Are physical activity levels, cardiorespiratory fitness and peak power associated with Parkinson's disease severity?

physical activity levels


Introduction
Parkinson's disease (PD) is a chronic, progressive, and neurodegenerative disorder of the central nervous system with an elusive etiology (1).Currently, only symptomatic pharmacological treatment is available (2), making identification of disease modifying interventions highly warranted.Interestingly, high levels of physical activity (PA), which includes routine daily activities (e.g., household chores, walking) and exercise (e.g., aerobic training, strength training), have been suggested as a potential disease modifying treatment strategy (3,4).Since people with PD (pwPD) are generally less physically active compared to healthy matched controls, increasing the PA levels in pwPD may constitute a course of action (5).If so, associations between markers of PA and PD severity could serve as a useful steppingstone to scientific advancement and as justification of further studies evaluating PA in pwPD.
The association between PA and PD severity has been investigated previously.Crosssectional studies report none to strong inverse associations between both subjectively and objectively reported PA and scores of the Unified Parkinson Disease Rating Scale (UPDRS) or the Movement Disorder Society-sponsored revision of the UPDRS (MDS-UPDRS) (5)(6)(7)(8)(9)(10).
Additionally, Snider et al. (8) investigated the associations between PA and the individual PD motor symptoms (i.e., rigidity, bradykinesia, postural instability, and tremor), quantified by specific items from the UPDRS III (motor examination).The findings included weak to moderate negative associations between non-exercise PA and bradykinesia and postural instability sub-scores.However, the study was limited by including primarily men, no adjustments for confounders, and use of self-reported PA (11).Consequently, there is a need to assess the associations between objectively measured PA (i.e., accelerometry) and the individual motor symptoms, while adjusting for potential confounders such as age and sex.
In PD, muscle peak power, muscle strength, and cardiorespiratory fitness (i.e., maximal oxygen consumption; VO 2 -max) are considered key performance and health indicators (3,(12)(13)(14)(15) that are modifiable by exercise and PA (3,16).The associations between these markers and (MDS-)UPDRS scores may reflect the impact of long-term exposure to high or low levels of PA and/or exercise on disease severity.However, the association between VO 2 -max and PD severity is currently inconclusive.One study reported a weak negative correlation between VO 2 -max and the MDS-UPDRS III score (17), while other studies did not find any association (18,19).A clearer trend exists for the association between lower extremity

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Journal Pre-proof muscle strength and PD severity, as studies report moderate to strong inverse associations between muscle strength and (MDS)-UPDRS II and III scores (20)(21)(22)(23).However, regarding the individual PD motor symptoms, only muscle power has been reported to be weakly associated with bradykinesia and rigidity (24).Overall, the associations between VO 2 -max or muscle power and MDS-UPDRS scores and the individual PD motor symptoms need further investigation.
While the MDS-UPDRS is a clinical marker of PD severity, the Parkinson's Disease Questionnaire-39 (PDQ-39) reflects the individual's perspective on disease impact (25).The PDQ-39 is frequently used and considered an important outcome in PD exercise studies (3).
Despite this, there is only sparse data on the associations between physical measures (e.g., PA, VO 2 -max, muscle power) and PDQ-39 total-and sub-scores.To our knowledge, only PA has been shown to be inversely associated with PDQ-39 total-and sub-scores (6,26).
However, these studies used self-reported PA and did not adjust for potential confounders.It is therefore also of relevance to investigate the associations between different physical measures and PDQ-39 scores, while adjusting for potential confounders.
Consequently, the objectives were to quantify and assess the associations between three physical outcomes (i.e., PA, VO 2 -max, muscle peak power) and the MDS-UPDRS, the individual motor symptoms, as well as the PDQ-39 total-and sub-scores.It was hypothesized that PA, VO 2 -max, and lower extremity muscle power would be associated with the MDS-UPDRS II and III score, as well as with the PDQ-39 total score and mobility and activities of daily living (ADL) sub-score.In addition, the associations between the three physical outcomes and each individual PD motor symptom would be investigated explorative.

Methods
This cross-sectional study presents baseline data from a randomized controlled trial (clinicaltrials.gov;NCT04379778) investigating the effects of a 24-week high-intensity aerobic exercise intervention on PD severity in low to moderately active pwPD.Baseline data from the randomized controlled trial are combined with simultaneously collected crosssectional data from highly active pwPD.The highly active group was included to increase the sample size and to provide a more representative spread of physical activity levels.In total, data from 105 pwPD (70 low to moderately active pwPD and 35 highly active pwPD) were

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Journal Pre-proof included.The study was approved by the ethical committee of the Central Denmark Region (record no.1-10-72-260-18) and conducted in accordance with the Helsinki Declaration.

Study design and participants
Participants were recruited through the Depts. of Neurology at Aarhus University Hospital, Kolding Hospital, and Odense University Hospital and via private neurological clinics in Esbjerg, Aarhus, Skanderborg, and Horsens.Furthermore, participants were recruited via the Danish Parkinson's Disease Association's website.Interested pwPD were screened via a phone-conversation regarding fulfilment of the eligibility criteria.
To be included, the participants had to give signed informed consent, be clinically diagnosed by a neurologist with idiopathic PD within the past five years, be ≥ 40 years, have a Hoehn & Yahr stage ≤ 3 (27), expect to be able to complete the scheduled tests and intervention, stable on PD medication or not expecting to begin taking PD medication during the period, and be able to transport themselves back and forth from the test and training facilities.Exclusion criteria were alcohol abuse (screened through their medical journal), depression (screened through their medical journal), pacemaker, pregnancy, metallic implants preventing MRI scans, blood pressure >160/100 on the test days, and cardiovascular, respiratory, orthopedic, or metabolic disorders or other medical comorbidities hindering participation in maximal exercise testing.
Group allocation of pwPD was based on telephone interviews covering specific questions about exercise duration, frequency, and intensity.The latter was specifically questioned by the participant's sensations of breathing and heart rate during the activities.High-intensity aerobic exercise was classified as longer lasting physical activity, where the participant experienced shortness of breath and/or high heart rate.Highly active pwPD were defined as performing high-intensity aerobic exercise ≥ 2 times/week, while low to moderately active pwPD were defined as performing < 2 times/week (28).After inclusion, all participants were scheduled to their baseline tests including the MDS-UPDRS, muscle peak power, VO 2 -max, PA, and the PDQ-39.All tests were completed by the same assessor on individual tests days.
Five MDS-UPDRS certified assessors were affiliated to the study, and they aligned test ratings between them before the start of the study and during the study.All tests were conducted at the Exercise Biology unit, Dept. of Public Health, Aarhus University, Denmark.

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PDQ-39
The PDQ-39 was completed online at home in the week leading up to the baseline test.The questionnaire is designed specifically to assess the impact of PD from an individual perspective.It consists of 39 items covering 8 dimensions.The score from each dimension is computed into a scale ranging from 0 (i.e., no problem) to 100 (i.e., maximum level of problem).The PDQ-39 is considered valid and reliable to assess health related quality of life (HRQoL) for pwPD (25).

Muscle peak power
Lower extremity muscle peak power was measured during the concentric phase of a chair rise.Peak power was measured using a linear encoder (CHRONOJUMP, Bosco system, v1.8.1, Barcelona, Spain; sampling rate 1000 Hz) and calculated using the built-in software, based on the characteristics of the participants (sex and weight).The participants were instructed to rise from the chair as fast and powerful as possible, reaching a fully standing erect position without lifting their feet.Two attempts were given, and the highest peak power was used in the analyses.

VO 2 -max
To determine directly measured VO 2 -max, an incremental exercise test until exhaustion was performed on a SRM bicycle ergometer (SRM, Jülich, Germany) in accordance with the protocol previously described by Jensen et al. (31).Briefly, five minute warm up was performed.Afterwards the load was increased with 10 Watt/min (women) or 15 Watt/min (men) until exhaustion.This protocol is considered both valid and reliable for pwPD (31).

Physical activity
The physical activity level was objectively measured using a triaxial accelerometer (Axivity AX3; Axivity Ltd, Newcastle, United Kingdom).The accelerometer was attached to the midthigh of the non-dominant leg using self-adhesive tape.Participants were instructed to wear the device day and night for seven consecutive days and only detach it if swimming.Ten hours of accepted data had to be reached per day, for a minimum of four days, to be valid and subsequently included (32).Raw activity data were sample at 100Hz+-8g and downloaded and analyzed using the OMGUI software (version 1.0.29),including data reduction and aggregation using a custom-built macro in MatLab (MathWorks, MatLab 2017, Natick, MA, USA; macro developed by Engineer Cuno Rasmussen, Exercise Biology, Aarhus University, Denmark).The vector magnitude counts data were presented in 30s epochs over an 18-h period, starting from 6AM.Ultimately, PA was presented as counts per minute (cpm), with higher cpm indicating a higher overall activity level.The Axivity AX3 accelerometer is considered valid for detecting activities in functionally impaired individuals (33).

Statistics
Variables modelled as continuous data followed a normal distribution and mean ± standard deviation (SD) were calculated unless stated otherwise.Simple linear regression analyses were conducted between each of the three physical outcomes (i.e., PA, VO 2 -max, and peak power) and MDS-UPDRS scores as well as the individual PD motor symptoms.Associations adjusted for age and sex were calculated using multiple linear regression analyses.Model validation was performed by inspecting the standard residuals (plots of the standardized residuals against fitted, QQ-plots, and plots of the standardized residuals against each variable).Data was log-transformed when appropriate (i.e., tremor score), but presented as raw point values.Log-transformed associations were back-transformed by the exponential function to median ratios.Moreover, the MDS-UPDRS IV score was not normally distributed and thus calculated with spearman rank correlation.Correlations ≥ 0.90 were considered very strong (corresponding to r 2 ≥ 0.81), 0.70-0.89as strong (corresponding to r 2 between 0.49-0.79),0.40-0.69as moderate (corresponding to r 2 between 0.16-0.48),0.10-0.39 as weak

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Journal Pre-proof (corresponding to r 2 between 0.01-0.15),and <0.10 as negligible (corresponding to r 2 < 0.01) (34).Hurdle regression analyses were applied to assess the associations between the three physical outcomes and PDQ-39 total-and sub scores, using both a univariate and multivariate (adjusting for age and sex) model.Based on the model validation (i.e., QQ-plots) hurdle exponential regression analysis was chosen.In general, hurdle regression analysis is preferred to determine associations when an outcome consists of excessive zeros (i.e., 2-66 zeroscores).A hurdle model consists of two parts; a zero-part equal to binomial logistic regression analysis that predicts the probability of having a positive dependent variable (e.g., PDQ-total score>0) and a count-part (i.e., only positive values) which estimates the contribution of an independent variable (e.g., muscle peak power) to the dependent variable (e.g., PDQ-39 total score).In this study, only the count-part was considered relevant and therefore presented.However, the results of the zero-part are also included in the supplemental material (Table S2).To elucidate the potential effect of medication for both MDS-UPDRS and PDQ-39, multiple linear regression analyses and hurdle exponential regression analyses were performed adjusting for both age, sex, and levodopa equivalent daily dose.Statistical calculations were performed in Stata version 17.0 (StataCorp LLC) and figures were made in GraphPad Prism version 9.0 (GraphPad Software, La Jolla, CA, USA, www.graphpad.com).

Results
Baseline demographics, physical and clinical outcomes of the participants are presented in table 1.A total of 105 pwPD were included in the study.However, three participants did not complete the patient-reported parts of the MDS-UPDRS (parts Ib and II) and seven did not complete the PDQ-39 questionnaire.Furthermore, the PA, VO 2 -max, and peak power analyses included between 99-101 participants.Reasons for this included a lost accelerometer (n=1), less than 4 days of valid accelerometer data (n=3) and technical problems during the VO 2 -max (n=6) and linear encoder (n=4) tests.All participants were tested on medication except for two participants who did not take dopaminergic medication.Median wear time of the accelerometers was 18 hours/day (range: 10-18 hours/day) for 7 days (range: 6-7 days), including 4-5 weekdays.

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Journal Pre-proof Tables 2 and 3 show the simple and multivariate regression analyses of the three physical measures (i.e., PA, VO 2 -max and peak power) and MDS-UPDRS and individual PD motor symptoms, respectively.PA, VO 2 -max, and peak power were weakly to moderately inversely related to the MDS-UPDRS III, bradykinesia, and postural instability scores (r 2 =0.14-0.26).
Furthermore, PA and peak power were weakly inversely related to the MDS-UPDRS II score (r 2 =0.05 & 0.06), while PA was also weakly inversely related to the rigidity score (r 2 =0.08).
All these associations persisted when adjusting for age and sex.We also adjusted for levodopa equivalent daily dose with no substantial changes (data not shown).

Discussion
The primary findings of the present study were that three objectively measured physical outcomes were all inversely associated with the MDS-UPDRS III, bradykinesia, and postural instability score, while PA and peak power were also inversely associated with the MDS-UPDRS II score.Furthermore, PA was inversely associated with rigidity.Lastly, PA and VO 2 -max were inversely related to mobility and ADL sub-scores.These consistent findings across the cardiovascular-and neuromuscular body systems support a potential link between three commonly used physical measures and PD disability, suggesting that PD severity could be positively impacted by changing the general PA levels and/or by improving key fitness indicators in pwPD.

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PA and PD severity
In the present study, PA was weakly to moderately inversely associated with MDS-UPDRS II and III scores.Comparable relationships with the MDS-UPDRS II (9) and III scores (6,7) have been reported previously, despite different methodologies.Also, moderate to strong associations with the MDS-UPDRS II score (5,6), as well as no or weaker associations with the MDS-UPDRS III score (5,8,10) have been reported.The discrepancies related to MDS-UPDRS III may be explained by methodological differences in either PA sampling (i.e., accelerometer vs. questionnaire or wrist-placed accelerometer vs. thigh-placed accelerometer), PA-outcome (i.e., total number of steps, bouts of brisk walking, total energy consumption), or study sample (i.e., men only and small sample size (<n=30)).The use of validated PA measure and a large study population consisting of women and men with PD in the present study support the studies (6,8,9) showing weak to moderate associations between PA and MDS-UPDRS II and III.To our knowledge, this is the first study to quantify the associations between objectively measured PA and the individual core PD motor symptoms.
Weak to moderate inverse associations were observed between PA and rigidity, bradykinesia, and postural instability scores.However, PA and the tremor score were not associated.In comparison, Snider et al. (8) showed comparable associations between self-reported nonexercise PA and bradykinesia and postural instability scores but no associations with rigidity or tremor scores.Overall, our results support our hypothesis, as well as the existing literature, with inverse associations between PA levels and PD motor symptom severity, thus highlighting the potential importance of maintaining/obtaining high PA levels in pwPD.
Another matter of importance from the perspective of pwPD's, is whether PA levels are associated with HRQoL.In accordance with our hypothesis, PA was inversely associated with mobility and ADL sub-scores.These results are supported by the existing literature reporting weak to strong inverse associations (6,26), as well as further inverse associations with other sub-scores (i.e., emotional well-being, stigma, social, cognition, communication, and bodily discomfort).However, these studies used self-reported PA information and different statistical analyses (i.e., spearman rank correlations and pearson correlations), thus complicating direct comparison.

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The existing evidence for the association between VO 2 -max and PD severity is inconclusive.Kolk et al. (17) reported a weak negative correlation between VO 2 -max and the MDS-UPDRS III score, while Ivey et al. (18) reported no association between the UPDRS III and VO 2 -peak when adjusting for age and sex.In contrast to the latter, a weak inverse association was observed in the present study between VO 2 -max and the MDS-UPDRS III score, which remained when adjusting for age and sex.This discrepancy may be explained by the use of different VO 2 test modalities as treadmill exercise brings higher demands for balance compared to cycling.The additional balance requirements could lead to test termination before reaching the true VO 2 -max.Additionally, Ivey et al. (18) reported VO 2 -peak, defined as the highest VO 2 value measured, which may not necessarily reflect the true VO 2 -max.This could blur the reported association with disease severity and may explain why Kolk et al. (17) observed an association when using VO 2 -max.
Although bradykinesia, postural instability, rigidity, and tremor are considered the hallmark motor symptoms of PD, no studies have previously investigated their associations with VO 2max.The present study found moderate associations between VO 2 -max and bradykinesia and postural instability, but no association with rigidity or tremor.Despite these mixed findings and unclear causality, the present results may suggest that, by increasing their VO 2 -max, pwPD may attenuate PD motor progression, especially bradykinesia and postural instability symptoms.However, this context needs further investigation in appropriately designed longitudinal studies.Furthermore, no studies have previously examined the association between VO 2 -max and PDQ-39 scores, despite HRQoL being a vital outcome.In this study, VO 2 -max showed inverse associations with mobility and ADL sub-scores after adjusting for age and sex.

Peak power and PD severity
Weak to moderate inverse associations between peak power and MDS-UPDRS II and III scores confirmed our hypothesis in the present study.In comparison, four studies (20)(21)(22)(23) have previously reported moderate to strong negative correlations between muscle strength outcomes and UPDRS II and III scores.This discrepancy may be explained by the use of different muscle strength/power outcomes (i.e., maximal voluntary contraction, rate of force development, peak power).This study assessed peak power, whereas muscle strength was assessed in the previous studies.When assessing the individual PD motor symptoms, peak J o u r n a l P r e -p r o o f Journal Pre-proof power was moderately inversely associated with bradykinesia and postural instability scores.
Only one study (24) has previously examined the same, reporting similar, although weaker, associations between muscle power and bradykinesia and rigidity scores.Lastly, contrary to our hypothesis and the findings regarding both PA and VO 2 -max, peak power was surprisingly not related to mobility and ADL sub-scores but instead the social sub-score in the unadjusted analysis.

Direction of causality
The present findings showed potential links between three commonly used physical measures and PD severity, suggesting a potential positive effect of increasing the general PA level, the VO 2 -max, and the peak power on disease severity.However, due to the cross-sectional nature of the study, the direction of causality cannot be determined.To this end, longitudinal studies have indicated a reduction of the MDS-UPDRS III score following both aerobic-and strength training interventions (3).Moreover, long-term exercise interventions (≥12 weeks) can (safely) increase both the VO 2 -max (aerobic exercise intervention) and lower extremity muscle strength (resistance training intervention) in pwPD (3).This notion is further supported by animal studies with PD models showing reduced alfa-synuclein aggregation (35) and toxin-induced lesions in the nigrostriatal pathway following aerobic exercise (36,37).The underlying mechanisms of such neuroprotective effects of exercise could be explained by an increase in neurotrophic factors (37).However, the present study adds further support to future human studies elucidating the potential beneficial effects of aerobic exercise and resistance training on PD severity, as well as on specific individual motor symptoms.
In the present study, stronger associations were generally observed between peak power and MDS-UPDRS scores and PD motor symptoms compared to VO 2 -max.Although reverse causality or bidirectional association cannot be excluded based on the current study design,

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Journal Pre-proof The same tendency was observed when comparing associations for PA and VO 2 -max with PD severity, with stronger associations for PA compared to VO 2 -max.This may be explained by PA encompassing all kinds of activities (routine daily activities and exercise), whereas VO 2 -max more specifically reflects engagement in moderate to high-intensity exercise.The potential additive positive effects of routine daily activities are supported by Snider et al. (8), who reported that only non-exercise PA was associated with PD severity (UPDRS III score).
One explanation could be that routine daily activities represent more fine motor-controlled movements compared to regular exercise.Wang et al. (39) showed broader functional connectivity of the prefrontal cortex with the striatum in PD rats completing skilled aerobic exercise compared to PD rats completing regular aerobic exercise.VO 2 -max, but not muscle power, was associated with mobility and ADL sub-scores.These findings contradict longitudinal studies showing positive effects on HRQoL only after completing resistance training (3).However, other factors (e.g., social interaction and participating in a training program) might explain this discrepancy.Thus, further studies are needed to clarify the associations between these physical measures and HRQoL.Lastly, the present study also found an inverse association between PA and PDQ-39 sub-scores, which might also be explained by the representation of all kinds of physical activities involved in PA.

Methodological considerations
The present study included three objective physical fitness indicators representing both the cardiovascular-and neuromuscular body systems.The simultaneous associations across body systems in the same sample of pwPD thus strengthen the potential link between PA/exercise and PD severity.However, the study also has several limitations.First, although PA was measured objectively, some activities are not registered (e.g., swimming, upper-body RT), which may impact the associations.Second, causality cannot be inferred from the present study and also reverse causality or bidirectional association cannot be elucidated due to the study design.Third, the study population consisted of newly diagnosed pwPD (≤ 5 years since diagnosis) with a Hoehn & Yahr ≤ 3. The results cannot be generalized to pwPD with more severe disability or more years since diagnosis.Fourth, we did not correct for multiple comparisons which increases the risk of type-1-errors.However, doing so would conversely increase the risk of type 2-errors (40).

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Conclusion
In relatively newly diagnosed pwPD, PA and physical fitness were weakly to moderately inversely associated with PD severity, thus highlighting the potential benefits of a physically active lifestyle.Furthermore, PA and VO 2 -max were inversely associated with sub-scores of the PDQ-39.This calls for confirmation of the potential effect of PA on HRQoL in PD.

MDS-UPDRS
I (0-52) 102 8.9 (5. this could indicate that resistance training interventions could be more effective in attenuating PD severity and specifically bradykinesia and postural instability symptoms.In support of this, Shulman et al. (38) compared three exercise interventions (high-and low-intensity endurance training and resistance training) and found that only the resistance training group significantly decreased in UPDRS III score following 12 weeks of training.However, future randomized controlled trials are needed to consolidate these findings.

Table 1 :
Demographic, physical and clinical measures of the participants