© 2011 Continuing Education Alliance. All Rights Reserved. CTE76611

INTRODUCTIONVast clinical needs exist in Parkinson’s disease (PD), a neurodegenerative

disorder that affects approximately 1 million persons in the United

States.1 These include strategies for early, accurate disease identification as

well as optimal treatment using interventions that go beyond short-term

control of motor symptoms to actually slow or halt the disease process.

Moreover, there is also a critical need for improved management strategies

of PD-associated nonmotor symptoms that can affect health-related

quality of life, worsen prognosis, and confound treatment.

GOAL: To update neurologists on current and emerging strategies for thediagnosis and treatment of Parkinson’s Disease.

LEARNING OBJECTIVES:After completing this activity, participants should be better able to:• Identify emerging screening and risk assessment tools that facilitate the

early diagnosis of Parkinson’s disease (PD)• Discuss present and emerging states of disease-modifying therapy in early PD• Discuss options for managing nonmotor disturbances in patients with PD

TARGET AUDIENCE: Neurologists

ACCREDITATION INFORMATIONJointly sponsored by:

This activity has been planned and implemented inaccordance with the Essential Areas and Policies of theAccreditation Council for Continuing Medical

Education (ACCME) through the joint sponsorship of Boston UniversitySchool of Medicine and Continuing Education Alliance. Boston UniversitySchool of Medicine is accredited by the ACCME to provide continuing med-ical education for physicians.Boston University School of Medicine designates this enduring material for amaximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim onlythe credit commensurate with the extent of their participation in the activity.

Release Date: December 28, 2011Expiration Date: December 27, 2012

ACKNOWLEDGMENTThis educational activity was supported by an educational grant from Teva Pharmaceuticals. continued

FACULTY

Regional Neurology Insights: Highlights From a Roundtable Meeting in Boston

Marie-Hélène Saint-Hilaire, MD,FRCPC(C), Faculty ChairAssociate Professor of NeurologyBoston University School of MedicineMedical Director, Movement Disorder

ProgramBoston Medical CenterBoston, Massachusetts

Joseph H. Friedman, MDProfessor and ChiefDivision of Movement DisordersDepartment of NeurologyProfessor Department of Psychiatry and

Human BehaviorAlpert Medical School of Brown UniversityProvidence, Rhode Island

Danna Jennings, MDSenior Clinical Research DirectorInstitute for Neurodegenerative DisordersNew Haven, Connecticut

Paula D. Ravin, MDAssociate Professor of NeurologyUniversity of Massachusetts

Medical SchoolWorcester, Massachusetts

Lewis R. Sudarsky, MDDirector, Movement DisordersDepartment of NeurologyBrigham and Women’s HospitalAssociate Professor of NeurologyHarvard Medical SchoolBoston, Massachusetts

Improving Clinical Outcomesin Early Parkinson’s Disease:CURRENT and EMERGING STRATEGIES

Genetic testing, imaging meth-ods, and/or screens for premotorsymptoms for facilitating early diag-nosis of PD are being actively inves-tigated and some are available foruse in the clinical setting.2,3

Disease-modifying interventionswith the potential to slow the pro-gression of PD, thereby preventingor delaying disability, are activelybeing sought.

In October 2011, a roundtablemeeting of experts was convened todiscuss the state-of-the-art in thediagnosis and management of earlyPD and the potential of emergingdiagnostic and treatment modalitiesto impact the clinical outcomes ofpatients with early PD. Participantsincluded Drs Joseph Friedman,Danna Jennings, Paula Ravin, andLewis Sudarsky. The discussions were moderated by Marie-HélèneSaint-Hilaire, MD, associate profes-sor of neurology at BostonUniversity School of Medicine, andmedical director of the MovementDisorder Program, Boston MedicalCenter, Massachusetts. The discus-sions that took place at this recentroundtable meeting are summarizedhere.

Diagnosis of PDCurrently Available StrategiesThe diagnosis of PD is delayed untilsymptoms reflecting motor impair-ment are apparent.4 In addition, it isestimated that up to 10% of patientswith PD are misdiagnosed withother conditions and approximately25% of patients diagnosed with PD reveal a different diagnosis atautopsy.5-7 These misdiagnoses delayaccurate identification of patientswith early PD and initiation ofappropriate therapy.

Dr Saint-Hilaire asked the round-table participants questions con-cerning the criteria they use todiagnose PD, and the risks andbenefits of diagnosing PD at anearly stage.• The roundtable members con-

curred that an accurate diagnosisin patients with early motorsymptoms can help provide thepatient with insight/understand-ing into his/her motor symptomcomplex. Nevertheless, theyemphasized that earlier diagnosisis more likely to be associatedwith misdiagnosis

• None of the roundtable mem-bers favored using premotorsymptoms as the basis for a diag-nosis of PD outside of a researchsetting although the presence ofrapid eye movement (REM)sleep behavior disorder (RBD) isa significant marker

Tools available to assist in making adiagnosis of PD include the UnifiedParkinson’s Disease Rating Scale(UPDRS) score, DaTSCAN imag-ing, as well as several commerciallyavailable genetic tests.

UPDRS ScoreThe UPDRS clinical rating scale hasbeen widely used in the assessment ofpatients with suspected or diagnosedPD in the clinical setting and as aclinical outcome measure for clinicaltrials. In the updated version of theUPDRS, called the MovementDisorder Society (MDS)-SponsoredUPDRS, each section has undergonechanges, but the 4 parts of the origi-nal version with the total summedscore have been retained (available at

DISCLAIMERSTHESE MATERIALS AND ALL OTHER MATERIALS PROVIDED INCONJUNCTION WITH CONTINUING MEDICAL EDUCATIONACTIVITIES ARE INTENDED SOLELY FOR PURPOSES OF SUP-PLEMENTING CONTINUING MEDICAL EDUCATION PROGRAMSFOR QUALIFIED HEALTHCARE PROFESSIONALS. ANYONEUSING THE MATERIALS ASSUMES FULL RESPONSIBILITY ANDALL RISK FOR THEIR APPROPRIATE USE. TRUSTEES OFBOSTON UNIVERSITY MAKES NO WARRANTIES OR REPRESEN-TATIONS WHATSOEVER REGARDING THE ACCURACY, COMPLETENESS, CURRENTNESS, NONINFRINGEMENT, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSEOF THE MATERIALS. IN NO EVENT WILL TRUSTEES OF BOSTONUNIVERSITY BE LIABLE TO ANYONE FOR ANY DECISION MADEOR ACTION TAKEN IN RELIANCE ON THE MATERIALS. IN NOEVENT SHOULD THE INFORMATION IN THE MATERIALS BEUSED AS A SUBSTITUTE FOR PROFESSIONAL CARE.

FACULTY DISCLOSURESBoston University School of Medicine asks all individ-uals involved in the development and presentation ofContinuing Medical Education (CME) activities todisclose all relationships with commercial interests.This information is disclosed to CME activity partici-pants. Boston University School of Medicine has pro-cedures to resolve any apparent conflicts of interest. Inaddition, faculty members are asked to disclose whenany discussion of unapproved use of pharmaceuticalsand devices is being discussed. This educational activity may contain discussion of published and/orinvestigational uses of agents that are not indicated bythe US Food and Drug Administration.

Dr Saint-Hilaire: research grants: Bayer, MerckSerono, Teva Pharmaceuticals; speakers bureau: TevaPharmaceuticals.

Dr Friedman: consultant: ACADIA PharmaceuticalsInc., Addex Pharmaceuticals, Genzyme Corporation,Roche, Teva Pharmaceuticals; research grants: ACADIAPharmaceuticals, EMD Serono, Inc., GE Healthcare,Merck & Co., Inc., Teva Pharmaceuticals; royalties:Demos; speakers bureau: Boehringer Ingelheim, GEHealthcare, Teva Pharmaceuticals.

Dr Jennings: speakers bureau: Lundbeck.

Dr Ravin: research grants: ACADIA PharmaceuticalsInc., Bayer, Chelsea Therapeutics, Teva Pharmaceuticals.

Dr Sudarsky has nothing to disclose with regard tocommercial interests.

The Planning Committee for this activity includedElizabeth Drury, Ilana Hardesty, and Okeanis Vaou,MD, of Boston University School of Medicine; andRuth Cohen and Susan J. Moench, PhD, PA-C, ofContinuing Education Alliance. The members of thePlanning Committee have no significant relationshipsto disclose.

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www.movementdisorders.org).8,9 A criti-cism of the original UPDRS was theirregular placement of nonmotor symp-toms of PD throughout the sections.8 Inthe new UPDRS, nonmotor symptomsare in part I (Non-motor Experiences ofDaily Living). Furthermore, sections ofpart I and all of part II (MotorExperiences of Daily Living) are nowdesigned to be completed by thepatient/caregiver. Part III in the originaland revised versions of the UPDRS is theMotor Examination, and part IV (MotorComplications) focuses exclusively onmotor fluctuations and dyskinesias. TheMDS-UPDRS has a 0 to 4 rating scale,eliminating the yes/no responses from theoriginal UPDRS.8 An important differ-ence between the 2 versions of theUPDRS is the focus on the impact ofsymptoms rather than the presence ofsymptoms in the updated tool.9

Dr Saint-Hilaire asked the roundtableparticipants for their opinions on theutility of the UPDRS score in clinicalpractice.• The roundtable members cited several

advantages of the MDS-sponsoredrevision of the UPDRS, including itsability to capture dyskinesias and

nonmotor symptoms and its increasedusefulness in patients with milder dis-ease

• Some participants use only part III ofthe UPDRS outside the context of aclinical trial. They cited the ability tomonitor changes in motor symptomsby administering part III of UPDRSover time as a useful follow-up meas-ure

• It also was noted that changes inmotor activities of daily living asassessed by part II of the UPDRS arelikely to be of greatest importance tothe patient

• Nonmotor symptoms usually areaddressed in the history at each visit

DaTSCAN ImagingThe dopamine transporter (DaT) ligand(Ioflupane I 123) is a radiopharmaceuti-cal agent recently approved by the Foodand Drug Administration (FDA) for stri-atal dopamine transporter visualizationusing single photon emission computedtomography (SPECT) brain imaging to assist in evaluating patients with suspected Parkinsonian syndromes.10

DaTSCAN imaging technology measuresthe binding of the injected DaT ligandin the basal ganglia and a qualitative

“picture” of the density of healthydopamine neurons associated withuptake of the imaging ligand is provided(Figure 1).3,11 Dopamine-based neu-roimaging techniques can be combinedwith clinical assessments to increase thecertainty of a PD diagnosis. However, amajor limitation of this imaging tech-nique is that dopaminergic dysfunctionoccurs in other diseases and, therefore, aDaTSCAN is not a definitive diagnostictool of PD.3 DaTSCAN imaging is effec-tive in differentiating Parkinsonian syn-drome characterized by reduced bindingof the imaging ligand in the striatumfrom essential tremor.10 Although charac-terizing tremor is likely the most com-mon use of DaTSCAN in thecommunity neurology setting, this imag-ing modality also may be used to identifypatients who have drug-inducedParkinsonism, an often reversible condi-tion,12 as such patients are thought tohave a normal DaTSCAN, althoughdefinitive evidence to support this islacking.13

Dr Saint Hilaire asked the roundtableparticipants if they incorporateDaTSCAN imaging into their prac-tices, and, if so, how they use andinterpret the results.• The participants do not recommend

this technique for use in clinical prac-tice in individuals who lack signs ofPD, even those with a family historyof PD, as the interpretation may beunclear in these cases and resultswould not impact clinical treatment.The likelihood that individuals withmild dopamine transporter deficiencywill develop PD is under investiga-tion. The utility of an abnormal find-ing on DaTSCAN in healthy patientswith RBD also is being evaluated inongoing research studies

FFiigguurree 11.. (a) Normal DaTSCAN SPECT image of a healthy volunteer; (b) normal DaTSCAN SPECTimage of a patient with a previous diagnosis of essential tremor; (c) abnormal DaTSCAN SPECTimage of a patient with a previous diagnosis of PD. DaTSCAN imaging is approved by the FDA todifferentiate essential tremor from Parkinsonian syndrome, but is not a definitive diagnostic tool ofPD. Varrone A, et al.11 Reprinted by permission of the Society of Nuclear Medicine.

3

• Parkinson’s disease is primarily a clini-cal diagnosis and a DaTSCAN resultwill not impact management of anindividual without a clinical diagnosisof PD

• Because treatment of PD is based onclinical presentation, not DaTSCANprogression, DaTSCAN is not recom-mended for monitoring disease pro-gression, as it will not influencetreatment. In addition, DaTSCANresults are too insensitive to be usedto assess disease severity

Genetic TestingAlthough the majority of PD cases areconsidered to arise sporadically, severalgenetic susceptibility factors may be perti-nent. A number of monogenic causes ofPD have been identified, and up to 15%of patients with PD have a family historyof this disorder.14 Mutations in 5causative genes may account for about2% to 3% of all cases of PD with clinicalfeatures similar to classical disease.15 Thebest studied of these are leucine-richrepeat kinase 2 (LRRK2, autosomal domi-nant pattern), and Parkin (autosomalrecessive pattern). Gene mutations identi-fied in familial PD include Parkin,PINK1, DJ1, LRRK2 and SNCA. LRRK2,Parkin, PINK1 and DJ1 mutations havebeen identified in sporadic PD.16

Commercially available genetic testsinclude Parkin, PINK1, DJ1, LLRK2, andSNCA.17

Dr Saint-Hilaire queried the panel asto whether they routinely carry outgenetic testing for patients with PD ora family history of the disease. • The roundtable members generally do

not order genetic testing for clinicalpurposes due to difficulties associatingthe presence or absence of ≥1 or more

of these mutations with clinical mani-festations of PD and the lack ofimpact on treatment decisions

• They cited possibilities of patient mis-interpretation with a positive result(ie, these mutations have variable pen-etrance) or a negative finding (ie,patient could be a carrier of anotherunidentified gene)

• However, all panelists agreed if apatient decides to undergo genetictesting, it is critical they receive geneticcounseling from a genetic counselorwith experience in PD

Emerging Strategies for EarlyDiagnosis There are no established biomarkers inPD, nor are specific premotor symptomsconsidered reliable indicators of early PD.Thus, identification of early predictors ofthe development and progression of PD isan active area of research. Studies todefine and extend the clinical uses ofavailable tests, such as DaTSCAN imag-ing and genetic analyses, also are ongoing.

Parkinson’s-Associated Risk Study (PARS)PARS is a multicenter observational studydesigned to evaluate individuals for earlysigns of PD. The goal of this study is toassess early changes in the density ofdopamine-producing neurons in the brainprior to onset of motor symptoms inindividuals with olfactory deficits. Morethan 15,000 individuals with or without arelative with PD have been screened usinga questionnaire and the University ofPennsylvania Smell Identification Test(UPSIT),18 and a group of 300 partici-pants are being followed for 5 years. Atthe time of enrollment, none of the par-ticipants have received a diagnosis of PD.These individuals are undergoing clinicalevaluations including neurologic examina-tion, cognitive testing, use of questionnaires

to assess RBD and autonomic function,mood evaluation, and DaT imaging usingSPECT. Approximately 300 participantsare being followed longitudinally in thestudy with 200 of these individualsexhibiting an olfactory deficit and 100having normal olfactory sense.Preliminary data from this study showthat of the 303 subjects (203 hyposmic,100 normosmic) who underwent baselineDaT imaging, 11% (23/203) of thehyposmic subjects demonstrated DaTdeficiency in the range expected to developa parkinsonian syndrome compared with1% (1/100) of the normosmic subjects,suggesting that hyposmic participants aremore likely to have a DaT deficit onimaging compared with normosmic par-ticipants (D. Jennings, MD, written com-munication, November 15, 2011).19

Although the percentage of currentlyenrolled subjects with a family history ofPD is 50%, positive findings did notappear more likely in this subgroup com-pared with subjects without a family his-tory of PD.

Parkinson’s Progression Markers Initiative(PPMI) Study

The Michael J. Fox Foundationrecently launched the PPMI study, a largeprospective observational cohort study.The study objectives are to identify bio-markers of PD progression and validateexisting candidate markers to provideresearchers with the tools needed todevelop more informative clinical trialsfor disease-modifying therapy. Specificaims of the study include the develop-ment of a comprehensive and uniformlyacquired clinical/imaging dataset withcorrelated biologic samples that can beused in biomarker verification studies;establishment of standardized protocolsfor acquisition, transfer, and analysis ofclinical and imaging data and biologicsamples that can be used by the research

4

community; investigation of existing bio-markers and identification of new clinical,imaging, and biologic markers to deter-mine interval changes in these markers inPD patients compared with control par-ticipants.20 This biomarker study is fol-lowing 400 de novo unmedicated PDpatients with a positive DaTSCAN, and200 age- and gender-matched controls for3 to 5 years. A biorepository/databank ofspecimens will be created and shared withthe research community. Motor assess-ment, cognitive testing, olfaction, andDaTSCAN imaging data are being col-lected along with biologic specimens ofDNA collected during the initial visit;serum and plasma collection at each visit;urine collected annually; and cere-brospinal fluid (CSF) collected at base-line, 6 months and then annually. Thelead biomarker candidates to be testedinclude α-synuclein, DJ1, total tau, phos-pho-tau (P-181), β-amyloid 1-42, andurate. The stored biologic samples will beavailable for future biomarker studies(Table 1).3,4,20 In discussing the PPMI

study, the panel emphasized the need forbiomarkers of both motor and nonmotorprogression of disease.

Management of PDAddressing Motor Symptoms inEarly PDTreatment to address motor symptoms ofPD focuses on increasing dopamine levelsin the brain and providing symptomaticcontrol in early/intermediate stages of thedisease. L-DOPA or levodopa, adopamine precursor, remains the mosteffective form of oral symptomatic treat-ment for motor symptoms,4,21 and ulti-mately is required by most patients.Other drugs providing symptomatic ben-efits include synthetic dopamine receptoragonists (eg, pramipexole; ropinirole; apo-morphine)22 and monoamine oxidase-B(MAO-B) inhibitors (eg, selegiline; rasagi-line), the latter agents providing mildsymptomatic benefit by inhibiting thebreakdown of dopamine in the brain.23

Amantidine and anticholinergic drugs,although used less frequently, can be used

for improving tremor in some patients.24

Decision making regarding when to initi-ate dopaminergic therapy for PD is indi-vidualized and can depend on age,employment status, family concerns, andpatient preference.

Dr Saint-Hilaire asked the roundtableparticipants to identify the factors theyconsider when selecting initialdopaminergic therapy for a patientwith early PD. • Roundtable members noted the devel-

opment of dyskinesias and motorfluctuations associated with prolongeduse of levodopa21 and impulsivitybehaviors experienced by somepatients receiving dopamine receptoragonist therapy22,25

• The majority of the participants sup-port initiation of therapy with adopamine receptor agonist in youngerpatients as a means of delaying dyski-nesias associated with levodopa. It was

SSttuuddyy ddeessiiggnn 5-year prospective observational cohort study, 21 clinical sites, visits at baseline and every 3-6 months thereafter

SSttuuddyy ppooppuullaattiioonn 400 de novo idiopathic PD patients in very early stages of the disease and gender-matched healthy controls

CClliinniiccaall ddaattaa aasssseessssmmeenntt Motor assessments; neuropsychiatric/cognitive testing; olfaction; DaTSCAN imaging; MRI (DTI) imaging

BBiioollooggiicc ssaammppllee ccoolllleeccttiioonn DNA, serum, plasma, urine, CSF

IInniittiiaall bbiioommaarrkkeerr Alpha-synuclein (CSF); DJ-1 (CSF and blood); urate (blood); beta-amyloid 1-42 (CSF);vveerriiffiiccaattiioonn ssttuuddiieess total tau, phospho-tau (P-181) (CSF)

DDaattaa aacccceessss Collected samples to be stored in central repository; data and biologic samples will be made widely available through www.ppmi-info.org

CSF = cerebrospinal fluid; DTI = diffusion tensor imaging; MRI = magnetic resonance imaging.

TABLE 1. Parkinson’s Progression Markers Initiative (PPMI) Study

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suggested that a combination of adopamine agonist and levodopa (start-ing with a dopamine agonist thenadding levodopa) may provide long-term benefit in patients able to toler-ate the side effects of dopaminergictherapy

• Impulsivity screening and an assess-ment of the potential for otheradverse drug effects is recommendedbefore starting a patient on dopamineagonist therapy

• Finally, several panel members sup-port use of an MAO-B inhibitor as agood first-choice option for patientswith mild symptoms who do notrequire levodopa, citing the excellentsafety profile and good dosing sched-ule of these agents23

Addressing Nonmotor Symptomsin Early PD Symptoms that do not directly affectmotor function are common in early PD.These nonmotor symptoms includedepression, anxiety, RBD, constipation,cognitive decline, fatigue, apathy, and uri-nary incontinence. Some of these symp-toms may be evident prior to the onset ofmotor symptoms.33,34

Mood disorders are common in earlyPD, eg, anxiety disorders including panicattacks and social phobias are seen inabout 40% of PD patients.34 A numberof rating scales including the BeckAnxiety Inventory, and the HamiltonAnxiety Rating Scale are used to assessanxiety although their validity has notbeen well assessed.34,35 Data supportingtreatment of anxiety in PD are lacking.34

Cognitive decline is another commonnonmotor problem. Acetylcholinestaraseinhibitors used in treating cognitivedecline in Alzheimer’s disease also havebeen used in PD.a A randomized, placebo-controlled cross-over study of acetyl-

cholinesterase inhibitors was conducted inPD patients reporting falls >2 times aweek. Patients were randomly assigned to6 weeks of donepezil or placebo with a 3-week washout between phases, and the

primary outcome measures included dailyfalls and near falls as reported on post-cards. The results of the study showedapproximately half the number of falls inpatients on donepezil compared with

IMPORTANCE OF EXERCISEThe National Parkinson Foundation recommends regular exercise to improve

strength and balance and help reduce risk of falling.26 A number of studies have

evaluated the association between exercise and motor function in the setting of

PD. For example, 413 patients of the 143,325 participants followed for 9 years in

the Cancer Prevention Study II Nutrition Cohort developed confirmed PD. When

the association of exercise with development of PD was investigated, the relative

risk was 0.6 when individuals in the highest category of moderate to vigorous

physical exercise were compared with those in the lowest category (P = .02).27

Nevertheless, it was unclear whether these results were attributable to PD risk

reduction due to vigorous physical exercise or decreased baseline activity in indi-

viduals with preclinical PD.

Several studies in animal models of PD showed improvement in balance with

weeks of forced exercise training (ie, regular maintenance of an exercise rate

beyond that preferred during voluntary exercise through use of a mechanical aug-

mentation device).28,29 In addition, there is recent evidence that forced exercise

involving use of a tandem bicycle also may be associated with improvement in

motor function in patients with PD.30,31 This hypothesis is being evaluated in a ran-

domized controlled trial.

When asked whether they consider exercise to be an important part of the

management of patients with early PD:

• All participants stressed the importance of encouraging PD patients to exer-

cise

• It was recommended that patients be given a customized, personalized writ-

ten prescription to exercise on a regular basis with instructions to display it in

a prominent place in the home (eg, on refrigerator door). Cited in support of

such a strategy was a study showing increased compliance with such recom-

mendations when patients were given written prescriptions32

• A well-defined exercise program involving dynamic movement (eg, dance ther-

apy) was cited as particularly beneficial

• An attendee said patients should be encouraged to keep in mind that medi-

cine is useful for how they feel now, but exercising is an investment in their

future

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aAgent is not indicated for usage by US Food and Drug Administration

placebo.36 Another randomized, placebo-controlled study investigated the effects ofthe dual cholinesterase inhibitor, rivastig-mine in PD patients with mild-to-moder-ate dementia. Patients were randomlyassigned to placebo or rivastigmine (3 or12 mg/d) for 24 weeks and the primaryoutcomes were the scores for the cogni-tive subscale of the Alzheimer’s DiseaseAssessment Scale (ADAS-cog) and theAlzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change(ADCS-CGIC). Rivastigmine producedmoderate but significant improvement indementia but nausea, vomiting, andtremor increased.37 Another studyaddressed the effects of rasagiline on cog-nitive deficits in PD patients withoutdementia who received stable dopaminer-gic therapy.a In a randomized, double-blind, placebo-controlled trial, 55patients with impairment in 2 of 4 cogni-tive domains (attention, executive func-tions, memory, visuospatial functions)were randomized to rasagiline or placebo.Results of the study showed significant

improvement in digit-span backwards,verbal fluency, composite domain Zscores when the rasagiline arm was com-pared with the control arm.38

Effective management of nonmotorsymptoms can have a profound effect onquality of life of patients with early PD.Nevertheless, dopaminergic therapy hasless impact on these symptoms39 andclinical studies evaluating strategies toaddress these symptoms are limited.33

When asked how they address nonmo-tor symptoms in patients with earlyPD, participants stated: • Mirtazapine, citalopram, and tricyclic

antidepressants are potentially usefultherapies for anxiety that is not fluc-tuation-dependent and not levodoparesponsivea

• Given the likelihood of the need formultiple medications to managepatients with PD, participants empha-sized the importance of being cog-nizant of potential drug interactions

• Cognitive decline was identified bythe panel as one of the most problem-atic nonmotor symptoms

• For men with nocturia and/or fre-quency/urgency during the day whoare not good candidates for overactivebladder therapies, disposable briefswith a collection system inside thepocket of the brief that attaches to aleg bag were highly recommended bya panel member with experience usingthis modality40

Disease-Modifying Therapy: DelayingDisease Progression

There is no approved treatment foraltering the progression of PD.3

Complicating investigations to addressthis need are the dearth of reliable mark-ers of disease progression, as well as possi-ble confounding effects of study agentswith symptomatic activity. Rather thanusing end points involving changes inbiomarker levels, clinical outcome measures(many of which are also used to evaluate

EEnndd PPooiinntt LLiimmiittaattiioonnss

Time to event (eg, time to additional motor Lack of standardized definitions; fluctuations or disability or need for additional may necessitate long-term follow-upantiparkinsonian therapy)

Change from baseline in total UPDRS score Confounded by symptomatic effects

Change from baseline in UPDRS Confounded by symptomatic effectssubscore (eg, ADL)

Change from baseline in other PD assessment tools Confounded by symptomatic effects(eg, Hoehn and Yahr and Schwab-England scales)

Neuroimaging biomarkers of dopaminergic function Possible effect of pharmacologic agent on ligand uptake

ADL = activities of daily living.

TABLE 2. Examples of Clinical Trial End Points Used in Studies of Potential Parkinson’s Disease-Modifying Therapy

7

aAgent is not indicated for usage by US Food and Drug Administration

symptomatic benefit) have been used toevaluate the effects of candidate agents ondisease progression in PD (Table 2).

Some of the clinical study designs ofpotential disease-modifying agents havebeen adjusted to separate possible con-founding effects of symptomatic activityof the candidate therapy from disease-modifying effects. Study designs used inclinical trials of investigating potentialdisease-modifying effects of candidateagents are shown in Figure 2.

Agents that have been and/or arebeing evaluated as potential disease-modi-fying therapies include coenzyme Q10(CoQ10), creatine, minocycline, isradip-ine, selegiline, rasagiline, and inosine.41-43

For example, there is evidence that levelsof CoQ10, a potent antioxidant and an

essential cofactor in the mitochondrialrespiratory chain, are reduced in PDpatients compared with nonparkinsoniansubjects.41 However, a recent phase 3 ran-domized, double-blind study (the QE3study) that enrolled 600 patients withearly PD to evaluate CoQ10 versus place-bo was terminated early when results of apreplanned analysis showed study com-pletion to be futile.44

A number of studies investigating thepotential disease-modifying effects ofdopaminergic agents with symptomaticbenefits used a clinical trial design incor-porating either a washout or a delayedstart (Figure 2). The Deprenyl andTocopherol Antioxidative Therapy ofParkinsonism (DATATOP) study was apivotal trial investigating selegiline as

disease-modifying therapy in the settingof early PD (Table 3).45 However, at thetime of trial initiation the symptomaticbenefit of MAO-B inhibitors was notknown. Although initial results showedreduced disability and delayed need forlevodopa in the selegiline arm, the ran-domized placebo-controlled trial designcomparing selegiline and placebo with orwithout tocopherol was not adequate toaddress this confounding effect. In theSwedish study, patients were randomizedto selegiline (10 mg/d) or placebo untilneed for levodopa therapy followed by an8-week washout phase. The patients inthe selegiline and placebo arms then con-tinued on selegiline plus levodopa orplacebo plus levodopa for up to 7 years oruntil the patient needed additional

ITT population

ITT population

ITT population

Placebo

Placebo

Study drug

Placebo

Study drug

Study drug

Single-arm phase 2 trial comparing studydrug with predetermined threshold

No difference = futile

Difference = continue with development

Evaluate clinical end points

Evaluate clinical end points

Evaluate clinical end points

Evaluate clinical end points

Evaluate clinical end points

Evaluate clinical end points

Washout

Washout

Study drug

R

R

R

ST

OP

TR

EAT

ME

NT

C

A

B

FFiigguurree 22.. CClliinniiccaall ttrriiaall ssttrraatteeggiieess uusseedd iinn tthhee eevvaalluuaattiioonn ooff ppootteennttiiaall ddiisseeaassee--mmooddiiffyyiinngg tthheerraappyy iinn PPDD.. A. Randomized placebo-controlled trial; B.Randomized controlled trial with washout; C. Randomized controlled trial with delayed-start arm; D. Futility study. ITT= intention to treat; R = randomized.

8

D

antiparkinsonian therapy. Compared withplacebo, patients receiving selegiline haddelayed initiation of levodopa therapy,and in the combination therapy phase,selegiline plus levodopa slowed the pro-gression of symptoms of PD (Table 3).46

The efficacy of rasagiline as disease-modifying therapy has been investigatedin 2 delayed-start clinical trials: TVP-1012 in Early Monotherapy for PDOutpatients (TEMPO) and AzilectGiven Once-daily (ADAGIO). This trialdesign has been proposed as a strategy for

overcoming some of the potential weak-nesses of trials involving a washout phase,such as uncertainty of the length of thewashout phase and patient withdrawalduring the washout phase.47 In theTEMPO trial, patients were randomlyassigned to 1 of 3 groups: 1 or 2 mg/d ofrasagiline for 1 year or placebo for 6months followed by 2 mg/d of rasagilinefor 6 months (Table 3).48,49 Comparedwith the delayed treatment group, thepatients receiving rasagiline at either dosehad smaller increases in total UPDRS

score, suggesting a possible disease-modi-fying effect of rasagiline.

The design of the ADAGIO studywas similar to the randomized, placebo-controlled double-blind TEMPO study,but considerably more patients wereenrolled and it was conducted over alonger time period. Meeting all 3 primaryend points, as detailed in Figure 3, wasspecified as a requirement for the ADA-GIO trial to be declared a positive study.Results for patients receiving early-startrasagiline at a dose of 1 mg/d met all

SSttuuddyy TTrriiaall CCoommppoonneennttss PPrriimmaarryy OOuuttccoommee RReessuulltt

DATATOP Selegiline (10 mg/d ) or Delay to levodopa Delay to levodopa greater withtocopherol (2000 IU/d ) or selegilinecombination vs placebo

SWEDISH Selegiline (10 mg/d) or Occurrence in fluctuations in Selegiline delayed initiationplacebo until need for levodopa disability defined as wearing of levodopa therapy and thefollowed by an 8-week washout off in the efficacy of levodopa combination of selegiline plusphase and restart of selegiline or therapy in patients taking levodopa slowed the progressionplacebo, both in combination levodopa 4×/d; time to of symptoms of PDwith levodopa addition of another

antiparkinsonian treatment

TEMPO Rasagiline (1 mg or 2 mg/d ) for Change in UPDRS Improvement in UPDRS at 12 months1 year vs placebo for 6 months at both rasagiline doses in early-followed by rasagiline 2 mg/d for start arms.6 months

ADAGIO Rasagiline (1 mg or 2 mg/d ) for Change in UPDRS between Early-start 1 mg/d dose of rasagiline 72 weeks vs placebo for 36 baseline and week 72; met all primary end points; early-startweeks followed by rasagiline UPDRS slope superiority from 2 mg/d dose did not meet one of 1 or 2 mg/d for 36 weeks weeks 12-36; UPDRS slope the end points as the UPDRS score

noninferiority from weeks between baseline and week 72 48-72 was not significantly different compared

with delayed-start arm

ADAGIO = Azilect Given Once-Daily; DATATOP = Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism;

TEMPO = TVP-1012 Early Monotherapy for PD Outpatient.

TABLE 3. Summary of Representative Clinical Trials Investigating Potential Disease-Modifying Effects of MAO-B Inhibitors

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primary end points. However, for patientsin the early-start rasagiline arm receiving2 mg/d, the total UPDRS score betweenbaseline and week 72 was not significantlydifferent compared with the placebogroup. The results of the ADAGIO studysuggest a possible benefit of early initia-tion of rasagiline at a dose of 1 mg/d,

although the difference in total UPDRSscore was only –1.7 points. It is possiblethat greater symptomatic benefit associatedwith the higher dose of rasagiline mayhave masked a possible disease-modifyingeffect in PD subjects with milder disease;it is also possible that the lower doseyielded a false-positive response (Table

3).50 In recently published secondary andpost-hoc analyses of the ADAGIO study,rasagiline was shown to significantly delaythe need for symptomatic antiparkinson-ian drugs at both 1 and 2 mg/d doses.51

When asked to comment on studiesinvestigating potential disease-modify-ing therapies in early PD, roundtableparticipants:• Discussed clinical significance com-

pared with statistical significance inthe ADAGIO study, and one partici-pant speculated that a small beneficialeffect of treatment on disease progres-sion may become significant if it con-tinues to accrue over a long period oftime

• With respect to other candidate thera-pies for slowing disease progression inPD, the roundtable participants sup-port use of single-arm phase 2 futilitystudies (Figure 2) to screen largenumbers of potential agents

SummaryDespite advances in the diagnosis andmanagement of early PD, many patients’clinical needs are not being met. In theirclosing remarks, the roundtable partici-pants emphasized the importance of indi-vidualizing the approach to themanagement of the patient with early PDand making the patient aware that theirdisease experience is likely to differ sub-stantially from that of another patientwith PD. Finally, they stressed the impor-tance of uncovering the underlying mech-anisms of PD as a critical step inadvancing treatment.

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2. Lang AE. A critical appraisal of the premotor

0 12 24 36 42 48 54 60 66 72Week

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FFiigguurree 33.. AADDAAGGIIOO ssttuuddyy ddeessiiggnn.. The 3 primary end points had to be met in a hierarchical fashionto declare positive results. Green arrows indicate the first end point: the superiority of early starttreatment vs placebo with respect to the estimate of the rate of change from baseline in the totalUPDRS score between weeks 12 and 36. Red arrow indicates the second end point: the superi-ority of early start treatment vs delayed start treatment with respect to estimate of change in thetotal UPDRS score between baseline and week 72. Blue arrows indicate the third end point: thenoninferiority of early start treatment compared with delayed start treatment with respect to esti-mated rate of change from baseline in the slope for the total UPDRS score between weeks 48 and72. The dashed blue line indicates placebo, and the solid blue lines indicate rasagiline. With per-mission from Olanow CW, et al.50 ©2009 Massachusetts Medical Society. All rights reserved.

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