daytime alertness in parkinson's disease: potentially dose-dependent, divergent effects by drug...

Daytime Alertness in Parkinson’s Disease: PotentiallyDose-Dependent, Divergent Effects by Drug Class

Donald L. Bliwise, PhD,1,2* Lynn Marie Trotti, MD, MS,1,2 Anthony G. Wilson, BS,1,2 Sophia A. Greer, MPH,1,2

Cathy Wood-Siverio, MS,1 Jorge J. Juncos, MD,1 Stewart A. Factor, DO,1 Alan Freeman, MD,1 and David B. Rye, MD, PhD1,2

1Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA2Program in Sleep Medicine, Emory University School of Medicine, Atlanta, Georgia, USA

ABSTRACT: Many patients with idiopathic Parkin-son’s disease experience difficulties maintaining daytimealertness. Controversy exists regarding whether thisreflects effects of antiparkinsonian medications, the dis-ease itself, or other factors such as nocturnal sleep dis-turbances. In this study we examined the phenomenonby evaluating medicated and unmedicated Parkinson’spatients with objective polysomnographic measurementsof nocturnal sleep and daytime alertness. Patients (n 563) underwent a 48-hour laboratory-based study incor-porating 2 consecutive nights of overnight polysomnog-raphy and 2 days of Maintenance of WakefulnessTesting. We examined correlates of individual differencesin alertness, including demographics, clinical features,nocturnal sleep variables, and class and dosage of anti-Parkinson’s medications. Results indicated that, first, rel-ative to unmediated patients, all classes of dopaminergicmedications were associated with reduced daytimealertness, and this effect was not mediated by disease

duration or disease severity. Second, the results showedthat increasing dosages of dopamine agonists wereassociated with less daytime alertness, whereas higherlevels of levodopa were associated with higher levels ofalertness. Variables unrelated to the Maintenance ofWakefulness Test defined daytime alertness includingage, sex, years with diagnosis, motor impairment score,and most nocturnal sleep variables. Deficits in objec-tively assessed daytime alertness in Parkinson’s diseaseappear to be a function of both the disease and the med-ications and their doses used. The apparent divergentdose-dependent effects of drug class in Parkinson’s dis-ease are anticipated by basic science studies of thesleep/wake cycle under different pharmacologicalagents.VC 2012 Movement Disorder Society

Key Words: Parkinson’s disease; daytime alertness;sleep; maintenance of wakefulness test; dopaminergictreatment

Difficulty in maintaining daytime alertness is a majorissue for many patients with Parkinson’s disease (PD).This problem has been well documented using both sub-jective1–4 and objective5–16 measurements and negativelyaffects quality of life,17 mood,18 ability to operate amotor vehicle,1 and cognition19 and may even be prog-

nostic for incident PD.20 Although generally thought toreflect medication effects,2,21–23 some evidence in bothhuman disease24 and animal models25,26 now suggeststhat sleepiness during the daytime may also be an integralcomponent of PD itself.5,12 In this study we examined theability of PD patients to remain awake during the daytimeusing objective measurements made with the Mainte-nance of Wakefulness Test (MWT). Our goals were: (1)to compare alertness in a group of well-characterized,unmedicated early-stage PD patients with those treatedmedically; and (2) to characterize medication effects onalertness, both as a function of medication class (ie, levo-dopa versus dopamine agonists) and of dose.

Patients and Methods

Patients

Sixty-three patients with a diagnosis of idiopathicPD participated. All patients were examined by a

------------------------------------------------------------*Correspondence to: Dr. Donald L. Bliwise, Department of Neurology,Emory University School of Medicine, 1841 Clifton Road, Room 509,Atlanta, Georgia 30329, USA; [email protected]

Funding agencies: This work was supported by R01 NS-050595 (DLB),UL1 RR-025008/KL2 RR-025009 (Atlanta Clinical and TranslationalScience Institute), U01 NS-050324 (CoQ10 trial), and a grant from theMichael J. Fox Foundation.Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 9 January 2012; Revised: 3 May 2012; Accepted: 14 May2012Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.25082

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board-certified neurologist (L.M.T.) who administeredthe motor component of the Unified Parkinson’s Dis-ease Rating Scale (UPDRS)27 and completed the modi-fied Hoehn–Yahr staging scale.28 For patientsreceiving dopaminergic medication, UPDRS ratingswere made in the medicated condition. We alsoadministered the Epworth Sleepiness Scale (ESS)29 andthe Mini–Mental State Exam (MMSE).30 Table 1shows demographics and clinically relevant variables(age, sex distribution, UPDRS, disease duration,MMSE, and ESS) for the group as a whole, as well asfor both those medicated (n ¼ 49) and unmedicated(n ¼ 14) with dopaminergics (including levodopa and/or dopamine agonists).

Medication Status

Forty-one patients took levodopa, whereas 34 tookdopamine agonists (DAs) including: pramipexole (n ¼17), ropinirole (n ¼ 16), and bromocriptine (n ¼ 1).Other medications used by more than 2 patientsincluded selegiline or rasagiline (n ¼ 17), CoQ10 sup-plement (n ¼ 15), amantadine (n ¼ 11), various ben-zodiazepines (n ¼ 7), and antidepressants, includingtrazodone (n ¼ 4) and various serotonin and norepi-nephrine reuptake inhibitors (n ¼ 18). Only 1 patientused stimulant medication (modafinil).Levodopa dose equivalents for all patients taking

any form of levodopa (including sustained-release andentacapone-combined formulations) were made with aconversion formula reported previously,2 whereas fordopamine agonists we employed pergolide dose equiv-alents.31 Because some patients (n ¼ 27) took bothlevodopa and dopamine agonists, we also combinedboth medication classes into a single combined-dopa-minergic equivalent (expressed as levodopa milli-

grams).2 Dose equivalents for those patients takingthese various medication classes are provided inTable 2.

Laboratory Procedures

Patients gave informed consent under an institu-tional review board–approved protocol. Meals and allmedications were taken at customary times while inthe laboratory. The protocol consisted of continuous48-hour in-laboratory polysomnographic (PSG) evalu-ation in which patients maintained their usual bedtimeand wakeup schedules for 2 consecutive nights. Dur-ing the daytime, patients underwent a 4-nap MWT(see below). In 9 cases, the study was scheduled forless than 48 hours. PSG recordings were conducted onan Embla Flaga A10 system and consisted of centraland occipital electroencephalography, left and rightmonopolar electrooculography, surface mentalis elec-tromyography (EMG), single-lead (modified lead II)electrocardiography, respiratory airflow and effort,pulse oximetry, and bilateral limb surface EMGrecordings from electrodes placed above the left andright anterior tibialis and brachioradialis. Recordswere scored by research staff in 30-second epochsunder the supervision of an experienced polysomnog-rapher (D.L.B.) with whom interrater reliability wasestablished previously at the 85% level or higher.32,33

There were no differences between the 54 patientswith 8 nap opportunities and the remaining 9 patientswith fewer than 8 nap opportunities in age, sex,Hoehn–Yahr score, UPDRS, years with diagnosis, ESS,or MMSE.As an alternative to the more conventionally used

Multiple Sleep Latency Test (MSLT),34 which meas-ures daytime sleepiness, the MWT measures daytime

TABLE 1. Description of patients

Demographics/clinical

variables

Overall

n ¼ 63

Receiving

dopaminergics n ¼ 49

Not receiving

dopaminergics n ¼ 14

Comparison

t or v2 (P)

Receiving dopaminergics

(truncated) n ¼ 13

Comparison

t or v2 (P)

Age 63.1 (9.7) 63.2 (9.4) 62.6 (11.0) .19 (.85) 61.0 (10.6) .39 (.697)Sex (% male) 0.651 0.653 0.643 .005 (.94) 0.615 .02 (1.00)Disease duration 5.6 (4.0) 6.6 (3.9) 1.8 (0.9) 7.67 (<.0001) 2.6 (0.8) 2.06 (.051)UPDRS (overall) 17.2 (8.4) 17.0 (8.7) 17.5 (7.9) .18 (.858) 15.5 (8.2) .60 (.554)Selected subscales

Rest tremor 2.0 (2.3) 1.9 (2.3) 2.4 (2.2) .71 (.86) 0.9 (1.2) 1.89 (.07)Gait/posture 1.6 (1.4) 1.7 (1.4) 1.4 (0.7) .57 (.57) 1.8 (1.9) .59 (.56)Rigidity/bradykinesia 10.8 (6.1) 10.8 (6.0) 10.9 (6.5) .09 (.68) 10.2 (5.8) .28 (.78)

Modified Hoehn–Yahr stage1 7 (11.1) 6 (12.2) 1 (7.1) 1.29 (.86) 3 (23.1) 4.20 (.38)1.5 5 (7.9) 3 (6.1) 2 (14.3) 0 (0)2 26 (41.2) 20 (40.8) 6 (42.9) 4 (30.8)2.5 16 (25.4) 13 (26.5) 3 (21.4) 5 (38.5)3 9 (14.3) 7 (14.3) 2 (14.3) 1 (7.7)

MMSE 28.6 (1.7) 28.5 (1.7) 28.7 (2.0) .38 (.707) 28.8 (1.5) .17 (.805)ESS 10.3 (4.4) 11.2 (4.3) 7.4 (3.6) 3.03 (.0037) 12.3 (3.1) 3.81 (.0008)MWT-derived variablesMedian SLAT 18.4 (14.8) 15.7 (14.7) 27.7 (11.0) 2.81 (.0066) 14.4 (13.5) 2.82 (.0092)Median SE 27.3 (26.8) 31.7 (27.3) 12.0 (18.6) 2.53 (.0140) 29.0 (24.4) 2.05 (.0515)

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2 Movement Disorders, Vol. 000, No. 000, 2012

alertness.35 Differentiatinng between the 2 tests isbased primarily, but not exclusively, on the instruc-tional set provided. In the MSLT, patients areinstructed to lie down in bed in a darkened room andtry to fall asleep. In the MWT, patients recline withthe head of the bed elevated in a darkened room andare given the instruction to try to remain awake andavoid falling asleep. The MSLT typically lasts 20minutes, whereas the MWT typically extends for 40minutes,36 although shorter versions of the latter testhave been described.37 For both tests, sleep is prohib-ited by continuous behavioral monitoring betweeneach nap opportunity; in our study, this was accom-plished by having a single technologist assigned to thepatient throughout the daytime hours. The MWTholds some advantages over the MSLT because ofgreater sensitivity to medication effects.38 In a PDpopulation, the MWT was shown to be more closelyrelated to agonist dose relative to the MSLT.15 Wemodified the MWT in this study by allowing the entire40-minute period to elapse (regardless of whethersleep did or did not occur). We quantified each MWTnap opportunity to derive: (1) sleep latency (SLAT;minutes), the time to the first 30-second epoch scoredas sleep; and (2) sleep efficiency (SE; %), the totaltime spent asleep during each nap divided by 40 multi-plied by 100.

Analyses

Our primary analyses focused on comparisonsbetween patients medicated and not medicated withdopaminergic drugs. Initially, we employed repeated-measures analysis of variance (ANOVA) to examinetime-of-day effects with MWT. To compare differentpatient groups, we relied on 2-sample t tests with cor-rections for unequal variance estimates. Because forthese comparisons, we generated 2 MWT variablesthat were partially redundant (ie, patients with longerlatency to fall asleep also typically had lower sleepefficiencies), we corrected all adjustments in our pri-mary analyses using family-wide Bonferroni adjust-

ments (P ¼ .025). Demographics and clinical variables(age, sex, disease duration, UPDRS, MMSE, and ESS)comparing medicated and unmedicated patients werealso subject to family-wide Bonferroni adjustment(P ¼ .008). Exploratory analyses to examine drugclasses and possible dose–response effects were unad-justed. We used Spearman correlation coefficients toinvestigate associations between nighttime sleep varia-bles and MWT data.

Results

Nonpharmacologic Correlates ofMWT-Defined Measures of Alertness

Median MWT values for SE and SLAT (Table 1) foreach patient were unrelated to nocturnal TST, ArousalIndex, REM %, AHI, or PLMSI. However, nocturnalSE was positively correlated to MWT SE (rho ¼ .27,P ¼ .036), suggesting that patients sleeping better noc-turnally were those who were sleepier during the day-time. Both median MWT SE and MWT SLAT wereunrelated to age, years with diagnosis, MMSE score,and UPDRS score. There was a marginal relationshipbetween MWT SE and ESS score (rho ¼ .21, P ¼.099), indicating that higher subjective sleepiness wasassociated with higher sleep efficiencies during thedaytime.We examined variability in alertness during the day

among those 54 cases who underwent the 2 full days(ie, 8 MWT nap opportunities) to allow for a morethorough assessment of time of day and/or time inprotocol influences. Spearman correlations between allpairs of nap opportunities showed highly significantcorrelations ranging from .40 to .78 for MWT SE andfrom .51 to .77 for MWT SLAT (all P < .003), indi-cating relatively stable levels of alertness across napopportunities. Repeated-measures ANOVAs showedstatistically significant main effects of MWT order (F¼ 7.79, P < .0001 for SE; F ¼ 7.70, P < .0001 forSLAT; both df ¼ 7, 371), with the majority of statisti-cally significant comparisons indicating that MWT 1(first nap opportunity of day 1) and MWT 8 (last nap

TABLE 2. Mean dosages among 49 patients receiving dopaminergic medications

Combined levodopa dose equivalent (mg)a Levodopa dose (mg)b Dopamine agonist (mg)c

Patient group (n ¼ 49) 595.0 (329.1) 454.0 (337.2) 1.90 (1.54)Taking only levodopa (n ¼ 14) 599.6 (347.8) 599.6 (347.8) —Taking only dopamine agonist (n ¼ 8) 196.2 (92.2) — 2.63 (1.29)Taking levodopa (n ¼ 41) 672.8 (300.7) 542.5 (295.3) 1.76 (1.55)Taking dopamine agonist (n ¼ 35) 593.1 (326.5) 395.7 (319.5) 2.66 (1.11)Taking both levodopa and dopamine agonist (n ¼ 27) 710.8 (272.5) 513.0 (266.5) 2.68 (1.08)

aCombined levodopa dose equivalent ¼ levodopa dose equivalent (see b below) þ pergolide dose equivalent (see c below) � 100.bLevodopa dose equivalent for all forms of levodopa, including sustained-release and entacapone-combined formulations followed reference 2 and wascomputed as the daily sum of: regular levodopa dose þ levodopa continuous-release dose � 0.75 þ (regular levodopa dose þ [continuous-release levodopadose � 0.75]) � 0.25 if taking entacapone.cPergolide dose equivalent for all dopamine agonist medications, including pramipexole, ropinirole, and bromocriptine, followed reference 31 and wascomputed as 1 mg pergolide ¼ 1 mg pramipexole ¼ 5 mg ropinirole ¼ 10 mg bromocriptine.

D A Y T I M E A L E R T N E S S I N P D


opportunity of day 2) were associated with higherlevels of alertness than any of the other MWTs, indi-cating probable procedural adaptation and end-of-pro-tocol effects, respectively.

Pharmacologic Correlates of MWT-DefinedMeasures of Alertness

We employed each patient’s median SE and SLATto examine the influence of medication. Table 1presents comparisons between patients receiving andnot receiving dopaminergic medications. Medicatedpatients as a group did not differ in age, sex composi-tion, UPDRS score, or MMSE score but had signifi-cantly longer disease duration than did unmedicatedpatients (difference exceeding Bonferroni threshold).They also were more likely to experience sleepinesssubjectively (ESS). Medicated patients were signifi-cantly less alert on both MWT measures, and thosedifferences were sufficiently strong to exceed the Bon-ferroni threshold. These differences persisted whenMWT 1 and MWT 8 data were excluded from analy-ses, indicating that inclusion of data from these napopportunities did not affect the results. Because theunmedicated patients’ disease duration was signifi-cantly shorter than that of the medicated patients, werepeated these comparisons and attempted to controlfor this quasi-experimentally by truncating disease du-ration of the medicated group at the highest diseaseduration of the unmedicated group (3.5 years). (Thiswas only partially successful as the disease durationdifference was still marginally significant [P ¼ .051];see Table 1). Nonetheless, MWT comparisonsremained statistically significant, still exceeding theBonferroni threshold for SLAT, despite the restrictedsample size. Differences persisted when MWT 1 andMWT 8 data were excluded from these analyses, aswell.There were no statistically significant differences in

MWT SE or SLAT comparing patients receiving withthose not receiving other classes of medications(CoQ10, selegiline/rasagiline, amantadine, variousbenzodiazepines [primarily clonazepam], or trazodoneor other antidepressants). The percentages of patientsreceiving either antidepressants or benzodiazepines didnot differ between those receiving and those notreceiving dopaminergics (36.7% vs 28.6%, Fisher’sexact P ¼ .75 for all antidepressants combined;12.2% vs 7.1%, Fisher’s exact P ¼ .35 for all benzo-diazepines combined), suggesting that these medica-tion classes were not contributing to the differencesseen in alertness between these groups.We also examined dose–response relationships with

MWT-defined alertness among the 49 patients usinglevodopa and/or DAs. Using the combined dopaminer-gic dose equivalents2 (see Table 2), there was no rela-tionship with median MWT SLAT (rho ¼ .20, P ¼

.17) or median MWT SE (rho ¼ �.12, P ¼ .40).However, a different pattern emerged when examiningassociations separately by drug class (ie, levodopa ver-sus DA). Patients with daily pergolide dose equivalents> 2.0 mg daily (median dose) had a significantlyhigher SE (39.7% [29.5%] vs 24.1% [23.2%], t ¼2.06, P ¼ .045) than those with dose equivalents <2.0 mg, suggesting higher dosages were associatedwith less daytime alertness. In contrast, the correlationbetween levodopa dose and MWT-defined SLAT waspositive (rho ¼ 0.27, P ¼ .06), indicating higher levo-dopa was associated with greater, not lesser, degreesof alertness. Linear regression entering both levodopaand pergolide equivalents as separate predictors ofMWT showed that only DAs contributed to MWT-defined SE (B ¼ 6.17, t ¼ 3.01, P ¼ .004) and SLAT(B ¼ �5.18, t ¼ 2.21, P ¼ .031), again indicating therelative independence of both drug classes in associa-tion with MWT-defined daytime alertness.

Discussion

Our data broadly confirm the objectively measureddeficits in daytime alertness in PD patients shown bymany other investigators, primarily5,9,12–14 but notexclusively11,15 using the MSLT. Our median MWTSLAT (18.6 minutes) for medicated and unmedicatedpatients combined represents a value approximately1.5 standard deviations below the normative valuesexpected for the 40-minute version of this test36,39 andare relatively consistent with MWT data presented inPD patients by Stevens et al.15 Although some non-pharmacologic factors were associated with alterationsin daytime alertness (ie, procedural MWT effects),parkinsonian medications were clearly associated withlarge effects in alertness, even when disease durationwas controlled. Unanticipated in our data, however,were the novel observations that the 2 major classesof dopaminergics used to treat PD symptoms (levo-dopa and DAs) appeared to show divergent dose-de-pendent effects on alertness. These findings have notbeen noted previously in human PD studies of objec-tively measured daytime alertness, but they havereceived some corroboration from animal work.The effects of dopaminergic stimulation on sleep

and wakefulness are complex. Many basic sciencestudies have suggested that both classic and newerstimulant medications operate through dopaminergicmechanisms (including but not limited to downregula-tion of the dopamine transporter) and that these maybe independent of effects on motor activity per se.40

Effects of dopaminergic pharmacologic stimulation onalertness, however, may depend on dose of the agentin question, its proclivity for 1 or more of the 5molecularly defined dopamine receptor subtypes, andits potential to limit its own activity (particularly at



low dosages) by autoreceptor binding.41 Experimentaltrials in normal subjects have suggested that both do-pamine agonists (at 0.50–0.75 mg pergolide equiva-lence)42,43 and levodopa (at 200 mg, eg, ref. 44; butnot 100 mg, eg, ref. 42) can induce sleepiness, but ani-mal studies suggest a far more nuanced picture. Apo-morphine administered to rats showed soporific effectsat low dosages but stimulating effects at high dos-ages.45 When given in sufficiently high dosages to rats(75 mg/kg), levodopa enhanced both locomotor activ-ity and wakefulness.46 Older literature on selective an-tagonism has suggested that a D1, relative to D2,blockade increased sleep duration in rats,47,48 whereasTrampus et al49 reported that D1 agonists increasewaking in a dose-dependent fashion, with those effectsdependent on specific binding affinities. Among thenewer, non-ergot-derived dopamine agonists, prami-pexole (with D3 specificity) was shown to causebiphasic effects on sleep in rats, with lower dosages(30 lg/kg) increasing sleep and higher dosages (500lg/kg) increasing alertness.50 In our patients, the high-est daily dosage of levodopa and DA (pergolide equiv-alent), 1250 and 5.25 mg, respectively, are still onlyabout 25% of the milligram-per-kilogram doses usedin this animal work. Insofar as we know, our studyrepresents the first PD data to raise the possibility thatthere may be selective, apparently divergent dose-de-pendent effects of dopaminergic class (ie, levodopaversus DAs) on objectively measured alertness withina dosage window encountered in humanpharmacotherapy.Previous MSLT/MWT studies examining sleepiness

and alertness in relation to medication usage in PDhave shown at best equivocal, if not negative,results.8,10,12–14,16 One MWT study showed that indi-viduals in the upper tertile (>867.5 mg) of combineddopaminergic equivalents were less likely to be alertbut did not separate DA and levodopa dose,11 whereasanother reported that pergolide equivalents, but notlevodopa dose, were associated with lower MWT-defined alertness.15 In an earlier study, Arnulf et al5

reported a modest correlation between levodopa doseand greater MSLT-defined alertness, similar to whatwe found here, but noted no relationship to DA dose.In our study, we noted divergent dose-dependenteffects of drug class in relation to daytime alertness;moreover, these were superimposed on an overalleffect of parkinsonian medication on alertness (Table1), regardless of class.We noted a small but statistically significant rela-

tionship between subjective (ESS) and objective(MWT) measures of daytime alertness. Weak or non-significant associations between ESS andMSLT5,6,11,14–16,51,52 or MWT15 in PD have beenshown previously, although a few studies report stron-ger associations.9,10 Modest relationships between sub-

jective and objective alertness have been noted foryears.53

Motivational factors can affect the MWT. Forexample, the possibility of losing driving privilegesmay be sufficient to promote alertness on the MWT insome non-PD patients (particularly the 20-minute ver-sion),54 and Bonnet et al55 have suggested that finan-cial incentives may even influence alertness on thistest. Although patients in our study were paid $400for their participation, we did not attempt to incentiv-ize performances via monetary reward. Patients wereinstead told of the importance of the research gener-ally, and we enlisted their participation in this spirit.Nonetheless, there was interpretable evidence formotivational factors operating here because MWT 8,for example, demonstrated a significantly longer SLATand lower SE than did other naps, perhaps reflectingthe common phenomenon of patients anticipatingtheir departure from the lab following their final pro-cedure of the day.Our evidence of possible dose-dependent divergent

effects of dopaminergic medications notwithstanding,these data in many respects converge considerablywith other work in this area. For example, 11 of 12studies using the MSLT in PD5–9,11–16 failed to findany association between overt sleep pathology such asthe AHI or PLMSI and next-day alertness, with theonly exception a single recent report.10 Many of thesestudies have also noted a dearth of relationshipsbetween PSG-defined TST and SE and daytime sleepi-ness in PD patients.5–10,13,14 In the current study, wealso found no relationship with AHI and PLMSI; how-ever, consistent with our earlier study with the MSLT,we reported that higher nocturnal SE was positivelyassociated with greater sleepiness the following day.12

Similarly, as in most other studies, age5,10,12,13,16 andUPDRS motor score5,7,8,10,15,16 were not impressivecorrelates of daytime sleepiness, although both Stevenset al15 and Razmy et al11 reported lower levels ofalertness associated with higher Hoehn–Yahr ratings.A frank weakness of our study is the absence of

validated measures of depression; instead, we are rely-ing on clinician’s usage of antidepressant medicationas a very rough proxy for low mood. Other weak-nesses of our study include absence of a nonpatientcontrol group and a cross-sectional design that did notallow for medication effects for each patient to betested against each patient’s own baseline. The impor-tance of the latter issue may be mitigated to someextent by the availability of untreated patients withinthe first 3–4 years after diagnosis. In addition, ourattempt to exercise some element of quasi-experimen-tal control via disease duration matching allowed forsome differentiation of early-stage disease versus medi-cation effects per se. Tracking these unmedicatedpatients throughout their ensuing treatment coursewill be one focus of our future efforts. Given the



importance of changes in the dopaminergic system tosleep/wakefulness, we strongly believe that prospectivetrials of new pharmacologic agents for PD shouldincorporate objective measurements of alertness as animportant adjunctive outcome.

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daytime alertness in parkinson's disease: potentially dose-dependent, divergent effects by drug...

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