2024
Validating new symptom emergence as a patient-centric outcome measure for PD clinical trials
Zou H, Stebbins G, Simuni T, Luo S, Cedarbaum J. Validating new symptom emergence as a patient-centric outcome measure for PD clinical trials. Parkinsonism & Related Disorders 2024, 128: 107118. PMID: 39353265, DOI: 10.1016/j.parkreldis.2024.107118.Peer-Reviewed Original ResearchPD clinical trialsClinical trialsEmergent symptomsPhase 3 clinical trialsPhase 3 studySlowing of disease progressionOutcome measuresParkinson's diseaseDe novo Parkinson's diseaseMDS-UPDRSItem-level dataFrequency of ESSymptomatic medicationsFrequent administrationMonths of observationEfficacy assessmentDisease progressionSymptom emergenceRating ScaleItem responsesIb and IIUrate elevationTrialsQuantification 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 adultsThe ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials
Genge A, Cedarbaum J, Shefner J, Chio A, Al-Chalabi A, Van Damme P, McDermott C, Glass J, Berry J, van Eijk R, Fournier C, Grosskreutz J, Andrews J, Bertone V, Bunte T, Couillard M, Cummings C, Kittle G, Polzer J, Salmon K, Straub C, van den Berg L. The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2024, 25: 382-387. PMID: 38396337, DOI: 10.1080/21678421.2024.2320880.Peer-Reviewed Original ResearchAmyotrophic Lateral Sclerosis Functional Rating ScaleALSFRS-RClinical trialsStatistical analysis planMonitor functional changesRating ScaleOutcome measuresFunctional Rating ScalePrimary outcome measureClinical trial designALS clinical trialsFunctional changesTrial designTrialsClinical trialistsScaleALS trialsCinpanemab 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
Digital Mobility Measures: A Window into Real‐World Severity and Progression of Parkinson's Disease
Mirelman A, Volkov J, Salomon A, Gazit E, Nieuwboer A, Rochester L, Del Din S, Avanzino L, Pelosin E, Bloem B, Della Croce U, Cereatti A, Thaler A, Roggen D, Mazza C, Shirvan J, Cedarbaum J, Giladi N, Hausdorff J. Digital Mobility Measures: A Window into Real‐World Severity and Progression of Parkinson's Disease. Movement Disorders 2023, 39: 328-338. PMID: 38151859, DOI: 10.1002/mds.29689.Peer-Reviewed Original ResearchRelative 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 functioningMapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early 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. Mapping Relevance of Digital Measures to Meaningful Symptoms and Impacts in Early Parkinson’s Disease. Journal Of Parkinson's Disease 2023, 13: 589-607. PMID: 37212073, PMCID: PMC10357170, DOI: 10.3233/jpd-225122.Peer-Reviewed Original ResearchThe 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
A qualitative evaluation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) by the patient community: a web-based cross-sectional survey
Boyce D, Robinson M, Cedarbaum J, Shank L, McDermott C, van Eijk R. A qualitative evaluation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) by the patient community: a web-based cross-sectional survey. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2022, 24: 272-280. PMID: 36330850, DOI: 10.1080/21678421.2022.2140592.Peer-Reviewed Original ResearchConceptsAmyotrophic Lateral Sclerosis Functional Rating ScaleFunctional Rating ScaleOutcome measuresRating ScaleWeb-based cross-sectional surveyAbility of patientsCross-sectional surveyALS studiesWeb-based surveyALSFRSPatient communityPerspectives of peopleCaregiversPatientsALSItem questionsLiteracy levelsLongitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort
Siderowf A, Seibyl J, Coffey C, Tosun-Turgut D, Shaw L, Trojanowski J, Singleton A, Kieburtz K, Toga A, Mollenhauer B, Galasko D, Poewe W, Foroud T, Poston K, Bressman S, Reimer A, Arnedo V, Clark A, Frasier M, Kopil C, Chowdhury S, Casaceli C, Dorsey R, Wilson R, Mahes S, Seibyl J, Salerno C, Ahrens M, Brumm M, Cho H, Fedler J, LaFontant D, Kurth R, Crawford K, Casalin P, Malferrari G, Weisz M, Orr-Urtreger A, Trojanowski J, Shaw L, Montine T, Baglieri C, Christini A, Russell D, Dahodwala N, Giladi N, Factor S, Hogarth P, Standaert D, Hauser R, Jankovic J, Saint-Hilaire M, Richard I, Shprecher D, Fernandez H, Brockmann K, Rosenthal L, Barone P, Espayc A, Rowe D, Marder K, Santiago A, Bressman S, Hu S, Isaacson S, Corvol J, Martinez J, Tolosa E, Tai Y, Politis M, Smejdir D, Rees L, Williams K, Kausar F, Williams K, Richardson W, Willeke D, Peacock S, Sommerfeld B, Freed A, Wakeman K, Blair C, Guthrie S, Harrell L, Hunter C, Thomas C, James R, Zimmerman G, Brown V, Mule J, Hilt E, Ribb K, Ainscough S, Wethington M, Ranola M, Santana H, Moreno J, Raymond D, Speketer K, Carvajal L, Carvalo S, Croitoru I, Garrido A, Payne L, Viswanth V, Severt L, Facheris M, Soares H, Mintun M, Cedarbaum J, Taylor P, Biglan K, Vandenbroucke E, Sheikh Z, Bingol B, Fischer T, Sardi P, Forrat R, Reith A, Egebjerg J, Hillert G, Saba B, Min C, Umek R, Mather J, De Santi S, Post A, Boess F, Taylor K, Grachev I, Avbersek A, Muglia P, Merchant K, Tauscher J. Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort. Npj Parkinson's Disease 2022, 8: 140. PMID: 36273008, PMCID: PMC9588016, DOI: 10.1038/s41531-022-00404-w.Peer-Reviewed Original ResearchNon-manifesting carriersParkinson's Progression Markers InitiativeHealthy controlsDAT deficitProgression Markers InitiativeLongitudinal changesBiofluid biomarkersCerebrospinal fluid AbetaNon-motor scalesDopamine transporter imagingPrevention clinical trialsNeurofilament light chainLRRK2 G2019S carriersClinical featuresClinical outcomesPhospho-tauTransporter imagingPPMI cohortTotal tauDAT bindingMean ageSerum biomarkersClinical trialsClinical measuresComprehensive motorNeuromelanin 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 alterationsGlucocerebrosidase 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 2022, 37: 651-652. PMID: 35064687, DOI: 10.1002/mds.28929.Peer-Reviewed Original Research
2021
Considerations to address missing data when deriving clinical trial endpoints from digital health technologies
Di J, Demanuele C, Kettermann A, Karahanoglu F, Cappelleri J, Potter A, Bury D, Cedarbaum J, Byrom B. Considerations to address missing data when deriving clinical trial endpoints from digital health technologies. Contemporary Clinical Trials 2021, 113: 106661. PMID: 34954098, DOI: 10.1016/j.cct.2021.106661.Peer-Reviewed Original ResearchConceptsStatistical approachFunctional data analysisStatistical methodsRobust modelingImputation approachComplex dataTime series dataSeries dataMissingnessHigh-frequency time series dataStarting pointLearning methodsData analysisApproachSummary measuresModelingImputationDeep learning methodsDigital health technologiesEvaluating 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 laboratoryTrials