2024
Quantification of Cinpanemab (BIIB054) Binding to α-Synuclein in Cerebrospinal Fluid of Phase 1 Single Ascending Dose Samples
Liu Y, Yang M, Fraser K, Graham D, Weinreb P, Weihofen A, Hirst W, Cedarbaum J, Pepinsky B. Quantification of Cinpanemab (BIIB054) Binding to α-Synuclein in Cerebrospinal Fluid of Phase 1 Single Ascending Dose Samples. Journal Of Pharmacology And Experimental Therapeutics 2024, jpet-ar-2024-002199. PMID: 38936981, DOI: 10.1124/jpet.124.002199.Peer-Reviewed Original ResearchCentral nervous systemCerebrospinal fluidMeso Scale DiscoveryCentral nervous system compartmentDrug concentrationsA-synCerebrospinal fluid samplesParkinson's diseasePassive immunotherapy approachesSite of actionImmunotherapy approachesLow drug concentrationsImmunotherapy trialsHealthy volunteersSystemic compartmentDrug-target interactionsCSF samplesObserved doseNervous systemTherapeutic targetA-syn levelsClinical samplesTime-dependent bindingComplex formationCross-linking methodValidity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers
Schejter‐Margalit T, Binyamin N, Thaler A, Maidan I, Cedarbaum J, Orr‐Urtreger A, Weisz M, Goldstein O, Giladi N, Mirelman A, Kizony R. Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers. European Journal Of Neurology 2024, 31: e16327. PMID: 38743695, PMCID: PMC11235808, DOI: 10.1111/ene.16327.Peer-Reviewed Original ResearchKnown-groups validityWeekly Calendar Planning ActivityColor Trails TestActivities of Daily Living ScaleKnown-groups construct validityIdiopathic PDPhysical Activity ScaleDaily Living ScaleEngland Activities of Daily Living ScaleNonmanifesting carriersPD to healthy controlsIdiopathic PD groupMontreal Cognitive AssessmentEcological validitySE-ADLActivity ScaleCompare personsConstruct validityOutcome measuresConvergent validityCognitive AssessmentGBA carriersEngland ActivitiesParkinson's diseaseCognitive testsMild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease
Thaler A, Livne V, Rubinstein E, Omer N, Faust-Socher A, Cohen B, Giladi N, Shirvan J, Cedarbaum J, Gana-Weisz M, Goldstein O, Orr-Urtreger A, Alcalay R, Mirelman A. Mild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease. Parkinsonism & Related Disorders 2024, 123: 106970. PMID: 38691978, DOI: 10.1016/j.parkreldis.2024.106970.Peer-Reviewed Original ResearchMild cognitive impairmentIdiopathic PDMovement Disorder SocietyIncidence of mild cognitive impairmentFrequency of mild cognitive impairmentDiagnosis of mild cognitive impairmentCognitive impairmentLRRK2-PDLevel I criteriaParkinson's diseaseLevel II criteriaCarriers of mutationsMotor symptom onsetHoehn and YahrGBA1-PDCognitive batteryGender-matched controlsCognitive domainsEarly-stage PDI criteriaClinical characteristicsPD cohortDisorder SocietySymptom onsetHealthy adultsCinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.
Hutchison R, Fraser K, Yang M, Fox T, Hirschhorn E, Njingti E, Scott D, Bedell B, Kistner K, Cedarbaum J, Evans K, Graham D, Martarello L, Mollenhauer B, Lang A, Dam T, Beaver J. Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial. Neurology 2024, 102: e209137. PMID: 38315945, DOI: 10.1212/wnl.0000000000209137.Peer-Reviewed Original ResearchConceptsDisease progressionDopaminergic deficitNeurofilament light chain levelsNigrostriatal dopamine pathwayDopamine transporter SPECTTerminated due to lackStriatal dopaminergic deficitsLight chain levelsClinical disease progressionEvidence of dopaminergic deficitParkinson's diseaseEvaluate disease severityBiomarker measurementsEarly Parkinson's diseaseStriatal binding ratiosDevelopment of therapiesStatistically significant differenceScale total scoreBiomarker resultsDouble-blindPlacebo-controlledUnified Parkinson's Disease Rating Scale total scoreDopamine pathwayClinical trialsPrimary outcome
2023
Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson’s Disease
Mammen J, Speck R, Stebbins G, Müller M, Yang P, Campbell M, Cosman J, Crawford J, Dam T, Hellsten J, Jensen-Roberts S, Kostrzebski M, Simuni T, Barowicz K, Cedarbaum J, Dorsey E, Stephenson D, Adams J. Relative Meaningfulness and Impacts of Symptoms in People with Early-Stage Parkinson’s Disease. Journal Of Parkinson's Disease 2023, 13: 619-632. PMID: 37212071, PMCID: PMC10357209, DOI: 10.3233/jpd-225068.Peer-Reviewed Original ResearchConceptsEarly Parkinson's diseaseMeaningful symptomsParkinson's diseaseEarly-stage Parkinson's diseaseMost bothersome symptomsImpact of symptomsStage Parkinson's diseaseBothersomeness of symptomsFine motor difficultiesBothersome symptomsImpact of diseasePatient's perspectiveImportant symptomNew therapiesFuture symptomsSymptom mappingSymptomsMotor difficultiesDiseaseExperiences of peopleJob functioningThe Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease
DeBroff J, Omer N, Cohen B, Giladi N, Kestenbaum M, Shirvan J, Cedarbaum J, Gana‐Weisz M, Goldstein O, Orr‐Urtreger A, Mirelman A, Thaler A. The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease. Movement Disorders Clinical Practice 2023, 10: 606-616. PMID: 37070047, PMCID: PMC10105114, DOI: 10.1002/mdc3.13722.Peer-Reviewed Original ResearchDiagnosis of PDParkinson's diseaseMood-related disordersTime of assessmentMood disordersIdiopathic PDNon-motor comorbiditiesNon-motor featuresIdiopathic Parkinson's diseaseNon-motor phenotypeFrequency of depressionMood related disordersState of depressionPD patientsSuch medicationsWorse motorGenetic statusMedicationsProdromal stageRelated disordersGBA genePD diagnosisDiseaseDiagnosisDisorders
2022
Neuromelanin and T2*-MRI for the assessment of genetically at-risk, prodromal, and symptomatic Parkinson’s disease
Ben Bashat D, Thaler A, Lerman Shacham H, Even-Sapir E, Hutchison M, Evans K, Orr-Urterger A, Cedarbaum J, Droby A, Giladi N, Mirelman A, Artzi M. Neuromelanin and T2*-MRI for the assessment of genetically at-risk, prodromal, and symptomatic Parkinson’s disease. Npj Parkinson's Disease 2022, 8: 139. PMID: 36271084, PMCID: PMC9586960, DOI: 10.1038/s41531-022-00405-9.Peer-Reviewed Original ResearchParkinson's diseaseGenotype-related differencesDAT-SPECTRadiomic featuresSymptomatic Parkinson's diseaseSignificant correlationProdromal phaseBrain regionsNeuromelanin MRIIron accumulationDiseaseMRIAssessment of individualsImaging valuesRadiomics analysisSignificant differencesPatientsNeuromelaninRiskAgeScoresT2Ratio scoresGroupLR scoresApplication of longitudinal item response theory models to modeling Parkinson’s disease progression
Zou H, Aggarwal V, Stebbins G, Müller M, Cedarbaum J, Pedata A, Stephenson D, Simuni T, Luo S. Application of longitudinal item response theory models to modeling Parkinson’s disease progression. CPT Pharmacometrics & Systems Pharmacology 2022, 11: 1382-1392. PMID: 35895005, PMCID: PMC9574723, DOI: 10.1002/psp4.12853.Peer-Reviewed Original ResearchConceptsEarly Parkinson's diseaseParkinson's diseaseDisease progressionProgression rateUnified Parkinson's Disease Rating Scale part 2Stage 1Yahr stage 1Higher baseline severityCommon clinical outcomeLongitudinal disease progressionSlow progression rateParkinson's disease progressionMovement Disorder SocietyStage 2Clinical outcomesMotor signsBaseline severitySlow progressionSum scoreTotal scoreLongitudinal item response theory modelProgressionSeverityPatientsDiseaseTrial of Cinpanemab in Early Parkinson’s Disease
Lang A, Siderowf A, Macklin E, Poewe W, Brooks D, Fernandez H, Rascol O, Giladi N, Stocchi F, Tanner C, Postuma R, Simon D, Tolosa E, Mollenhauer B, Cedarbaum J, Fraser K, Xiao J, Evans K, Graham D, Sapir I, Inra J, Hutchison R, Yang M, Fox T, Budd Haeberlein S, Dam T. Trial of Cinpanemab in Early Parkinson’s Disease. New England Journal Of Medicine 2022, 387: 408-420. PMID: 35921450, DOI: 10.1056/nejmoa2203395.Peer-Reviewed Original ResearchConceptsEarly Parkinson's diseasePrimary end pointSecondary end pointsWeek 52Parkinson's diseaseEnd pointControl groupUnified Parkinson's Disease Rating Scale (UPDRS) total scoreDisease pathogenesisHuman-derived monoclonal antibodiesΑ-synucleinCommon adverse eventsPhase 2 trialDisease-modifying treatmentsMDS-UPDRS scoresLack of efficacyDAT SPECT imagingAdjusted mean differenceMovement Disorder SocietyParkinson's disease pathogenesisScale total scoreAdverse eventsIntravenous infusionDAT-SPECTDisease progressionTracking Emergence of New Motor and Non-Motor Symptoms Using the MDS-UPDRS: A Novel Outcome Measure for Early Parkinson’s Disease?
Tosin M, Simuni T, Stebbins G, Cedarbaum J. Tracking Emergence of New Motor and Non-Motor Symptoms Using the MDS-UPDRS: A Novel Outcome Measure for Early Parkinson’s Disease? Journal Of Parkinson's Disease 2022, 12: 1345-1351. PMID: 35466955, PMCID: PMC9198734, DOI: 10.3233/jpd-223170.Peer-Reviewed Original ResearchConceptsEmergent symptomsDisease progressionOutcome measuresParkinson's disease clinical trialsNon-motor symptomsEarly Parkinson's diseaseDaily Living ScalePatient-reported experiencesClinical rating scalesNovel outcome measuresSymptomatic treatmentPD progressionClinical trialsMedian numberDaily livingLiving ScaleParkinson's diseaseSummary scoresMDS-UPDRSUseful markerRating ScaleSTX groupProgressionStxSymptomsAberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers
Droby A, Artzi M, Lerman H, Hutchison R, Bashat D, Omer N, Gurevich T, Orr-Urtreger A, Cohen B, Cedarbaum J, Sapir E, Giladi N, Mirelman A, Thaler A. Aberrant dopamine transporter and functional connectivity patterns in LRRK2 and GBA mutation carriers. Npj Parkinson's Disease 2022, 8: 20. PMID: 35241697, PMCID: PMC8894349, DOI: 10.1038/s41531-022-00285-z.Peer-Reviewed Original ResearchStriatal binding ratiosGBA-NMCFunctional connectivity patternsDopamine transporterHealthy first-degree relativesNigrostriatal dopaminergic activityGBA mutation carriersStriatal dopamine uptakeRs-fMRI scansFirst-degree relativesPre-clinical stageResting-state fMRIClinical assessment batteryConnectivity patternsPD patientsDopaminergic deficiencyDopaminergic activityRight putamenMutation carriersStudy groupClinical measuresStriatal regionsParkinson's diseaseDopamine uptakeFunctional alterations
2021
Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson’s disease trial
Hutchison R, Evans K, Fox T, Yang M, Barakos J, Bedell B, Cedarbaum J, Brys M, Siderowf A, Lang A. Evaluating dopamine transporter imaging as an enrichment biomarker in a phase 2 Parkinson’s disease trial. BMC Neurology 2021, 21: 459. PMID: 34814867, PMCID: PMC8609885, DOI: 10.1186/s12883-021-02470-8.Peer-Reviewed Original ResearchConceptsDAT-SPECTParkinson's diseaseClinical trialsDisease trialsPhase 2 trialDopaminergic nerve terminalsEarly Parkinson's diseaseDisease-modifying therapiesIdiopathic Parkinson's diseaseMulticenter clinical trialParkinson's disease trialStudy design aspectsSingle photon emissionStages of progressionDegenerative parkinsonismEnrichment biomarkerResultsIn totalClinical assessmentNerve terminalsBlinded neuroradiologistsClinical diagnosisDopamine transporterMonoclonal antibodiesCentral laboratoryTrialsGlucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity
Omer N, Giladi N, Gurevich T, Bar‐Shira A, Gana‐Weisz M, Glinka T, Goldstein O, Kestenbaum M, Cedarbaum J, Mabrouk O, Fraser K, Shirvan J, Orr‐Urtreger A, Mirelman A, Thaler A. Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity. Movement Disorders 2021, 37: 190-195. PMID: 34550621, PMCID: PMC9292990, DOI: 10.1002/mds.28792.Peer-Reviewed Original ResearchConceptsNon-manifesting carriersProdromal Parkinson's diseaseParkinson's diseaseGCase activityClinical phenotypeLower GCase activityCarriers of mutationsLysosomal enzyme glucocerebrosidaseGBA-NMCGBA-PDPD patientsRisk factorsGBA mutationsPD phenotypeG2019S LRRK2GBA geneEnzyme glucocerebrosidaseLRRK2 genePerformance-based measuresAshkenazi JewsDiseaseGroups of participantsPhenotypeMutationsParticipantsSeeking progress in disease modification in Parkinson disease
Lungu C, Cedarbaum J, Dawson T, Dorsey E, Faraco C, Federoff H, Fiske B, Fox R, Goldfine A, Kieburtz K, Macklin E, Matthews H, Rafaloff G, Saunders-Pullman R, Schor N, Schwarzschild M, Sieber B, Simuni T, Surmeier D, Tamiz A, Werner M, Wright C, Wyse R. Seeking progress in disease modification in Parkinson disease. Parkinsonism & Related Disorders 2021, 90: 134-141. PMID: 34561166, DOI: 10.1016/j.parkreldis.2021.09.006.Peer-Reviewed Original ResearchConceptsDisease modificationParkinson's diseaseDisease-modifying benefitsNovel trial designsDrug therapyPatient populationTrial failuresTherapeutic targetTrial designNeurological disordersRelevant biomarkersTherapeutic developmentNational InstituteDiseaseReview articleResearch prioritiesKey stakeholder groupsFailureLikelihood of successTherapyStrokeBiomarkersMutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers
Thaler A, Omer N, Giladi N, Gurevich T, Bar-Shira A, Gana-Weisz M, Goldstein O, Kestenbaum M, Shirvan J, Cedarbaum J, Orr-Urtreger A, Regev K, Shenhar-Tsarfaty S, Mirelman A. Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers. Journal Of Parkinson's Disease 2021, 11: 1285-1296. PMID: 33998549, PMCID: PMC8461659, DOI: 10.3233/jpd-212624.Peer-Reviewed Original ResearchConceptsNon-manifesting carriersRole of inflammationGBA-PDParkinson's diseaseGenetic Parkinson's diseaseLRRK2-PDPD patientsCerebrospinal fluidNon-manifesting mutation carriersAnti-inflammatory treatmentProdromal Parkinson's diseaseGeneral medical conditionsIdiopathic Parkinson's diseaseLRRK2-PD patientsCSF cytokinesGBA-NMCLRRK2-NMCPeripheral cytokinesInflammatory markersIL-10Inflammatory measuresDisease characteristicsIL-1βIL-6Peripheral bloodDetecting Sensitive Mobility Features for Parkinson's Disease Stages Via Machine Learning
Mirelman A, Frank M, Melamed M, Granovsky L, Nieuwboer A, Rochester L, Del Din S, Avanzino L, Pelosin E, Bloem B, Della Croce U, Cereatti A, Bonato P, Camicioli R, Ellis T, Hamilton J, Hass C, Almeida Q, Inbal M, Thaler A, Shirvan J, Cedarbaum J, Giladi N, Hausdorff J. Detecting Sensitive Mobility Features for Parkinson's Disease Stages Via Machine Learning. Movement Disorders 2021, 36: 2144-2155. PMID: 33955603, DOI: 10.1002/mds.28631.Peer-Reviewed Original ResearchConceptsParkinson's diseaseDisease stageMid-stage Parkinson's diseaseAge-matched healthy controlsEarly Parkinson's diseaseHigh discriminatory valueBilateral anklesDisease progressionClinical trialsHealthy controlsDisease spectrumGait measuresSeverity stagesAdvanced stageTrunk sensorDisease severityStride timingStudy participantsDiscriminatory valueObjective monitoringMobility measuresDiseaseCohort selectionMean sensitivityLongitudinal Changes in Neuromelanin MRI Signal in Parkinson's Disease: A Progression Marker
Gaurav R, Yahia‐Cherif L, Pyatigorskaya N, Mangone G, Biondetti E, Valabrègue R, Ewenczyk C, Hutchison R, Cedarbaum J, Corvol J, Vidailhet M, Lehéricy S. Longitudinal Changes in Neuromelanin MRI Signal in Parkinson's Disease: A Progression Marker. Movement Disorders 2021, 36: 1592-1602. PMID: 33751655, PMCID: PMC8359265, DOI: 10.1002/mds.28531.Peer-Reviewed Original ResearchConceptsTotal intracranial volumePD patientsHealthy volunteersParkinson's diseaseIntracranial volumeObservational case-control studySubstantia nigra pars compactaDirect noninvasive assessmentDisease-modifying treatmentsEarly PD patientsFemale PD patientsTherapeutic drug trialsCase-control studyNeuromelanin-sensitive MRI techniquesNeuromelanin-sensitive imagingMale patientsFemale patientsPars compactaCohort IICohort IDrug trialsPatientsImaging biomarkersNoninvasive assessmentDisease severityBiochemical markers for severity and risk in GBA and LRRK2 Parkinson’s disease
Thaler A, Omer N, Giladi N, Gurevich T, Bar-Shira A, Gana-Weisz M, Goldstein O, Kestenbaum M, Cedarbaum J, Orr-Urtreger A, Shenhar-Tsarfaty S, Mirelman A. Biochemical markers for severity and risk in GBA and LRRK2 Parkinson’s disease. Journal Of Neurology 2021, 268: 1517-1525. PMID: 33388928, DOI: 10.1007/s00415-020-10325-4.Peer-Reviewed Original ResearchConceptsNon-manifesting carriersProdromal Parkinson's diseaseWhite blood countParkinson's diseaseMicroalbumin/creatinine ratioNeutrophil/lymphocyte ratioGBA-PD patientsWorse motor performanceGlomerular filtration rateLRRK2 mutation carriersC-reactive proteinIdiopathic Parkinson's diseaseGBA-NMCGBA-PDLRRK2-NMCCreatinine ratioLRRK2-PDLymphocyte ratioVitamin DBlood countFiltration rateIdiopathic PDMutation carriersPD severityBiochemical markers
2020
Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science
Stephenson D, Alexander R, Aggarwal V, Badawy R, Bain L, Bhatnagar R, Bloem B, Boroojerdi B, Burton J, Cedarbaum J, Cosman J, Dexter D, Dockendorf M, Dorsey E, Dowling A, Evers L, Fisher K, Frasier M, Garcia-Gancedo L, Goldsack J, Hill D, Hitchcock J, Hu M, Lawton M, Lee S, Lindemann M, Marek K, Mehrotra N, Meinders M, Minchik M, Oliva L, Romero K, Roussos G, Rubens R, Sadar S, Scheeren J, Sengoku E, Simuni T, Stebbins G, Taylor K, Yang B, Zach N. Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science. Digital Biomarkers 2020, 4: 28-49. PMID: 33442579, PMCID: PMC7768153, DOI: 10.1159/000512500.Peer-Reviewed Original ResearchPD clinical trialsParkinson's diseaseDigital health technologiesClinical trialsUse of DHTParkinson’s Disease Drug DevelopmentSymptoms of PDEuropean Medicines AgencyCritical Path InstituteHealth technologiesDrug development studiesClinical manifestationsPD signsRelentless progressionDisease continuumNew therapiesDrug development pipelineNovel treatmentsUS FoodDrug AdministrationMedicines AgencySubsequent approvalDrug developmentCOVID-19 pandemicTherapyMetabolic syndrome does not influence the phenotype of LRRK2 and GBA related Parkinson’s disease
Thaler A, Shenhar-Tsarfaty S, Shaked Y, Gurevich T, Omer N, Bar-Shira A, Gana-Weisz M, Goldstein O, Kestenbaum M, Cedarbaum JM, Orr-Urtreger A, Giladi N, Mirelman A. Metabolic syndrome does not influence the phenotype of LRRK2 and GBA related Parkinson’s disease. Scientific Reports 2020, 10: 9329. PMID: 32518334, PMCID: PMC7283235, DOI: 10.1038/s41598-020-66319-9.Peer-Reviewed Original ResearchConceptsMetabolic syndromeParkinson's diseaseLRRK2-NMCLRRK2-PDComponents of MSGBA-Parkinson diseaseMetabolic componentsProdromal Parkinson's diseaseHigh triglyceride levelsIdiopathic Parkinson's diseaseGBA-NMCGBA-PDElevated triglyceridesBlood pressureLRRK2 carriersProdromal featuresTriglyceride levelsPD groupDiseaseDisease statesLaboratory test resultsPrediabetesSyndromeHigh rateTriglycerides