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The effects of exercise on cognition in Parkinson’s disease: a systematic review Murray, Danielle K; Sacheli, Matthew A; Eng, Janice J; Stoessl, A J Feb 24, 2014

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REVIEW Open AccessThe effects of exercise on cognition in Parkinson’sdisease: a systematic reviewDanielle K Murray1*, Matthew A Sacheli1, Janice J Eng2 and A Jon Stoessl1AbstractCognitive impairments are highly prevalent in Parkinson’s disease (PD) and can substantially affect a patient’s qualityof life. These impairments remain difficult to manage with current clinical therapies, but exercise has been identifiedas a possible treatment. The objective of this systematic review was to accumulate and analyze evidence for theeffects of exercise on cognition in both animal models of PD and human disease. This systematic review wasconducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.Fourteen original reports were identified, including six pre-clinical animal studies and eight human clinical studies.These studies used various exercise interventions and evaluated many different outcome measures; therefore, only aqualitative synthesis was performed. The evidence from animal studies supports the role of exercise to improvecognition in humans through the promotion of neuronal proliferation, neuroprotection and neurogenesis. Thesefindings warrant more research to determine what roles these neural mechanisms play in clinical populations.The reports on cognitive changes in clinical studies demonstrate that a range of exercise programs can improvecognition in humans. While each clinical study demonstrated improvements in a marker of cognition, therewere limitations in each study, including non-randomized designs and risk of bias. The Grading of RecommendationsAssessment, Development and Evaluation (GRADE) system was used and the quality of the evidence for human studieswere rated from “low” to “moderate” and the strength of the recommendations were rated from “weak” to “strong”.Studies that assessed executive function, compared to general cognitive abilities, received a higher GRADE rating.Overall, this systematic review found that in animal models exercise results in behavioral and correspondingneurobiological changes in the basal ganglia related to cognition. The clinical studies showed that various typesof exercise, including aerobic, resistance and dance can improve cognitive function, although the optimal type,amount, mechanisms, and duration of exercise are unclear. With growing support for exercise to improve notonly motor symptoms, but also cognitive impairments in PD, health care providers and policy makers shouldrecommend exercise as part of routine management and neurorehabilitation for this disorder.Keywords: Parkinson’s disease, Exercise, Cognition, Humans, AnimalsIntroductionRationale and objectiveAside from well-documented motor symptoms, mostParkinson’s disease (PD) patients suffer from associatednon-motor complications, including cognitive impair-ment, mood disorders, olfactory dysfunction, sleep dis-turbance, fatigue and anxiety [1-3]. Of the non-motorsymptoms, cognitive impairments are particularly preva-lent in PD with up to 83% of patients developingdementia after 20 years [4]. The non-motor symptomsof PD can be at least as detrimental as motor manifesta-tions for a patient’s health and overall quality of life, butunfortunately remain difficult to manage with currentclinical therapies [1-3].The current gold-standard for testing global cognitivecapacity in clinical practice includes objective verbal andwritten tests. Of the quick screening cognitive testsavailable, the Montreal Cognitive Assessment (MoCA)[5] has been widely accepted for use in PD populations[6] by assessing multiple domains of cognitive functionincluding memory, language, complex visuospatial pro-cessing, and executive function. This validated tool has* Correspondence: danielle.k.murray@gmail.com1Pacific Parkinson’s Research Centre and Department of Medicine, Division ofNeurology, University of British Columbia & Vancouver Coastal Health,Vancouver, BC V6T 2B5, CanadaFull list of author information is available at the end of the articleTranslational Neurodegeneration© 2014 Murray et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.Murray et al. Translational Neurodegeneration 2014, 3:5http://www.translationalneurodegeneration.com/content/3/1/5been helpful to measure the impact of treatments oncognition. Animal models of PD provide a more readilycontrolled means to assess cellular dysfunction, neuro-chemical alterations and other neural mechanisms thatmay contribute to disease pathogenesis in humans.Exercise is thought to improve overall wellbeing inolder adults and benefit cognitive functions of those withneurodegenerative diseases [7]. It has been suggestedthat exercise may improve the motor manifestations ofPD and that restricted use in rats may potentiate neuro-degeneration [8]. Specifically, evidence has shown thatexercise is beneficial for bradykinesia, postural balanceand quality of life in patients with PD [9-12]. The extentto which exercise specifically impacts cognition in PD,and how, is unclear. A non-systematic review from 2011suggested that vigorous exercise may have a neuroprotec-tive effect in PD [13]. A more recent systematic reviewsimilarly showed that non-pharmacological interventionsimprove cognition in PD. However, this review includedonly those studies published before December 2011 andused limited search terms related to cognition, resulting inthe review of only four clinical studies [14]. A subsequentanalysis of the literature was needed to include recentclinical studies and to incorporate animal-based researchthat might help identify potential mechanisms in humans.Therefore, this systematic review was conducted to evalu-ate all original research reports that assessed exercise in-terventions in human PD or in animal models of PD, witha primary or secondary outcome to examine cognitivefunction. To provide the most comprehensive overview ofthe literature, non-randomized, pre-post and cohort trialswere included in addition to randomized controlled trials.The combination of these findings should be used to fur-ther guide clinical practice and neurorehabilitation exer-cise programs toward treating cognitive deficits in PD.MethodsSystematic review protocolThis systematic review was conducted according to the Pre-ferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement guidelines [15]. The PRISMAstatement includes a 27-item checklist (Additional file 1)and standardized instructions for conducting a systematicreview. The complete search methodology, informationsources and results for this review are described within thisreport and Appendix 1.Eligibility criteria for study characteristicsThe participants included healthy human subjects, sub-jects with PD and animals with experimental PD. Studieswere included if their primary intervention was exerciseand their primary or secondary outcomes were to assesseither behavioral or neurobiological markers of cognitivefunction. All articles were included where the authorstreated the outcome measure as a test of cognition. Insome cases, the measure was a surrogate (e.g., biomarkerassociated with cognitive function), was a sub-score ofcognition from a larger scale, or was influenced bymotor capacity. An exercise intervention was defined asany purposeful increase in the subject’s physical activitythrough a single bout of exercise or prolonged exerciseover the course of a structured or unstructured program.Cohort and experimental study designs were included,whereas case series, case–control, cross-sectional anddescriptive studies were excluded. Original research arti-cles were included from 1966 through October 2013.Studies were considered if they were written in theEnglish language and either published or “in press”.ResultsStudy selection and synthesisThere were 14 records included in this analysis (Figure 1).Thirteen records were found through searching databasesand one record [16] was found through searching the ref-erences of articles identified for inclusion in the analysis.The records comprised six pre-clinical animal studies (allon rodents) and eight clinical studies in humans. Of thesix pre-clinical studies, all were randomized controlledstudies. Two studies examined the effects of exercise onunspecified aspects of cognition [17,18], and four studiesexamined the effects of exercise specifically on learningand memory [16,19-21]. Of the eight clinical studies, fourstudies examined the effects of exercise on unspecified as-pects of cognition [22-25], and four studies examined theeffects of exercise specifically on tasks of executive func-tion [26-29]. The clinical studies included five randomizedcontrolled trials, one controlled trial and two pre-post tri-als. A quantitative comparison or meta-analysis could notbe performed for either the pre-clinical or clinical studiesbecause there were only a small number of reports identi-fied, and when compiled together they had heterogeneouspatient populations, exercise interventions and outcomemeasures.Study characteristics and results for pre-clinical studiesAll six pre-clinical studies were randomized controlled trials.Three different toxins were used to generate basal ganglia le-sions and develop models of PD in rodents. Three studiesused 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)in mice [16,17,20], two studies used 6-hydroxydopamine(6-OHDA) in rats [18,30], and one study used reser-pine in rats [19], resulting in reversible monoamine de-pletion. The timing of toxin administration variedrelative to the onset of the exercise program. Fourstudies tested the effect of exercise that started follow-ing the lesion [16-18,30]. The interventions were fivedays per week for 30 days starting within a week afteradministration of either MPTP or 6-OHDA. One studyMurray et al. Translational Neurodegeneration 2014, 3:5 Page 2 of 13http://www.translationalneurodegeneration.com/content/3/1/5tested the effects of exercise for one week before, fiveweeks during, and for 8–12 weeks following chronicMPTP administration [20]. The study that used reserpinetested exercise five days per week for 30 days prior to ad-ministration of the toxin in order to assess how exercisemay prevent cognitive impairment in PD [19].Four studies looked at forced exercise on a treadmillcompared to no exercise [16,18,20,30]. Three studiesshowed potential neurobiological correlates of observedbehavioral changes that the authors related to cognition,including findings from one study that rats forced to ex-ercise had better behavioral recovery on tests of motorfunction (i.e., cylinder and amphetamine-induced rota-tional tests), and better preservation of tyrosine hydroxy-lase immunoreactivity in both striatum and substantianigra [18]. The authors also found that exercise in-creased the migration of BrdU and doublecortin-positivecells as well as increased brain-derived neurotrophic fac-tor (BDNF) and glial cell line-derived neurotrophic fac-tor (GDNF) in the striatum on the side of the lesion. Inanother study, exercise resulted in enhanced durationand velocity of running behavior, indicating that rats hadlearned to maintain a forward position on a treadmill[16]. Exercise in these MPTP- and saline-injected miceresulted in significant down-regulation of striatal dopa-mine transporter protein (DAT) as well as increased D2(but not D1) receptor mRNA expression. Exercise atten-uated the increase in striatal glutamate nerve terminallabeling following MPTP, but there was no change inglutamate immunolabeling in CA1 in the hippocampus.In both of these studies exercise improved behavioralmarkers that were interpreted by the authors as indica-tive of enhanced cognitive function. It should be notedthat these measures rely heavily on motor capacity andare typically associated more with motor than with cog-nitive function. The third study that showed neurobio-logical changes associated with corresponding behavioralchanges tested effects of aerobic swimming in mice. Therodents showed improved long-term memory on a testof object recognition following exercise and had at-tenuation of impairments from exposure to 6-OHDA,including decreased pro-inflammatory cytokines, im-proved markers of oxidative stress and increased DAtransmission [30]. The last study that looked at forcedexercise on a treadmill compared to no exercise con-ducted in a chronic model of PD found that endurance351 recordsidentified through electronic database33 additional recordsidentified throughancestry searching102 records excluded47: non-original research articles 33: cognition was not the primary outcome14 : exercise was not the  primary intervention5: not on PD subjects3: case-reports/case-series 14 records included in systematic review 116 full-text recordsassessed for eligibility74 records excluded 274 records afterduplicates removed190 records screened based on title and keywordsIdentificationScreeningEligibilityIncluded84 records excludedFigure 1 PRISMA Flow Diagram of Study Selection.Murray et al. Translational Neurodegeneration 2014, 3:5 Page 3 of 13http://www.translationalneurodegeneration.com/content/3/1/5exercise improved only motor function related to gaitambulation and balance, with no improvement in cog-nitive measures [20]. This study was also the only oneof these four where exercise did not improve a neuro-biological outcome following toxin administration, in-cluding no raise in striatal DA and no reversed loss oftyrosine-hydroxylase fibers in the substantia nigra parscompacta.Two studies (one with MPTP and one with reserpine)looked at the effects of voluntary exercise (wheel run-ning), compared to forced exercise on a treadmill or noexercise [17,19]. In one study, exercise was introducedprior to the administration of reserpine [19], while in theother [17], exercise was not initiated until after theMPTP lesion. Both studies found that either form of ex-ercise improved behavior underlying cognitive capacityin a PD-like model. Interestingly, only forced exercise,following the lesion, improved a test of motor learning(transfer of treadmill performance to Rotarod). The au-thors suggested this finding reflects learning as the ani-mals had presumably transferred skill from the treadmillto the Rotarod task [17]. The rodents forced to exerciseon the treadmill showed a greater improvement on theRotarod test, even though rodents on the wheel willinglyspent more time exercising than those forced to run onthe treadmill. Both voluntary and forced exercise hadanxiolytic effects as assessed using the elevated plusmaze, which the authors linked to cognition and mem-ory, but neither type of exercise had any effect on de-pressive behavior as assessed by sucrose preference andtail suspension. These improvements were not associ-ated with changes in the striatal DA or amygdalar sero-tonin (5HT) levels following the exercise intervention, ascompared to saline-treated sedentary controls [17].However, both MPTP- and saline-treated mice had asimilar relative increase in striatal DA following forcedor voluntary exercise compared to saline-treated seden-tary controls. Forced exercise also increased 5HT in thenucleus accumbens in the MPTP-treated mice comparedto saline controls. In the second study, when eitherforced or voluntary exercise was introduced prior to re-serpine administration, both exercise paradigms resultedin improved motor learning on the Rotarod and open-field tasks (tests of exploratory activity), as well as im-proved social memory [19]. Social memory improvedwith a low dose or reserpine which, unlike the high doseof the toxin, did not affect the animals’ motor function.Biomarkers were not assessed in this study.Further details of study characteristics and results forpre-clinical studies are summarized in Tables 1 and 2.Major sources of risk of bias for pre-clinical studiesOne of the six pre-clinical animal studies was at risk ofselection bias because the investigators did not include asaline-only control group or an exercise and probenecidgroup, although it was still a randomized controlled trial[20]. Three other pre-clinical studies were at risk of in-formation biases; in one case the cognitive assessmentrelied on motor capacity [16], in another case the behav-ioral testing began soon after administration of thetoxin, which may have interrupted the lesion process(not measured) and made the model less comparable toPD in human subjects [19] and in the third case the ex-ercise was started soon after the toxin was administered,which may also have interrupted the lesion process [16].Two studies had performance biases, specifically thateach animal was only evaluated on one test [17] and thatexercised mice were trained for swimming for two weeksbefore toxin administration and handled each session,whereas the sedentary animals were not trained or han-dled [30]. Additionally, the social interaction (i.e., hous-ing environment) the animals experienced was differentin each of the six studies, making it difficult to compareresults across studies. The number of rodents housed ina cage ranged from one to ten, and one study did notspecify the housing environment. Paired housing com-pared to single housing in rodents has been shown tomediate the effects of MPTP on nigrostriatal degener-ation and motor behavior [31] and may have a substan-tial effect on behavioral and histological outcomes. Therisk of bias for each pre-clinical study is summarized inTable 2.Study characteristics and results for clinical studiesAll eight studies showed that exercise improved amarker of cognition (Table 3). Based on the GRADEranking system, the quality of the evidence and strength ofrecommendations for the four studies on executive func-tion were greater (“moderate” and “strong”) than for stud-ies testing unspecified aspects of cognitive function (“low”and “weak”).The sample size for the eight clinical studies variedfrom six to 60 subjects, with a mean of 15 subjects pergroup. The PD participants had a mean age between 60to 70 years and had mild to moderate PD according tothe Hoehn and Yahr scale [34], and were compared toage-matched healthy control subjects. All of these stud-ies examined subjects while they were taking their regu-larly prescribed medication. These studies did not reportwhen subjects took their regular medication and whichmedications they continued to take during the study.Each of the four studies that tested the effect of exer-cise on unspecified aspects of cognition found benefitson general markers of overall function which the authorsrelated to cognition, including the cognition componentof PDQ-39, MoCA, memory, reaction time and peg in-sertion time (requiring visual and spatial cognition, sort-ing and planning) [22-25]. The evidence from two of theMurray et al. Translational Neurodegeneration 2014, 3:5 Page 4 of 13http://www.translationalneurodegeneration.com/content/3/1/5studies is limited as they were pilot trials designed to testfeasibility [22,23]. Additionally, the measures of cogni-tion these studies used, the cognition component ofPDQ-39, reaction time and peg insertion, are not clearmeasures of cognitive function. However, the two otherstudies clearly demonstrated that exercise had an effecton cognitive capacity [24,25]. Of these two trials, bothtested the Wii FitTM program. They showed that aftertraining, PD subjects can retain and transfer learning, de-pending on the cognitive demands of the game, [25] butWii FitTM may not provide additional advantage in com-parison to balance exercises without cognitive stimulationor feedback [24].Across studies, exercise interventions varied signifi-cantly in terms of the intensity, mode and duration ofthe program. One study involved an individualized walk-ing program (PoleStriding) using Nordic poles threetimes per week for eight weeks [22]. Another studyassessed outcomes before and after a single bout ofhigh-intensity cycling [23]. The two studies that used theWii FitTM program for their exercise intervention in-cluded two sessions per week for seven weeks andfollow-up after 60 days [24,25]. One of the two studiesusing Wii FitTM compared PD subjects to healthy con-trols [25] and the other study looked at differences be-tween PD subjects participating in the combined WiiFitTM program with balance-based and cognitive trainingcompared to multimodal global exercises [24].Each of the four studies that specifically tested execu-tive function showed that exercise improved perform-ance on some measure of executive function, such astests of abstraction, mental flexibility, spatial workingmemory, verbal fluency, mental imagery, and cognitiveprocessing speed [26-29]. The tools used to test execu-tive function include the Wisconsin Card Sorting Task,Trail-Making Test A and B, Cambridge Neuropsycho-logical Test Automated Battery, and tests of verbal andsemantic fluency. Two studies assessed mood as a po-tential confounding factor affecting executive function;one study found that exercise improved executive func-tion independent of improvements in mood, attention,disease-specific quality of life or reduced anxiety [27].Another study found that exercise possibly improvedmood, but did not affect quality of life [26]. This lack ofTable 1 Study characteristics of pre-clinical studies on rodent models of Parkinson’s diseaseAuthors Study title Subjects InterventionGoes et al., 2013 [21] Neuroprotective effects of swimmingtraining in a mouse model of Parkinson’sdisease induced by 6-hydroxydopamine• 2 groups (n = 20 each): 6-OHDA, saline • 20–60 min/day, 5 days/weekfor 4 weeks• 2 treatment cohorts (n = 10 each):swimming training, no exercise • Starting 4 days after toxinadministrationGorton et al., 2010 [17] Exercise effects on motor andaffective behavior and catecholamineneurochemistry in the MPTP-lesionedmouse• 2 groups (n = 24 each): MPTP, saline • Up to 1 hr/day, 5 days/weekfor 4 weeks• 3 treatment cohorts (n = 8/group):forced exercise, voluntary exercise,no exercise• Starting 5 days after toxinadministrationTajiri et al., 2010 [18] Exercise exerts neuroprotective effectson Parkinson's disease model of rats• 1 group (n = 60): 6-OHDA • 30 min/day, 5 days/week for4 weeks• 2 treatment cohorts (n = 30 each):forced exercise, no exercise • Starting 1 day after toxinadministrationAguiar et al., 2009 [19] Physical exercise improves motor andshort-term social memory deficits inreserpinized rats• 4 groups (n = 24 each): high/lowdose reserpine or high/low dosesaline• 20–25 min/day, 5 days/weekfor 4 weeks• Starting 4 weeks before toxinadministration• 3 treatment cohorts± (n = 8/group):forced exercise, voluntary exercise,no exercisePothakos et al., 2009[20]Restorative effect of endurance exerciseon behavioral deficits in the chronicmouse model of Parkinson's diseasewith severe neurodegeneration• 2 groups (n = 29 each): probenecid/MPTP(model of chronic PD), probenecid only• 40 min/day, 5 days/week for8–12 weeks• Starting 1 week before, 5 weeksduring, 8–12 weeks after toxinadministration• 2 treatment cohorts (n = 5-10/group):forced endurance exercise, noexercise – for probenicid/MPTP grouponlyFisher et al., 2004 [16] Exercise-induced behavioral recovery andneuroplasticity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- lesioned mousebasal ganglia• 2 groups (n = 60 each): MPTP, saline • Up to 2x 30 min/day, 5 days/weekfor 4 weeks• 2 treatment cohorts (n = 20/group):forced exercise, no exercise* • Starting 4 days after toxinadministration±Only rats able to maintain a forward position on the treadmill were assigned to the treadmill exercise group.*Only rats able to maintain a forward position on the treadmill were randomized to either exercise or no exercise cohort.Murray et al. Translational Neurodegeneration 2014, 3:5 Page 5 of 13http://www.translationalneurodegeneration.com/content/3/1/5Table 2 Outcomes and risk of bias for pre-clinical studies on rodent models of Parkinson’s diseaseStudy Behavioral outcomes Neurobiological outcomes Major sources of risk of biasGoes et al., 2013 [21] Forced exercise following onset ofexperimental PD:Changes in the striatum from forced exercisefollowing onset of experimental PD:Performance bias: sedentary controlanimals were not exposed to theswimming training program, thewarm water or handled to be driedoff following each session.• Decreased marker of depression(tail suspension)• Decreased interleukin 1-beta levels(proinflammatory cytokines)• Improved motor coordination(decreased falls on Rotarod test)• Attenuated inhibition of glutathioneperoxidase activity, decreased glutathionereductase and glutathione S-transferaseactivity (all markers of oxidative stress)• Improved long-term memory,but not short-term memory inobject recognition test • Increased dopamine, homovanillic acid,and 3,4-dihydroxyphenylacetic acid levelsGorton et al., 2010 [17] Forced and voluntary exercisefollowing onset of experimental PD:Forced and voluntary exercise followingonset of experimental PD:Performance bias: each animal wasonly evaluated on one test.• Improved motor learning (Rotarod) • Had no effect on levels of DA in thestriatum and serotonin in the amygdalacompared to saline controls• Reduced anxiety in elevatedplus maze (passive avoidancetask, authors linked tocognition/memory)• Forced and voluntary exercise increasedDA in the striatum to similar levelsfollowing MPTP or saline administration• Had no effect on markers ofdepression, sucrose preferenceand tail suspension (MPTP lesionalso had no effect)• Forced exercise increased 5HT in thenucleus accumbens in MPTP-treatedmice compared to saline controlsTajiri et al., 2010 [18] Exercise following onset of experimentalPD:Exercise following onset of experimentalPD:Information bias: exercise was startedsoon (24 hrs) after toxin administration,so the lesion may not represent acomplete PD-like model.• Improved cylinder test, amphetamine-induced rotational test (authors linkedto cognitive-related behavior)• Preserved nigrostriatal dopamine neurons(increased tyrosine hydroxylase-positivefibers)• Increased migration of new-born neuralstem/progenitor cells toward striatum• Up-regulated neurotrophic factors, BDNFand GDNF, in the striatumAguiar et al., 2009 [19] Forced and voluntary exercise beforeonset of experimental PD:Neurobiological outcomes not assessed Information bias: behavioral testingwas soon (24 hrs) after the reserpineadministration, so the lesion may notrepresent a complete PD-like model.• Improved motor deficits following ahigh dose of reserpine• Improved short-term social memory(tested through olfactory discrimination),with no deficit on motor or olfactoryfunction from the low dose of reserpinePothakos et al., 2009 [20] Endurance exercise before and followingonset of experimental chronic PD:Endurance exercise before and after onsetof experimental chronic PD:Selection biases: there was not a groupthat received exercise and probenecid.There was also not a control groupwith only a saline injection. The effectsof the control solution, probenecid, oncognition are not known.• Reversed balance and gait performance,restored regular movement• Did not raise striatal DA (n = 6)• Did not reverse loss of tyrosine-hydroxylasefibers in substantia nigra (pars compacta)• Had no effect on learning (cued Morriswater maze), amphetamine-stimulatedlocomotion or motor coordinationFisher et al., 2004 [16] Exercise following onset of experimental PD: Exercise following onset of experimental PD: Information bias: the learning paradigmfor behavioral results (learning to stayon the treadmill) relied substantially onmotor capacity.• Improved velocity and endurance ontreadmill• Had no effect on tyrosine hydroxylase• Sensory feedback not needed over timefor behavioral response (i.e., maintaininga forward position on treadmill), authorssuggested indicative of learning• Up-regulated dopamine D2 receptor mRNAexpression• Down-regulated striatal DAT• Reversed increased nerve terminalglutamate in striatum (as a result of MPTP)Murray et al. Translational Neurodegeneration 2014, 3:5 Page 6 of 13http://www.translationalneurodegeneration.com/content/3/1/5impact on quality of life is interesting given that thisstudy did not control for the benefits of social inter-action received by the exercise group in comparison tothe control group, who were instructed to continuewith their normal routine. Both low-intensity passiveaerobic cycling [28] as well as moderate-intensity aer-obic and anabolic exercise [26,27] were found to im-prove executive function in PD. The fourth studydiffered from the other exercise interventions becauseit assessed 20 sessions of tango classes compared toeducation over 12 weeks. The subjects were assessedfor cognitive function 10–12 weeks following the inter-vention. Subjects in the tango arm improved on theBrooks Spatial Task, a test of spatial cognition (i.e.,mental imagery) [29]. The authors interpreted this asan improvement in executive function.There was substantial variety in the intensity, modeand duration of the exercise interventions in these fourstudies. One study included an exercise intervention in-volving low-intensity passive cycling once per week forfour weeks. Another study included moderate-to-highintensity anabolic and aerobic exercise 60 minutes persession twice per week for 12 weeks. The intensity andthe work load of the sessions were increased over time.Each session involved a short low-intensity aerobicwarm-up, six resistance exercises for both upper andlower body muscle groups, and then 25–30 minutes ofaerobic exercise on a stationary bicycle, rowing machineor treadmill. A third study included moderate-intensitymultimodal exercise training involving aerobic exercisewith the addition of resistance, coordination and balancetraining 60 minutes per session, three times per week for24 weeks. The 24-week intervention was divided into sixphases and the load was increased after each phase. Asession included five components: warm-up, stretchingbefore exercise, exercise, cool-down, and stretching afterexercise. The fourth study on tango implemented a stan-dardized structured tango program for 90-minute ses-sions twice per week for 12 weeks.Further details of study characteristics and results forclinical studies are summarized in Tables 4 and 5.Major sources of risk of bias for clinical studiesMost of the studies had a selection bias from not ad-equately standardizing control subjects. More specifically,the subjects’ physical fitness levels and their concomitantmedications before and during the study period were notdocumented and may have impacted their ability to exer-cise and the ability to compare their potential benefits oncognition. Additionally, information bias resulted fromvariability with the timing and intensity of the exerciseintervention between subjects. Individuals may havereceived different amounts and types of exercisewhich could have affected the impact of exercise oncognition.Of the five randomized controlled clinical trials, fourstudies included control groups that received the samesocial interaction as the exercise intervention group.One study [26] included a control group receiving usualcare, which did not control for the potential benefits tothe subjects’ mood and cognition from increased socialinteraction through participation in the exercise inter-vention. Overall, both the pre-clinical and clinical stud-ies showed a trend of selective reporting for onlysignificant outcomes. A risk of bias across studies in-cludes a publication bias, as studies with insignificant ornegative findings are less likely to be published. The riskof bias for each clinical study is summarized in Table 5.Table 3 Quality of the evidence and strength of recommendations for human clinical trials1Study Can exercise improve a marker ofcognitive function?Quality of evidence2 Strength of recommendation3Studies that specifically measured executive function (n = 4)McKee et al. 2013 [29] Yes Moderate StrongCruise et al. 2011 [26] Yes Moderate StrongRidgel et al. 2011 [28] Yes Moderate StrongTanaka et al. 2009 [27] Yes Moderate StrongStudies that measured unspecified aspects of cognition (n = 4)Dos Santos Mendes et al. 2012 [25] Yes Low WeakPompeu et al. 2012 [24] Yes Low WeakMüller et al. 2010 [23] Yes Low WeakBaatile et al. 2000 [22] Yes Low Weak1Quality of evidence and strength of recommendations based on the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) rankingsystem [32,33].2The GRADE system offers four levels of evidence: high, moderate, low and very low.3The GRADE system offers three levels for the strength of a recommendation: strong, weak, or no recommendation.Murray et al. Translational Neurodegeneration 2014, 3:5 Page 7 of 13http://www.translationalneurodegeneration.com/content/3/1/5DiscussionPre-clinical evidenceThe rodent studies identified in this review have sug-gested potential mechanisms for the benefits of exerciseon cognitive improvements in PD, particularly related tolearning and memory. The mechanisms include:1) enhanced availability of DA in projections to thedorsal and/or ventral striatum;2) enhanced expression of neurotrophic factors BDNFand GDNF, which could promote plasticity forlearning and memory; and3) decreased oxidative stress and/or neuroinflammationin the basal ganglia.Two of the five studies that assessed biomarkers did notfind effects from exercise following toxin administration.However, in one case forced and voluntary exercisesimilarly elevated striatal DA in both MPTP- andsaline-treated groups, although there was no diffe-rence compared to sedentary saline-treated controls[17]. The other study used a model of chronic PDwhere the toxin was administered with probenecidover five weeks; while exercise restored regular motorTable 4 Study characteristics of clinical trials on human Parkinson’s diseaseAuthors Study title Subjects Intervention Study designStudies that specifically measured executive function (n = 4)McKee et al. 2013 [29] The Effects of Adapted Tango on SpatialCognition and Disease Severity inParkinson’s DiseaseTotal n = 33 PD • Tango or education lessons Randomizedcontrolled trial• n = 15 tango • Sessions 90 minutes long, 20 sessions over12 weeks, follow-up after 10–12 weeks• n = 13 controlCruise et al. 2011 [26] Exercise and Parkinson's: benefits forcognition and quality of lifeTotal n = 28 PD • Moderate-to-high-intensity anabolic andaerobic exercise or usual careSingle-blindrandomizedcontrolled trial• n = 15 exercise• n = 13 control • Sessions 1 hr/day, 2x/week for 12 weeksRidgel et al. 2011 [28] Changes in executive function after acutebouts of passive cycling in Parkinson'sdiseaseTotal n = 19 PD • Low-intensity passive aerobic exercise(cycling)Randomizedcontrolled trial,cross-over• Sessions 1/week for 4 weeksTanaka et al. 2009 [27] Benefits of physical exercise on executivefunctions in older people with Parkinson'sdiseaseTotal n = 20 PD • Moderate-intensity multimodal exercisetraining (aerobic, resistance, coordinationand balance) or usual careControlled trial*• n = 10 exercise• n = 10 control • Sessions 1 hr/day, 3x/week for 24 weeks,intensity increased every 4 weeksStudies that measured unspecified aspects of cognition (n = 4)Dos Santos Mendeset al. 2012 [25]Motor learning, retention and transfer aftervirtual-reality-based training in Parkinson'sdisease - effect of motor and cognitivedemands of games: a longitudinal,controlled clinical studyTotal n = 27 • Low-intensity Wii FitTM training, involvingmotor shifts and cognitive skillsLongitudinalpre-post trial• n = 16 PD• n = 11 healthycontrol• Sessions 1 hr/day, 2x/week for 7 weeks,follow-up at 60 daysPompeu et al. 2012[24]Effect of Nintendo WiiTM-based motor andcognitive training on activities of dailyliving in patients with Parkinson's disease:A randomised clinical trialTotal n = 32 PD • Both groups: low-intensity stretching,strengtheningSingle-blindrandomizedcontrolled trial• n = 16 exercise& Wii • Experimental group: Wii FitTM -basedmotor/cognitive training• n = 16 exerciseno Wii Control group: balance exercises withoutfeedback or cognitive stimulation• Sessions 1 hr/day, 2x/wk for 7 weeks,follow-up at 60 daysMüller et al. 2010 [23] Effect of exercise on reactivity and motorbehaviour in patients with Parkinson'sdiseaseTotal n = 22 PD • Single bout of high-intensity enduranceaerobic exercise (heart rate-targeted cycling)or rest following L-dopa administrationRandomizedcontrolledfeasibility trial,cross-over• Randomized order 1 day apartBaatile et al. 2000 [22] Effect of exercise on perceived quality oflife of individuals with Parkinson's diseaseTotal n = 6 PD • Low-intensity aerobic exercise programwith Nordic walking poles (PoleStriding)Nonrandomizedfeasibility trial,no control• Sessions 3x/week for 8 weeks*Subjects were assigned into the training group based on previous participation as a control in another study and upon referral by their physician. Baselinecharacteristics did not differ between the groups.Murray et al. Translational Neurodegeneration 2014, 3:5 Page 8 of 13http://www.translationalneurodegeneration.com/content/3/1/5function, it had no effect on learning [20]. DA levelsfollowing the chronic toxin administration were lowand potentially more difficult to increase with exercisedue to the substantial neurodegeneration.The obvious caveat to all studies using rodents toassess cognition is that the tasks of cognition, learn-ing and memory require motor function to evaluatetheir performance. The models used in these studiesTable 5 Outcomes and risk of bias of clinical trials on human Parkinson’s diseaseStudy Behavioral outcomes Major sources of risk of biasStudies that specifically measured executive function (n = 4)McKee et al. 2013 [29] • Tango improved disease severity (UPDRS-III)and spatial cognition/mental imagery (Brooks SpatialTask) more than education group, maintainedgains 10–12 weeks post-intervention• Detection bias: study was underpowered(n = 23 tango, n = 8 education) to evaluatesome main effects within groups, so maineffect of time was evaluatedCruise et al. 2011 [26] • Exercise improved verbal fluency and spatial workingmemory on Cambridge Neuropsychological TestAutomated Battery• Selection bias: the control group receivedusual care, no control for the effect of socialinteraction with exercise• Exercise was of “possible benefit” on semanticfluency and mood• Information bias: the variable intensity levelof the intervention could have affectedoutcomes• Exercise did not benefit spatial or pattern recognition,quality of life, had no negative impactRidgel et al. 2011 [28] • Time to complete Trail Making Test A & B (tests executivefunction) decreased after passive cycling• Selection bias: no control• Information bias: the same test pattern wasused pre- and post-intervention, althoughpractice effects were attempted to becontrolled through pre-test training withthe task• Performance improved on Trail Making Test B followingpassive cyclingTanaka et al. 2009 [27] • Exercise improved executive function for “CategoriesCompleted” (i.e., capacity for abstraction) and “PreservativeErrors” (i.e., mental flexibility) on the Wisconsin CardSorting Task• Selection bias: small sample size, no long-termfollow-up, not purely randomized•Information bias: no mention of medicationadministration; only one participant in the grouphad a heart rate monitor, so the intensity wastargeted towards the group and not theindividual• No interactions for confounding variables: concentratedattention, trait or state anxiety, depressionStudies that measured unspecified aspects of cognition (n = 4)Dos Santos Mendes et al. 2012 [25] • PD showed no deficit in learning or retention on 7/10games, deficits related to cognitive demands of tasks• Selection bias: the baseline physical fitness ofthe subjects was not compared• PD had worse performance than healthy individuals on5 tests• Performance bias: no PD controls not performingintervention, no control for enjoyment ormotivation• PD could transfer learning to an untrained motor task atfollow-upPompeu et al. 2012 [24] • Both groups improved UPDRS-II, MoCA and balance, noadditional advantage from Wii FitTM• Information bias: the baseline physical fitnessof the subjects was not compared, so potentialfor differences between groups• Improved scores on Wii FitTM games, maintained atfollow-up• No differences in outcomes between groups pre- topost-intervention or in follow-upMüller et al. 2010 [23] • Reaction time increased after rest and decreased afterexercise, movement time decreased after exercise• Selection bias: no PD control group, no healthycontrols• Information bias: one-day washout period(24 hours) may not have been long enough; pilot trial• Number of correct answers decreased after rest• Tapping rate increased after exercise• Detection bias: unclear how reactivity wasmeasured• Peg insertion interval time decreased after exercise(complex movement sequences, visual and spatialcognition, sorting and planning)Baatile et al. 2000 [22] • Improved UPDRS score (only total score significant) • Selection bias: limited sample size, no controlgroup; pilot trial• Improved PDQ-39 score, most improved in cognitioncomponent • Information bias: exercise intensity notstandardizedMurray et al. Translational Neurodegeneration 2014, 3:5 Page 9 of 13http://www.translationalneurodegeneration.com/content/3/1/5(i.e., MPTP, 6-OHDA and reserpine) are widely ac-cepted, although none of them recapitulates the indo-lent and progressive nature of PD [35-40]. It isunknown how the time of onset or intensity of theexercise paradigm initiated during or following the le-sion/toxin may affect the severity of parkinsonism.More promising models for the future would includetransgenic or knock-in rodents characterized by ex-pression of mutant or overexpression of wild-type α-synuclein. A related model is the injection of syn-thetic α-synuclein fibrils into the rodent brain. Thismodel shows progressive and selective loss of DAneurons in the substantia nigra pars compacta, aswell as cell-to-cell transmission in anatomically con-nected regions [41]. As cortical Lewy body pathologyis a major contributing factor to dementia in PD [42],future research with models of abnormal α-synucleindeposition may translate better into clinical researchand practice than models that create basal ganglialesions.The potential for exercise to improve cognition by re-ducing the impact of neuroinflammation is promising.Another study in a rodent model not dependent upon aselective dopaminergic neurotoxin found that forcedtreadmill and voluntary wheel exercise in rats can alsoalleviate impairments from brain inflammation on long-term potentiation and spatial learning [43]. The authorsinjected rats with lipopolysaccharides into the cerebralventricles to induce brain inflammation. They found thatboth treadmill and wheel training improved the resultingdeterioration in spatial learning. The effects of exerciseon learning were attributed to enhanced expression ofBDNF, tyrosine kinase B and phosphorylated cyclic AMPresponse element binding protein in the hippocampus.The impact of the injection on neuroinflammation wasnot documented. This model results in preferential butnot entirely selective nigral DA cell degeneration andthe findings may thus provide insight into potentialmechanisms of exercise in humans to reduce brain in-flammation and improve cognition.Overall, the results from these studies on rodent modelsof PD offer promising support for exercise to improvecognition in humans with PD through the promotion ofneuronal proliferation, neuroprotection, neurogenesis, andpotentially reduction in brain inflammation. These resultssupport recent work that highlights how exercise likelypromotes neurorestoration through activation of signalingcascades by neurotrophic factors [44]. Exercise has beenshown to affect regulation of DA function, including up-regulated DA D2 receptor mRNA and down-regulatedstriatal DAT in rodents [16]. High-intensity exercise alsoincreased DA D2 receptor availability in a recent feasibilitystudy by the same group using five human subjects (n = 2PD exercise, n = 2 PD no exercise, n = 1 healthy control)and positron emission tomography with [18F]fallypride[45]. While this small human trial does not assess cogni-tion, these findings encourage more clinical trials basedon rodent outcomes in this field. Overall, the evidencefrom rodent studies in this systematic review cannot bedirectly applied to mechanisms in humans yet, but theysuggest that PD patients would likely experience a mean-ingful improvement in cognition in response to exercise.Clinical evidenceClinical studies in humans demonstrate that various mo-dalities and intensity levels of exercise can improve cog-nitive capacity in PD, and especially executive function,although the mechanisms have not yet been determined.Cognitive dysfunction in PD is commonly associatedwith impaired executive function [46]. However, evaluat-ing research on cognition, and particularly executivefunction, in PD is challenging because mild cognitiveimpairment (MCI) in PD has only recently been definedand formal diagnostic criteria are still in development[47]. Selection and interpretation of measures of execu-tive function in PD have been challenging and the clin-ical implications are not yet fully appreciated [48].Executive function is generally related to goal-directedbehaviors processed by the frontal lobes of the brain. Ex-ecutive function has been categorized into four compo-nents: planning, purposive action, effective performanceand volition [49]. It is not known what frequency, inten-sity, type or timing of exercise might be most effectiveto improve executive function in PD, but there is evi-dence in older adults without PD that light aerobic exer-cise (walking), and not anaerobic exercise (stretchingand toning), selectively improves executive functionsprocessed in the frontal and prefrontal areas of the brain[50]. The potential different effects of aerobic comparedto anaerobic exercise on cognition in PD have not yetbeen studied.Exercise in animal models of PD may induce DA re-lease and enhance DA transmission via up-regulation ofDA D2 receptors [51,52]. A systematic review on the ef-fects of exercise in the elderly showed that moderate-intensity exercise can effectively increase peripheralBDNF [53]. Serum BDNF crosses the blood–brain bar-rier so these results may have implications for brain neu-rotrophin levels [54]. One of the animal studies reviewedin this paper also found that exercise increased BDNFand GDNF in the striatum [18]. The findings from thisreview support the theory of potential neuroprotectivebenefits of exercise for human PD. A recent review onthe benefit of exercise to improve cognition emphasizedthe potential neuroprotective effects of vigorous exercisein PD [13]. The authors provided guidelines includingvigorous exercise, structured programs for cognitivelyimpaired patients, and therapies that replenish DA toMurray et al. Translational Neurodegeneration 2014, 3:5 Page 10 of 13http://www.translationalneurodegeneration.com/content/3/1/5provide the maximum capability and motivation to exer-cise [13]. In addition to these guidelines, the current sys-tematic review shows that any exercise should beencouraged as it may benefit numerous aspects of pa-tients’ cognitive function and these effects could betransferrable to other tasks. Importantly, the effects ofvigorous exercise can last up to 60 days [25,29]. In thesestudies there was overall a high retention rate for subjectscommitting to a twice or three times weekly exercise pro-gram, suggesting that these interventions could be feasiblyimplemented as treatment programs. A recent meta-analysis showed that very light to vigorous exercise seemsto have a small effect on cognition in the acute phase fol-lowing exercise, but larger longer-lasting effects are pos-sible with more intense exercise [55].The benefits of exercise on cognition in PD are com-parable to those seen in healthy older adults. A recentreview showed that endurance and resistance exercisecan improve cognition in healthy seniors [7]. There isless research on the effects of exercise in frail olderadults, but recent evidence showed that a three-monthphysical activity intervention improved physical abilities,executive functions, processing speed and working mem-ory [56]. The effects of exercise on cognition in olderadults with MCI are less promising, as a recent meta-analysis showed only limited potential to improve cogni-tion [57]. However, the interpretation is constrainedbecause many of the publications were deemed by theauthors of this analysis to be of moderate quality andmany of the studies were underpowered. It is possiblethat exercise may have an impact on dopaminergic sig-naling that renders it particularly valuable in PD.Whether cognition in PD is improved due to dopa-minergic mechanisms of exercise or other mechanismssuch as increased neurotrophic factor availability orreduced neuroinflammation remains to be determined.LimitationsLimitations at the level of each study include risk of in-formation, performance and/or selection biases (Tables 2and 5) as well as confounds inherent with the limitationsof non-randomized trials. There was overall a lack ofreporting of concomitant medications (i.e., PD therapiesand antidepressants) as well as the medical condition ofthe subjects, which could have affected the results. Thelimitations of this review include potential for incom-plete retrieval of information given the search strategyand inclusion criteria. Additionally, it is not knownwhether there are genetic factors underlying response toexercise in PD.ConclusionsOverall, this systematic review found that exercise can im-prove cognitive function in animal models and human PD.Pre-clinical studies showed exercise results in behavioraland corresponding neurobiological changes in the basalganglia related to cognition. Specifically, learning andmemory improved after exercise in the rodents, althoughthe exact mechanisms remain unclear and merit further re-search. Pre-clinical studies also showed that any exercise isbetter than inactivity and that forced exercise has a greaterimpact than self-paced voluntary exercise. Exercise resultedin structural, neurochemical and molecular changes in ro-dents, which may be of relevance to the human disorder.The clinical studies showed that various types of exercise,including aerobic, resistance and dance can improve cogni-tive function, especially executive function in PD patients.However, the best type, amount, mechanisms, and durationof exercise are not yet known. The evidence from clinicalstudies suggests that a more intensive aerobic exercise pro-gram including strength and balance training can promotegreater cognitive gains. However, low-intensity exerciseand balance-based exercises also showed benefits.Research on the effects of exercise on cognition in PDis a relatively new area. As outlined in this review, thereare several limitations with the current studies in termsof study design and risks of bias. Questions that remainto be addressed include the prescription of exercise, ifany, which elicits the most gains as well as the durationof effects. Future research on the effects of exercise oncognition in PD should include a longitudinal random-ized controlled clinical trial examining neurobiologicalmechanisms in vivo, including neuroimaging. Under-standing the mechanism of benefit from exercise couldhelp us to harness its potential neuroprotective effects.Patients should use these findings as further rationale toincrease their daily physical activity. With growing sup-port for exercise to improve not only motor symptoms,but also cognitive impairments in PD, health care pro-viders and policy makers should recommend exerciseas part of routine management and neurorehabilitationfor PD.AppendixAppendix 1: Methodology on information sources, studysearch and collectionThe following electronic databases were searched for ar-ticles: PubMed, Web of Knowledge, and EBM Reviews(OvidSP). The primary search parameter for each data-base used the keywords, “Parkinson’s disease” AND “ex-ercise” AND “cognition” with the Boolean operator“AND”. Additional keywords related to cognition werealso searched by replacing “cognition” in the primarykeyword phrase one at a time with each of “dementia”,“Alzheimer”, “memory”, “executive function”, and “im-pulse”. Additional studies were identified by ancestrysearches of the articles yielded from the electronicsearch. No limits were provided for any of the databaseMurray et al. Translational Neurodegeneration 2014, 3:5 Page 11 of 13http://www.translationalneurodegeneration.com/content/3/1/5searches. Study author DM performed all aspects of thesearch, screen and identification of eligible studies (Figure 1).All studies identified through the information sources werecompiled on the citation manager, EndNote. The titles ofeach study were then screened to identify PD participants,including human subjects or PD-like animal models. Theabstracts of each remaining study were then searched manu-ally for the eligibility criteria. The full text was searched forarticles deemed to meet the eligibility criteria based on theirtitle and abstract. All data were extracted by the study au-thor DM in their existing form from the articles. The col-lected data and risk of bias [32] was used to assess theclinical studies for their quality of the evidence and deter-mine the strength of the recommendations (Table 3) basedon the Grades of Recommendations, Assessment, Develop-ment, and Evaluation (GRADE) ranking system [33]. Theclinical studies were assigned the same GRADE rankings bytwo independent raters (DM and MS).Additional fileAdditional file 1: PRISMA Guidelines Checklist.AbbreviationsMPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 5HT: Serotonin;6-OHDA: 6-hydroxydopamine; BDNF: Brain-derived neurotrophic factor;BDNF: Bromodeoxyuridine; DA: Dopamine; DAT: Dopamine transporter;EF: Executive function; GDNF: Glial cell-derived neurotrophic factor;L-dopa: Levodopa; LTP: Long-term potentiation; MCI: Mild cognitiveimpairment; MoCA: Montreal Cognitive Assessment; MPTP: 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine; ORP: Overall Rotarod performance;PDQ-39: Parkinson’s Disease Questionnaire; PD: Parkinson’s disease;p-CREB: Phosphorylated cyclic AMP response binding protein;5HT: Serotonin; PDQ-39-SI: Parkinson’s Disease Questionnaire-39-SingleIndex; TH: Tyrosine hydroxylase; TMT: Trail-Making Test; Trk-B: Tyrosinekinase B; UPDRS: Unified Parkinson’s Disease Rating Scale.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsDM conducted all aspects of the literature search and primary preparation ofthis manuscript. All authors critically revised drafts of this manuscript, andread and approved the final manuscript.Authors’ informationDanielle K. Murray is a graduate student in the Graduate Program inNeuroscience at the University of British Columbia.Matthew A. Sacheli is a graduate student in the Graduate Program inNeuroscience at the University of British Columbia.Janice J. Eng is a Professor in the Department of Physical Therapy at theUniversity of British Columbia.A. Jon Stoessl is a Canada Research Chair in Parkinson’s disease, Director ofthe Pacific Parkinson’s Research Centre and Professor and Head of Neurologyat the University of British Columbia.AcknowledgementFundingThis systematic review was not funded. AJS is supported by the CanadaResearch Chairs, Canadian Institute of Health Research, Michael J. FoxFoundation, Pacific Alzheimer Research Foundation and the PacificParkinson’s Research Institute.Author details1Pacific Parkinson’s Research Centre and Department of Medicine, Division ofNeurology, University of British Columbia & Vancouver Coastal Health,Vancouver, BC V6T 2B5, Canada. 2Department of Physical Therapy, Universityof British Columbia, Vancouver, BC V6T 1Z3, Canada.Received: 10 December 2013 Accepted: 14 February 2014Published: 24 February 2014References1. Aarsland D, Larsen JP, Lim NG, Janvin C, Karlsen K, Tandberg E, CummingsJL: Range of neuropsychiatric disturbances in patients with Parkinson'sdisease. J Neurol Neurosurg Psychiatry 1999, 67:492–496.2. Chaudhuri KR, Healy DG, Schapira AHV: Non-motor symptoms ofParkinson's disease: diagnosis and management. Lancet Neurol 2006,5:235–245.3. Macht M, Schwarz R, Ellgring H: Patterns of psychological problems inParkinson's disease. Acta neurologica Scandinavica 2005, 111:95–101.4. 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