2022
Dimethyl 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
Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
Rui J, Deng S, Perdigoto AL, Ponath G, Kursawe R, Lawlor N, Sumida T, Levine-Ritterman M, Stitzel ML, Pitt D, Lu J, Herold KC. Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes. Nature Communications 2021, 12: 5074. PMID: 34417463, PMCID: PMC8379260, DOI: 10.1038/s41467-021-25367-z.Peer-Reviewed Original ResearchConceptsImmune cellsΒ-cellsNOD/SCID recipientsDiabetogenic immune cellsDiabetogenic T cellsBone marrow transplantType 1 diabetesExpression of TET2Human β-cellsIslet infiltratesSCID recipientsMarrow transplantInflammatory pathwaysTransfer of diseaseT cellsInflammatory genesImmune killingPathologic interactionsReduced expressionDiabetesInflammationTET2MiceRecipientsCellsIn 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 MRSQSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions
Gillen KM, Mubarak M, Park C, Ponath G, Zhang S, Dimov A, Levine‐Ritterman M, Toro S, Huang W, Amici S, Kaunzner UW, Gauthier SA, Guerau‐de‐Arellano M, Wang Y, Nguyen TD, Pitt D. QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions. Annals Of Clinical And Translational Neurology 2021, 8: 877-886. PMID: 33704933, PMCID: PMC8045922, DOI: 10.1002/acn3.51338.Peer-Reviewed Original ResearchConceptsNormal-appearing white matterMyeloid cellsLesion rimReactive oxygen speciesQuantitative susceptibility mappingChronic active lesionsChronic glial activationPro-inflammatory cytokinesBlood-brain barrierWhite matter lesionsAdjacent normal-appearing white matterMultiple sclerosis lesionsGlial activationActivated microgliaHistopathological correlatesChronic inflammationActive lesionsCytokine productionMatter lesionsMS lesionsWhite matterHuman-induced pluripotent stem cellsSclerosis lesionsLesionsLesion perimeter
2020
Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS
Lucca LE, Lerner BA, Park C, DeBartolo D, Harnett B, Kumar VP, Ponath G, Raddassi K, Huttner A, Hafler DA, Pitt D. Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS. Neurology Neuroimmunology & Neuroinflammation 2020, 7: e712. PMID: 32269065, PMCID: PMC7188477, DOI: 10.1212/nxi.0000000000000712.Peer-Reviewed Original ResearchConceptsTumor-infiltrating T cellsT cellsPD-1/PD-L1Anti-TIGIT therapyExpression of CD226Expression of TIGITPostmortem CNS tissueLymphocytes of patientsFresh surgical resectionsLigand CD155TIGIT expressionSurgical resectionPD-1PD-L1CNS diseaseHealthy controlsHealthy donorsLymphocytic expressionImmune responseCNS tissueMS lesionsTIGITImmune pathwaysPatientsGlioblastoma multiforme
2019
The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions
Park C, Ponath G, Levine-Ritterman M, Bull E, Swanson EC, De Jager PL, Segal BM, Pitt D. The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions. Acta Neuropathologica Communications 2019, 7: 130. PMID: 31405387, PMCID: PMC6689891, DOI: 10.1186/s40478-019-0779-2.Peer-Reviewed Original ResearchConceptsMultiple sclerosis lesionsLesion rimAstrocyte phenotypeMyeloid cellsSclerosis lesionsActive multiple sclerosis lesionsAcute multiple sclerosis lesionsGlial activation markersActive MS lesionsNovel therapeutic targetDifferent lesion stagesPredominant cell typeAcute demyelinationDemyelinating lesionsCell typesActivation markersChronic inflammationDistinct myeloidCell-extrinsic factorsGlial cellsPhenotypic subsetsLesion stageGlial phenotypeMS lesionsLesion cellsMultiplexed 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
Quantitative 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 stage
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 developmentCNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment
Cao Y, Nylander A, Ramanan S, Goods BA, Ponath G, Zabad R, Chiang VL, Vortmeyer AO, Hafler DA, Pitt D. CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 2016, 86: 1553-1556. PMID: 26984943, PMCID: PMC5573201, DOI: 10.1212/wnl.0000000000002594.Peer-Reviewed Original Research
2015
Basal Ganglia Iron in Patients with Multiple Sclerosis Measured with 7T Quantitative Susceptibility Mapping Correlates with Inhibitory Control
Schmalbrock P, Prakash RS, Schirda B, Janssen A, Yang GK, Russell M, Knopp MV, Boster A, Nicholas JA, Racke M, Pitt D. Basal Ganglia Iron in Patients with Multiple Sclerosis Measured with 7T Quantitative Susceptibility Mapping Correlates with Inhibitory Control. American Journal Of Neuroradiology 2015, 37: 439-446. PMID: 26611996, PMCID: PMC7960135, DOI: 10.3174/ajnr.a4599.Peer-Reviewed Original Research
2014
Quantitative susceptibility mapping (QSM) of white matter multiple sclerosis lesions: Interpreting positive susceptibility and the presence of iron
Wisnieff C, Ramanan S, Olesik J, Gauthier S, Wang Y, Pitt D. Quantitative susceptibility mapping (QSM) of white matter multiple sclerosis lesions: Interpreting positive susceptibility and the presence of iron. Magnetic Resonance In Medicine 2014, 74: 564-570. PMID: 25137340, PMCID: PMC4333139, DOI: 10.1002/mrm.25420.Peer-Reviewed Original ResearchConceptsMultiple sclerosisQuantitative susceptibility mappingIron depositionMS brain tissueMicroglia/macrophagesWhite matter multiple sclerosis lesionsPresence of myelinMultiple sclerosis lesionsSubstantial iron depositionChronic inflammationMS lesionsSclerosis lesionsLesionsBrain tissueMyelinMicrogliaB cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes
Stern JN, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, Huttner AJ, Laman JD, Nagra RM, Nylander A, Pitt D, Ramanan S, Siddiqui BA, Vigneault F, Kleinstein SH, Hafler DA, O'Connor KC. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Science Translational Medicine 2014, 6: 248ra107. PMID: 25100741, PMCID: PMC4388137, DOI: 10.1126/scitranslmed.3008879.Peer-Reviewed Original ResearchConceptsCervical lymph nodesCentral nervous systemB cellsCerebrospinal fluidLymph nodesMultiple sclerosisLymphoid tissueCNS of patientsCNS B cellsAntigen-experienced B cellsMultiple sclerosis brainSecondary lymphoid tissuesB cell compartmentB cell trafficB cell maturationImmunomodulatory therapyImmune infiltratesPeripheral bloodInflammatory diseasesLymphocyte transmigrationPeripheral tissuesNervous systemMembers of clonesCell maturationCell traffic
2013
Quantitative Susceptibility Mapping of Multiple Sclerosis Lesions at Various Ages
Chen W, Gauthier SA, Gupta A, Comunale J, Liu T, Wang S, Pei M, Pitt D, Wang Y. Quantitative Susceptibility Mapping of Multiple Sclerosis Lesions at Various Ages. Radiology 2013, 271: 183-92. PMID: 24475808, PMCID: PMC4263629, DOI: 10.1148/radiol.13130353.Peer-Reviewed Original ResearchConceptsNormal-appearing white matterMS lesionsMultiple sclerosis lesionsEnhanced lesionsQuantitative susceptibility mappingMR examinationsSclerosis lesionsConventional magnetic resonance imagingMagnetic resonance imagingT2-weighted imagesMS patientsPathophysiologic featuresCerebrospinal fluidOnline supplemental materialWhite matterLesionsQSM imagesResonance imagingPatientsMR imagingThree-dimensional gradient-echo sequenceGradient echo sequenceMonthsBonferroni correctionAge
2012
Detecting cortical lesions in multiple sclerosis at 7 T using white matter signal attenuation
Bluestein KT, Pitt D, Sammet S, Zachariah CR, Nagaraj U, Knopp MV, Schmalbrock P. Detecting cortical lesions in multiple sclerosis at 7 T using white matter signal attenuation. Magnetic Resonance Imaging 2012, 30: 907-915. PMID: 22578928, PMCID: PMC3402634, DOI: 10.1016/j.mri.2012.03.006.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAlgorithmsCerebral CortexFemaleHumansImage EnhancementImage Interpretation, Computer-AssistedMagnetic Resonance ImagingMaleMiddle AgedMultiple SclerosisNerve Fibers, MyelinatedReproducibility of ResultsSensitivity and SpecificitySubtraction TechniqueYoung Adult
2011
T1 and proton density at 7 T in patients with multiple sclerosis: an initial study
Bluestein KT, Pitt D, Knopp MV, Schmalbrock P. T1 and proton density at 7 T in patients with multiple sclerosis: an initial study. Magnetic Resonance Imaging 2011, 30: 19-25. PMID: 21937183, PMCID: PMC3375320, DOI: 10.1016/j.mri.2011.07.018.Peer-Reviewed Original ResearchConceptsCortical lesionsMultiple sclerosisWhite matterGray matterHealthy control subjectsWhite matter lesionsNormal-appearing tissueMS patientsMagnetic resonance sequencesMatter lesionsControl subjectsCerebrospinal fluidMS researchLesionsPatientsMR imagingUltrahigh-field MR imagingField MR imagingSclerosisProton densityResonance sequencesTissue responseTurbo fieldMagnetic resonanceInitial study
2010
Imaging Cortical Lesions in Multiple Sclerosis With Ultra–High-Field Magnetic Resonance Imaging
Pitt D, Boster A, Pei W, Wohleb E, Jasne A, Zachariah CR, Rammohan K, Knopp MV, Schmalbrock P. Imaging Cortical Lesions in Multiple Sclerosis With Ultra–High-Field Magnetic Resonance Imaging. JAMA Neurology 2010, 67: 812-818. PMID: 20625086, DOI: 10.1001/archneurol.2010.148.Peer-Reviewed Original ResearchConceptsCortical lesion detectionCortical lesionsMultiple sclerosisLesion typeCortical multiple sclerosis lesionsBrain tissueCortical lesion typesMultiple sclerosis tissueAutopsied brain tissueInversion recoveryMagnetic resonance imagingMultiple sclerosis lesionsCorresponding histological sectionsLesion detectionMyelin basic proteinHypointense ringUndetected lesionsImmunohistochemical analysisSclerosis lesionsLesionsResonance imagingSensitivity of T2SclerosisMagnetic resonance imagesLesion visibility
2009
Dysmyelinated axons in shiverer mice are highly vulnerable to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity
Pitt D, Gonzales E, Cross AH, Goldberg MP. Dysmyelinated axons in shiverer mice are highly vulnerable to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated toxicity. Brain Research 2009, 1309: 146-154. PMID: 19896473, PMCID: PMC7343376, DOI: 10.1016/j.brainres.2009.10.066.Peer-Reviewed Original ResearchMeSH KeywordsAlpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic AcidAnimalsBiomarkersBrainDisease Models, AnimalExcitatory Amino Acid AgonistsFemaleHereditary Central Nervous System Demyelinating DiseasesLuminescent ProteinsMiceMice, Inbred C57BLMice, Neurologic MutantsMovement DisordersMyelin Basic ProteinNerve DegenerationNerve Fibers, MyelinatedNeurotoxinsN-MethylaspartateReceptors, AMPAConceptsNMDA receptorsShiverer miceAMPA/kainate receptorsLumbar dorsal columnWhite matter injuryWidespread axonal degenerationSpinal cord axonsActivation of receptorsReceptor-mediated toxicitySubset of axonsMyelin basic proteinAxonal vulnerabilityNeuroprotective therapiesGlutamate excitotoxicityNMDA injectionAxonal degenerationAxonal injuryDorsal columnsRotarod performanceAxon damageGlutamate toxicityCentral axonsGlial cellsS-AMPAAxonal toxicity
2003
Glutamate uptake by oligodendrocytes
Pitt D, Nagelmeier IE, Wilson HC, Raine CS. Glutamate uptake by oligodendrocytes. Neurology 2003, 61: 1113-1120. PMID: 14581674, DOI: 10.1212/01.wnl.0000090564.88719.37.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAstrocytesAutoradiographyBiological TransportCell SurvivalCells, CulturedDose-Response Relationship, DrugExcitatory Amino Acid Transporter 1Excitatory Amino Acid Transporter 2FemaleGene ExpressionGlutamic AcidHumansIn Situ HybridizationMaleMiddle AgedMultiple SclerosisNeurotoxinsOligodendrogliaRNA, MessengerSpinal CordTritiumTumor Necrosis Factor-alphaConceptsMS white matterEAAT-2EAAT-1White matterExtracellular glutamateGlutamate uptakePredominant cellsHuman oligodendrocytesGlutamate removalProinflammatory cytokine tumor necrosisHuman white matterNormal human white matterCommon pathologic eventGlutamate transporter expressionGlutamate receptor expressionCytokine tumor necrosisExcess extracellular glutamateInhibited glutamate uptakeHigh extracellular glutamateSubsequent overstimulationExcitotoxic damageGlutamate excitotoxicityGlutamate clearanceTumor necrosisReceptor expression