2024
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
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 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 compositeTau Positron Emission Tomography and Neurocognitive Function Among Former Professional American-Style Football Players
Dhaynaut M, Grashow R, Normandin M, Wu O, Marengi D, Terry D, Sanchez J, Weisskopf M, Speizer F, Taylor H, Guehl N, Seshadri S, Beiser A, Daneshvar D, Johnson K, Iverson G, Zafonte R, Fakhri G, Baggish A. Tau Positron Emission Tomography and Neurocognitive Function Among Former Professional American-Style Football Players. Journal Of Neurotrauma 2023, 40: 1614-1624. PMID: 37282582, PMCID: PMC10458363, DOI: 10.1089/neu.2022.0454.Peer-Reviewed Original ResearchConceptsPositron emission tomographyDistribution volume ratioNeuropsychological testsNeurocognitive functionStandardized uptake value ratioControl participantsMeasures of neurocognitive functionStructural magnetic resonance imagingMeasures of memoryDepressive symptom severityMale control participantsEmission tomographyCerebellar gray matterNeuropsychological measuresTau positron emission tomographyExecutive functionSymptom severityBrain regionsEntorhinal cortexRepetitive head impactsP-tauReference regionFormer playersRepetitive head impact exposureMale controls
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 modelsImpact 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 clearanceSynthesis 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
Near-Infrared Fluorescence Imaging of Carotid Plaques in an Atherosclerotic Murine Model
Wu X, Ulumben A, Long S, Katagiri W, Wilks M, Yuan H, Cortese B, Yang C, Kashiwagi S, Choi H, Normandin M, Fakhri G, Zaman R. Near-Infrared Fluorescence Imaging of Carotid Plaques in an Atherosclerotic Murine Model. Biomolecules 2021, 11: 1753. PMID: 34944397, PMCID: PMC8698491, DOI: 10.3390/biom11121753.Peer-Reviewed Original ResearchIn vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker
Mody M, Petibon Y, Han P, Kuruppu D, Ma C, Yokell D, Neelamegam R, Normandin M, Fakhri G, Brownell A. In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker. Scientific Reports 2021, 11: 15897. PMID: 34354107, PMCID: PMC8342610, DOI: 10.1038/s41598-021-94967-y.Peer-Reviewed Original ResearchConceptsFragile X syndromeFragile X mental retardation proteinX syndromeLoss of fragile X mental retardation proteinMGlu5 receptor expressionMetabotropic glutamate subtype 5 receptorsDrug occupancy studiesSignificant group differencesFragile X mental retardationHealthy controlsAnterior cingulateMGluR5 availabilityVisuospatial processingMGlu5 receptorsOlfactory cortexBrain areasGroup differencesRetardation proteinGlutamate signalingImages of maleNeurodevelopmental disordersExcessive glutamate signalingGender-matched controlsDisordersMGluR5Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Yuan G, Guehl N, Zheng B, Qu X, Moon S, Dhaynaut M, Shoup T, Afshar S, Kang H, Zhang Z, El Fakhri G, Normandin M, Brownell A. Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Molecular Imaging And Biology 2021, 23: 527-536. PMID: 33559035, PMCID: PMC8277681, DOI: 10.1007/s11307-021-01586-0.Peer-Reviewed Original ResearchConceptsNon-human primatesIn vivo PET imaging studiesNucleus accumbensGlutamate receptor 2PET imaging ligandsImaging ligandsParietal cortexBrain regionsPET imaging studiesPET radioligandIn vivo PET imaging experimentsVolume of distributionMGluR2C57BL/6 J micePET imaging experimentsPET studiesBrainSprague-Dawley ratsAlzheimer's diseaseBrain permeabilityPre-treatment studyImaging studiesDisordersRat studiesReversible kinetics
2020
Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques
Guehl N, Ramos-Torres K, Linnman C, Moon S, Dhaynaut M, Wilks M, Han P, Ma C, Neelamegam R, Zhou Y, Popko B, Correia J, Reich D, Fakhri G, Herscovitch P, Normandin M, Brugarolas P. Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. Cerebrovascular And Brain Metabolism Reviews 2020, 41: 1721-1733. PMID: 33090071, PMCID: PMC8221756, DOI: 10.1177/0271678x20963404.Peer-Reviewed Original ResearchConceptsFocal brain injuryMyelin repair therapyContributions of demyelinationDrivers of disabilityImaging demyelinationBrain injuryMeasurements of molecular changesTool's sensitivity to changesLower myelin contentDemyelinating lesionsNeuronal conductionImpaired conductionDemyelinationBrain penetrationGold standardRhesus macaquesInjured areaMultiple sclerosisMolecular changesMyelin sheathNeurological diseasesHigh metabolic stabilityMRI methodsMRIInjury
2019
Assessment 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 courseAutoradiography 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
2018
[18F]Fluorocholine and [18F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM
Verwer E, Kavanagh T, Mischler W, Feng Y, Takahashi K, Wang S, Shoup T, Neelamegam R, Yang J, Guehl N, Ran C, Massefski W, Cui Y, El-Chemaly S, Sadow P, Oldham W, Kijewski M, Fakhri G, Normandin M, Priolo C. [18F]Fluorocholine and [18F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM. Clinical Cancer Research 2018, 24: 5925-5938. PMID: 30054282, PMCID: PMC6816044, DOI: 10.1158/1078-0432.ccr-17-3693.Peer-Reviewed Original ResearchMeSH KeywordsAgedAnimalsBiomarkersCholineDisease Models, AnimalFemaleFluoroacetatesHeterograftsHumansImage Processing, Computer-AssistedImmunohistochemistryLipid MetabolismLymphangioleiomyomatosisMaleMiceMice, TransgenicMitochondriaOxygen ConsumptionPhosphatidylcholinesPositron-Emission TomographyRatsTuberous SclerosisConceptsTuberous sclerosis complexMetabolic imaging biomarkersPreclinical modelsImaging biomarkersTSC2-deficient cellsStandardized uptake valueTuberous sclerosis complex manifestationsModels of tuberous sclerosis complexAutosomal dominant disorderPotential clinical interestBenign tumorsOvariectomized miceUptake valueSubcutaneous tumorsPreclinical studiesPulmonary nodulesCystic destructionLymphangioleiomyomatosisDominant disorderProliferative lesionsInactivating mutationsTumorMetabolic reprogrammingNeurocognitive impairmentPET imaging
2017
Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation
Kaiser R, Treadway M, Wooten D, Kumar P, Goer F, Murray L, Beltzer M, Pechtel P, Whitton A, Cohen A, Alpert N, Fakhri G, Normandin M, Pizzagalli D. Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation. Cerebral Cortex 2017, 28: 4281-4290. PMID: 29121332, PMCID: PMC6454484, DOI: 10.1093/cercor/bhx281.Peer-Reviewed Original ResearchConceptsDA transporterRL behaviourVentral striatumDA clearanceFunctional connectivityBinding potentialLevel of neurocognitive functioningIncreased intrinsic functional connectivityMulti-modal neuroimaging studiesResting-state functional connectivityPhasic DA activityStriatal DA transporterIntrinsic functional connectivityReinforcement learning behaviorMulti-modal investigationsFrontostriatal circuitsFrontostriatal connectivityFrontostriatal regionsOrbitofrontal cortexDA activityNeuroimaging studiesOrbitofrontal regionsDopamine markersNeurocognitive functionDopamineLessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case
Marquié M, Verwer E, Meltzer A, Kim S, Agüero C, Gonzalez J, Makaretz S, Siao Tick Chong M, Ramanan P, Amaral A, Normandin M, Vanderburg C, Gomperts S, Johnson K, Frosch M, Gómez-Isla T. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathologica Communications 2017, 5: 75. PMID: 29047416, PMCID: PMC5648451, DOI: 10.1186/s40478-017-0482-0.Peer-Reviewed Original ResearchConceptsPositron emission tomographyBasal gangliaBinding to neuromelaninPositron emission tomography studiesDementia of AD typeInferior temporal cortexParkinson's diseaseTau pathologyPositron emission tomography scanAlzheimer's diseaseMild cognitive impairmentTemporal cortexAutoradiographic bindingBrain regionsNeurofibrillary tau pathologyOccipital cortexPositron emission tomography signalCognitive impairmentPostmortem materialEntorhinal cortexSubstantia nigraParenchymal hemorrhagePD diagnosisAutoradiography experimentsChoroid plexusMature B cells accelerate wound healing after acute and chronic diabetic skin lesions
Sîrbulescu R, Boehm C, Soon E, Wilks M, Ilieş I, Yuan H, Maxner B, Chronos N, Kaittanis C, Normandin M, Fakhri G, Orgill D, Sluder A, Poznansky M. Mature B cells accelerate wound healing after acute and chronic diabetic skin lesions. Wound Repair And Regeneration 2017, 25: 774-791. PMID: 28922523, PMCID: PMC5760362, DOI: 10.1111/wrr.12584.Peer-Reviewed Original ResearchConceptsB cell treatmentB cellsKinetics of neutrophil infiltrationImmune cell populationsNaive B cellsWild-type miceSaline-treated controlsMature B cellsGrowth-associated protein 43Wound healingIncreased collagen depositionDiabetic murine woundsObese diabetic micePro-healing responseIncreased fibroblast proliferationWound granulation tissueT cellsIncreased relative expressionNeutrophil infiltrationLive B cellsScar sizeDiabetic miceDecreased apoptosisTopical applicationMMP2 expressionRapid computation of single PET scan rest‐stress myocardial blood flow parametric images by table look up
Guehl N, Normandin M, Wooten D, Rozen G, Ruskin J, Shoup T, Woo J, Ptaszek L, Fakhri G, Alpert N. Rapid computation of single PET scan rest‐stress myocardial blood flow parametric images by table look up. Medical Physics 2017, 44: 4643-4651. PMID: 28594441, PMCID: PMC5603217, DOI: 10.1002/mp.12398.Peer-Reviewed Original Research[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging
Marquié M, Siao Tick Chong M, Antón-Fernández A, Verwer E, Sáez-Calveras N, Meltzer A, Ramanan P, Amaral A, Gonzalez J, Normandin M, Frosch M, Gómez-Isla T. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Acta Neuropathologica 2017, 134: 619-628. PMID: 28612291, PMCID: PMC5772971, DOI: 10.1007/s00401-017-1740-8.Peer-Reviewed Original ResearchConceptsNeurofibrillary tanglesNeurofibrillary tau pathologyTau burdenBraak stageStaging of neurofibrillary tanglesBrain regionsAccurate diagnosis of Alzheimer's diseaseTau pathologyPhospho-tauStereotyped spatiotemporal patternBraak NFT stageNeurofibrillary tangle Braak stagePhosphor-screen autoradiographyAlzheimer's diseaseMild cognitive impairmentTau measuresNFT stageCognitively normal controlsObserved patternBraakCognitive impairmentWestern blottingBindingDiagnosis of Alzheimer's diseaseBraak staging of neurofibrillary tangles