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
APOE4 moderates the association between cerebral small vessel disease and cortical tau accumulation in midlife
Espinoza L, Scott M, Beiser A, Banh A, Philip V, Ghosh S, Thibault E, Maillard P, Decarli C, Fakhri G, Johnson K, Seshadri S, Satizabal C. APOE4 moderates the association between cerebral small vessel disease and cortical tau accumulation in midlife. Alzheimer's & Dementia 2024, 20: e091824. PMCID: PMC11714429, DOI: 10.1002/alz.091824.Peer-Reviewed Original ResearchAPOE-e4 genotypeAPOE-e4APOE-e4 carriersBiomarkers of cerebral small vessel diseaseIncreased risk of ADSignificant associationFramingham Heart StudyThird Generation cohortsRegional tauCerebral small vessel diseaseCognitively healthy participantsRisk of ADMiddle-aged adultsBorderline significant associationCardiovascular risk factorsSmall vessel diseaseDementia onsetNo significant associationHeart StudyPotential confoundersAlzheimer's diseaseLinear regression modelsE4 genotypeTau accumulationIncreased riskDiffusion-based Bayesian posterior distribution prediction of kinetic parameters in dynamic PET
Djebra Y, Liu X, Marin T, Tiss A, Dhaynaut M, Guehl N, Johnson K, Fakhri G, Ma C, Ouyang J. Diffusion-based Bayesian posterior distribution prediction of kinetic parameters in dynamic PET. 2024, 00: 1-1. DOI: 10.1109/nss/mic/rtsd57108.2024.10657955.Peer-Reviewed Original ResearchConditional variational autoencoderEfficient deep learning-based approachMarkov chain Monte CarloDenoising diffusion probabilistic modelDeep learning-based approachDiffusion probabilistic modelLearning-based approachApproximate posterior distributionPosterior distributionVariational autoencoderHeavy computationTau protein aggregationBayesian inferenceProbabilistic modelData-drivenStudy molecular processesBayesian posterior distributionProtein aggregationMetropolis-Hastings Markov chain Monte CarloMolecular processesAlzheimer's diseaseNeurodegenerative diseasesKinetic parametersEstimate posterior distributionsAutoencoderDiffusion Model-Based Posterior Distribution Prediction for Kinetic Parameter Estimation in Dynamic PET
Djebra Y, Liu X, Marin T, Tiss A, Dhaynaut M, Guehl N, Johnson K, Fakhri G, Ma C, Ouyang J. Diffusion Model-Based Posterior Distribution Prediction for Kinetic Parameter Estimation in Dynamic PET. 2011 IEEE International Symposium On Biomedical Imaging: From Nano To Macro 2024, 00: 1-5. PMID: 39530051, PMCID: PMC11554386, DOI: 10.1109/isbi56570.2024.10635805.Peer-Reviewed Original ResearchPosterior distributions of kinetic parametersDenoising diffusion probabilistic modelHyperphosphorylated tauP-tauDiffusion probabilistic modelAlzheimer's diseaseNeurodegenerative diseasesKinetic parametersPosterior distributionInference efficiencyComputational needsEstimate kinetic parametersProbabilistic modelComputation time
2023
Locus coeruleus metabolic changes as a predictor of tau accumulation and cognitive decline
Koops E, Dutta J, Becker A, Van Egroo M, Riphagen J, Hanseeuw B, Sperling R, Fakhri G, Johnson K, Jacobs H. Locus coeruleus metabolic changes as a predictor of tau accumulation and cognitive decline. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.073715.Peer-Reviewed Original ResearchBeta-amyloidTau pathologyAlzheimer's diseaseNeuropathological hallmarks of Alzheimer's diseaseHallmarks of Alzheimer's diseaseP-tauBeta-amyloid levelsP-tau accumulationMetabolic turnoverAccumulation of p-tauMarkers of AD progressionTau formationLocus coeruleusAD pathological changesTau accumulationNeuropathological hallmarksAD progressionPhosphorylated-tauPositron emission tomographyLate stageLociPairwise analysisMetabolismPair-wise differencesFDG-PET signalHigher circulating cortisol is associated with amyloidogenesis in post‐menopausal women: The Framingham Heart Study
Salardini A, Zilli E, Himali J, Gonzales M, Himali D, Ghosh S, McGrath E, Buckley R, Satizabal C, Johnson K, Decarli C, Fakhri G, Vasan R, Seshadri S. Higher circulating cortisol is associated with amyloidogenesis in post‐menopausal women: The Framingham Heart Study. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.080594.Peer-Reviewed Original ResearchFramingham Heart StudyHeart StudyProspective cohort studyCross sectional studyPostmenopausal womenCognitively normal individualsPost-menopausal womenSectional studyAPOE4 statusAPOE4-positiveLongitudinal cohortSuperior temporal sulcusCortisol levelsMenopausal statusSecondary outcomesAlzheimer's diseaseAssociated with amyloidogenesisCortisol dysregulationBaseline plasma cortisolMorning plasma cortisolTertileFraminghamWomenAssess interactionsProgression of Alzheimer's diseaseAssociation 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 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 ResearchConceptsStandardized 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 accumulation
2022
Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex
Hanseeuw B, Jacobs H, Schultz A, Buckley R, Properzi M, Becker A, Farrell M, Sanchez J, Papp K, Yang H, Chhatwal J, Price J, Fakhri G, Rentz D, Sperling R, Johnson K. Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex. Alzheimer's & Dementia 2022, 18 DOI: 10.1002/alz.069271.Peer-Reviewed Original ResearchNetwork 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 ResearchConceptsCognitive 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 researchHippocampusCognition
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 ResearchImpact 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 clearanceLocus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations
Jacobs H, Becker A, Kwong K, Engels N, Prokopiou P, Papp K, Properzi M, Hampton O, Sanchez J, Rentz D, Fakhri G, Normandin M, Bennett D, Sperling R, Johnson K. Locus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations. Alzheimer's & Dementia 2021, 17 DOI: 10.1002/alz.056391.Peer-Reviewed Original ResearchHarvard Aging Brain StudyMini-Mental State ExaminationLC integrityLocus coeruleusMini-Mental State Examination scoreNeuronal densityTangle densityLocus coeruleus integrityAging Brain StudyTau pathologyAlzheimer's diseaseAD-related processesVertex-wiseTemporal regionsBraak stageLC measurementsMini-MentalMCI/AD patientsState ExaminationBrain studiesPiB-PET imagingTau-PETPET measurementsPiB-PETTangle burdenIn 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 ADSynthesis 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 kineticsThe 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 ResearchConceptsPositron 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
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