2025
Molecular hallmarks of hydrocephalus
Hale A, Zhou B, Rajan A, Duy P, Goolam M, Alper S, Lehtinen M, Lancaster M, Fame R, Kahle K. Molecular hallmarks of hydrocephalus. Science Translational Medicine 2025, 17: eadq1810. PMID: 40465691, DOI: 10.1126/scitranslmed.adq1810.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidBrain-CSF interfacePluripotent stem cell-derived cerebral organoidsStem cell dysfunctionAssociated with dilatationDisrupts synaptogenesisNeural stem cell dysfunctionMolecular classificationPharmacological treatmentCell dysfunctionImpaired neurogenesisBiomechanical instabilityHC subtypesGenome-widePleiotropic mechanismsCSF dynamicsNeural circuitryHydrocephalusEnvironmental insultsCerebral organoidsNeurodevelopmental comorbiditiesSingle-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus
Duy P, Kiziltug E, Greenberg A, Mehta N, Hao L, Fortes C, Mullany S, Fan B, Manichaikul A, Teich A, Chan D, Alper S, Hyman B, Arnold S, McKhann G, Frosch M, Kahle K. Single-cell elderly blood–CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2412159122. PMID: 40324076, PMCID: PMC12087963, DOI: 10.1073/pnas.2412159122.Peer-Reviewed Original ResearchConceptsIdiopathic normal pressure hydrocephalusNormal pressure hydrocephalusImmune dysregulationPeripheral bloodPressure hydrocephalusIdiopathic normal pressure hydrocephalus patientsProinflammatory alterationsVentricular CSFSingle-cell transcriptomicsINPH patientsCell populationsPatientsNeuroglial cellsCSFBloodHydrocephalusBaseline cognitive functionCognitive functionDysregulationMonocytes
2024
A Systematic Review of Human Paenibacillus Infections and Comparison of Adult and Pediatric Cases
Smith D, Bastug K, Burgoine K, Broach J, Hammershaimb E, Hehnly C, Morton S, Osman M, Schiff S, Ericson J. A Systematic Review of Human Paenibacillus Infections and Comparison of Adult and Pediatric Cases. The Pediatric Infectious Disease Journal 2024, 44: 455-461. PMID: 39705610, PMCID: PMC11991890, DOI: 10.1097/inf.0000000000004668.Peer-Reviewed Original ResearchClinical presentation of infectionSurgical management of hydrocephalusPresentation of infectionManagement of hydrocephalusEpidemiology of infectionCentral nervous systemNeonatal infectionBrain abscessSepsis syndromeClinical presentationPediatric casesSurgical managementRare involvementCystic encephalomalaciaAdult patientsInfant casesPatient populationClinical syndromeHydrocephalusCerebral destructionInfectionNervous systemInfantsSystematic reviewBrain destructionGenetics and molecular pathophysiology of normal pressure hydrocephalus.
Mehta N, Maury E, Buller Z, Duy P, Fortes C, Alper S, Erson-Omay E, Kahle K. Genetics and molecular pathophysiology of normal pressure hydrocephalus. Journal Of Neurosurgery 2024, 142: 346-352. PMID: 39178477, DOI: 10.3171/2024.5.jns24980.Peer-Reviewed Original ResearchIdiopathic normal pressure hydrocephalusNormal pressure hydrocephalusPathophysiology of idiopathic normal pressure hydrocephalusIntegrative genetic analysisPressure hydrocephalusPathophysiology of normal pressure hydrocephalusGenomic studiesGenetic analysisGenetic insightsUrinary incontinenceSurgical interventionCerebral ventricleClinical studiesFamilial casesMolecular pathophysiologyCSF dynamicsDisease pathogenesisNeuroinflammatory processesCerebral pressureHydrocephalusGeneticsCognitive impairmentVentricular-subventricular zone stem cell niche adaptations in a mouse model of post-infectious hydrocephalus
Herman J, Rittenhouse N, Mandino F, Majid M, Wang Y, Mezger A, Kump A, Kadian S, Lake E, Verardi P, Conover J. Ventricular-subventricular zone stem cell niche adaptations in a mouse model of post-infectious hydrocephalus. Frontiers In Neuroscience 2024, 18: 1429829. PMID: 39145299, PMCID: PMC11322059, DOI: 10.3389/fnins.2024.1429829.Peer-Reviewed Original ResearchPost-infectious hydrocephalusVentricular-subventricular zoneInfluenza virusMouse modelMouse-adapted influenza virusIntact ependymaStem cellsPostnatal day 4Stem cell numbersStem cell nicheCell-to-cell transmissionOlfactory bulbMultiorgan hemorrhageLateral ventricleIntracerebroventricular injectionVentriculomegalyEmbryonic dayVentricular systemDay 4Cell nicheNo significant reductionHydrocephalusSignificant reductionVentricleCell numberDysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus
Bertino F, Mukherjee D, Bonora M, Bagowski C, Nardelli J, Metani L, Venturini D, Chianese D, Santander N, Salaroglio I, Hentschel A, Quarta E, Genova T, McKinney A, Allocco A, Fiorito V, Petrillo S, Ammirata G, De Giorgio F, Dennis E, Allington G, Maier F, Shoukier M, Gloning K, Munaron L, Mussano F, Salsano E, Pareyson D, di Rocco M, Altruda F, Panagiotakos G, Kahle K, Gressens P, Riganti C, Pinton P, Roos A, Arnold T, Tolosano E, Chiabrando D. Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. Cell Reports Medicine 2024, 5: 101647. PMID: 39019006, PMCID: PMC11293339, DOI: 10.1016/j.xcrm.2024.101647.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCalcium handlingNeural progenitor cellsMitochondrial calcium handlingMouse neural progenitor cellsFLVCR1 geneMitochondrial calcium levelsVentricular dilatationLive birthsCalcium levelsProgenitor cellsClinical challengeVentricle enlargementPathogenetic mechanismsSevere formCortical neurogenesisNeural progenitorsFLVCR1aMitochondria-associated membranesHydrocephalusMiceFLVCR1CH genesMolecular mechanismsMetabolic activityBiomechanical instability of the brain–CSF interface in hydrocephalus
Duy P, Mehta N, Kahle K. Biomechanical instability of the brain–CSF interface in hydrocephalus. Brain 2024, 147: 3274-3285. PMID: 38798141, PMCID: PMC11449143, DOI: 10.1093/brain/awae155.Peer-Reviewed Original ResearchBrain-CSF interfaceBrain parenchymaPost-hemorrhagic hydrocephalusLow intracranial pressureAbnormal biomechanical propertiesNormal pressure hydrocephalusPost-infectiousCongenital hydrocephalusImpaired neurodevelopmentCommunicating hydrocephalusCSF homeostasisBiomechanical instabilityHydrocephalusIntracranial pressureAnimal studiesPressure hydrocephalusArachnoid granulationsPrimary derangementBrain surgeryStudy of hydrocephalusAge groupsCSF reabsorptionVentriculomegalyVentricleSecondary enlargementThe genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact
Hale A, Boudreau H, Devulapalli R, Duy P, Atchley T, Dewan M, Goolam M, Fieggen G, Spader H, Smith A, Blount J, Johnston J, Rocque B, Rozzelle C, Chong Z, Strahle J, Schiff S, Kahle K. The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact. Fluids And Barriers Of The CNS 2024, 21: 24. PMID: 38439105, PMCID: PMC10913327, DOI: 10.1186/s12987-024-00513-z.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidOverview of genesEtiology of HCPathogenesis of HCChoroid plexus cauterizationEndoscopic third ventriculostomyIncreased intracranial pressureGenetic architectureGenetic basisImpact of geneticsVentricular shuntSurgical treatmentThird ventriculostomyPhenotypic heterogeneityHeterogeneous diseasePharmacological treatmentGenetic syndromesMolecular pathogenesisIntracranial pressureHydrocephalusTherapeutic measuresGenesGeneticsBrain injuryPathwayHydrocephalus
Reeves B, Karimy J, Duy P, Kahle K. Hydrocephalus. 2024, 335-347. DOI: 10.1017/9781108917339.025.Peer-Reviewed Original ResearchPeripheral nerve injuryDegenerative cervical myelopathyCervical myelopathyNerve injuryDisease burdenPatient prognosisPathophysiological underpinningsNeurological conditionsNeurosurgical conditionsNeurosurgical diseasesBasic neuroscienceTranslational researchKey investigative toolInvestigative toolMyelopathyHydrocephalusPrognosisClinicInjuryGliomasDiseaseSurgeonsNeurosurgeons
2023
Paenibacillus spp infection among infants with postinfectious hydrocephalus in Uganda: an observational case-control study
Morton S, Hehnly C, Burgoine K, Ssentongo P, Ericson J, Kumar M, Hagmann C, Fronterre C, Smith J, Movassagh M, Streck N, Bebell L, Bazira J, Kumbakumba E, Bajunirwe F, Mulondo R, Mbabazi-Kabachelor E, Nsubuga B, Natukwatsa D, Nalule E, Magombe J, Erickson T, Ngonzi J, Ochora M, Olupot-Olupot P, Onen J, Ssenyonga P, Mugamba J, Warf B, Kulkarni A, Lane J, Whalen A, Zhang L, Sheldon K, Meier F, Kiwanuka J, Broach J, Paulson J, Schiff S. Paenibacillus spp infection among infants with postinfectious hydrocephalus in Uganda: an observational case-control study. The Lancet Microbe 2023, 4: e601-e611. PMID: 37348522, PMCID: PMC10529524, DOI: 10.1016/s2666-5247(23)00106-4.Peer-Reviewed Original ResearchConceptsMother-newborn pairsPostinfectious hydrocephalusCerebrospinal fluidNeonatal sepsisSpp infectionUgandan infantsMaternal bloodObservational case-control studyHospital OfficeInfant's cerebrospinal fluidBurden of morbidityCase-control studyRoute of infectionSubset of participantsMaternal feverCranial ultrasoundNeonatal infectionSepsis cohortOptimise treatmentTransplacental transmissionCord bloodObservational studyPlacental samplesSepsisHydrocephalus195 Aberrant Brain Biomechanics Initiates Ventricular Dilation in a Genetic Subtype of Congenital Hydrocephalus
Phan D, Dahl P, Koundal S, Pedram M, Deniz E, Benveniste H, Malvankar N, Kahle K. 195 Aberrant Brain Biomechanics Initiates Ventricular Dilation in a Genetic Subtype of Congenital Hydrocephalus. Neurosurgery 2023, 69: 32-32. DOI: 10.1227/neu.0000000000002375_195.Peer-Reviewed Original ResearchVentricular dilationCongenital hydrocephalusCongenital brain malformationsHuman congenital hydrocephalusCerebrospinal fluid circulationNeural stem cell proliferationCortical hypoplasiaAqueductal obstructionBrain parenchymaBrain malformationsMouse modelHydrocephalus patientsNeurogenesis resultsVentricular expansionNeural stem cell fateCSF circulationIntracranial physiologyCSF flowGenetic subtypesPrimary physiological factorCSF dynamicsCell proliferationCSFSame point mutationHydrocephalusThe choroid plexus links innate immunity to CSF dysregulation in hydrocephalus
Robert S, Reeves B, Kiziltug E, Duy P, Karimy J, Mansuri M, Marlier A, Allington G, Greenberg A, DeSpenza T, Singh A, Zeng X, Mekbib K, Kundishora A, Nelson-Williams C, Hao L, Zhang J, Lam T, Wilson R, Butler W, Diluna M, Feinberg P, Schafer D, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick D, Schiff S, Carter B, Gunel M, Simard J, Lifton R, Alper S, Delpire E, Kahle K. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell 2023, 186: 764-785.e21. PMID: 36803604, PMCID: PMC10069664, DOI: 10.1016/j.cell.2023.01.017.Peer-Reviewed Original ResearchConceptsPost-infectious hydrocephalusTLR4-dependent immune responseBlood-cerebrospinal fluid barrierSmall molecule pharmacotherapyCell cross talkPharmacological immunomodulationCytokine stormNeuroimmune disordersBrain infectionDrug treatmentImmune responseAcquired hydrocephalusHydrocephalus modelChoroid plexusFluid barrierHydrocephalusEpithelial cellsCSFMulti-omics investigationsCross talkHypersecretionHemorrhagePharmacotherapyImmunomodulationPlexusIn Reply to the Letter to Editor Regarding "Hospital Frailty Risk Score Predicts Adverse Events and Readmission Following Ventriculoperitoneal Shunt Surgery for Normal Pressure Hydrocephalus"
Koo A, Elsamadicy A, Matouk C. In Reply to the Letter to Editor Regarding "Hospital Frailty Risk Score Predicts Adverse Events and Readmission Following Ventriculoperitoneal Shunt Surgery for Normal Pressure Hydrocephalus". World Neurosurgery 2023, 169: 124. PMID: 36585096, DOI: 10.1016/j.wneu.2022.11.023.Peer-Reviewed Original Research
2022
Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus
Hehnly C, Shi A, Ssentongo P, Zhang L, Isaacs A, Morton S, Streck N, Erdmann-Gilmore P, Tolstoy I, Townsend R, Limbrick D, Paulson J, Ericson J, Galperin M, Schiff S, Broach J. Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus. MBio 2022, 13: e02688-22. PMID: 36374038, PMCID: PMC9765702, DOI: 10.1128/mbio.02688-22.Peer-Reviewed Original ResearchConceptsPostinfectious hydrocephalusClinical isolatesVirulence factorsCritical virulence factorPotential virulence factorsPoor long-term outcomesPrevention of hydrocephalusLong-term outcomesBacterial pathogensDevastating sequelaeNeonatal sepsisMiddle-income countriesNeonatal infectionSurgical interventionReference strainsNovel bacterial pathogensAfrican cohortBeta-lactamase genesChildhood mortalityHydrocephalusTherapeutic targetInfectionVirulent strainDevastating diseaseWhole-genome sequencingA neural stem cell paradigm of pediatric hydrocephalus
Duy PQ, Rakic P, Alper SL, Robert SM, Kundishora AJ, Butler WE, Walsh CA, Sestan N, Geschwind DH, Jin SC, Kahle KT. A neural stem cell paradigm of pediatric hydrocephalus. Cerebral Cortex 2022, 33: 4262-4279. PMID: 36097331, PMCID: PMC10110448, DOI: 10.1093/cercor/bhac341.Peer-Reviewed Original ResearchConceptsPediatric hydrocephalusPrimary treatment strategyOptimal surgical managementDevelopmental brain malformationsAnimal model studiesSurgical managementCerebral ventricleCSF diversionVentricular distentionHydrocephalic childrenTreatment strategiesBrain malformationsNeurodevelopmental disabilitiesGerminal neuroepitheliumHydrocephalusStem cell paradigmNeural stem cell fateRecent human geneticBrain surgeryCSF circulationBrain ventriclesCSF volumeNeuroprogenitor cellsBrain defectsCSF homeostasisSevere Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM
Tuysuz B, Department of Pediatric Genetics I, Sencicek A, Ozer E, Goc N, Yalcinkaya C, Bilguvar K, Department of Neurosurgery P, Department of Neurology I. Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM. Turkish Archives Of Pediatrics 2022, 57: 521-525. PMID: 35950747, PMCID: PMC9524456, DOI: 10.5152/turkarchpediatr.2022.22070.Peer-Reviewed Original ResearchWhole-exome sequencingL1 syndromeSevere phenotypeMissense mutationsHemizygous missense mutationClinical characteristicsDifferential diagnosisIndex patientsPatientsCarrier mothersPathogenic missense mutationsMale childrenL1CAM mutationsPathogenic variantsMild formHydrocephalusSpeech delaySyndromeExon 18Truncating mutationsGenetic etiologyIntellectual disabilityL1CAML1CAM geneFamily membersMolecular genetics of human developmental neurocranial anomalies: towards “precision surgery”
Duy PQ, Timberlake AT, Lifton RP, Kahle KT. Molecular genetics of human developmental neurocranial anomalies: towards “precision surgery”. Cerebral Cortex 2022, 33: 2912-2918. PMID: 35739418, PMCID: PMC10016031, DOI: 10.1093/cercor/bhac249.Peer-Reviewed Original ResearchConceptsFuture clinical trialsSurgical treatmentClinical trialsCongenital hydrocephalusWhole-exome sequencing studiesDisease classification systemDevelopmental anomaliesNeuropsychiatric diseasesNonsyndromic craniosynostosisGenetic counselingPrecision surgeryHuman brainNovel disease genesClassification systemMolecular nomenclatureSequencing studiesHydrocephalusSurgeryPathogenesisTherapyMolecular geneticsPrognosticationDiseaseTrialsBrainImpaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature Neuroscience 2022, 25: 458-473. PMID: 35379995, PMCID: PMC9664907, DOI: 10.1038/s41593-022-01043-3.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventricular dilatationPrimary defectNeuroepithelial cell differentiationRisk genesCerebrospinal fluid homeostasisWhole-exome sequencingNeuroepithelial stem cellsCortical hypoplasiaReduced neurogenesisVentricular dilatationVentricular enlargementCH mutationsPrenatal hydrocephalusDisease heterogeneityBrain surgeryCSF circulationHydrocephalusGenetic subtypesFluid homeostasisNeuroepithelial cellsNovo mutationsBrain transcriptomicsStem cellsCell differentiationSustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
Xue Y, Gursky Z, Monte B, Koundal S, Liu X, Lee H, Michurina TV, Mellanson KA, Zhao L, Nemajerova A, Kahle KT, Takemaru KI, Enikolopov G, Peunova NI, Benveniste H. Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus. Fluids And Barriers Of The CNS 2022, 19: 20. PMID: 35248089, PMCID: PMC8898469, DOI: 10.1186/s12987-022-00319-x.Peer-Reviewed Original ResearchConceptsGlymphatic transportIntracranial pressureMagnetic resonance imagingNasal cavityCribriform plateMouse modelFluid homeostasisOlfactory bulb hypoplasiaDistinct mouse modelsNormal intracranial pressureAquaporin-4 expressionKnock-out (KO) miceWild-type littermatesConditional knockout miceChronic rhinitisCommon findingSeparate cohortAQP4 expressionAQP4 polarizationKnockout miceHydrocephalusResonance imagingConclusionsThe combinationGadoteric acidBrain morphometryCytomegalovirus infections in infants in Uganda: Newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus
Hehnly C, Ssentongo P, Bebell L, Burgoine K, Bazira J, Fronterre C, Kumbakumba E, Mulondo R, Mbabazi-Kabachelor E, Morton S, Ngonzi J, Ochora M, Olupot-Olupot P, Mugamba J, Onen J, Roberts D, Sheldon K, Sinnar S, Smith J, Ssenyonga P, Kiwanuka J, Paulson J, Meier F, Ericson J, Broach J, Schiff S. Cytomegalovirus infections in infants in Uganda: Newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus. International Journal Of Infectious Diseases 2022, 118: 24-33. PMID: 35150915, PMCID: PMC9058984, DOI: 10.1016/j.ijid.2022.02.005.Peer-Reviewed Original ResearchConceptsNewborn-mother pairsCMV prevalenceClinical sepsisCytomegalovirus infectionCerebrospinal fluidPrevalence of CMVQuantitative PCRCMV positivityPostinfectious hydrocephalusVaginal sheddingCMV infectionHIV seropositivityNeonatal ageMaternal ageMaternal vaginalRisk factorsMedical CenterLong-term consequencesMother pairsSepsisNeonatesInfantsPrevalenceHydrocephalusCMV
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