2025
Elevated serum cortisol associated with early‐detected increase of brain amyloid deposition in Alzheimer's disease imaging biomarkers among menopausal women: The Framingham Heart Study
Salardini A, Himali J, Abdullah M, Chaudhari R, Young V, Zilli E, McGrath E, Gonzales M, Thibault E, Salinas J, Aparicio H, Himali D, Ghosh S, Buckley R, Satizabal C, Johnson K, DeCarli C, Fakhri G, Vasan R, Beiser A, Seshadri S. Elevated serum cortisol associated with early‐detected increase of brain amyloid deposition in Alzheimer's disease imaging biomarkers among menopausal women: The Framingham Heart Study. Alzheimer's & Dementia 2025, 21: e70179. PMID: 40271551, PMCID: PMC12019305, DOI: 10.1002/alz.70179.Peer-Reviewed Original ResearchConceptsPost-menopausal womenFramingham Heart Study participantsIncreased risk of ADFramingham Heart StudyRisk of ADNo significant associationHeart StudyEarly risk factorsStudy participantsMenopausal statusMultivariate regression analysisApolipoprotein E4Significant associationAlzheimer's diseaseIncreased riskRisk factorsCognitive impairmentMenopausal womenBrain amyloid depositionRegression analysisWomenAnalyzed dataPositron emission tomographyIncreased amyloid depositionBurden[18F]MK-6240 Radioligand Delivery Indices as Surrogates of Cerebral Perfusion: Bias and Correlation Against [15O]Water.
Fu J, Juttukonda M, Garimella A, Salvatore A, Lois C, Ranasinghe A, Efthimiou N, Sari H, Aye W, Guehl N, El Fakhri G, Johnson K, Dickerson B, Izquierdo-Garcia D, Catana C, Price J. [18F]MK-6240 Radioligand Delivery Indices as Surrogates of Cerebral Perfusion: Bias and Correlation Against [15O]Water. Journal Of Nuclear Medicine 2025, 66: 410-417. PMID: 39947916, PMCID: PMC11876731, DOI: 10.2967/jnumed.124.268701.Peer-Reviewed Original ResearchPreliminary Evidence for Perturbation‐Based tACS‐EEG Biomarkers of Gamma Activity in Alzheimer's Disease
Palmisano A, Pezanko L, Cappon D, Tatti E, Macone J, Koch G, Smeralda C, Romanella S, Ruffini G, Rivolta D, Press D, Pascual‐Leone A, El‐Fakhri G, Santarnecchi E. Preliminary Evidence for Perturbation‐Based tACS‐EEG Biomarkers of Gamma Activity in Alzheimer's Disease. International Journal Of Geriatric Psychiatry 2025, 40: e70025. PMID: 39799469, DOI: 10.1002/gps.70025.Peer-Reviewed Original ResearchConceptsPeripheral neuroinflammationIdentification of novel biomarkersResponse to TACPatient's clinical phenotypeSpectral powerGABAergic dysfunctionNo significant correlationPrognostic valueInhibitory circuitryClinical severityClinical phenotypeAnimal modelsCognitive statusNeuroinflammatory markersAlzheimer's diseaseHuman patientsNeuroinflammatory biomarkersNovel biomarkersPatientsDisease severityTherapeutic targetGamma activityBiomarkersMild to moderate dementiaSignificant correlation
2024
Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study
Ramos-Cejudo J, Scott M, Tanner J, Pase M, McGrath E, Ghosh S, Osorio R, Thibault E, Fakhri G, Johnson K, Beiser A, Seshadri S. Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study. Journal Of Alzheimer’s Disease 2024, 100: 487-494. PMID: 38875034, DOI: 10.3233/jad-231320.Peer-Reviewed Original ResearchConceptsCommunity-based Framingham Heart StudyFramingham Heart StudyHeart StudyCross-sectional associationsPlasma total tauMiddle-aged participantsRisk of ADCognitively healthy individualsCommunity-basedCompound B (PiB)-PETMiddle-agedPositive associationPlasma tauParticipantsTau-PETAssociationTotal tau levelsAD brain pathologyTotal-tauHealthy individualsAPOEe4Tau levelsBurdenRhinal cortexPrecuneus regionsAssociations of Physical Activity Engagement with Cerebral Amyloid-β and Tau from Midlife
Gonzales M, Kojis D, Spartano N, Thibault E, DeCarli C, Fakhri G, Johnson K, Beiser A, Seshadri S. Associations of Physical Activity Engagement with Cerebral Amyloid-β and Tau from Midlife. Journal Of Alzheimer’s Disease 2024, 100: 935-943. PMID: 39031362, PMCID: PMC12050109, DOI: 10.3233/jad-240322.Peer-Reviewed Original ResearchConceptsPhysical activity indexPhysical activity engagementAssociated with lower dementia riskPhysical activity index scoreAssociation of physical activityActive engagementPhysical activity levelsFramingham Heart StudyCross-sectional associationsCommunity-based cohortCardiovascular risk factorsDementia riskPhysical activityLifestyle interventionHeart StudyLinear regression modelsStratified analysisTau-PET retentionSelf-reportSex disparitiesActivity levelsLate lifeTau positron emission tomographyRisk factorsAge groupsAccelerated 3D metabolite T1 mapping of the brain using variable‐flip‐angle SPICE
Zhao Y, Li Y, Guo R, Jin W, Sutton B, Ma C, Fakhri G, Li Y, Luo J, Liang Z. Accelerated 3D metabolite T1 mapping of the brain using variable‐flip‐angle SPICE. Magnetic Resonance In Medicine 2024, 92: 1310-1322. PMID: 38923032, PMCID: PMC12120684, DOI: 10.1002/mrm.30200.Peer-Reviewed Original ResearchConceptsLow-rank tensor modelGeneralized series modelMetabolite TExperimental resultsBrain metabolitesClinically acceptable scan timeEfficient encodingPhantom experimental resultsAcceptable scan timeNoisy dataSparse samplingImaging problemsData processingHealthy subject dataVariable flip angleFlip angleTensor modelSaturation effectsQuantitative metabolic imagingMRSI techniquePhantomScan timeData acquisitionMetabolic imagingT1 mappingPET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator
Belov V, Guehl N, Duvvuri S, Iredale P, Moon S, Dhaynaut M, Chakilam S, MacDonagh A, Rice P, Yokell D, Renger J, Fakhri G, Normandin M. PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator. Cerebrovascular And Brain Metabolism Reviews 2024, 44: 1329-1342. PMID: 38477292, PMCID: PMC11342722, DOI: 10.1177/0271678x241238820.Peer-Reviewed Original ResearchConceptsPositive allosteric modulatorsReceptor occupancyNon-human primatesBinding potentialPositron emission tomographyMuscarinic acetylcholine receptorsAllosteric modulatorsNon-human primate brainM4 muscarinic acetylcholine receptorStriatal hyperdopaminergiaAcetylcholine receptorsBrain regionsCaudate nucleusTotal volume of distributionDose-dependent blockReference regionVolume of distributionPositron emission tomography imagingEmission tomographyReceptor levelsFunction of dosePET scansClinical trialsBlood-basedRhesus macaques
2023
Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology
Baril A, Kojis D, Himali J, Decarli C, Sanchez E, Johnson K, El Fakhri G, Thibault E, Yiallourou S, Himali D, Cavuoto M, Pase M, Beiser A, Seshadri S. Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology. Neurology 2023, 102: e207807. PMID: 38165370, PMCID: PMC10834132, DOI: 10.1212/wnl.0000000000207807.Peer-Reviewed Original ResearchConceptsHigher WMH burdenSelf-reported sleep durationLong sleep durationNeuroimaging metricsSleep durationAssociated with incident dementiaNeurodegenerative trajectoriesSleep duration categoriesNeuroimaging markersTAU outcomesIncident dementiaNeuroimagingSleep duration changesNeuroimaging testsLinear regression modelsDuration changesMRI metricsAlzheimer's diseaseAssociation 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 atrophyCognitionAssociation 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 compositeLongitudinal Imaging in a Patient With Opioid-associated Amnestic Syndrome
Barash J, Schmahmann J, Xie Z, Lev M, Fakhri G. Longitudinal Imaging in a Patient With Opioid-associated Amnestic Syndrome. Cognitive And Behavioral Neurology 2023, 36: 194-197. PMID: 37389894, PMCID: PMC10527331, DOI: 10.1097/wnn.0000000000000347.Peer-Reviewed Original ResearchConceptsOpioid-associated amnestic syndromeFluid-attenuated inversion recoveryPositron emission tomographyAmnestic syndromeHistory of attention-deficit hyperactivity disorderAttention-deficit hyperactivity disorderBrain regions of individualsSubstance use disordersOpioid misuseMild memory lossN-acetyl aspartate/creatineUrine toxicology screenFollow-up imagingHistory of opioid misuseRegions of individualsTau depositionTau positron emission tomographyHyperactivity disorderIntravenous heroinRight hippocampusAnterograde amnesiaRestricted diffusionBrain regionsHippocampal abnormalitiesLongitudinal imaging
2022
Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP
Brugarolas P, Wilks M, Noel J, Kaiser J, Vesper D, Ramos-Torres K, Guehl N, Macdonald-Soccorso M, Sun Y, Rice P, Yokell D, Lim R, Normandin M, El Fakhri G. Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP. European Journal Of Nuclear Medicine And Molecular Imaging 2022, 50: 344-351. PMID: 36197499, PMCID: PMC9816249, DOI: 10.1007/s00259-022-05980-w.Peer-Reviewed Original ResearchConceptsRadiation dosimetryTime-activity curvesAdverse eventsEffective doseMultiple bed positionsComprehensive metabolic panelNonhuman primatesHealthy human volunteersNo adverse eventsDynamic PET scansVoltage-gated potassiumAnimal models of neurological diseasesNonhuman primate studiesModels of neurological diseasesHuman biodistributionAverage effective doseMetabolic panelDosimetryOLINDA softwareHealthy volunteersUrinary bladderPET scansDemyelinating lesionsBed positionAnimal modelsSynthesis and Characterization of 5‑(2-Fluoro-4‑[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro‑2H‑pyrano[2,3‑b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Yuan G, Dhaynaut M, Lan Y, Guehl N, Huynh D, Iyengar S, Afshar S, Jain M, Pickett J, Kang H, Wang H, Moon S, Ondrechen M, Wang C, Shoup T, Fakhri G, Normandin M, Brownell A. Synthesis and Characterization of 5‑(2-Fluoro-4‑[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro‑2H‑pyrano[2,3‑b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Journal Of Medicinal Chemistry 2022, 65: 2593-2609. PMID: 35089713, PMCID: PMC9434702, DOI: 10.1021/acs.jmedchem.1c02004.Peer-Reviewed Original ResearchConceptsNegative allosteric modulatorsMetabotropic glutamate receptor 2Positron emission tomographyGlutamate receptor 2MGluR2 functionNeuropsychiatric disordersDrug effectsBrain heterogeneityReceptor 2Allosteric modulatorsMGluR2Nonhuman primatesBrain imagingPositron emission tomography imagingPositron emission tomography imaging ligandsHigh molar activityEmission tomographyExcellent radiochemical purityImaging ligandsBlocking agentsPET imagingMolar activityTherapeutic targetMetabotropicDisorders
2021
Impact 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 2021, 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
2019
Attenuation correction using 3D deep convolutional neural network for brain 18F-FDG PET/MR: Comparison with Atlas, ZTE and CT based attenuation correction
Blanc-Durand P, Khalife M, Sgard B, Kaushik S, Soret M, Tiss A, Fakhri G, Habert M, Wiesinger F, Kas A. Attenuation correction using 3D deep convolutional neural network for brain 18F-FDG PET/MR: Comparison with Atlas, ZTE and CT based attenuation correction. PLOS ONE 2019, 14: e0223141. PMID: 31589623, PMCID: PMC6779234, DOI: 10.1371/journal.pone.0223141.Peer-Reviewed Original ResearchConceptsZero echo timeAC mapsAttenuation correctionPET attenuation correctionCT-based ACComputed tomographyAC methodPhoton attenuationZTE-ACInvestigation of suspected dementiaMR imagingBrain computed tomographyAtlas-ACBrain metabolismZTE-MRIConvolutional neural networkEcho timeHead atlasFDG-PET/MRPET imagingLow biasRegions-of-interestPatientsCorrectionNeural networkMulti-Modal Signatures of Tau Pathology, Neuronal Fiber Integrity, and Functional Connectivity in Traumatic Brain Injury
Wooten D, Ortiz-Terán L, Zubcevik N, Zhang X, Huang C, Sepulcre J, Atassi N, Johnson K, Zafonte R, Fakhri G. Multi-Modal Signatures of Tau Pathology, Neuronal Fiber Integrity, and Functional Connectivity in Traumatic Brain Injury. Journal Of Neurotrauma 2019, 36: 3233-3243. PMID: 31210098, PMCID: PMC6857466, DOI: 10.1089/neu.2018.6178.Peer-Reviewed Original ResearchConceptsTraumatic brain injuryTraumatic brain injury subjectsDistribution volume ratioWhite matter integrityFunctional connectivityDiffusion tensor imagingPositron emission tomographyTBI subjectsResting-state functional magnetic resonance imagingResting state functional connectivityFunctional magnetic resonance imagingFractional anisotropyDecreased white matter integrityGroup of TBI subjectsIncreased functional connectivityFunctional MRI resultsGraph theory metricsBrain injuryLiving human brainMagnetic resonance imagingNoninvasive neuroimaging techniquesBrain regionsFunctional MRINeuroimaging techniquesDiffusion tractography imagingAssessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder
Pizzagalli D, Berretta S, Wooten D, Goer F, Pilobello K, Kumar P, Murray L, Beltzer M, Boyer-Boiteau A, Alpert N, Fakhri G, Mechawar N, Vitaliano G, Turecki G, Normandin M. Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder. JAMA Psychiatry 2019, 76: 854-861. PMID: 31042280, PMCID: PMC6495358, DOI: 10.1001/jamapsychiatry.2019.0801.Peer-Reviewed Original ResearchConceptsMajor depressive disorderDA transporter availabilityVentral tegmental areaDA transporterDAT availabilityTegmental areaDepressive disorderDA signalingPositron emission tomographyDAT expressionMcLean HospitalHealthy controlsMajor depressive disorder groupsNumbers of depressive episodesStriatal dopamine transporter bindingDA transporter levelsLevels of DAT expressionStriatal DAT expressionStriatal DAT availabilityDA transporter densityDAT binding potentialDopamine transporter bindingOlder healthy controlsMesolimbic pathwayDA clearanceEvaluation 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 atrophyAutoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue
Aguero C, Dhaynaut M, Normandin M, Amaral A, Guehl N, Neelamegam R, Marquie M, Johnson K, El Fakhri G, Frosch M, Gomez-Isla T. Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue. Acta Neuropathologica Communications 2019, 7: 37. PMID: 30857558, PMCID: PMC6410510, DOI: 10.1186/s40478-019-0686-6.Peer-Reviewed Original ResearchConceptsIn vivo detection of neurofibrillary tanglesNeurofibrillary tanglesDetection of neurofibrillary tanglesAlzheimer's diseaseTDP-43Binds to neurofibrillary tanglesFrontotemporal lobar degeneration-tauOff-target bindingDNA-binding protein 43Binding patternsNon-Alzheimer tauopathiesHuman postmortem brain tissueTau aggregationPostmortem brain tissueBinding signalBinding targetsCerebral amyloid angiopathyIn vivo detectionB-amyloidNeurodegenerative diseasesHuman brain tissueTauTau positron emission tomographyBindingMK-6240
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