2019
A Proposed Roadmap for Parkinson’s Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein
Merchant KM, Cedarbaum JM, Brundin P, Dave KD, Eberling J, Espay AJ, Hutten SJ, Javidnia M, Luthman J, Maetzler W, Menalled L, Reimer AN, Stoessl AJ, Weiner DM, . A Proposed Roadmap for Parkinson’s Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein. Journal Of Parkinson's Disease 2019, Preprint: 1-31. PMID: 30400107, PMCID: PMC6398545, DOI: 10.3233/jpd-181471.Peer-Reviewed Original ResearchConceptsParkinson's diseaseProgression of PDDisease-modifying therapiesConcept clinical trialMichael J. Fox FoundationDisease-modifying therapeuticsLewy pathologyClinical outcomesClinical trialsTargeting therapyAnimal modelsClinical proofAlpha-synucleinBiomarker toolkitΑ-synClinical researchInvestigational moleculesTherapyPD researchTranslational frameworkParkinson's ResearchDiseaseBiomarkersConcept studyMeaningful strides
2018
Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models
Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA, Baeriswyl JL, Cavegn N, Senn L, Su L, Marsh G, Auluck P, Montrasio F, Nitsch RM, Hirst WD, Cedarbaum JM, Pepinsky R, Grimm J, Weinreb PH. Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models. Neurobiology Of Disease 2018, 124: 276-288. PMID: 30381260, DOI: 10.1016/j.nbd.2018.10.016.Peer-Reviewed Original ResearchConceptsΑ-Syn pathologyParkinson's diseaseΑ-synDisease progressionMouse modelPrevention of PDPhase 2 clinical trialPD mouse modelPD brain tissueDisease modelsDopamine transporter densityParkinson's disease modelΑ-synuclein antibodyPromising therapeutic approachDifferent mouse modelsHealthy elderly individualsΑ-syn fibrilsEpitope mapping studiesDopaminergic terminalsRecombinant α-synPreclinical dataClinical trialsTherapeutic approachesMotor impairmentElderly individualsElephants, Parkinson's Disease, and Proof‐of‐Concept Clinical Trials
Cedarbaum JM. Elephants, Parkinson's Disease, and Proof‐of‐Concept Clinical Trials. Movement Disorders 2018, 33: 697-700. PMID: 29722454, DOI: 10.1002/mds.27398.Peer-Reviewed Original ResearchTargeted Therapies for Parkinson's Disease: From Genetics to the Clinic
Sardi SP, Cedarbaum JM, Brundin P. Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic. Movement Disorders 2018, 33: 684-696. PMID: 29704272, PMCID: PMC6282975, DOI: 10.1002/mds.27414.Peer-Reviewed Original ResearchConceptsParkinson's diseaseGreat unmet medical needDisease-modifying treatmentsNew therapeutic approachesUnmet medical needClinical stageClinical trialsRelentless progressionTherapeutic approachesPotential therapyClinical developmentTherapeutic paradigmMedical needDiseaseGenetic variantsPD geneticsNew arsenalTreatmentGenetic discoveriesKey outstanding questionsTherapySymptomsPathologyProgressionTrials
2005
NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients
Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, Mendell JR. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology 2005, 65: 681-689. PMID: 16157899, DOI: 10.1212/01.wnl.0000171978.70849.c5.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsCharcot-Marie-Tooth DiseaseDisease Models, AnimalDouble-Blind MethodFemaleHumansMaleMiceMice, Neurologic MutantsMice, NudeMice, TransgenicMiddle AgedMyelin ProteinsNerve RegenerationNeurotrophin 3Pilot ProjectsRecovery of FunctionSciatic NeuropathySural NerveTransplantation, HeterologousTreatment OutcomeConceptsNeuropathy Impairment ScoreNT-3 groupNT-3 treatmentNeurotrophin-3Placebo groupAnimal modelsNerve regenerationNude mice axonsQuantitative muscle testingSural nerve biopsyPrimary outcome measurePeripheral myelin proteinPilot clinical studyTooth type 1ANerve biopsyMuscle testingAxonal regenerationClinical studiesImpairment scoresOutcome measuresPreclinical studiesMouse modelEndpoint measuresElectrophysiologic measurementsNude mice
1998
Physiological characterization of taxol‐induced large‐fiber sensory neuropathy in the rat
Cliffer K, Siuciak J, Carson S, Radley H, Park J, Lewis D, Zlotchenko E, Nguyen T, Garcia K, Tonra J, Stambler N, Cedarbaum J, Bodine S, Lindsay R, Distefano P. Physiological characterization of taxol‐induced large‐fiber sensory neuropathy in the rat. Annals Of Neurology 1998, 43: 46-55. PMID: 9450768, DOI: 10.1002/ana.410430111.Peer-Reviewed Original ResearchConceptsLarge-fiber sensory neuropathySensory neuropathyGeneral healthSensory compound nerve action potentialMature ratsCompound nerve action potentialSensory conduction velocityForelimb grip strengthSevere axonal degenerationNerve action potentialsFrequency of dosingH-wave amplitudeAbility of ratsMotor amplitudeDosing schedulesPeripheral neuropathyAxonal degenerationDorsal rootsProprioceptive deficitsClinical syndromeMuscle strengthGrip strengthHeat nociceptionVentral rootsChemotherapeutic agent taxol
1996
Treatment with ciliary neurotrophic factor does not improve regeneration in experimental autoimmune neuritis of the Lewis rat
Gold R, Zielasek J, Schröder J, Sellhaus B, Cedarbaum J, Hartung H, Sendtner M, Toyka K. Treatment with ciliary neurotrophic factor does not improve regeneration in experimental autoimmune neuritis of the Lewis rat. Muscle & Nerve 1996, 19: 1177-1180. PMID: 8761279, DOI: 10.1002/(sici)1097-4598(199609)19:9<1177::aid-mus17>3.0.co;2-s.Peer-Reviewed Original ResearchRe: Pharmacokinetics and pharmacodynamics of rHCNTF in rodents
Cedarbaum J, Distcfano P, Lakings D, Lindsay R. Re: Pharmacokinetics and pharmacodynamics of rHCNTF in rodents. Annals Of Neurology 1996, 39: 552-553. PMID: 8619536, DOI: 10.1002/ana.410390420.Peer-Reviewed Original Research
1995
Effects of brain‐derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease
Ikeda K, Klinkosz B, Greene T, Cedarbaum J, Wong V, Lindsay R, Mitsumoto H. Effects of brain‐derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Annals Of Neurology 1995, 37: 505-511. PMID: 7717687, DOI: 10.1002/ana.410370413.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorMouse motor neuron diseaseWobbler mouse motor neuron diseaseMotor neuron diseaseBDNF treatmentMotor dysfunctionNeurotrophic factorNeuron diseaseVentral rootsMotor neuronsWobbler miceExogenous brain-derived neurotrophic factorAxotomy-induced cell deathHuman brain-derived neurotrophic factorBDNF-treated miceBiceps muscle weightCervical ventral rootsDenervation muscle atrophyExogenous BDNF administrationMotor axon lossRecombinant human brain-derived neurotrophic factorVehicle-treated miceVehicle-treated animalsEnd of treatmentMuscle twitch tensionHistometric effects of ciliary neurotrophic factor in wobbler mouse motor neuron disease
Ikeda K, Wong V, Holmlund T, Greene T, Cedarbaum J, Lindsay R, Mitsumoto H. Histometric effects of ciliary neurotrophic factor in wobbler mouse motor neuron disease. Annals Of Neurology 1995, 37: 47-54. PMID: 7818257, DOI: 10.1002/ana.410370110.Peer-Reviewed Original ResearchConceptsCiliary neurotrophic factorMotor neuron diseaseNeurotrophic factorMotor neuronsHuman ciliary neurotrophic factorNeuron diseaseWobbler miceWobbler mouse motor neuron diseaseMouse motor neuron diseaseCalcitonin gene-related peptideAcute axonal degenerationAxonal branching pointsBiceps muscle weightC5 ventral rootsGene-related peptidePercentage of axonsAtrophied muscle fibersUntreated control groupRat ciliary neurotrophic factorMean muscle fiber diameterMusculocutaneous nerveAxonal degenerationVentral rootsSubcutaneous injectionVacuolar degeneration
1994
Arrest of Motor Neuron Disease in wobbler Mice Cotreated with CNTF and BDNF
Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum J, Wong V, Lindsay R. Arrest of Motor Neuron Disease in wobbler Mice Cotreated with CNTF and BDNF. Science 1994, 265: 1107-1110. PMID: 8066451, DOI: 10.1126/science.8066451.Peer-Reviewed Original ResearchConceptsBrain-derived neurotrophic factorCiliary neurotrophic factorMotor neuron diseaseNeurotrophic factorNeuron diseaseWobbler miceMotor neuron dysfunctionNeuron dysfunctionDisease progressionSubcutaneous injectionMotor neuronsHistological criteriaAnimal modeAnimal modelsAlternate daysSignaling pathwaysDiseaseMiceCellular signaling pathwaysProgressionDysfunctionFactorsCotreatmentNeuronsAdministrationThe effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease
Mitsumoto H, Ikeda K, Holmlund T, Greene T, Cedarbaum J, Wong V, Lindsay R. The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Annals Of Neurology 1994, 36: 142-148. PMID: 8053649, DOI: 10.1002/ana.410360205.Peer-Reviewed Original ResearchConceptsCiliary neurotrophic factorNeurotrophic factorMotor neuron diseaseHuman ciliary neurotrophic factorGrip strengthNeuron diseaseBody weightWobbler mouse motor neuron diseaseMotor neuron disease modelMouse motor neuron diseaseFirst neurotrophic factorMean grip strengthImproved muscle strengthVehicle-treated animalsWeeks of treatmentMuscle twitch tensionSurvival-promoting effectsWobbler mouse modelRat ciliary neurotrophic factorMotor dysfunctionControl miceMuscle strengthDisease progressionMotor neuronsTwitch tension
1993
The Therapeutic Potential of Neurotrophic Factors in the Treatment of Parkinson's Disease
Lindsay R, Altar C, Cedarbaum J, Hyman C, Wiegand S. The Therapeutic Potential of Neurotrophic Factors in the Treatment of Parkinson's Disease. Experimental Neurology 1993, 124: 103-118. PMID: 8282068, DOI: 10.1006/exnr.1993.1181.Peer-Reviewed Original ResearchConceptsNeurotrophic factorParkinson's diseaseNeurodegenerative disordersTherapeutic agentsNeurodegenerative diseasesFetal nigral graftsTransplantation of neuronsDopamine neurotrophic factorPartial symptomatic reliefDopamine receptor agonistsNeurotrophic growth factorsPotential clinical useHuman neurodegenerative disordersAppropriate neurotransmittersObvious therapeutic strategyNeuronal lossNigral graftsSymptomatic reliefDevelopment of drugsDopaminergic neuronsNeuroprotective agentsSubstantia nigraNeuronal degenerationNeurotrophin familyDopamine neuronsAdministration of the new COMT inhibitor OR‐611 increases striatal uptake of fluorodopa
Guttman M, Léger G, Reches A, Evans A, Kuwabara H, Cedarbaum JM, Gjedde A. Administration of the new COMT inhibitor OR‐611 increases striatal uptake of fluorodopa. Movement Disorders 1993, 8: 298-304. PMID: 8341294, DOI: 10.1002/mds.870080308.Peer-Reviewed Original ResearchConceptsPositron emission tomographyNew COMT inhibitorL-DOPACOMT inhibitorsTreatment of patientsStriatal uptakeBrain uptakeBrain 6Cynomolgus monkeysParkinson's diseaseL-dopa analogEmission tomographyPromising agentSame animalsPET measurementsDiseaseMetabolismInhibitorsControl statePretreatmentPatientsFluorodopaAdjunctAdministrationUptake
1992
3‐O‐methyldopa administration does not alter fluorodopa transport into the brain
Guttman M, Léger G, Cedarbaum J, Reches A, Woodward W, Evans A, Diksic M, Gjedde A. 3‐O‐methyldopa administration does not alter fluorodopa transport into the brain. Annals Of Neurology 1992, 31: 638-643. PMID: 1514775, DOI: 10.1002/ana.410310611.Peer-Reviewed Original ResearchConceptsChronic L-DOPA therapyAdvanced Parkinson's diseaseL-dopa therapyPositron emission tomographic studiesL-DOPA administrationEmission tomographic studiesPositron emission tomographyL-dopa preparationsParkinsonian patientsPlasma concentrationsCynomolgus monkeysParkinson's diseasePatientsEmission tomographyL-DOPABrainTomographic studiesDiseaseAdministrationInfusionTherapyBlood
1991
Reduction of Circulating 3-O-Methyldopa by Inhibition of Gatechol-O-Methyltransferase With OR-611 and OR-462 in Cynomolgus Monkeys: Implications for the Treatment of Parkinson's Disease.
Cedarbaum J, Leger G, Guttman M. Reduction of Circulating 3-O-Methyldopa by Inhibition of Gatechol-O-Methyltransferase With OR-611 and OR-462 in Cynomolgus Monkeys: Implications for the Treatment of Parkinson's Disease. Clinical Neuropharmacology 1991, 14: 330. PMID: 1913700, DOI: 10.1097/00002826-199108000-00005.Peer-Reviewed Original Research
1990
Effect of Nitecapone (OR-462) on the Pharmacokinetics of Levodopa and 3-O-Methyldopa Formation in Cynomolgus Monkeys.
Cedarbaum JM, Léger G, Reches A, Guttman M. Effect of Nitecapone (OR-462) on the Pharmacokinetics of Levodopa and 3-O-Methyldopa Formation in Cynomolgus Monkeys. Clinical Neuropharmacology 1990, 13: 544. PMID: 2276119, DOI: 10.1097/00002826-199012000-00006.Peer-Reviewed Original ResearchConceptsCynomolgus monkeysEffect of nitecaponePeripheral COMT inhibitorSingle-dose studyPharmacokinetics of levodopaBlood-brain barrierConcentration-time curveLevodopa administrationPlasma pharmacokineticsCOMT inhibitorsAdverse physiological effectsFurther inhibitionLevodopaDoseNitecaponePhysiological effectsMonkeysPharmacokineticsNovel inhibitorsInhibitorsInhibitionCarbidopaAdministration
1988
Clinical significance of the relationship between O-methyldopa levels and levodopa intake.
Cedarbaum J, Kutt H, McDowell F. Clinical significance of the relationship between O-methyldopa levels and levodopa intake. Neurology 1988, 38: 533-6. PMID: 3352906, DOI: 10.1212/wnl.38.4.533.Peer-Reviewed Original ResearchConceptsDaily intakeRecent clinical trialsMean daily intakeTotal daily intakeLevodopa intakeStandard SinemetClinical responseLevodopa preparationsBrain uptakeClinical trialsPlasma concentrationsClinical significanceBlood samplingLevodopaTherapeutic efficacyMethyldopa levelsControlled-release formulationPatientsIntakeTime curveAUCSinemetLevelsTrials
1978
Activation of locus coeruleus neurons by peripheral stimuli: Modulation by a collateral inhibitory mechanism
Cedarbaum J, Aghajanian G. Activation of locus coeruleus neurons by peripheral stimuli: Modulation by a collateral inhibitory mechanism. Life Sciences 1978, 23: 1383-1392. PMID: 214648, DOI: 10.1016/0024-3205(78)90398-3.Peer-Reviewed Original ResearchConceptsLocus coeruleusNerve stimulationLocus coeruleus neuronsRat locus coeruleusPeripheral nerve stimulationBursts of spikesNeuronal responsivityNoradrenergic neuronsCoeruleus neuronsAntidromic activationAxon collateralsAdrenergic antagonistsPutative transmittersNoxious stimuliPeripheral stimuliUnit firingReduced responsivityAutoinhibitory actionInhibitory mechanismPiperoxaneNeuronsAdditional stimulusStimulationCollateralsStimuliAfferent projections to the rat locus coeruleus as determined by a retrograde tracing technique
Cedarbaum J, Aghajanian G. Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. The Journal Of Comparative Neurology 1978, 178: 1-15. PMID: 632368, DOI: 10.1002/cne.901780102.Peer-Reviewed Original ResearchConceptsLocus coeruleusRat locus coeruleusCentral gray substanceLateral hypothalamic areaRetrograde tracing techniquesLateral reticular nucleusCatecholamine cell groups A1Magnocellular preoptic areaSingle-cell recordingsDorsal hornReactive neuronsNoradrenergic neuronsSolitary tractAfferent innervationLabeled neuronsHypothalamic areaReticular nucleusHRP injectionsPreoptic areaSpinal cordInsular cortexAfferent projectionsGray substanceReticular formationAfferent connections