Hope Center member publications

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain
(2022) Molecular Cell, 82 (1), pp. 90-105.e13.

Ferguson, C.J.^a b , Urso, O.^a , Bodrug, T.^c , Gassaway, B.M.^d , Watson, E.R.^e , Prabu, J.R.^e , Lara-Gonzalez, P.^f g , Martinez-Chacin, R.C.^h , Wu, D.Y.^a , Brigatti, K.W.ⁱ , Puffenberger, E.G.ⁱ , Taylor, C.M.^j , Haas-Givler, B.^j , Jinks, R.N.^k , Strauss, K.A.ⁱ , Desai, A.^f g , Gabel, H.W.^a , Gygi, S.P.^d , Schulman, B.A.^e , Brown, N.G.^h , Bonni, A.^a

^a Department of Neuroscience, Washington University, St. Louis, MO 63110, United States
^b Department of Pathology & Immunology, Neuropathology Division, Physician-Scientist Training Program, Washington University, St. Louis, MO 63110, United States
^c Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
^d Department of Cell Biology, Harvard University, Boston, MA 02138, United States
^e Max Planck Institute for Biochemistry, Munich, Germany
^f Department of Cellular and Molecular Medicine, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, United States
^g Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, United States
^h Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
ⁱ Clinic for Special Children, Strasburg, PA 17579, United States
^j Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, United States
^k Department of Biology, Franklin and Marshall College, Lancaster, PA 17603, United States

Abstract
Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease. © 2021 Elsevier Inc.

Author Keywords
anaphase-promoting complex;  APC7;  brain;  Cdh1;  chromatin;  heterochromatin;  Ki-67;  neurodevelopment;  ubiquitin;  ubiquitin ligase

Funding details
P30CA021765, R37GM065930
National Science FoundationNSFDGE-1650116, OD021629, R01GM074215
National Institutes of HealthNIHK08HD099314, NS051255, R35GM128855
Max-Planck-GesellschaftMPGGM67945, T32GM008570

Document Type: Article
Publication Stage: Final
Source: Scopus

Psychotic-like Experiences and Polygenic Liability in the Adolescent Brain Cognitive Development Study
(2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 7 (1), pp. 45-55. 

Karcher, N.R.^a , Paul, S.E.^b , Johnson, E.C.^a , Hatoum, A.S.^a , Baranger, D.A.A.^c , Agrawal, A.^a , Thompson, W.K.^d , Barch, D.M.^a b , Bogdan, R.^b

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^d Population Neuroscience and Genetics Laboratory, University of California San Diego, San Diego, CA, United States

Abstract
Background: Childhood psychotic-like experiences (PLEs) often precede the development of later severe psychopathology. This study examined whether childhood PLEs are associated with several psychopathology-related polygenic scores (PGSs) and additionally examined possible neural and behavioral mechanisms. Methods: Adolescent Brain Cognitive Development Study baseline data from children with European ancestry (n = 4650, ages 9–10 years, 46.8% female) were used to estimate associations between PLEs (i.e., both total and presence of significantly distressing) and PGSs for psychopathology (i.e., schizophrenia, psychiatric cross-disorder risk, PLEs) and related phenotypes (i.e., educational attainment [EDU], birth weight, inflammation). We also assessed whether variability in brain structure indices (i.e., volume, cortical thickness, surface area) and behaviors proximal to PGSs (e.g., cognition for EDU) indirectly linked PGSs to PLEs using mediational models. Results: Total and significantly distressing PLEs were associated with EDU and cross-disorder PGSs (all %ΔR2s = 0.202%–0.660%; false discovery rate–corrected ps <.006). Significantly distressing PLEs were also associated with higher schizophrenia and PLE PGSs (both %ΔR2 = 0.120%–0.216%; false discovery rate–corrected ps <.03). There was evidence that global brain volume metrics and cognitive performance indirectly linked EDU PGS to PLEs (estimated proportion mediated = 3.33%–32.22%). Conclusions: Total and significantly distressing PLEs were associated with genomic risk indices of broad-spectrum psychopathology risk (i.e., EDU and cross-disorder PGSs). Significantly distressing PLEs were also associated with genomic risk for psychosis (i.e., schizophrenia, PLEs). Global brain volume metrics and PGS-proximal behaviors represent promising putative intermediary phenotypes that may indirectly link genomic risk to psychopathology. Broadly, polygenic scores derived from genome-wide association studies of adult samples generalize to indices of psychopathology risk among children. © 2021 Society of Biological Psychiatry

Author Keywords
Educational attainment;  MRI;  Polygenic;  Psychopathology;  Psychotic-like experiences;  Schizophrenia

Funding details
National Institutes of HealthNIHDA032573, F32 AA027435, K23MH121792, L30MH120574, MH109532, R01-AG045231, R01-AG052564, R01-DA046224, R01-HD083614, R21-AA027827, T32-DA007261, U01 DA041120, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147

Document Type: Article
Publication Stage: Final
Source: Scopus

The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study: A resource for genetic discovery
(2022) Alzheimer’s and Dementia, . 

Reyes-Dumeyer, D.^a , Faber, K.^b , Vardarajan, B.^a , Goate, A.^c , Renton, A.^c , Chao, M.^c , Boeve, B.^d , Cruchaga, C.^e , Pericak-Vance, M.^f , Haines, J.L.^g , Rosenberg, R.^h , Tsuang, D.ⁱ , Sweet, R.A.^j , Bennett, D.A.^k , Wilson, R.S.^k , Foroud, T.^b , Mayeux, R.^a

^a Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University in the City of New York, New York, NY, United States
^b Department of Medical and Molecular Genetics, National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), Indiana University School of Medicine, Indianapolis, IN, United States
^c Department of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Neurology, Mayo Clinic, Rochester, MN, United States
^e Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^f John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
^g Department of Population & Quantitative Health Sciences and Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, United States
^h Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
ⁱ GRECC VA Puget Sound, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
^j Departments of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, PA, United States
^k Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

Abstract
Introduction: The National Institute on Aging Late-Onset Alzheimer’s Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer’s disease (AD). Methods: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. Results: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. Discussion: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD. © 2021 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute of Mental HealthNIMH
National Institute on AgingNIA
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAA
American Academy of NeurologyAAN
JPB Foundation
Sächsische AufbaubankSAB

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

IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state
(2022) Brain, Behavior, and Immunity, 99, pp. 383-396. 

Soung, A.L.^a b , Davé, V.A.^a b , Garber, C.^a b , Tycksen, E.D.^c , Vollmer, L.L.^a b , Klein, R.S.^a b d e

^a Center for Neuroimmunology & Neuroinfectious Diseases, 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
^c McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Innate immune responses to emerging RNA viruses are increasingly recognized as having significant contributions to neurologic sequelae, especially memory disorders. Using a recovery model of West Nile virus (WNV) encephalitis, we show that, while macrophages deliver the antiviral and anti-neurogenic cytokine IL-1β during acute infection; viral recovery is associated with continued astrocyte inflammasome-mediated production of inflammatory levels of IL-1β, which is maintained by hippocampal astrogenesis via IL-1R1 signaling in neural stem cells (NSC). Accordingly, aberrant astrogenesis is prevented in the absence of IL-1 signaling in NSC, indicating that only newly generated astrocytes exert neurotoxic effects, preventing synapse repair and promoting spatial learning deficits. Ex vivo evaluation of IL-1β-treated adult hippocampal NSC revealed the upregulation of developmental differentiation pathways that derail adult neurogenesis in favor of astrogenesis, following viral infection. We conclude that NSC-specific IL-1 signaling within the hippocampus during viral encephalitis prevents synapse recovery and promotes spatial learning defects via altered fates of NSC progeny that maintain inflammation. © 2021 The Author(s)

Author Keywords
Adult neural stem cell;  Astrogenesis;  Flavivirus encephalitis;  Interleukin-1;  Post-infectious cognitive dysfunction;  Spatial learning;  Synapse elimination

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHR012052632, R01NS104471, R01NS116788
Center for Cellular Imaging, Washington UniversityWUCCI

Document Type: Article
Publication Stage: Final
Source: Scopus

Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices the IPaNeMA Study
(2021) Neurology: Genetics, 7 (6), art. no. e623, . 

Wencel, M.^a , Shaibani, A.^b , Goyal, N.A.^a , Dimachkie, M.M.^c , Trivedi, J.^d , Johnson, N.E.^e f , Gutmann, L.^g h , Wicklund, M.P.^j k , Bandyopadhay, S.ⁱ , Genge, A.L.^l , Freimer, M.L.^m , Goyal, N.ⁿ , Pestronk, A.^o p q , Florence, J.^o , Karam, C.^p q , Ralph, J.W.^r , Rasheed, Z.^b , Hays, M.^c , Hopkins, S.^d , Mozaffar, T.^a s

^a Department of Neurology, University of California, Irvine, United States
^b Nerve and Muscle Center of Texas, Houston, TX, United States
^c Department of Neurology, University of Kansas Medical Center, Dallas, United States
^d Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, United States
^e Department of Neurology, Virginia Commonwealth University, Richmond, United States
^f University of Utah, Salt Lake City, United States
^g Department of Neurology, Indiana University, School of Medicine, Indianapolis, United States
^h University of Iowa, United States
ⁱ Department of Neurology, Pennsylvania State University, Hershey, United States
^j Department of Neurology, UC DenverCO, United States
^k Department of Neurology, Pennsylvania State University, Hershey, United States
^l Department of Neurology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
^m Department of Neurology, Ohio State University, Columbus, United States
ⁿ Department of Neurology, Stanford University, Palo Alto, CA, United States
^o Department of Neurology and Pathology, Washington University, St. Louis, MO, United States
^p Department of Neurology, University of Pennsylvania, Philadelphia, United States
^q Oregon Health and Science University, Portland, United States
^r Department of Neurology, University of California, San Francisco, United States
^s Departments of Neurology, Orthopaedic Surgery and Pathology and Laboratory Medicine, University of California, Irvine, United States

Abstract
Background and Objectives We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada. Methods All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine. Results GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic. Discussion The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Funding details
National Institutes of HealthNIH
Centers for Disease Control and PreventionCDCDD19-002
U.S. Food and Drug AdministrationFDA7R01FD006071-02
National Institute of Neurological Disorders and StrokeNINDS4K23NS091511, R01NS104010
Bristol-Myers SquibbBMS
Sanofi
Muscular Dystrophy AssociationMDA
Biogen
Alexion Pharmaceuticals
CytokineticsCYTK
Myositis AssociationTMA

Document Type: Article
Publication Stage: Final
Source: Scopus

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
(2021) Science Translational Medicine, 13 (622), art. no. abe3947, . 

Sayed, F.A.^a b , Kodama, L.^a b c d , Fan, L.^c , Carling, G.K.^c , Udeochu, J.C.^c , Le, D.^b , Li, Q.^e , Zhou, L.^e , Ying Wong, M.^c , Horowitz, R.^c , Ye, P.^c , Mathys, H.^f , Wang, M.^g , Niu, X.^h , Mazutis, L.ⁱ , Jiang, X.^f , Wang, X.^c , Gao, F.^j , Brendel, M.^k , Telpoukhovskaia, M.^b , Tracy, T.E.^b , Frost, G.^l , Zhou, Y.^b , Li, Y.^b , Qiu, Y.^m , Cheng, Z.ⁿ , Yu, G.ⁿ , Hardy, J.^o , Coppola, G.^j , Wang, F.^p , DeTure, M.A.^q , Zhang, B.^g , Xie, L.^l , Trajnowski, J.Q.^r , Lee, V.M.Y.^r , Gong, S.^c , Sinha, S.C.^c , Dickson, D.W.^q , Luo, W.^c , Gan, L.^b c

^a Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94158, United States
^b Gladstone Institute of Neurological Disease, San Francisco, CA 94107, United States
^c Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, United States
^d Medical Scientist Training Program and Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, United States
^e Department of Neuroscience, Department of Genetics, Washington University, School of Medicine, St Louis, MO 63110, United States
^f The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
^g Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, NY 10029, United States
^h Tri-Institutional Computational Biology and Medicine Program, Weill Cornell Medical CollegeNY 10065, United States
ⁱ Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
^j Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States
^k Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, United States
^l Chemical Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, United States
^m Department of Computer Science, Hunter College, The Graduate Center, The City University of New York, New York, NY 10065, United States
ⁿ Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061, United States
^o Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1E 6BT, United Kingdom
^p Department of Population Health Sciences, Weill Cornell Medical College, New York, NY 10065, United States
^q Mayo Clinic, Jacksonville, FL 32224, United States
^r Center for Neurodegenerative Disease Research, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, United States

Abstract
The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)-TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD. © 2021 The Authors.

Document Type: Article
Publication Stage: Final
Source: Scopus

Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 62, . 

Otun, A.^a , Morales, D.M.^a , Garcia-Bonilla, M.^a , Goldberg, S.^b , Castaneyra-Ruiz, L.^e , Yan, Y.^c , Isaacs, A.M.^d , Strahle, J.M.^a , McAllister, J.P., II^a , Limbrick, D.D., Jr.^a

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^b Department of Nephrology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^c Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^d Division of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N 2T9, Canada
^e Children’s Hospital Orange County, Children’s Research Institute, Orange, CA 92868, United States

Abstract
Background: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell–cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. Methods: CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey’s post-test ANOVA analysis were used for pair-wise comparisons. Results: CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 − < 0.0001), LGIVH (p = 0.023 − < 0.0001), and HGIVH (p = 0.015 − 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 − 0.0008) in the whole cohort. Conclusions: CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition. © 2021, The Author(s).

Author Keywords
Cerebrospinal fluid (CSF);  CSF electrolytes;  CSF osmolality;  Intraventricular hemorrhage (IVH);  Post-hemorrhagic hydrocephalus (PHH)

Funding details
Washington State UniversityWSU
Cosmetic Surgery FoundationCSF

Document Type: Article
Publication Stage: Final
Source: Scopus