Clinical Determinants of Progression of Parkinson Disease: Predicting Prognosis by Subtype

Parkinson disease (PD) is one of the most common agerelatedneurodegenerative diseases, affecting 1%of thepopulationolder than60years of age and0.3%of the general population. It is a chronic, progressive disorderwhose spectrumof clinical features canaffect an individual formore than40years of his or her natural life span. Idiopathic PD is clinically and pathologically aheterogeneousdisorder that is variable inprogression and phenotypic expression. Withnoknownbiomarker fordiseasediagnosisorprogression, clinicians and scientists have long recognized the importance of classifying patterns of PD into distinct subtypes in order to identify features that influence rate of progression and response to interventionsand that correlatewithneural and biochemical substratesofdisease pathogenesis. To that end,HoehnandYahr in their landmark studyof 1967mayhave been among the earliest clinical scientists to recognize the heterogeneity of PD by describing that “the clinical picture of one may be dominated by tremor, of another by rigidity or akinesia,”1(p433) andsubsequentlydevelopedascale to ratehow symptomsof PDprogress.Disability stagingby theHoehnand Yahrscalecontinues tobeuseduniversally in ratingdiseaseand progressionas it relates towalkingandpostural stability.1More recently, the global Unified Parkinson’s Disease Rating Scale (with its subscales that assessmentation,mood andbehavior, activities of daily living,motor and nonmotor symptoms, and complicationsoftherapy)has introducedtheimportanceofnonmotorsymptoms in impactingqualityof life.TheMontrealCognitive Assessment, which allows for a bedside evaluation of 8 domainsof cognition,hasbeenadded to the repertoireof clinicalmeasures that informcliniciansof the functional stateof the patientwith PD. Although powerfully informative, thesemeasures, which are routinely performed by neurologists, and the standardof care formovementdisorders fall short indetermining prognosis or predicting rate of change for patientswith PD. In this issue of JAMA Neurology, Fereshtehnejad et al2 introduceanovel subtypingschemederivedfromclusteranalysis of a prospectively observed large cohort of patients with earlyPDidentifiedat theCenter forAdvancedResearch inSleep Medicine, Hopital du Sacre–Coeur deMontreal, andMontreal General Hospital, Montreal, Quebec, Canada. To our knowledge, it is the second data-driven clinical research studywith longitudinal observation, and the first to propose a scheme in whichnonmotor symptomsare theclinicaldeterminants indefining subtypes of PD. Importantly, orthostatic hypotension (OH), mild cognitive impairment (MCI), and rapid eye movementsleepbehaviordisorder (RBD)presentat initialvisitswere thedefining features for a“diffuse/malignant” subgroupofpatients with PD who had the most rapid rate of progression. Overthelastseveraldecades,differentphenotypicsubtypes havebeenproposed, largelybasedon2classificationmethods: an empirically assigned (predefined) classification scheme or adata-drivenclassificationscheme.Specificclinical featuresthat favoredhypothesis-drivenempiricalclassificationschemeswere developed fromclinical observationsof study cohorts that examinedsuchfactorsasageatsymptomonset, levodoparesponsiveness, familial history,motor symptompredominance, dementia,depression,andrateofprogression.Themostdominant clinical subtyping of PD emerged from motor subtyping into tremor-dominantvsnontremor-dominantPD(patientswithpredominant bradykinesia, akinesia, and postural instability and gait dysfunction [PIGD]) and indeterminate or mixed phenotypes.Thedistinctionbetweenthesephenotypicmotorsubtypes wasoften referred toasbenignvsmalignant in reference to the more rapid rate of deterioration and greater cognitive impairmentexhibitedbypatientswiththeakinetic-dominantsubtype. Current practice parameter guidelines for disease prognosis predict that older age at onset and the presence of rigidity/ hypokinesiaorPIGDas initial symptomsdescribe amore rapid rateofmotorprogressionandearly cognitivedecline,whereas thepresenceof tremor as an initial symptompredicts a slower progression and a longer response to levodopa therapy.3 Contrary to this conventional knowledge, a 2012 studybyVuet al4 proposed that tremorandPIGD-dominant subtypeswere not distinctsubtypesreflectingtheheterogeneityofPDbutweredifferent stagesof thediseaseprocess, and that tremorprogresses moreslowlythanothercardinalmotorsymptoms,whereasPIGD is less responsive to levodopa therapy. In fact, the cardinalmotor featuresofPD (including tremor, rigidity, bradykinesia, and PIGD)progress atdifferent rates andshowvariable responsiveness to levodopatherapy,challengingthe ideathatbaselinemotor subtypeclassification is a significantpredictorofdeath,depression, or cognitive decline.4,5 Some clinician-scientists advocate that clinical subtypes derived fromempirical classification schemescreatemoredistinct groups,which are simpler to identify using readily available rating scales, while others advocate that this approach is limitedbecause thecomplexityof the features frommotor and nonmotor symptoms isnot assessed.6As a consequence, cluster analysis has become the preferred method for subtyping, mostly because it is a hypothesis-free analysis that removes the conditional bias of choosing specific criteria based on experience, thusallowingunexpectedpatterns toappearandproRelated article page 863 Opinion