, p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Results: In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p-tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. Discussion: Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. Highlights: Creatinine and body mass index (BMI) are related to certain plasma biomarker levels. Adjusting for creatinine and BMI has minor influence on plasma-cerebrospinal fluid (CSF) associations. Adjusting for creatinine and BMI has minor influence on prediction of dementia using plasma biomarkers. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; cerebrospinal fluid; dementia; glial fibrillary acidic protein; neurofilament light; p-tau
Funding details
715986
JPND2019‐466‐236
1280/20
2020‐0314
2019‐0228
720931
2018‐Projekt0279
National Institutes of HealthNIH1R01AG068398‐01
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
BrightFocus FoundationBFFA2021013F
Familjen Erling-Perssons Stiftelse
Stiftelsen för Gamla Tjänarinnor2019‐00845
EU Joint Programme – Neurodegenerative Disease ResearchJPND2019‐03401
Fonds de Recherche du Québec – SantéFRQS298314
European Research CouncilERC681712
Lunds Universitet
HjärnfondenFO2019‐0029, FO2019‐0326
Knut och Alice Wallenbergs Stiftelse2017‐0383
VetenskapsrådetVR2016‐00906
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse2018‐02532
Horizon 2020860197
AlzheimerfondenAF‐745911, AF‐930655
Region Skåne
Marcus och Amalia Wallenbergs minnesfondMAW2015.0125
UK Dementia Research InstituteUK DRI2017‐00915, 2017‐0243, 201809‐2016615, 742881
University Hospital FoundationUHF2020‐O000028
Olav Thon Stiftelsen
Stiftelsen Bundy Academy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Survival After Resection of Newly-Diagnosed Intracranial Grade II Ependymomas: An Initial Multicenter Analysis and the Logistics of Intraoperative Magnetic Resonance Imaging
(2022) World Neurosurgery, .
Yahanda, A.T.a , Rich, K.M.a , Dacey, R.G., Jr.a , Zipfel, G.J.a , Dunn, G.P.a , Dowling, J.L.a , Smyth, M.D.a , Leuthardt, E.C.a , Limbrick, D.D., Jr.a , Honeycutt, J.b , Sutherland, G.R.c , Jensen, R.L.d , Evans, J.a , Chicoine, M.R.a
a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Neurological Surgery, Cook Children’s Medical Center, Fort Worth, TX, United States
c Department of Neurological Surgery, University of Calgary School of Medicine, Calgary, AB, Canada
d Department of Neurological Surgery, University of Utah School of Medicine, Salt Lake City, UT, United States
Abstract
Objective: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions. Methods: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined. Results: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan–Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72). Conclusions: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI. © 2022 Elsevier Inc.
Author Keywords
Ependymoma; Extent of resection; Grade II glioma; Intraoperative MRI; Overall survival; Progression-free survival
Funding details
UL1 TR000448
National Cancer InstituteNCIP30 CA091842
Alvin J. Siteman Cancer Center
Head for the Cure FoundationHFTC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus