2024
Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways
Gurrea-Rubio M, Wang Q, Mills E, Wu Q, Pitt D, Tsou P, Fox D, Mao-Draayer Y. Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways. International Journal Of Molecular Sciences 2024, 25: 2454. PMID: 38473703, PMCID: PMC10931690, DOI: 10.3390/ijms25052454.Peer-Reviewed Original ResearchConceptsSecondary progressive MSRelapsing-remitting MSCentral nervous systemMultiple sclerosisProgressive MSModulator of sphingosine-1-phosphateCytokine tumor necrosis factor-alphaEffects of siponimodTumor necrosis factor-alphaHeterogeneous clinical courseBouts of inflammationNeuroprotective effectsPreclinical animal modelsAutoimmune demyelinating diseaseNecrosis factor-alphaMitochondrial oxidative phosphorylationHuman induced pluripotent stem cell (iPSC)-derived neuronsSphingosine-1-phosphateCytokine signaling pathwaysClinical courseLive cell analysisProgressive diseaseOral treatmentMitochondrial pathwayFactor-alphaImaging chronic active lesions in multiple sclerosis: a consensus statement
Bagnato F, Sati P, Hemond C, Elliott C, Gauthier S, Harrison D, Mainero C, Oh J, Pitt D, Shinohara R, Smith S, Trapp B, Azevedo C, Calabresi P, Henry R, Laule C, Ontaneda D, Rooney W, Sicotte N, Reich D, Absinta M. Imaging chronic active lesions in multiple sclerosis: a consensus statement. Brain 2024, 147: 2913-2933. PMID: 38226694, PMCID: PMC11370808, DOI: 10.1093/brain/awae013.Peer-Reviewed Original ResearchChronic active lesionsMagnetic resonance imagingConsensus statementMultiple sclerosisActive lesionsManifestations of chronic inflammationParamagnetic rim lesionsMRI-definedNorth American ImagingRadiological definitionChronic inflammationRim lesionsClinical translationLesionsResonance imagingMRI sequencesIn vivoT1-wBrains of personsBiomarkers
2023
Pathological Validation of Multiple Sclerosis Lesion Rims on Phase and Quantitative Susceptibility Mapping (QSM) images
Gillen K, Nguyen T, Dimov A, Demmon E, Kovanlikaya I, Bagnato F, Romano D, Pitt D, Gauthier S, Wang Y. Pathological Validation of Multiple Sclerosis Lesion Rims on Phase and Quantitative Susceptibility Mapping (QSM) images. Proceedings Of The International Society For Magnetic Resonance In Medicine ... Scientific Meeting And Exhibition. 2023 DOI: 10.58530/2023/0035.Peer-Reviewed Original Research
2022
Toward Precision Phenotyping of Multiple Sclerosis
Pitt D, Lo CH, Gauthier SA, Hickman RA, Longbrake E, Airas LM, Mao-Draayer Y, Riley C, De Jager PL, Wesley S, Boster A, Topalli I, Bagnato F, Mansoor M, Stuve O, Kister I, Pelletier D, Stathopoulos P, Dutta R, Lincoln MR. Toward Precision Phenotyping of Multiple Sclerosis. Neurology Neuroimmunology & Neuroinflammation 2022, 9: e200025. PMID: 36041861, PMCID: PMC9427000, DOI: 10.1212/nxi.0000000000200025.Peer-Reviewed Original ResearchConceptsMultiple sclerosisSecondary progressive multiple sclerosisPathological processesProgressive multiple sclerosisKey pathological processClinical trial designDevelopment of biomarkersPerilesional inflammationNeuroaxonal degenerationMS phenotypeTrial designClinical importancePersonalized careM phenotypeSclerosisPhenotypeRemyelinationInflammationSyndromePrognosticationDegenerationProgressionBiomarkersCareClinical trials in multiple sclerosis: past, present, and future
Manouchehri N, Shirani A, Salinas VH, Tardo L, Hussain RZ, Pitt D, Stuve O. Clinical trials in multiple sclerosis: past, present, and future. Neurologia I Neurochirurgia Polska 2022, 56: 228-235. PMID: 35712986, DOI: 10.5603/pjnns.a2022.0041.Peer-Reviewed Original ResearchConceptsDisease-modifying therapiesMultiple sclerosisClinical trialsManagement of MSEffective disease-modifying therapiesDisability Assessment ScaleDisease-specific interventionsDisease diagnostic criteriaBurden of diseaseClinical trial developmentDisease-specific biomarkersMS pathophysiologyDiagnostic criteriaClinical practiceTrial developmentAssessment ScaleSclerosisTrialsPatientsNeuroimmunologyPathophysiologyTherapyDiseaseDiagnosisContinued progressEfficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure
Manouchehri N, Salinas VH, Yeganeh N, Pitt D, Hussain RZ, Stuve O. Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure. Frontiers In Neurology 2022, 13: 854390. PMID: 35432156, PMCID: PMC9009145, DOI: 10.3389/fneur.2022.854390.Peer-Reviewed Original ResearchProgressive multiple sclerosisSecondary progressive MSMultiple sclerosisImmune senescenceSecondary progressive multiple sclerosisDifferent MS phenotypesDisease-Modifying TherapiesSuccessful clinical managementAge-related factorsAdvent of diseaseModifying therapiesProgressive MSRelapse frequencyClinical managementImmune responseDistinct pathogenesesImmune systemM phenotypeDisease transitionTherapyMain correlatesDisease phenotypePatientsRRMSSignal changesDimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions
Zinger N, Ponath G, Sweeney E, Nguyen TD, Lo CH, Diaz I, Dimov A, Teng L, Zexter L, Comunale J, Wang Y, Pitt D, Gauthier SA. Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions. Neurology Neuroimmunology & Neuroinflammation 2022, 9: e1138. PMID: 35046083, PMCID: PMC8771666, DOI: 10.1212/nxi.0000000000001138.Peer-Reviewed Original ResearchConceptsChronic active lesionsGlatiramer acetateRim lesionsHuman microgliaDimethyl fumarateMultiple sclerosisActive lesionsChronic active multiple sclerosis lesionsEffects of DMFActive multiple sclerosis lesionsClass III evidenceMarkers of inflammationRelapsing-remitting MSRetrospective observational studyQuantitative susceptibility mappingMultiple sclerosis lesionsActivation stateTreatment-induced changesMRI quantitative susceptibility mappingMicroglial activityGlial activityInflammatory activationMicroglial cellsObservational studyMS lesions
2021
In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis
Swanberg KM, Prinsen H, DeStefano K, Bailey M, Kurada AV, Pitt D, Fulbright RK, Juchem C. In vivo evidence of differential frontal cortex metabolic abnormalities in progressive and relapsing‐remitting multiple sclerosis. NMR In Biomedicine 2021, 34: e4590. PMID: 34318959, DOI: 10.1002/nbm.4590.Peer-Reviewed Original ResearchConceptsProgressive multiple sclerosisRelapsing-remitting multiple sclerosisMultiple sclerosis patientsMultiple sclerosisDisease durationSclerosis patientsRelapsing-remitting multiple sclerosis patientsSignificant negative correlationAvailable disease-modifying therapiesFrontal cortex metabolismH-MRS protocolDisease-modifying therapiesHealthy control adultsN-acetyl aspartateCross-sectional analysisCortex metabolismMetabolic abnormalitiesΓ-aminobutyric acidMetabolites glutamateFrontal cortexSclerosisNegative correlationControl adultsGABAProton MRS
2019
Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker
Swanberg KM, Landheer K, Pitt D, Juchem C. Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker. Frontiers In Neurology 2019, 10: 1173. PMID: 31803127, PMCID: PMC6876616, DOI: 10.3389/fneur.2019.01173.Peer-Reviewed Original ResearchMultiple sclerosisProton magnetic resonance spectroscopyDiagnostic biomarkersH-MRSStudy designVivo proton magnetic resonance spectroscopyCentral nervous system tissueNormal-appearing white matterNumerous metabolic alterationsPotential diagnostic biomarkersNervous system tissueMetabolic abnormalitiesH-MRS dataSpinal cordLesion compositionSclerosisMetabolic alterationsWhite matterGray matterMagnetic resonance spectroscopyMetabolic signaturesBiomarkersExperimental cohortLines of evidenceTechnical considerationsMultiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry
Ramaglia V, Sheikh-Mohamed S, Legg K, Park C, Rojas OL, Zandee S, Fu F, Ornatsky O, Swanson EC, Pitt D, Prat A, McKee TD, Gommerman JL. Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry. ELife 2019, 8: e48051. PMID: 31368890, PMCID: PMC6707785, DOI: 10.7554/elife.48051.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMS disease activityT-cell phenotypeMass cytometryTypes of lymphocytesMultiple sclerosis lesionsNatalizumab cessationDisease activityMS patientsInflammatory lesionsImmune cellsSpinal cordLesion morphometryMS lesionsB cellsLesion typeSclerosis lesionsLesionsBlood vesselsCell phenotypeFunctional stateCytometryCellular contentCell-cell interactionsPhenotype
2018
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nature Communications 2018, 9: 5337. PMID: 30559390, PMCID: PMC6297228, DOI: 10.1038/s41467-018-07785-8.Peer-Reviewed Original ResearchConceptsMultiple sclerosisAstrocyte responseRisk variantsLocal autoimmune inflammationPeripheral immune cellsCentral nervous system cellsPeripheral immune systemCultured human astrocytesNervous system cellsNF-κB signalingCNS accessDysfunctional lymphocytesAstroglial functionAutoimmune inflammationLymphocytic infiltrateLymphocyte recruitmentImmune cellsGenetic risk allelesGenetic risk variantsMS lesionsMS susceptibilityHuman astrocytesLesion sizeImmune systemSystem cellsQuantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions
Kaunzner UW, Kang Y, Zhang S, Morris E, Yao Y, Pandya S, Rua S, Park C, Gillen KM, Nguyen TD, Wang Y, Pitt D, Gauthier SA. Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions. Brain 2018, 142: 133-145. PMID: 30561514, PMCID: PMC6308309, DOI: 10.1093/brain/awy296.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntigens, CDAntigens, Differentiation, MyelomonocyticBrainCarbon RadioisotopesChronic DiseaseCross-Sectional StudiesFemaleHumansInflammationIronIsoquinolinesMacrophagesMagnetic Resonance ImagingMaleMicrogliaMiddle AgedMultiple SclerosisPositron-Emission TomographyRetrospective StudiesYoung AdultConceptsChronic active lesionsMultiple sclerosisChronic lesionsActive lesionsMultiple sclerosis lesionsHyperintense rimQuantitative susceptibility mappingChronic active multiple sclerosis lesionsSclerosis lesionsChronic multiple sclerosis lesionsActive multiple sclerosis lesionsPersistent inflammatory activityProgressive multiple sclerosisMicroglia/macrophagesInnate immune activationEarly disease stagesTranslocator proteinGreater tissue damagePost-mortem studiesProgressive patientsActivated microgliaInflammatory activityPersistent inflammationImmune activationDisease stageThe Role of Astrocytes in Multiple Sclerosis
Ponath G, Park C, Pitt D. The Role of Astrocytes in Multiple Sclerosis. Frontiers In Immunology 2018, 9: 217. PMID: 29515568, PMCID: PMC5826071, DOI: 10.3389/fimmu.2018.00217.Peer-Reviewed Original ResearchConceptsRole of astrocytesImmune cell accessCentral nervous systemMultiple sclerosis lesionsAstrocyte activationMultiple sclerosisGlial scarAstrocyte functionMS treatmentMS lesionsNervous systemAstrocytesSclerosis lesionsLesion formationFunctional polarizationLesionsCell accessSclerosisInflammationPathogenesisSignificance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions
Gillen KM, Mubarak M, Nguyen TD, Pitt D. Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions. Frontiers In Immunology 2018, 9: 255. PMID: 29515576, PMCID: PMC5826076, DOI: 10.3389/fimmu.2018.00255.Peer-Reviewed Original ResearchConceptsCentral nervous systemChronic active lesionsMultiple sclerosisActive lesionsWhite matterWhite matter MS lesionsQuantitative susceptibility mappingNovel MS therapiesResident immune cellsChronic inflammatory activityWhite matter lesionsMyeloid cell activationAdjacent white matterWhite matter multiple sclerosis lesionsChronic tissue damageMultiple sclerosis lesionsMS therapyInflammatory activityMagnetic resonance imaging techniquesChronic inflammationMatter lesionsAged brainImmune cellsMyelin phagocytosisChronic diseasesMyeloid cell plasticity in the evolution of central nervous system autoimmunity
Giles DA, Washnock‐Schmid J, Duncker PC, Dahlawi S, Ponath G, Pitt D, Segal BM. Myeloid cell plasticity in the evolution of central nervous system autoimmunity. Annals Of Neurology 2018, 83: 131-141. PMID: 29283442, PMCID: PMC5876132, DOI: 10.1002/ana.25128.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginaseAutoimmune Diseases of the Nervous SystemBone Marrow CellsCell PlasticityChimeraDisease ProgressionEncephalomyelitis, Autoimmune, ExperimentalHumansImmunohistochemistryLectins, C-TypeMannose ReceptorMannose-Binding LectinsMiceMice, Inbred C57BLMultiple SclerosisMyeloid CellsNitric Oxide Synthase Type IIPhenotypeReceptors, Cell SurfaceConceptsInducible nitric oxide synthaseExperimental autoimmune encephalomyelitisCNS myeloid cellsCentral nervous systemCentral nervous system autoimmunityChronic active MS lesionsActive MS lesionsMultiple sclerosisMyeloid cellsMS lesionsAnimal model experimental autoimmune encephalomyelitisRemission of EAEModel experimental autoimmune encephalomyelitisMyeloid cell plasticityEncephalitogenic T cellsNitric oxide synthaseMyeloid cell phenotypeFuture therapeutic strategiesHuman myeloid cellsAnn NeurolNoninflammatory phenotypePolarized subsetsClinical remissionAutoimmune encephalomyelitisProinflammatory markers
2016
Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology
Ponath G, Ramanan S, Mubarak M, Housley W, Lee S, Sahinkaya FR, Vortmeyer A, Raine CS, Pitt D. Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology. Brain 2016, 140: 399-413. PMID: 28007993, PMCID: PMC5841057, DOI: 10.1093/brain/aww298.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAnimalsAnimals, NewbornAstrocytesCell ProliferationCells, CulturedChild, PreschoolCultureCytokinesDemyelinating Autoimmune Diseases, CNSEndocytosisFemaleHumansHydrazonesMacrophagesMaleMiddle AgedMyelin SheathPhagocytosisRatsRats, Sprague-DawleyStrokeTime FactorsTransforming Growth Factor betaConceptsMyelin injuryMyelin phagocytosisMyelin debrisMultiple sclerosis lesionsMultiple sclerosisLesion pathologySclerosis lesionsAcute multiple sclerosis lesionsCentral nervous system pathologyProgressive multifocal leukoencephalopathyNervous system pathologySecretion of chemokinesNF-κB activationElevated chemokine expressionHypertrophic astrocytesMost astrocytesMyelin uptakeMultifocal leukoencephalopathyFirst-line responseAcute lesionsMyelin damageReactive astrocytesChemokine expressionAstroglial responseImmune cellsQuantitative Susceptibility Mapping and R2* Measured Changes during White Matter Lesion Development in Multiple Sclerosis: Myelin Breakdown, Myelin Debris Degradation and Removal, and Iron Accumulation
Zhang Y, Gauthier SA, Gupta A, Chen W, Comunale J, Chiang G, Zhou D, Askin G, Zhu W, Pitt D, Wang Y. Quantitative Susceptibility Mapping and R2* Measured Changes during White Matter Lesion Development in Multiple Sclerosis: Myelin Breakdown, Myelin Debris Degradation and Removal, and Iron Accumulation. American Journal Of Neuroradiology 2016, 37: 1629-1635. PMID: 27256856, PMCID: PMC5018433, DOI: 10.3174/ajnr.a4825.Peer-Reviewed Original ResearchConceptsMyelin breakdownQuantitative susceptibility mappingExpanded Disability Status Scale scoreEarly active MS lesionsDisability Status Scale scoreIron accumulationDifferent enhancing patternStatus Scale scoreActive MS lesionsWhite matter lesionsMultiple sclerosis lesionsDisease durationChronic lesionsEarly chronicMatter lesionsMultiple sclerosisActive lesionsMyelin debrisMS lesionsLesion changesScale scoreLesion typeSclerosis lesionsLesionsLesion developmentIron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping
Stüber C, Pitt D, Wang Y. Iron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping. International Journal Of Molecular Sciences 2016, 17: 100. PMID: 26784172, PMCID: PMC4730342, DOI: 10.3390/ijms17010100.Peer-Reviewed Original ResearchConceptsMultiple sclerosisMagnetic resonance imagingBrain tissueQuantitative susceptibility mappingMS brain tissueAdvanced MRI methodsMS patientsChronic inflammationImmunohistochemical investigationBrain ironMyeloid cellsResonance imagingNon-invasive studyHistological studyRole of ironOxidative stressNoninvasive imagingSclerosisInflammationCellular distributionMRI methodsNeurodegenerationTissueImagingPatients
2015
Biomarkers in multiple sclerosis
Housley WJ, Pitt D, Hafler DA. Biomarkers in multiple sclerosis. Clinical Immunology 2015, 161: 51-58. PMID: 26143623, DOI: 10.1016/j.clim.2015.06.015.Peer-Reviewed Original ResearchConceptsMultiple sclerosisB cell chemoattractant CXCL13Myelin-reactive T cellsMacrophage marker CD163Reactive T cellsMarkers of neurodegenerationKIR4.1 antibodiesMS seraClinical outcomesOligoclonal bandsYKL-40Disease progressionT cellsMS susceptibilityCerebrospinal fluidPotential biomarkersViral titersClinical useBiomarkersBiomarker researchSclerosisProgressionDisease diagnosisCD163CXCL13Excess Lipid Accumulation in Cortical Neurons in Multiple Sclerosis May Lead to Autophagic Dysfunction and Neurodegeneration (P5.237)
Kim I, DeBartolo D, Ramanan S, Ponath G, Pitt D. Excess Lipid Accumulation in Cortical Neurons in Multiple Sclerosis May Lead to Autophagic Dysfunction and Neurodegeneration (P5.237). Neurology 2015, 84 DOI: 10.1212/wnl.84.14_supplement.p5.237.Peer-Reviewed Original Research