2024
Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE)
Hanin A, Zhang L, Huttner A, Plu I, Mathon B, Bielle F, Navarro V, Hirsch L, Hafler D. Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE). Neurology Neuroimmunology & Neuroinflammation 2024, 11: e200259. PMID: 38810181, PMCID: PMC11139018, DOI: 10.1212/nxi.0000000000200259.Peer-Reviewed Original ResearchConceptsNew-onset refractory status epilepticusTemporal lobe epilepsyGABAergic neuronsExcitatory neuronsInfiltrating macrophagesProportion of GABAergic neuronsChronic temporal lobe epilepsyRefractory status epilepticusInhibitory GABAergic neuronsSingle-cell transcriptome analysisDecreased expression of genesDegree of demyelinationImmune disturbancesNeuronal excitabilityImmune dysregulationNew-onsetStatus epilepticusPoor outcomeRefractory epilepsyHealthy childrenMicroglial reactivitySingle-nucleus RNA sequencingNLRP3 inflammasome activationInflammatory responseLobe epilepsy
2023
Application of novel PACS-based informatics platform to identify imaging based predictors of CDKN2A allelic status in glioblastomas
Tillmanns N, Lost J, Tabor J, Vasandani S, Vetsa S, Marianayagam N, Yalcin K, Erson-Omay E, von Reppert M, Jekel L, Merkaj S, Ramakrishnan D, Avesta A, de Oliveira Santo I, Jin L, Huttner A, Bousabarah K, Ikuta I, Lin M, Aneja S, Turowski B, Aboian M, Moliterno J. Application of novel PACS-based informatics platform to identify imaging based predictors of CDKN2A allelic status in glioblastomas. Scientific Reports 2023, 13: 22942. PMID: 38135704, PMCID: PMC10746716, DOI: 10.1038/s41598-023-48918-4.Peer-Reviewed Original ResearchConceptsInformatics platformDeep learning algorithmsImaging featuresCDKN2A alterationsLearning algorithmHeterozygous lossHomozygous deletionLarge datasetsDeep white matter invasionGBM molecular subtypesNew informaticsQualitative imaging biomarkersWhole-exome sequencingQualitative imaging featuresGBM resectionRadiographic evidenceWorse prognosisPACSMolecular subtypesPial invasionImaging biomarkersCDKN2A mutationsAllele statusNoninvasive identificationMagnetic resonance imagesChromosome instability and aneuploidy in the mammalian brain
Albert O, Sun S, Huttner A, Zhang Z, Suh Y, Campisi J, Vijg J, Montagna C. Chromosome instability and aneuploidy in the mammalian brain. Chromosome Research 2023, 31: 32. PMID: 37910282, PMCID: PMC10833588, DOI: 10.1007/s10577-023-09740-w.Peer-Reviewed Original ResearchConceptsChromosome instabilityExcess of chromosomesRole of aneuploidyNon-transformed cellsSomatic tissuesDiploid setChromosomal countsAneuploid cellsChromosomal alterationsMammalian brainCancer cellsAneuploidyCellsAging processChromosomesDevelopmental disordersPresent understandingSpecific consequencesDNAValuable insightsFuture research effortsBroad rangeHallmarkStructural modificationsIntrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma
Khang M, Lee J, Lee T, Suh H, Lee S, Cavaliere A, Rushing A, Geraldo L, Belitzky E, Rossano S, de Feyter H, Shin K, Huttner A, Roussel M, Thomas J, Carson R, Marquez-Nostra B, Bindra R, Saltzman W. Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma. Science Translational Medicine 2023, 15: eadi1617. PMID: 37910601, PMCID: PMC11078331, DOI: 10.1126/scitranslmed.adi1617.Peer-Reviewed Original ResearchConceptsCerebrospinal fluidDelivery of drugsEffective therapyTherapeutic indexPARP inhibitorsBlood-brain barrierSite of tumorRapid systemic clearanceXenograft mouse modelSolvent evaporation processAdministration of substancesLeptomeningeal spreadIntrathecal deliveryLeptomeningeal metastasesBrain penetrationSystemic clearanceTumor regressionPolymer nanoparticlesMetastatic medulloblastomaMouse modelPediatric medulloblastomaDrug accumulationCSF turnoverEncapsulated drugsPET imagingNeuropathology of New-Onset Refractory Status Epilepticus (NORSE)
Hanin A, Cespedes J, Huttner A, Strelnikov D, Gopaul M, DiStasio M, Vezzani A, Hirsch L, Aronica E. Neuropathology of New-Onset Refractory Status Epilepticus (NORSE). Journal Of Neurology 2023, 270: 3688-3702. PMID: 37079033, DOI: 10.1007/s00415-023-11726-x.Peer-Reviewed Original ResearchConceptsNew-onset refractory status epilepticusCryptogenic new-onset refractory status epilepticusRefractory status epilepticusNeuropathology findingsStatus epilepticusSecondary neuronal injuryCryptogenic casesFebrile illnessNeuronal injuryExtensive workupNeuropathological evaluationEpilepsy surgeryPathophysiological mechanismsUnknown causePatient managementLong-term consequencesSevere formSpecific treatmentEpilepticusTissue samplesBiopsyPatientsFindings of studiesAutopsiesFindingsReview and standard operating procedures for collection of biospecimens and analysis of biomarkers in new onset refractory status epilepticus
Hanin A, Cespedes J, Pulluru Y, Gopaul M, Aronica E, Decampo D, Helbig I, Howe C, Huttner A, Koh S, Navarro V, Taraschenko O, Vezzani A, Wilson M, Xian J, Gaspard N, Hirsch L. Review and standard operating procedures for collection of biospecimens and analysis of biomarkers in new onset refractory status epilepticus. Epilepsia 2023, 64: 1444-1457. PMID: 37039049, PMCID: PMC10756682, DOI: 10.1111/epi.17600.Peer-Reviewed Original ResearchConceptsNew-onset refractory status epilepticusFebrile infection-related epilepsy syndromeRefractory status epilepticusStatus epilepticusCollection of biospecimensManagement of patientsStatus epilepticus patientsBetter clinical managementDisease-specific therapiesFebrile illnessStudy cohortEpilepsy syndromesOutcome endpointsStandard operating proceduresClinical managementRare conditionSevere formAnalysis of biomarkersPatientsMulticenter researchEpilepticusSpecific biomarkersExact causeSmall sample sizeBiospecimen collection
2022
The changing landscape in epilepsy imaging: Unmasking subtle and unique entities
Adin ME, Department of Radiology and Biomedical Imaging Y, Durand D, Zucconi W, Huttner A, Spencer D, Bronen R, Department of Radiology Abbott Northwestern Hospital M, Department of Pathology Y, Department of Neurosurgery Y. The changing landscape in epilepsy imaging: Unmasking subtle and unique entities. Diagnostic And Interventional Radiology 2022, 28: 503-515. PMID: 35997478, PMCID: PMC9682800, DOI: 10.5152/dir.2022.21339.Peer-Reviewed Original ResearchConceptsHippocampal sclerosisCortical developmentLocalization-related epilepsyTemporal lobe encephaloceleFocal cortical dysplasiaFocal cortical dysplasia IIbField of epilepsyEpileptogenic abnormalitiesAutoimmune encephalitisRasmussen's encephalitisCommon etiologyCortical dysplasiaEpilepsy surgeryEpileptogenic substrateTuberous sclerosisEpilepsy imagingHippocampal malformationsMTOR pathwayEncephalitisSclerosisMR imagingMalformationsUnique entitySurgeryEpilepsySpectrum of qualitative and quantitative imaging of pilomyxoid, intermediate pilomyxoid and pilocytic astrocytomas in relation to their genetic alterations
Fadel SA, von Reppert M, Kazarian E, Omay EZE, Marks A, Linder N, Hoffmann KT, Darbinyan A, Huttner A, Aboian MS. Spectrum of qualitative and quantitative imaging of pilomyxoid, intermediate pilomyxoid and pilocytic astrocytomas in relation to their genetic alterations. Neuroradiology 2022, 65: 195-205. PMID: 35984480, DOI: 10.1007/s00234-022-03027-3.Peer-Reviewed Original ResearchConceptsPilocytic astrocytomaImaging characteristicsADC valuesAggressive imaging characteristicsSuprasellar pilocytic astrocytomaRecurrence/progressionPediatric brain tumorsFrontal white matterWhole-exome sequencingPilomyxoid astrocytomaIntraventricular extensionSuprasellar regionThird ventriclePosterior fossaAtypical locationBrain tumorsWhite matterGrade 1TumorsAstrocytomasDriver mutationsExome sequencingGenetic alterationsPatientsHippocampusCross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion
Chen AT, Xiao Y, Tang X, Baqri M, Gao X, Reschke M, Sheu WC, Long G, Zhou Y, Deng G, Zhang S, Deng Y, Bai Z, Kim D, Huttner A, Kunes R, Günel M, Moliterno J, Saltzman WM, Fan R, Zhou J. Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion. Neuro-Oncology 2022, 25: 482-494. PMID: 35901838, PMCID: PMC10013636, DOI: 10.1093/neuonc/noac186.Peer-Reviewed Original ResearchConceptsCrystallin alpha BTumor invasionGBM invasionHistology samplesMolecular landscapeTreatment of glioblastomaPostoperative recurrenceGBM patientsInvasive glioblastomaResection modelGlioblastomaNon-invasive counterpartsGBM samplesGlioblastoma invasionCD44PatientsInvasionAlpha BCellular levelTranscriptomic featuresRNA sequencing dataRecurrenceHistology stainsLevelsDiseaseAnalysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Bae T, Fasching L, Wang Y, Shin JH, Suvakov M, Jang Y, Norton S, Dias C, Mariani J, Jourdon A, Wu F, Panda A, Pattni R, Chahine Y, Yeh R, Roberts RC, Huttner A, Kleinman JE, Hyde TM, Straub RE, Walsh CA, Urban A, Leckman J, Weinberger D, Vaccarino F, Abyzov A, Walsh C, Park P, Sestan N, Weinberger D, Moran J, Gage F, Vaccarino F, Gleeson J, Mathern G, Courchesne E, Roy S, Chess A, Akbarian S, Bizzotto S, Coulter M, Dias C, D’Gama A, Ganz J, Hill R, Huang A, Khoshkhoo S, Kim S, Lee A, Lodato M, Maury E, Miller M, Borges-Monroy R, Rodin R, Zhou Z, Bohrson C, Chu C, Cortes-Ciriano I, Dou Y, Galor A, Gulhan D, Kwon M, Luquette J, Sherman M, Viswanadham V, Jones A, Rosenbluh C, Cho S, Langmead B, Thorpe J, Erwin J, Jaffe A, McConnell M, Narurkar R, Paquola A, Shin J, Straub R, Abyzov A, Bae T, Jang Y, Wang Y, Molitor C, Peters M, Linker S, Reed P, Wang M, Urban A, Zhou B, Zhu X, Pattni R, Serres Amero A, Juan D, Lobon I, Marques-Bonet T, Solis Moruno M, Garcia Perez R, Povolotskaya I, Soriano E, Antaki D, Averbuj D, Ball L, Breuss M, Yang X, Chung C, Emery S, Flasch D, Kidd J, Kopera H, Kwan K, Mills R, Moldovan J, Sun C, Zhao X, Zhou W, Frisbie T, Cherskov A, Fasching L, Jourdon A, Pochareddy S, Scuderi S. Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability. Science 2022, 377: 511-517. PMID: 35901164, PMCID: PMC9420557, DOI: 10.1126/science.abm6222.Peer-Reviewed Original ResearchConceptsTranscription factorsSomatic mutationsPutative transcription factorEnhancer-like regionSingle nucleotide mutationsWhole-genome sequencingGene regulationSomatic duplicationGenome sequencingDamaging mutationsBackground mutagenesisMutationsHypermutabilityClonal expansionMotifDiseased brainPotential linkVivo clonal expansionMutagenesisGenesDuplicationSequencingRegulationAlzheimer disease neuropathology in a patient previously treated with aducanumab
Plowey ED, Bussiere T, Rajagovindan R, Sebalusky J, Hamann S, von Hehn C, Castrillo-Viguera C, Sandrock A, Budd Haeberlein S, van Dyck CH, Huttner A. Alzheimer disease neuropathology in a patient previously treated with aducanumab. Acta Neuropathologica 2022, 144: 143-153. PMID: 35581440, PMCID: PMC9217863, DOI: 10.1007/s00401-022-02433-4.Peer-Reviewed Original ResearchConceptsAmyloid-related imaging abnormalitiesLong-term extensionStandard uptake value ratioAlzheimer's diseaseAmyloid positron emission tomographyBraak stage VPhase 1b studyPhospho-tau immunohistochemistryPostmortem neuropathologic examinationSpecies of AβAD neuropathologic changeFirst autopsy reportAlzheimer's disease neuropathologyUptake value ratioAmyloid PET scanMild Alzheimer's diseasePositron emission tomographyLast doseReactive microgliaNeuropathologic evidenceNeuropathologic examinationPlacebo armImaging abnormalitiesMonthly dosesNeuropathologic changes
2021
Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells
Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z, Spajic A, Santpere G, Li M, Zhang S, Liu Y, Spurrier J, Zhang L, Gudelj I, Rapan L, Takahashi H, Huttner A, Fan R, Strittmatter SM, Sousa AMM, Rakic P, Sestan N. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 2021, 110: 452-469.e14. PMID: 34798047, PMCID: PMC8813897, DOI: 10.1016/j.neuron.2021.10.036.Peer-Reviewed Original ResearchConceptsDisease-related proteinsCellular diversityCross-species analysisSingle-nucleus transcriptomesLipid droplet proteinsSpecies-specific propertiesImmature neuron populationTranscriptomic taxonomyAlzheimer's disease-related proteinsEndoplasmic reticulumCell typesHuman neuronsSpecies differencesHistologic signatureNeurogenic capabilityProteinExcitatory neuronsDiversityAdult miceGranule cellsAlzheimer's diseaseNeuron populationsCognitive functionEntorhinal cellsAdult humansSurgical strategies for older patients with glioblastoma
Barak T, Vetsa S, Nadar A, Jin L, Gupte TP, Fomchenko EI, Miyagishima DF, Yalcin K, Vasandani S, Gorelick E, Zhao AY, Antonios J, Theriault BC, Lifton N, Marianayagam N, Omay B, Omay ZE, Huttner A, McGuone D, Blondin NA, Corbin Z, Fulbright RK, Moliterno J. Surgical strategies for older patients with glioblastoma. Journal Of Neuro-Oncology 2021, 155: 255-264. PMID: 34626296, PMCID: PMC8651607, DOI: 10.1007/s11060-021-03862-z.Peer-Reviewed Original ResearchConceptsKarnofsky performance scoreLength of surgeryOlder patientsOverall survivalPostoperative complicationsSurgical resectionSurgical strategyLow preoperative KPS scorePoor Karnofsky performance scoreLow Karnofsky performance scoreYale-New Haven HospitalPostoperative adjuvant treatmentPreoperative KPS scoreAdjuvant treatment regimensExtent of resectionNew Haven HospitalUse of ioMRIAdjuvant treatmentHospital stayKPS scoreMethodsClinical dataConsecutive patientsPrognostic factorsTreatment regimensExperienced handsENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody
Rattray Z, Deng G, Zhang S, Shirali A, May CK, Chen X, Cuffari BJ, Liu J, Zou P, Rattray N, Johnson CH, Dubljevic V, Campbell JA, Huttner A, Baehring JM, Zhou J, Hansen JE. ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody. JCI Insight 2021, 6: e145875. PMID: 34128837, PMCID: PMC8410084, DOI: 10.1172/jci.insight.145875.Peer-Reviewed Original ResearchConceptsBlood-brain barrierAnti-DNA autoantibodiesBrain tumorsBreast cancer brain metastasesBlood-brain barrier transportBrain tumor immunotherapyCancer brain metastasesBrain endothelial cellsEndothelial cell penetrationCNS lupusNeurotoxic autoantibodiesBrain metastasesTumor immunotherapyBarrier transportAntibody-based approachesCNS penetrationAutoantibodiesEfficacy studiesOrthotopic glioblastomaEndothelial cellsTumorsCancer cellsNucleoside fluxesActionable mechanismsKey transportersHemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis
Barbiero FJ, Huttner AJ, Fulbright RK, Baehring JM. Hemorrhage Into a Subependymal Giant Cell Astrocytoma in an Adult With Tuberous Sclerosis. The Neurologist 2021, 26: 122-124. PMID: 34190204, DOI: 10.1097/nrl.0000000000000338.Peer-Reviewed Original ResearchConceptsIntracranial hemorrhageMagnetic resonance imaging (MRI) brainSubependymal giant cell astrocytomaCentral nervous system tumorsYoung adultsLife-threatening complicationsGiant cell astrocytomaNervous system tumorsTuberous sclerosis complexForamen of MonroRare genetic disorderGerm-line mutationsUncommon causeHematoma evacuationDiagnostic delaySpontaneous hemorrhageUnusual causeSubependymal nodulesSurveillance imagingSkin changesTumor resectionSystem tumorsAdenoma sebaceumTuberous sclerosisSkin lesionsTET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy
Ostriker AC, Xie Y, Chakraborty R, Sizer AJ, Bai Y, Ding M, Song WL, Huttner A, Hwa J, Martin KA. TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy. Circulation 2021, 144: 455-470. PMID: 34111946, PMCID: PMC8643133, DOI: 10.1161/circulationaha.120.050553.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsApoptosisBiomarkersDioxygenasesDisease Models, AnimalDisease SusceptibilityDNA-Binding ProteinsHeart TransplantationHumansImmunohistochemistryInterferon-gammaMiceMice, KnockoutMyocytes, Smooth MuscleSignal TransductionSTAT1 Transcription FactorTunica IntimaVascular DiseasesConceptsCoronary allograft vasculopathyGraft arteriopathyIntimal thickeningCAV progressionRole of TET2VSMC apoptosisTransplant samplesGraft modelHigh-dose ascorbic acidTET2 expressionVSMC phenotypeContext of transplantCoronary blood flowEffect of IFNγTET2 activityTET2 depletionSmooth muscle cell apoptosisVascular smooth muscle cell apoptosisMuscle cell apoptosisAllograft vasculopathyDevastating sequelaeMedial thinningAortic graftHeart transplantTransplant failureProtein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination
Omer S, Jin SC, Koumangoye R, Robert SM, Duran D, Nelson‐Williams C, Huttner A, DiLuna M, Kahle KT, Delpire E. Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination. Clinical Genetics 2021, 100: 176-186. PMID: 33904160, DOI: 10.1111/cge.13973.Peer-Reviewed Original ResearchConceptsProtein kinase D1Kainate-induced seizure activityHomozygote micePeripheral nerve diseaseWild-type miceBrain hyperexcitabilityPatient's epilepsyPeripheral neuropathyNerve diseaseSeizure activityHuman epilepsyCotransporter 3Nervous systemProgressive epilepsyHeterozygote miceHuman nervous systemPKD1 variantsMiceEpilepsyInactivating variantPotential targetSignificant increaseNovel roleDiseaseLocomotor behaviorNanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance
Wang Y, Jiang Y, Wei D, Singh P, Yu Y, Lee T, Zhang L, Mandl HK, Piotrowski-Daspit AS, Chen X, Li F, Li X, Cheng Y, Josowitz A, Yang F, Zhao Y, Wang F, Zhao Z, Huttner A, Bindra RS, Xiao H, Mark Saltzman W. Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance. Nature Biomedical Engineering 2021, 5: 1048-1058. PMID: 34045730, PMCID: PMC8497438, DOI: 10.1038/s41551-021-00728-7.Peer-Reviewed Original ResearchConceptsConvection-enhanced deliveryPatient-derived xenograftsTMZ-resistant gliomasTMZ-resistant cellsGlioma cell linesSurvival benefitTemozolomide resistanceChemotherapeutic temozolomideDetectable toxicityTemozolomideOxaliplatin prodrugHuman glioblastomaGenome-wide RNA profilingTranslational strategiesDrugsCell linesGliomasAnticancer drugsMetabolomic analysisGlioblastomaDeliveryDistinct mechanismsRNA profilingMetabolic pathwaysPatientsExome sequencing identifies SLIT2 variants in primary CNS lymphoma
Kaulen LD, Erson‐Omay E, Henegariu O, Karschnia P, Huttner A, Günel M, Baehring JM. Exome sequencing identifies SLIT2 variants in primary CNS lymphoma. British Journal Of Haematology 2021, 193: 375-379. PMID: 33481259, DOI: 10.1111/bjh.17319.Peer-Reviewed Original ResearchConceptsPrimary central nervous system lymphomaShorter progression-free survivalCentral nervous system lymphomaRole of SLIT2Primary CNS lymphomaProgression-free survivalLarger validation cohortNervous system lymphomaShorter overall survivalPossible prognostic implicationsWarrants further investigationCNS lymphomaTumor DNA samplesOverall survivalPCNSL patientsSystem lymphomaPrognostic implicationsValidation cohortPCNSL pathogenesisLymphoid malignanciesFunction variantsTumor suppressor geneExome sequencingLuciferase assayLymphomaDual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma
Fomchenko EI, Reeves BC, Sullivan W, Marks AM, Huttner A, Kahle KT, Erson‐Omay E. Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma. Molecular Genetics & Genomic Medicine 2021, 9: e1597. PMID: 33448156, PMCID: PMC8077124, DOI: 10.1002/mgg3.1597.Peer-Reviewed Original ResearchConceptsPilomyxoid astrocytomaPediatric patientsVariant allele frequencyHypothalamic/chiasmatic regionPathologic tissue diagnosisTreatment-related morbidityHigh recurrence ratePI3K/mTOR inhibitionYears of ageExome sequencing resultsSimilar time pointsWhole exome sequencing resultsHypothalamic dysfunctionClinical presentationSurgical managementRecurrence rateShorter survivalAggressive subtypeVision lossChiasmatic regionTissue diagnosisPatient tumorsRadiation therapyFGFR inhibitorsFGFR1 mutations