2024
Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases
Aguero C, Dhaynaut M, Amaral A, Moon S, Neelamegam R, Scapellato M, Carazo-Casas C, Kumar S, El Fakhri G, Johnson K, Frosch M, Normandin M, Gómez-Isla T. Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases. Acta Neuropathologica 2024, 147: 25. PMID: 38280071, PMCID: PMC10822013, DOI: 10.1007/s00401-023-02672-z.Peer-Reviewed Original ResearchConceptsNon-AD tauopathiesTau aggregationTau PET tracersDNA-binding proteinsBinds to neurofibrillary tanglesSecond-generation tau tracersTransactive response DNA-binding proteinSpectrum of neurodegenerative diseasesNeurofibrillary tanglesTau lesionsMelanin-containing cellsTDP-43Binding signalTauopathiesBinding targetsCerebral amyloid angiopathyOff-target bindingB-amyloidBinding patternsNeurodegenerative diseasesTau tracersTauBinding to areasBinding profilesBinding
2023
Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults
Hanseeuw B, Jacobs H, Schultz A, Buckley R, Farrell M, Guehl N, Becker J, Properzi M, Sanchez J, Quiroz Y, Vannini P, Sepulcre J, Yang H, Chhatwal J, Gatchel J, Marshall G, Amariglio R, Papp K, Rentz D, Normandin M, Price J, Healy B, El Fakhri G, Sperling R, Johnson K. Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults. Neurology 2023, 101: e2533-e2544. PMID: 37968130, PMCID: PMC10791053, DOI: 10.1212/wnl.0000000000207962.Peer-Reviewed Original ResearchConceptsAssociated with cognitive declineOlder adultsNon-AD pathologyCognitive declineHippocampal volumeCognitive dataPreclinical Alzheimer Cognitive CompositeInferior temporal tauProspective cohort studyClinically normal older adultsHarvard Aging Brain StudyPittsburgh compound B PET scansOvert cognitive impairmentAnalyzed dataNormal older adultsAging Brain StudyClinically normal adultsLongitudinal associationsAlzheimer's diseaseCohort studyMemory impairmentCognitive compositeCognitive impairmentHippocampal atrophyCognitionTau-PET abnormality as a biomarker for Alzheimer’s disease staging and early detection: a topological perspective
Ding J, Shen C, Wang Z, Yang Y, Fakhri G, Lu J, Liang D, Zheng H, Zhou Y, Sun T, Study F. Tau-PET abnormality as a biomarker for Alzheimer’s disease staging and early detection: a topological perspective. Cerebral Cortex 2023, 33: 10649-10659. PMID: 37653600, DOI: 10.1093/cercor/bhad312.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesBiomarkersBrainCognitive DysfunctionHumansPositron-Emission TomographyTau ProteinsConceptsStandardized uptake value ratioMild cognitive impairmentBrain regionsCognitive impairmentPositron emission tomographyMedial temporal lobeAlzheimer's diseaseVisual-related regionsTopological perspectiveTau positron emission tomographyMode networkTau PET imagingTopological featuresIndependent data cohortsTemporal lobeConnection strengthExtract topological featuresTau networksAbnormal networkProgression of Alzheimer's diseaseAbnormal protein accumulationAssociation of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease
Prokopiou P, Engels-Domínguez N, Schultz A, Sepulcre J, Koops E, Papp K, Marshall G, Normandin M, El Fakhri G, Rentz D, Sperling R, Johnson K, Jacobs H. Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease. Neurology 2023, 101: e1206-e1217. PMID: 37491329, PMCID: PMC10516269, DOI: 10.1212/wnl.0000000000207646.Peer-Reviewed Original ResearchConceptsLC activityMemory declineLocus coeruleusCognitive declineEC tauHarvard Aging Brain StudyHuman neuroimaging studiesSteeper memory declineNoradrenergic brainstem nucleiLongitudinal cognitive dataFunctional MRI dataTau depositionAging Brain StudyPreclinical Alzheimer's diseaseTau progressionCortical tau depositionElevated beta-amyloidInterventions promoting resilienceMild cognitive impairmentExecutive dysfunctionExecutive functionNeuroimaging studiesTau spreadingTemporal cortexCognitive compositeImpact of motion correction on [18F]-MK6240 tau PET imaging
Tiss A, Marin T, Chemli Y, Spangler-Bickell M, Gong K, Lois C, Petibon Y, Landes V, Grogg K, Normandin M, Becker A, Thibault E, Johnson K, Fakhri G, Ouyang J. Impact of motion correction on [18F]-MK6240 tau PET imaging. Physics In Medicine And Biology 2023, 68: 105015. PMID: 37116511, PMCID: PMC10278956, DOI: 10.1088/1361-6560/acd161.Peer-Reviewed Original ResearchMeSH KeywordsAgedAlzheimer DiseaseBrainHumansImage Processing, Computer-AssistedMotionPositron-Emission TomographyConceptsMotion correctionPET quantitationImpact of motion correctionList-mode reconstructionMotion correction methodList-mode dataMotion-corrected imagesEffect of motion correctionVoxel displacementsPhantom experimentsOptical tracking dataLong acquisitionBrain PET scansSlow motionImage qualityPET imagingPositron emission tomographyCorrectionMotionCorrection methodRates of tau accumulationHead motionMotion metricsPhantomPositronMeasurement of Cerebral Perfusion Indices from the Early Phase of [18F]MK6240 Dynamic Tau PET Imaging
Guehl N, Dhaynaut M, Hanseeuw B, Moon S, Lois C, Thibault E, Fu J, Price J, Johnson K, El Fakhri G, Normandin M. Measurement of Cerebral Perfusion Indices from the Early Phase of [18F]MK6240 Dynamic Tau PET Imaging. Journal Of Nuclear Medicine 2023, 64: 968-975. PMID: 36997330, PMCID: PMC10241011, DOI: 10.2967/jnumed.122.265072.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAniline CompoundsBrainCerebrovascular CirculationCognitive DysfunctionHumansPositron-Emission TomographyConceptsTime-activity curvesCerebral perfusionMetabolite-corrected arterial input functionBrain time-activity curvesEarly phaseRegional time-activity curvesIndices of cerebral perfusionDynamic [<sup>18</sup>FBlood-brain barrierPlasma to brain tissueStatistically significant differenceArterial blood samplesForty-nine subjectsCNArterial input functionPathophysiological mechanismsPerfusion indicatorsPET imagingBlood samplesSignificant differenceSurrogate indexNoninvasive estimationAnatomical informationCompound BForty-nine
2022
Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes
Montal V, Diez I, Kim C, Orwig W, Bueichekú E, Gutiérrez-Zúñiga R, Bejanin A, Pegueroles J, Dols-Icardo O, Vannini P, El-Fakhri G, Johnson K, Sperling R, Fortea J, Sepulcre J. Network Tau spreading is vulnerable to the expression gradients of APOE and glutamatergic-related genes. Science Translational Medicine 2022, 14: eabn7273. PMID: 35895837, PMCID: PMC9942690, DOI: 10.1126/scitranslmed.abn7273.Peer-Reviewed Original ResearchConceptsTau spreadingIntracellular accumulation of tau proteinAccumulation of tau proteinAlzheimer's diseasePathological tau accumulationGenetic gradientGenetic dataTau proteinNeurofibrillary tanglesSynaptic genesTau accumulationGenetic traitsGenesDrug development strategiesExpression gradientIntracellular accumulationTauExpressionCognitively normal older participantsHuman brain cortexTanglesProteinApoTraitsAlzheimerLower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals
Prokopiou P, Engels-Domínguez N, Papp K, Scott M, Schultz A, Schneider C, Farrell M, Buckley R, Quiroz Y, El Fakhri G, Rentz D, Sperling R, Johnson K, Jacobs H. Lower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals. Nature Communications 2022, 13: 1571. PMID: 35322012, PMCID: PMC8943159, DOI: 10.1038/s41467-022-28986-2.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseAmyloid beta-PeptidesAnimalsCognitive DysfunctionLocus CoeruleusPositron-Emission TomographyTau ProteinsConceptsCognitive declineLC activityLC-FCFunctional connectivityLocus coeruleusAssociated with altered neuronal activityNeuronal activityFace-name paradigmAD-related cognitive declineHuman imaging researchIn vivo neuronal activityLongitudinal cognitive dataAssociated with cognitive declineBeta-amyloid-PETIndividuals at-riskAlzheimer's diseaseCognitively unimpaired older individualsBeta-amyloidSubcortical regionsFunctional MRICognitive dataNeurofibrillary tauImaging researchHippocampusCognitionImpact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series1
Dhaynaut M, Sprugnoli G, Cappon D, Macone J, Sanchez J, Normandin M, Guehl N, Koch G, Paciorek R, Connor A, Press D, Johnson K, Pascual-Leone A, Fakhri G, Santarnecchi E. Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series1. Journal Of Alzheimer's Disease 2022, 85: 1667-1676. PMID: 34958021, PMCID: PMC9023125, DOI: 10.3233/jad-215072.Peer-Reviewed Original ResearchConceptsMicroglia activationGamma spectral powerDecrease of microglia activationNo adverse eventsTranscranial alternating current stimulationSlow disease progressionPlacebo-controlled conditionsPreclinical dataCase seriesAdverse eventsGamma oscillationsElectrophysiological assessmentP-tauMouse modelDisease progressionMesial regionMild to moderate ADAnimal modelsPatientsPET imagingAlzheimer's diseaseSpectral powerAD mouse modelAD patientsProtein clearance
2021
Toward noninvasive brain stimulation 2.0 in Alzheimer’s disease
Menardi A, Rossi S, Koch G, Hampel H, Vergallo A, Nitsche M, Stern Y, Borroni B, Cappa S, Cotelli M, Ruffini G, El-Fakhri G, Rossini P, Dickerson B, Antal A, Babiloni C, Lefaucheur J, Dubois B, Deco G, Ziemann U, Pascual-Leone A, Santarnecchi E. Toward noninvasive brain stimulation 2.0 in Alzheimer’s disease. Ageing Research Reviews 2021, 75: 101555. PMID: 34973457, PMCID: PMC8858588, DOI: 10.1016/j.arr.2021.101555.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseBrainCognitionHumansTranscranial Direct Current StimulationTranscranial Magnetic StimulationImpact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer’s disease
Sprugnoli G, Munsch F, Cappon D, Paciorek R, Macone J, Connor A, El Fakhri G, Salvador R, Ruffini G, Donohoe K, Shafi M, Press D, Alsop D, Pascual Leone A, Santarnecchi E. Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer’s disease. Alzheimer's Research & Therapy 2021, 13: 203. PMID: 34930421, PMCID: PMC8690894, DOI: 10.1186/s13195-021-00922-4.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseCognitive DysfunctionHippocampusHumansPerfusionTranscranial Direct Current StimulationConceptsTemporal lobeMethodsIn two open-label studiesMild to moderate AD participantsPreclinical models of ADGamma bandBrain oscillatory activityModerate AD participantsBilateral temporal lobesEpisodic memoryAdministered 1 hSpectral power changesBrain areasModulates cerebral perfusionAD participantsPlacebo-controlled trialHippocampal perfusionModel of ADOpen-label studyNeural activityAssociated with alterationsNon-invasive countermeasureCognitive AssessmentCognitive impairmentCognitive protectionOscillatory activityIn vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline
Jacobs H, Becker J, Kwong K, Engels-Domínguez N, Prokopiou P, Papp K, Properzi M, Hampton O, d'Oleire Uquillas F, Sanchez J, Rentz D, El Fakhri G, Normandin M, Price J, Bennett D, Sperling R, Johnson K. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline. Science Translational Medicine 2021, 13: eabj2511. PMID: 34550726, PMCID: PMC8641759, DOI: 10.1126/scitranslmed.abj2511.Peer-Reviewed Original ResearchConceptsLC integrityLongitudinal cognitive measuresCognitive measuresLocus coeruleusIndicators of Alzheimer's disease pathologyLocus coeruleus integrityMedial temporal lobeTangle densityRush Memory and Aging ProjectBraak stageMemory and Aging ProjectHyperphosphorylated tau aggregatesAlzheimer's diseaseB-amyloidAD-related processesMemory declineCognitive dysfunctionDisease pathologyCognitive trajectoriesTemporal lobeLC neuronsPostmortem correlationsCognitive declineEntorhinal cortexPreclinical ADEvaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer’s Disease
Shoup T, Griciuc A, Normandin M, Quinti L, Walsh L, Dhaynaut M, Moon S, Guehl N, Brugarolas P, Elmaleh D, Fakhri G, Tanzi R. Evaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer’s Disease. Journal Of Alzheimer's Disease 2021, 80: 775-786. PMID: 33579853, DOI: 10.3233/jad-201419.Peer-Reviewed Original ResearchConceptsMicroglial cellsCell toxicityPET imagingMultifactorial mechanism of actionBV2 microglial cellsDose-dependent mannerBV2 microglial cell lineMicroglial cell lineMechanism of actionF-18Multifactorial mechanismsPro-inflammatoryHigher perfusionLow perfusionRhesus macaquesCromolynCell linesIncreased uptakeTracer penetrationEnhanced uptakePotential therapeuticsPerfusionToxicityClearance assayClearanceThe cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography
Sanchez J, Becker J, Jacobs H, Hanseeuw B, Jiang S, Schultz A, Properzi M, Katz S, Beiser A, Satizabal C, O'Donnell A, DeCarli C, Killiany R, El Fakhri G, Normandin M, Gómez-Isla T, Quiroz Y, Rentz D, Sperling R, Seshadri S, Augustinack J, Price J, Johnson K. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography. Science Translational Medicine 2021, 13 PMID: 33472953, PMCID: PMC7978042, DOI: 10.1126/scitranslmed.abc0655.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlzheimer DiseaseAmyloid beta-PeptidesHumansPositron-Emission TomographyTau ProteinsTauopathiesConceptsPositron emission tomographyTemporal lobeMedial temporal lobe tauAlzheimer's diseaseMedial temporal lobeStudy of normal agingAssociated with baseline measuresMolecular positron emission tomographyTau-PET signalDegree of clinical impairmentEmission tomographyModel of Alzheimer's diseaseTemporal lobe anatomyCognitive declineClinical impairmentNormal agingAdult participantsStudy of AgingRhinal sulcusBrain pathologyExtratemporal regionsPET measurementsLongitudinal studyTau progressionClinically normal people
2019
Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects
Guehl N, Wooten D, Yokell D, Moon S, Dhaynaut M, Katz S, Moody K, Gharagouzloo C, Kas A, Johnson K, El Fakhri G, Normandin M. Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects. European Journal Of Nuclear Medicine And Molecular Imaging 2019, 46: 2099-2111. PMID: 31332496, PMCID: PMC6709592, DOI: 10.1007/s00259-019-04419-z.Peer-Reviewed Original ResearchConceptsReference tissue methodDistribution volume ratioTissue methodIn vivo quantificationPharmacokinetic modeling strategiesArterial plasma input functionMultilinear reference tissue methodsTwo-tissue compartment modelBlood:plasma ratioTissue-to-plasmaPlasma input functionPlasma concentration time courseBlood-based methodMethodsThirty-five subjectsSUV ratioBlood-based analysesData setsArterial input functionPET scansControl subjectsMild cognitive impairmentPlasma ratioRadiometabolite analysisHealthy controlsConcentration time courseVisual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy
Putcha D, Brickhouse M, Touroutoglou A, Collins J, Quimby M, Wong B, Eldaief M, Schultz A, Fakhri G, Johnson K, Dickerson B, McGinnis S. Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy. NeuroImage Clinical 2019, 23: 101889. PMID: 31200149, PMCID: PMC6562373, DOI: 10.1016/j.nicl.2019.101889.Peer-Reviewed Original ResearchConceptsVisual cognitive testsNeuropsychological batteryAssociated with tauVariant of ADCortical atrophyCognitive testsLogopenic variant primary progressive aphasiaVariant primary progressive aphasiaMagnetic resonance imagingPrimary progressive aphasiaStructural magnetic resonance imagingVentral occipitotemporal cortexSuperior parietal cortexCognitive test performanceVisual cognitive dysfunctionCognitive task performanceNon-amnestic variantsSpatial patterns of tauAlzheimer's diseasePosterior cortical dysfunctionVisual cortical regionsOccipital association corticesAmyloid PETAmyloid-positive patientsPosterior cortical atrophy
2018
Neurogenetic contributions to amyloid beta and tau spreading in the human cortex
Sepulcre J, Grothe M, d’Oleire Uquillas F, Ortiz-Terán L, Diez I, Yang H, Jacobs H, Hanseeuw B, Li Q, El-Fakhri G, Sperling R, Johnson K. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nature Medicine 2018, 24: 1910-1918. PMID: 30374196, PMCID: PMC6518398, DOI: 10.1038/s41591-018-0206-4.Peer-Reviewed Original ResearchConceptsAmyloid-betaGenetic profileIdentified distinct pathwaysTau positron emission tomography imagingTau propagationTau pathwayTau spreadingGenetic backgroundAllen Human Brain AtlasDistinct pathwaysAlzheimer's diseaseTauLipid metabolismAb accumulationAdult individualsPathwayHuman Brain AtlasPathological progressionTranscriptomeMechanisms of pathological progressionBetaAmyloidProteinopathiesNeuronal circuitsApo
2017
Partial volume correction for PET quantification and its impact on brain network in Alzheimer’s disease
Yang J, Hu C, Guo N, Dutta J, Vaina L, Johnson K, Sepulcre J, Fakhri G, Li Q. Partial volume correction for PET quantification and its impact on brain network in Alzheimer’s disease. Scientific Reports 2017, 7: 13035. PMID: 29026139, PMCID: PMC5638902, DOI: 10.1038/s41598-017-13339-7.Peer-Reviewed Original ResearchMeSH KeywordsAlzheimer DiseaseBrainCohort StudiesFemaleHumansImage Processing, Computer-AssistedMaleNerve NetPositron-Emission TomographyConceptsQuantitative accuracy of PET imagesSpatial resolution of PET scannersAccuracy of PET imagesPET scannerBrain networksPET imagingQuantitative accuracyPartial volume effectsClassification performanceImage registrationPositron emission tomography quantificationPartial volume correctionSpatial resolutionJoint entropyVolume correctionNetwork structure analysisCorrected imagesVolume effectClinical datasetsParameter settingsPositron emission tomographyClassification testsCompare network propertiesNoise sensitivityHierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex
Sepulcre J, Grothe M, Sabuncu M, Chhatwal J, Schultz A, Hanseeuw B, Fakhri G, Sperling R, Johnson K. Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex. JAMA Neurology 2017, 74: 813-820. PMID: 28558094, PMCID: PMC5710537, DOI: 10.1001/jamaneurol.2017.0263.Peer-Reviewed Original ResearchConceptsHeteromodal areasTemporal lobeHarvard Aging Brain StudyHeteromodal association regionsAging Brain StudyCognitively normal participantsElderly brainsPositron emission tomographicPrimary somatomotor cortexDistribution volume ratioAlzheimer's diseaseTau depositionStandardized uptake value ratioVisual regionsNormal participantsAb depositionSomatomotor cortexTemporal areaPittsburgh compound BCarbon 11-labeled Pittsburgh Compound BBrain studiesAssociation regionsHuman brainPathological hallmarks of Alzheimer's diseaseCortical distribution
2015
Matched signal detection on graphs: Theory and application to brain imaging data classification
Hu C, Sepulcre J, Johnson K, Fakhri G, Lu Y, Li Q. Matched signal detection on graphs: Theory and application to brain imaging data classification. NeuroImage 2015, 125: 587-600. PMID: 26481679, DOI: 10.1016/j.neuroimage.2015.10.026.Peer-Reviewed Original ResearchConceptsImage data classificationWeighted energy detectorGraph-signalGraph Laplacian eigenvaluesEnergy detectorManifold structureProblem of Alzheimer's diseaseData classificationGraph LaplacianSubspace detectorWeighted graphMSD approachSignal processingSignal detectionIntrinsic structureLaplacian eigenvaluesSubspaceTest statisticsGraphRandom signalsData setsLowest eigenvalueGaussian distributionTraditional methodsEigenvalues