2024
Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F, Group F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Journal Of Alzheimer's Disease 2024, 101: s79-s93. PMID: 39422941, PMCID: PMC11494639, DOI: 10.3233/jad-231126.Peer-Reviewed Original ResearchConceptsGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesA framework for translating tauopathy therapeutics: Drug discovery to clinical trials
Feldman H, Cummings J, Boxer A, Staffaroni A, Knopman D, Rizzo S, Territo P, Arnold S, Ballard C, Beher D, Boeve B, Dacks P, Diaz K, Ewen C, Fiske B, Gonzalez M, Harris G, Hoffman B, Martinez T, McDade E, Nisenbaum L, Palma J, Quintana M, Rabinovici G, Rohrer J, Rosen H, Troyer M, Kim D, Tanzi R, Zetterberg H, Ziogas N, May P, Rommel A. A framework for translating tauopathy therapeutics: Drug discovery to clinical trials. Alzheimer's & Dementia 2024 PMID: 39316411, DOI: 10.1002/alz.14250.Peer-Reviewed Original ResearchPrimary tauopathiesClinically heterogeneous neurodegenerative diseasesTau protein aggregationHeterogeneous neurodegenerative diseaseSurrogate disease biomarkersTauopathiesProtein aggregationDefinition of rare diseasesAlzheimer's diseaseNeurodegenerative diseasesClinical trialsEarly-phase clinical trialsEarly-phase trialsDisease biomarkersFrontotemporal degenerationDrug developmentProgressive supranuclear palsyDiscovery to clinical trialsSelection of targetsTherapeuticsPharmacodynamic biomarkersRelationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients
Matthews D, Kinney J, Ritter A, Andrews R, Strom E, Lukic A, Koenig L, Revta C, Fillit H, Zhong K, Tousi B, Leverenz J, Feldman H, Cummings J. Relationships between plasma biomarkers, tau PET, FDG PET, and volumetric MRI in mild to moderate Alzheimer's disease patients. Alzheimer's & Dementia: Translational Research & Clinical Interventions 2024, 10: e12490. PMID: 38988416, PMCID: PMC11233274, DOI: 10.1002/trc2.12490.Peer-Reviewed Original ResearchFluorodeoxyglucose positron emission tomographyGlial fibrillary acidic proteinPositron emission tomographyMagnetic resonance imagingPlasma biomarkersVolumetric magnetic resonance imagingMild to moderate ADFDG positron emission tomographyPhase 2 clinical trialNeurofilament light chainGlial fibrillary acidic protein concentrationFibrillary acidic proteinInflammation-related proteinsTemporal cortexLeft inferior temporal cortexModerate ADCognitive endpointsFluorodeoxyglucosePET uptakeInflammation biomarkersBaseline MMSEMild-to-moderate Alzheimer's disease patientsImaging biomarkersBiomarker heterogeneityEmission tomographyA multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease
Galasko D, Farlow M, Lucey B, Honig L, Elbert D, Bateman R, Momper J, Thomas R, Rissman R, Pa J, Aslanyan V, Balasubramanian A, West T, Maccecchini M, Feldman H. A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease. Alzheimer's Research & Therapy 2024, 16: 151. PMID: 38970127, PMCID: PMC11225352, DOI: 10.1186/s13195-024-01490-z.Peer-Reviewed Original ResearchConceptsOrally administered small moleculeFractional synthesis rateAscending dose studyDose-dependent loweringIRB-approved protocolEarly ADMini-Mental State ExamDose-dependent effectAlzheimer's diseaseBlood patchDouble-blindWell-toleratedCatheter placementPreclinical modelsLumbar punctureDose studyIntravenous infusionMild cognitive impairmentEvaluate safetyPlacebo participantsCognitive measuresStable isotope labeling kineticsActive drugClinical trialsADAS-Cog12Asian Cohort for Alzheimer Disease (ACAD) Pilot Study
Peavy G, Võ N, Revta C, Lu A, Lupo J, Nam P, Nguyễn K, Wang L, Feldman H. Asian Cohort for Alzheimer Disease (ACAD) Pilot Study. Alzheimer Disease & Associated Disorders 2024, 38: 277-284. PMID: 39177172, PMCID: PMC11340683, DOI: 10.1097/wad.0000000000000631.Peer-Reviewed Original ResearchConceptsSubjective cognitive complaintsOlder Vietnamese AmericansVascular risk factorsMild cognitive impairmentVietnamese AmericansRisk factorsMeasuring subjective cognitive complaintsPilot studyCommunity advisory boardNongenetic risk factorsCommunity-based researchAD risk factorsAlzheimer's diseaseDepressive symptomsConsensus teamCognitive complaintsBilingual/bicultural staffAD riskAssessment toolAdvisory boardVietnamese communityExploratory analysisCognitive difficultiesCognitive impairmentParticipantsPharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease
Morales J, Gabriel N, Natarajan L, LaCroix A, Shadyab A, Xu R, Silverman J, Feldman H, Hernandez I, Aslanyan V, Bang A, Bevins E, Bowman G, Boyarko B, Chen X, Clelland C, Dodge H, Durant J, Edland S, Evans A, Galasko D, Gerwick W, Greenberg B, Herman M, Herold T, Hook V, Jacobs D, Kaye J, Kim D, Koo E, Kosik K, Léger G, Lupo J, Messer K, Momper J, Nygaard H, Pa J, Quinti L, Revta C, Rexach J, Rizzo S, Rynearson K, Schneider L, Slusher B, Tanzi R, Territo P, Yokoyama J. Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease. Alzheimer's & Dementia 2024, 20: 5236-5246. PMID: 39030734, PMCID: PMC11350022, DOI: 10.1002/alz.13872.Peer-Reviewed Original ResearchRisk of ADCross-sectional analysis of electronic health recordsAnalysis of electronic health recordsAD riskAssociated with risk of ADAssociated with AD riskAssociated with decreased prevalenceElectronic health recordsRetrospective cohort study designMedicare claims dataCohort study designCox proportional hazards regressionAssociated with riskCross-sectional analysisProportional hazards regressionPrevalence of ADMultiple sensitivity analysesAlzheimer's diseaseHealth recordsMedicare beneficiariesMedicare dataClaims dataStudy designHazards regressionPatient characteristicsProtocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam)
Feldman H, Luchsinger J, Léger G, Taylor C, Jacobs D, Salmon D, Edland S, Messer K, Revta C, Flowers S, Jones K, Koulman A, Yarasheski K, Verghese P, Venkatesh V, Zetterberg H, Durant J, Lupo J, Gibson G, Group F. Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam). PLOS ONE 2024, 19: e0302998. PMID: 38809849, PMCID: PMC11135745, DOI: 10.1371/journal.pone.0302998.Peer-Reviewed Original ResearchConceptsPhase 2bPhase 2aRandomized double-blind placebo-controlled trialDouble-blind placebo-controlled trialCo-primary efficacy endpointsTolerability eventsBest-tolerated dosePlacebo-controlled trialWell-tolerated dosesAlzheimer's diseaseLonger-term safetyEfficacy of drug deliveryWeeks of treatmentTargeted therapeutic approachesErythrocyte transketolase activityGroups of participantsDouble-blindPlacebo armEfficacy endpointSecondary endpointsOral treatmentPharmacokinetic measurementsClinical trialsTherapeutic approachesBlood markersPersonal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective
Patel K, Yang D, Feldman H, Hsiung G, Nygaard H, Best J, Dwosh E, Robillard J, DeMarco M. Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective. Alzheimer's & Dementia: Translational Research & Clinical Interventions 2024, 10: e12463. PMID: 38596482, PMCID: PMC10999946, DOI: 10.1002/trc2.12463.Peer-Reviewed Original ResearchCare partnersSemi-structured phone interviewsCare partner perspectivesCare partners' experiencesPatients' decision-making processPre-test counsellingRoutine medical careBiomarker testingHealthy behaviorsCaregiving responsibilitiesPost-disclosureRoutine carePositive lifestyleLifestyle changesPhone interviewsMedical carePartners' experiencesCarePartner's perspectiveMedical interventionsAlzheimer's diseaseObservational studyClinic patientsStudy findingsPositive feelingsClinical value of Alzheimer's disease biomarker testing
Patel K, Yang D, Best J, Chambers C, Lee P, Henri‐Bhargava A, Funnell C, Foti D, Pettersen J, Feldman H, Nygaard H, Hsiung G, DeMarco M. Clinical value of Alzheimer's disease biomarker testing. Alzheimer's & Dementia: Translational Research & Clinical Interventions 2024, 10: e12464. PMID: 38596484, PMCID: PMC10999950, DOI: 10.1002/trc2.12464.Peer-Reviewed Original ResearchAD biomarker testsHealth care resource useLevel of cognitive impairmentCare resource useLongitudinal cohort studyRoutine medical careAlzheimer's Disease DiagnosticHealth system economicsBiomarker testingClinical management planMedical decision-makingDementia specialistsMemory clinicIncreased referralsBaseline clinical presentationQuestionnaires pre-Increase patientsAD biomarker profileMedical careMedical utilizationFamily members' counselingManagement questionnaireCohort studyDrug prescriptionsPersonal utilityDeveloping the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia program
Moukarzel S, Zlatar Z, Hartman S, Lomas D, Feldman H, Banks S, Group H. Developing the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia program. Alzheimer's & Dementia: Translational Research & Clinical Interventions 2024, 10: e12457. PMID: 38440783, PMCID: PMC10909928, DOI: 10.1002/trc2.12457.Peer-Reviewed Original ResearchHealthy actionsChanging support needsDelay dementia onsetCommunity advisory boardCultural adaptation frameworkIncreased self-efficacyPersonal goal settingRisk factorsModifiable risk factorsBehavioral changesPositive behavior changePublic health challengeEffect behavior changeCommunity feedbackSocial cognitive theoryDementia onsetProgram usabilitySupport needsADRDGoal settingHealth challengesMultidisciplinary teamSelf-efficacyPilot testAdvisory boardPotentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison
Son S, Speechley M, Zou G, Kivipelto M, Mangialasche F, Feldman H, Chertkow H, Belleville S, Nygaard H, Hachinski V, Pieruccini-Faria F, Montero-Odasso M. Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison. The Journal Of Prevention Of Alzheimer's Disease 2024, 11: 1490-1499. PMID: 39350396, PMCID: PMC11436427, DOI: 10.14283/jpad.2024.105.Peer-Reviewed Original ResearchModifiable risk factorsCanadian Longitudinal StudyPhysical inactivityHearing lossDementia casesRisk factorsModifiable dementia risk factorsSleep disturbanceAssociated with modifiable risk factorsAssociated with less educationMidlife hearing lossTargeting physical inactivityDementia risk factorsDesignCross-sectional analysisLife course modelLongitudinal studyRisk reduction strategiesDementia preventionMidlife obesityMidlife hypertensionCanadian adultsLess educationPopulation impactObjectiveTo estimateTraumatic brain injury
2023
Number of completed exercise sessions is associated with slower brain atrophy in MCI over 12 months in the EXERT trial
Digma L, Aslanyan V, Brewer J, Bevins E, Katula J, Chmelo E, Hodge H, LaCroix A, Shadyab A, Jacobs D, Salmon D, Feldman H, Pa J, Baker L. Number of completed exercise sessions is associated with slower brain atrophy in MCI over 12 months in the EXERT trial. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.079285.Peer-Reviewed Original ResearchSupervised exercise sessionsBrain atrophyExercise sessionsAlzheimer's Disease Cooperative StudyLess brain atrophySupervised exercise interventionLower dementia riskLate-life exerciseAmount of exerciseInferior lateral ventricleExercise armExercise interventionDementia riskBaseline ageCDR-SBAerobic trainingLateral ventricleHigh adherenceIntervention adherenceNumber of sessionsVentricular expansionExercise typePlasma Aβ42/40Amnestic MCICognitive declineCSF tau markers are associated with fine memory discrimination in older adults with amnestic MCI in the EXERT trial
Fenton L, Aslanyan V, Jacobs D, Salmon D, Brewer J, Rissman R, Feldman H, Shadyab A, LaCroix A, Baker L, Pa J. CSF tau markers are associated with fine memory discrimination in older adults with amnestic MCI in the EXERT trial. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.080157.Peer-Reviewed Original ResearchAmnestic mild cognitive impairmentMemory discriminationOlder adultsMemory testLogical memoryHippocampal volumeAuditory Verbal Learning TestLogical memory testVerbal Learning TestBehavioral pattern separationVerbal memory testsMedial temporal lobeLarger hippocampal volumesMemory measuresList learningStory recallLearning TestObject taskMemory assessmentCognitive performanceMild cognitive impairmentPattern separationCognitive AssessmentStructural brain imagesTemporal lobeStable Isotope Labelling Kinetics: Models and methods to evaluate APP production rates with Posiphen treatment in the DISCOVER clinical trial
Elbert D, Galasko D, Farlow M, Aslanyan V, Pa J, Lucey B, Honig L, Moghekar A, Bateman R, Momper J, Rissman R, Balasubramanian A, Maccecchini M, Feldman H, Group A. Stable Isotope Labelling Kinetics: Models and methods to evaluate APP production rates with Posiphen treatment in the DISCOVER clinical trial. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.077287.Peer-Reviewed Original ResearchAβ40 concentrationsBeta-amyloid precursor protein (APP) mRNAAmyloid precursor protein (APP) mRNASequential dose cohortsHigh-dose groupMild AD dementiaPrecursor protein mRNADose cohortsVenous cathetersStudy armsAD dementiaDose groupDrug exposureVenous bloodPosiphenAβ kineticsDay 22Therapeutic potentialPlaceboDecreased productionGroup differencesPatientsPharmacodynamicsFurther clarificationHoursVirtual Design of the Brain Health Support Program and CAN‐THUMBS UP
Feldman H, Belleville S, Nygaard H, Montero‐Odasso M, Chertkow H, Group C. Virtual Design of the Brain Health Support Program and CAN‐THUMBS UP. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.075153.Peer-Reviewed Original ResearchRisk of dementiaHealth support programRisk factorsMultidomain interventionEducational interventionPilot studyLifestyle intervention trialModifiable lifestyle factorsDementia risk factorsPopulation attributable riskClinical trial developmentHome-based interventionCohort of individualsHigh rateOnline educational interventionHome saliva collectionTarget enrollmentLifestyle factorsIntervention trialsAttributable riskPlatform trialsInterventional approachesTrial developmentStrong rationaleSupport programsBrain Health PRO: An Interactive, Online, Educational Program for Dementia
Belleville S, Chertkow H, Feldman H, Nygaard H, Montero‐Odasso M, Anderson N, Bherer L, Ferland G, Camicioli R, Chan S, Cuesta M, Dwosh E, Fiocco A, Gilbert B, Itzhak I, Jarrett P, Laurin D, Liu‐Ambrose T, Lupo J, McGibbon C, Middleton L, Murphy K, Phillips N, Pichora‐Fuller M, Revta C, Savundranayagam M, Sexton A, Smith E, Speechley M, Trigui A, Wittich W, Group C. Brain Health PRO: An Interactive, Online, Educational Program for Dementia. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.075156.Peer-Reviewed Original ResearchOlder adultsModifiable risk factorsRisk factorsGroups of participantsPilot studyIntervention Mapping frameworkYears of educationScale IIAdvisory GroupDementia literacyFocus groupsVirtual settingEmail interactionsExperience QuestionnaireEfficacy trialsEducational programsShort versionExpert contentEfficacy studiesLifestyle improvementRisk profileOnline programOnline questionnaireOnline educational programAdultsVirtual Cognitive Testing‐ Neuropsychology, MyCogHealth and Cogniciti
Brewster P, Hofer S, Jacobs D, Feldman H, Belleville S, Montero‐Odasso M, Nygaard H, Chertkow H, Group C. Virtual Cognitive Testing‐ Neuropsychology, MyCogHealth and Cogniciti. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.075157.Peer-Reviewed Original ResearchDementia prevention trialsNeuropsychological assessmentStudy phonePrevention trialsRemote neuropsychological assessmentModifiable dementia risk factorsCognitive testingDementia risk factorsHealth support programCognitive screening assessmentMixed linear regressionClinic visitsLifestyle interventionCognitive testing sessionsRisk factorsThree-month intervalsTraditional neuropsychological assessmentFeasibility pilotStudy coordinatorsHealth behaviorsMore interventionsEvidence basePerson assessmentSelf-reported satisfactionScreening assessmentA Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease
Grill J, Tam S, Thai G, Pierce A, Green K, Gillen D, Teng E, Kremen S, Beigi M, Rissman R, Leger G, Zhang J, Jin S, Messer K, Feldman H. A Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.077979.Peer-Reviewed Original ResearchPhase 2a proofP-Tau 181Placebo armTotal tauCDR-SBEarly ADAmyloid beta 40Placebo-controlled trialCerebrospinal fluid levelsEarly Alzheimer's diseaseAlzheimer's disease biomarkersDisease biomarkersPhosphorylation of tauClass III histoneSecondary outcomesAdverse eventsClinical characteristicsPrimary outcomeADCS-ADLStudy armsTreatment initiationCSF biomarkersADAS-Cog13Biomarker outcomesMean changeCAN‐THUMBS UP: Recruitment in the Virtual Era
Nygaard H, Slack P, Feldman H, Chertkow H, Belleville S, Montero‐Odasso M, Anderson N, Bennett D, Borrie M, Chan S, Jarrett P, Lee A, Lupo J, Matthews G, McGibbon C, Revta C, Robillard J, Shadyab A, Shajan S. CAN‐THUMBS UP: Recruitment in the Virtual Era. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.075155.Peer-Reviewed Original ResearchMajority of participantsUp StudyModifiable lifestyle risk factorsLifestyle risk factorsHealth support programInteractive educational interventionComprehensive recruitment strategyConclusions RecruitmentDementia literacyClinical trialsRisk factorsSpecialty clinicClinical cohortBasic demographic informationFuture recruitment effortsClinical sitesMedical clinicsSpecific target populationCohortTraditional recruitment methodsDiverse Canadian populationEducational interventionTarget cohortCanadian populationDemographic informationScalable Multi‐Sensor At Home Assessment of Sleep and Activity in Adults At High Risk for Dementia
Lim A, Centen A, Montazeri N, Gibson E, Dang‐Vu T, Carrier J, Chan S, Belleville S, Nygaard H, Montero‐Odasso M, Feldman H, Chertkow H, Group C. Scalable Multi‐Sensor At Home Assessment of Sleep and Activity in Adults At High Risk for Dementia. Alzheimer's & Dementia 2023, 19 DOI: 10.1002/alz.076469.Peer-Reviewed Original ResearchLifestyle interventionHigh riskSleep featuresOlder adultsSleep electroencephalographyRisk factor interventionHealth support programAccelerometry data collectionNights of recordingFactor interventionSleep disruptionDays of wearWrist accelerometrySleep assessmentHome assessmentDementiaWrist accelerometerCognitive outcomesStudy centersInterventionAdultsEEG recordingsElectroencephalographySleepRisk