Hope Center Member Publications

Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering
(2024) Nature Communications, 15 (1), art. no. 354, . 

Yang, Z.^a b , Wen, J.^a c , Abdulkadir, A.^d , Cui, Y.^a , Erus, G.^a , Mamourian, E.^a , Melhem, R.^a , Srinivasan, D.^a , Govindarajan, S.T.^a , Chen, J.^a , Habes, M.^e , Masters, C.L.^f , Maruff, P.^f , Fripp, J.^g , Ferrucci, L.^h , Albert, M.S.ⁱ , Johnson, S.C.^j , Morris, J.C.^k , LaMontagne, P.^l , Marcus, D.S.^l , Benzinger, T.L.S.^k l , Wolk, D.A.^m , Shen, L.ⁿ , Bao, J.ⁿ , Resnick, S.M.^o , Shou, H.ⁿ , Nasrallah, I.M.^a p , Davatzikos, C.^a

^a Artificial Intelligence in Biomedical Imaging Laboratory (AIBIL), Center for and Data Science for Integrated Diagnostics (AI2D), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Graduate Group in Applied Mathematics and Computational Science, University of Pennsylvania, Philadelphia, PA, United States
^c Laboratory of AI and Biomedical Science (LABS), Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
^d Laboratory for Research in Neuroimaging, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
^e Biggs Alzheimer’s Institute, University of Texas San Antonio Health Science Center, San Antonio, TX, United States
^f The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
^g CSIRO Health and Biosecurity, Australian e-Health Research Centre CSIRO, Brisbane, QLD, Australia
^h Translational Gerontology Branch, Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital, 3001 S. Hanover Street, Baltimore, MD, United States
ⁱ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^k Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^l Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
ⁿ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, United States
^o Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, United States
^p Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN – a multi-view, weakly-supervised deep clustering method – which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer’s disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes. © 2024, The Author(s).

Funding details
National Institutes of HealthNIH191026, 1U24AG074855-01, 206795, HHSN271201600059C, U01AG068057, U19-AG033655
National Institute on AgingNIARF1 AG054409
National Institute of Biomedical Imaging and BioengineeringNIBIB
University of Southern CaliforniaUSC
Alzheimer’s Disease Neuroimaging InitiativeADNI
Northern California Institute for Research and EducationNCIRE
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF35148

Document Type: Article
Publication Stage: Final
Source: Scopus

Postnatal meningeal CSF transport is primarily mediated by the arachnoid and pia maters and is not altered after intraventricular hemorrhage-posthemorrhagic hydrocephalus
(2024) Fluids and Barriers of the CNS, 21 (1), art. no. 4, . 

Pan, S., Koleske, J.P., Koller, G.M., Halupnik, G.L., Alli, A.-H.O., Koneru, S., DeFreitas, D., Ramagiri, S., Strahle, J.M.

Department of Neurosurgery, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Background: CSF has long been accepted to circulate throughout the subarachnoid space, which lies between the arachnoid and pia maters of the meninges. How the CSF interacts with the cellular components of the developing postnatal meninges including the dura, arachnoid, and pia of both the meninges at the surface of the brain and the intracranial meninges, prior to its eventual efflux from the cranium and spine, is less understood. Here, we characterize small and large CSF solute distribution patterns along the intracranial and surface meninges in neonatal rodents and compare our findings to meningeal CSF solute distribution in a rodent model of intraventricular hemorrhage-posthemorrhagic hydrocephalus. We also examine CSF solute interactions with the tela choroidea and its pial invaginations into the choroid plexuses of the lateral, third, and fourth ventricles. Methods: 1.9-nm gold nanoparticles, 15-nm gold nanoparticles, or 3 kDa Red Dextran Tetramethylrhodamine constituted in aCSF were infused into the right lateral ventricle of P7 rats to track CSF circulation. 10 min post-1.9-nm gold nanoparticle and Red Dextran Tetramethylrhodamine injection and 4 h post-15-nm gold nanoparticle injection, animals were sacrificed and brains harvested for histologic analysis to identify CSF tracer localization in the cranial and spine meninges and choroid plexus. Spinal dura and leptomeninges (arachnoid and pia) wholemounts were also evaluated. Results: There was significantly less CSF tracer distribution in the dura compared to the arachnoid and pia maters in neonatal rodents. Both small and large CSF tracers were transported intracranially to the arachnoid and pia mater of the perimesencephalic cisterns and tela choroidea, but not the falx cerebri. CSF tracers followed a similar distribution pattern in the spinal meninges. In the choroid plexus, there was large CSF tracer distribution in the apical surface of epithelial cells, and small CSF tracer along the basolateral surface. There were no significant differences in tracer intensity in the intracranial meninges of control vs. intraventricular hemorrhage-posthemorrhagic hydrocephalus (PHH) rodents, indicating preserved meningeal transport in the setting of PHH. Conclusions: Differential CSF tracer handling by the meninges suggests that there are distinct roles for CSF handling between the arachnoid-pia and dura maters in the developing brain. Similarly, differences in apical vs. luminal choroid plexus CSF handling may provide insight into particle-size dependent CSF transport at the CSF-choroid plexus border. © 2024, The Author(s).

Funding details
National Institutes of HealthNIHOD021694, R01 NS110793
Washington University in St. LouisWUSTL
Children’s Discovery InstituteCDI
McDonnell Center for Systems Neuroscience
Rudi Schulte Research InstituteRSRI
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
Hydrocephalus AssociationHA

Document Type: Article
Publication Stage: Final
Source: Scopus

Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease
(2024) Molecular Neurodegeneration, 19 (1), art. no. 1, . 

Wang, L.^a b , Nykänen, N.-P.^a b , Western, D.^a b , Gorijala, P.^a b , Timsina, J.^a b , Li, F.^c , Wang, Z.^a b , Ali, M.^a b , Yang, C.^a b , Liu, M.^a b , Brock, W.^a b , Marquié, M.^d e , Boada, M.^d e , Alvarez, I.^f , Aguilar, M.^f , Pastor, P.^g , Ruiz, A.^d e , Puerta, R.^d e , Orellana, A.^d e , Rutledge, J.^h , Oh, H.^h , Greicius, M.D.^h , Le Guen, Y.^h , Perrin, R.J.ⁱ , Wyss-Coray, T.^h , Jefferson, A.^j , Hohman, T.J.^j , Graff-Radford, N.^k , Mori, H.^l , Goate, A.^m , Levin, J.ⁿ , Sung, Y.J.^a b o , Cruchaga, C.^a b p

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Networking Research Center on Neurodegenerative Disease (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
^e Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
^f Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain
^g Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
^h Wu-Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
ⁱ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^j Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, United States
^k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^l Nagaoka Sutoku University, Osaka, Japan
^m Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁿ Department of Neurology, University Hospital of Munich, Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
^o Division of Biostatistics, Washington University School of Medicine, BJC Institute of Health, 425 S. Euclid Ave, Box 8134, St. Louis, MO 63110, United States
^p Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, United States

Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. © 2024, The Author(s).

Funding details
115975, 115985, PI13/02434, PI16/01861, PI17/01474, PI19/01240, PI19/01301, PI22/01403
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG066444, R01AG044546, RF1AG053303, RF1AG058501, RF1AG074007, U01 AG024904, U01AG058922
U.S. Department of DefenseDODLI- W81XWH2010849, W81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAIIRG-08-88733, SG-20-690363-DIAN, ZEN-22-848604
Washington University in St. LouisWUSTL
Alzheimer’s Disease Neuroimaging InitiativeADNI
Takeda Pharmaceuticals U.S.A.TPUSA
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
EU Joint Programme – Neurodegenerative Disease ResearchJPNDAC19/00097, FI20/00215
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGAD
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
European Research CouncilERC681712, R01-AG059716
Korea Health Industry Development InstituteKHIDI
VetenskapsrådetVR2018-02532
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
European Regional Development FundERDFAC17/00100, JCT2017
Servier
Fleni

Document Type: Article
Publication Stage: Final
Source: Scopus

Absolute quantification of nicotinamide mononucleotide in biological samples by double isotope-mediated liquid chromatography-tandem mass spectrometry (dimeLC-MS/MS)
(2024) npj Aging, 10 (1), art. no. 2, . 

Unno, J.^a b , Mills, K.F.^b , Ogura, T.^c , Nishimura, M.^d , Imai, S.-I.^b

^a Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan
^b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Innovation Center, Shimadzu Scientific Instruments, Inc., Columbia, MD, United States
^d New Strategy Department, Shimadzu Scientific Instruments, Inc., Columbia, MD, United States

Abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite for fundamental biological phenomena, including aging. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that has been extensively tested as an effective NAD+-boosting compound in mice and humans. However, the accurate measurement of NMN in biological samples has long been a challenge in the field. Here, we have established an accurate, quantitative methodology for measuring NMN by using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) with double isotopic NMN standards. In this new methodology, the matrix effects of biological samples were properly adjusted, and the fate of NMN could be traced during sample processing. We have demonstrated that this methodology can accurately quantitate NMN levels in mouse plasma and confirmed quick, direct NMN uptake into blood circulation and cells. This double isotope-mediated LC-MS/MS (dimeLC-MS/MS) can easily be expanded to other NAD+-related metabolites as a reliable standard methodology for NAD+ biology. © 2024, The Author(s).

Funding details
University of WashingtonUW
Shimadzu

Document Type: Article
Publication Stage: Final
Source: Scopus

Assessing Needs and Perceptions of Research Participation in Pediatric-Onset Multiple Sclerosis: A Multistakeholder Survey
(2024) Pediatric Neurology, 151, pp. 115-120. 

Gambrah-Lyles, C.^a b , Kannan, V.^c , Lotze, T.^c , Abrams, A.^d , Schreiner, T.^e , Rodriguez, M.^f , Casper, T.C.^g , Rose, J.W.^h , Gorman, M.P.ⁱ , Chitnis, T.^j , Loud, S.^k , Wheeler, Y.^l , Mar, S.^m , US Network of Pediatric MS Centersⁿ

^a Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
^b Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States
^c Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine at Texas Children’s Hospital, Houston, Texas, United States
^d Cleveland Clinic, Center for Pediatric Neurosciences and Mellen Center for MS, Neurologic Institute, Cleveland, Ohio, United States
^e Departments of Pediatrics and Neurology, Children’s Hospital Colorado, University of Colorado, Aurora, Colorado, United States
^f Department of Pediatrics, Mayo Clinic Pediatric MS Center, Rochester, Minnesota, United States
^g Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, United States
^h Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, United States
ⁱ Department of Neurology, Boston Children’s Hospital, Pediatric Multiple Sclerosis and Related Diseases Program, Boston, Massachusetts, United States
^j Department of Neurology, Brigham and Women’s Hospital, Pediatric Multiple Sclerosis Center, Boston, Massachusetts, United States
^k Accelerated Cure Project, Inc. and iConquerMS, Waltham, Massachusetts, United States
^l Department of Pediatrics, Center for Pediatric Onset Demyelinating Disease, University of Alabama at Birmingham, Birmingham, Alabama, United States
^m Department of Neurology, Washington University in Saint Louis, St. Louis, Missouri, United States

Abstract
Background: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey. Methods: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS). Results: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs. Conclusions: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation. © 2023 Elsevier Inc.

Author Keywords
Multiple sclerosis;  Patient engagement;  Patient perspective;  Pediatric multiple sclerosis;  Survey

Funding details
National Multiple Sclerosis SocietyNMSSSI-2110-38420
Patient-Centered Outcomes Research InstitutePCORI20262-ACPMS

Document Type: Article
Publication Stage: Final
Source: Scopus

Time-resolved single-cell transcriptomics defines immune trajectories in glioblastoma
(2024) Cell, 187 (1), pp. 149-165.e23. 

Kirschenbaum, D.^a , Xie, K.^a , Ingelfinger, F.^a , Katzenelenbogen, Y.^a , Abadie, K.^a , Look, T.^b , Sheban, F.^a , Phan, T.S.^a , Li, B.^a , Zwicky, P.^a , Yofe, I.^a , David, E.^a , Mazuz, K.^a , Hou, J.^c , Chen, Y.^c , Shaim, H.^d , Shanley, M.^d , Becker, S.^e , Qian, J.^f , Colonna, M.^c , Ginhoux, F.^f g , Rezvani, K.^d , Theis, F.J.^e , Yosef, N.^a h i , Weiss, T.^b , Weiner, A.^a , Amit, I.^a

^a Department of Systems Immunology, Weizmann Institute of Science, Rehovot, 7610001, Israel
^b Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Stem Cell Transplantation and Cellular Therapy, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
^e Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
^f Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
^g Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, 138648, Singapore
^h Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, United States
ⁱ Center for Computational Biology, University of California, Berkeley, CA, United States

Abstract
Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies. © 2023 Elsevier Inc.

Author Keywords
cancer;  computational biology;  dynamics;  glioblastoma;  immunology;  immunotherapy;  single-cell biology;  systems immunology;  temporal transcriptomics;  tumor-associated-macrophages

Funding details
101055341-TROJAN-Cell
607/20
Howard Hughes Medical InstituteHHMI
European Molecular Biology OrganizationEMBO
Deutsche ForschungsgemeinschaftDFG259373024
Israel Science FoundationISF1944/22
Azrieli Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication
(2024) Cell Metabolism, . 

Tokizane, K.^a , Brace, C.S.^a , Imai, S.-I.^a b

^a Departments of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control. © 2023 The Author(s)

Author Keywords
aging;  DMH;  dorsomedial hypothalamus;  eNAMPT;  longevity;  PKG;  Ppp1r17;  protein kinase G;  sympathetic nervous system;  white adipose tissue

Funding details
National Institute on AgingNIAAG037457, AG047902
American Federation for Aging ResearchAFAR
Glenn Foundation for Medical ResearchGFMR
University of WashingtonUW
Washington University School of Medicine in St. LouisWUSM

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Helmet Therapy for the Management of Deformational Plagiocephaly in Pediatric Patients with Shunted Hydrocephalus
(2024) Cleft Palate Craniofacial Journal, . 

Johnson, E.A.^a , Koller, G.M.^a , Jafrani, R.^a , Patel, K.^b , Naidoo, S.^b , Strahle, J.M.^a

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Plastics & Reconstructive Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Objective: To evaluate the safety and efficacy of helmet therapy for deformational plagiocephaly in patients with shunted hydrocephalus. Design: Retrospective chart review. Setting: Institutional, tertiary-care hospital. Patients: All patients at St. Louis Children’s Hospital between 2014 and 2021 with shunted hydrocephalus who underwent helmet therapy for deformational plagiocephaly. Interventions: Helmet therapy. Main Outcome Measures: Cranial vault asymmetry (CVA), cranial vault asymmetry index (CVAI), and cephalic index (CI) were measured before and after completion of helmet therapy. Results: There were 37 patients with shunted hydrocephalus and documented deformational plagiocephaly. Twelve were managed with helmet therapy. Average age at helmeting initiation and time between shunt placement and helmeting initiation was 5.8 and 4.6 months, respectively. Average CVA, CVAI, and CI at helmeting initiation and termination was 11.6, 7.98, and 85.2, and 6.95, 4.49, and 83.7, respectively. Average duration of helmeting was 3.7 months. CVA and CVAI were significantly lower after helmeting (P =.0028 and.0021) and 11/12 patients had overall improvement in plagiocephaly. Conclusions: Helmet therapy appears to be a safe and efficacious management strategy for deformational plagiocephaly in patients with shunted hydrocephalus. Despite the occasional need for additional fittings and surveillance beyond the normal schedule, in all cases appropriately fitting helmets were achieved and no major adverse events occurred. This cohort represents a proof of principle for the safety and efficacy of helmet therapy in patients with shunted hydrocephalus. Further work in larger prospective cohorts is needed to confirm these initial findings. © 2024, American Cleft Palate Craniofacial Association.

Author Keywords
cranial molding orthosis;  deformational plagiocephaly;  helmeting;  hydrocephalus;  ventriculoperitoneal shunt

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Laser interstitial thermal therapy compared with open resection for treating subependymal giant cell astrocytoma
(2024) Journal of Neurosurgery. Pediatrics, 33 (1), pp. 95-104. 

Aum, D.J.^a , Reynolds, R.A.^b , McEvoy, S.D.^a , Wong, M.^c , Roland, J.L.^a , Smyth, M.D.^b

^a 2Department of Neurological Surgery, Washington University in St. Louis, Missouri; and
^b 1Division of Pediatric Neurosurgery, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, Puerto Rico
^c Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE: Subependymal giant cell astrocytomas (SEGAs) are WHO grade 1 tumors associated with tuberous sclerosis that classically arise from the ventricular wall near the caudate groove and foramen of Monro. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique, which works by heating a stereotactically placed laser fiber to ablative temperatures under MRI thermometry monitoring. In this paper, the authors present LITT as a surgical alternative to open resection of SEGAs. METHODS: Twelve patients with SEGAs who underwent 16 procedures between 2007 and 2022 at a single institution were retrospectively reviewed. These patients underwent either open resection or LITT. Clinical data, imaging, recurrence rate, further treatments, and related complications were analyzed. RESULTS: Among the 16 procedures, 9 were open resection and 7 were LITT. An external ventricular drain was placed in 66% (6/9) of open procedures and 57.1% (4/7) of LITT cases. A septostomy was performed in 56% (5/9) of open procedures and 29% (2/7) of LITT cases. Complication rates were higher in open cases than in LITT procedures (44% vs 0%, p < 0.05). Complications included hydrocephalus, transient venous ischemia, wound infection, and bone flap migration. The median length of hospital stay was 4 days (IQR 3.3-5.5 days) for open cases and 4 days (IQR 3.0-7.0 days) for LITT procedures. Recurrence or progression occurred after 3 open cases and 2 LITT cases (33% vs 33%, p = 0.803). For the recurrences, 2 open cases underwent stereotactic radiosurgery, 1 open case underwent LITT, and 1 LITT case underwent repeat LITT. Among the LITT cases, only the patients with no decrease in tumor size by 6 months experienced tumor progression afterward. The 2 LITT cases with progression were the only ones with calcification present on preoperative imaging. The median follow-up times for cases assessed for progression were 8.4 years (IQR 3.8-14.4 years) for open resection and 3.9 years (IQR 3.4-5.1 years) for LITT. CONCLUSIONS: The small size of this case series limits generalizability or adequate comparison of safety. However, this series adds to the literature supporting LITT as a less invasive surgical alternative to open resection of SEGAs and demonstrates that LITT has similar recurrence and/or progression rates to open resection. Additional studies with more data are necessary for comprehensive comparisons between open resection and LITT for treating SEGA.

Author Keywords
laser interstitial thermal therapy;  LITT;  SEGA;  subependymal giant cell astrocytoma;  tuberous sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo
(2023) Frontiers in Molecular Neuroscience, 16, art. no. 1320182, . 

Vemula, P., Schoch, K.M., Miller, T.M.

Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Many preclinical and clinical studies support the use of antisense oligonucleotides (ASOs) as effective therapeutic strategies. However, acquiring ASOs for research purposes may be limited by partnerships with the pharmaceutical companies. Our lab previously developed an effective ASO strategy to lower human tau and reverse pathology in aged tauopathy model mice. Testing the efficacy of purchased tau lowering ASOs would provide support for these reagents as broad research tools. Purchased mouse and human tau lowering ASOs were infused or injected intracerebroventricularly into wildtype and tau transgenic mice. Following treatment, brain tissue evaluated for ASO distribution and levels of tau mRNA, protein, and phosphorylated tau. We show that purchased ASOs enter cell types of the brain and effectively decrease mouse or human tau mRNA and protein levels. Human tau lowering ASO treatment in PS19 mice decreased phosphorylated tau and gliosis relative to saline-treated PS19 mice, consistent with our previous study using a non-commercial tau lowering ASO. The results of this study demonstrate the efficacy of purchased tau targeting ASOs in vivo to support their broad use by researchers. Copyright © 2023 Vemula, Schoch and Miller.

Author Keywords
Alzheimer’s disease;  antisense oligonucleotides;  human tau mouse model;  tau protein;  tauopathies

Funding details
National Institutes of HealthNIH
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
University of WashingtonUWS10 RR027552
Tau Consortium
Office of Research Infrastructure ProgramsORIP, NIHOD021629
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813

Document Type: Article
Publication Stage: Final
Source: Scopus