Aerobic Exercise Preserves Olfaction Function in Individuals with Parkinson’s Disease

Abstract

Introduction。Based on anecdotal reports of improved olfaction following aerobic exercise, the aim of this study was to evaluate the effects of an 8-week aerobic exercise program on olfaction function in individuals with Parkinson’s disease (PD).Methods。三十八个参与者与特发性PD被随机分为有氧运动组（) or a nonexercise control group ()。有氧运动组完成了60-minute cycling session three times per week for eight weeks while the nonexercise control group received no intervention. All participants completed the University of Pennsylvania Smell Identification Test (UPSIT) at baseline, end of treatment, and a four-week follow up.Results。变化从基线锻炼和nonexercise组EOT之间UPSIT得分（) and from baseline to EOT+4 () favored the aerobic exercise group. Individuals in the nonexercise group had worsening olfaction function over time, while the exercise group was spared from decline.Discussion。在UPSIT得分的差异表明，有氧运动可以改变中枢神经系统通路调节生理和认知过程控制与PD个人的嗅觉。虽然这些结果提供了有前途的初步证据表明运动可以改变疾病进程，进一步系统评估是必要的。

1. Introduction

The majority of individuals with Parkinson’s disease (PD) experience olfaction dysfunction [1,2]。Hyposmia and anosmia are associated with loss of enjoyment of food, difficulty managing body weight, safety concerns (i.e., detecting gas and smoke), insecurities with body odor, and social isolation [3]。These factors lead to a decreased quality of life and increased rates of depression when compared to individuals with normal sense of smell [4]。

Although the exact mechanism for olfaction loss in Parkinson’s disease is unknown, it is likely that olfaction dysfunction is due to changes in the central nervous system (CNS) and is not a result of damage to the peripheral olfactory system [5]。It has been proposed that olfaction dysfunction in Parkinson’s disease evolves from Lewy bodies formed in the olfactory bulb and progresses to brain stem nuclei such as the locus coeruleus and substantia nigra and eventually to the cerebral cortex [6]。In addition, neurotransmitters such as acetylcholine, norepinephrine, serotonin, and, to a lesser extent, dopamine, all of which are typically altered in Parkinson’s disease, impact olfaction through various direct and indirect pathways [7]。

The clinical importance of hyposmia continues to evolve, and in individuals with PD olfaction testing can be used at a diagnostic tool [8] and is predictive of long-term cognitive decline and postoperative delirium [9–11]。在一大群从头患者，据报道，PD患者嗅觉减退表现出更严重的运动症状，并需要更大的左旋多巴当量为2.5年的随访相比，这些患者的正常嗅觉功能[12]。嗅觉在个体与PD的诊断和预测工具的重要性日益凸显作进一步检查的必要。

While hyposmia is not a target of PD treatment per se, antiparkinsonian medications have no effect on olfaction dysfunction [13,14]。它已经提出了深部脑刺激（DBS）可能会间接影响嗅觉;然而，大多数大型随机DBS的研究还没有利用的嗅觉成果的措施，并已报告的嗅觉结果的少数DBS的研究已相对较小的样本量进行并取得了相互矛盾的结果[15–18]。There is preliminary evidence that exercise may have a positive impact on olfaction. In an 8-week swimming intervention in adult rats, synapsin and neurotrophic factors in the olfactory bulb were greater in the exercise group than the nonexercise control group [19]。In a longitudinal study of over 1800 older adults, those who exercised three times per week were at a lower risk of developing olfaction dysfunction over a 10-year follow-up period [20]。These studies provide rationale to investigate the idea that exercise may facilitate neuroplasticity of the olfaction system.

Aerobic exercise, in animal models of Parkinsonism, has been shown to have neuroprotective and neurorestorative effects, likely through modulation of neurotrophic factors that support angiogenesis and synaptogenesis, suppress oxidative stress, and enhance mitochondrial function [21]。最近，我们已证明，有氧运动的具体方式，强迫运动（FE），如由盲临床评估测量减少运动症状，改善上肢运动功能和控制，并产生在皮层和皮层下的功能连接的变化[22–25]。在我们的初步研究，探讨强制和自愿的速度骑车，一些与会者与下面的有氧运动在嗅觉PD自我报告的改善，从而导致假设，即有氧运动可能是促进嗅觉系统中的神经可塑性。该项目的目的是评估正式的为期8周的强制和自愿的有氧运动计划对嗅觉功能与帕金森氏病的个体的影响。

2. Methods

2.1. Participants

Thirty-eight individuals with a diagnosis of idiopathic PD completed the informed consent process approved by the Cleveland Clinic Institutional Review Board. Primary inclusion criteria were clinical diagnosis of idiopathic PD by a neurologist, age between 30–75 years, and Hoehn and Yahr stages II-III when off antiparkinsonian medication. Primary exclusion criteria were existing cardiopulmonary disease or stroke, presence of dementia, and any medical or musculoskeletal contraindications to exercise. Participants completed a cardiopulmonary exercise (CPX) test on a stationary bicycle equipped with MedGraphics CardiO2/CP system with Breeze software and a twelve-lead electrocardiograph to screen for cardiac abnormalities that may warrant exclusion from the study.

2.2. Outcome Measure

The University of Pennsylvania Smell Identification Test (UPSIT), a 40-item “scratch and sniff” test, has been established as a valid and reliable tool for individuals with olfaction dysfunction and healthy controls [26]。After scratching the scent area, the participant selects a smell from 4 options in a forced-choice paradigm. A higher score (out of 40 points) indicates better odor identification. The UPSIT is a self-administered test that is objectively scored with an answer key. Testing was completed at baseline, end of treatment (EOT), and 4-week followup after end of treatment (EOT+4). In order to test participants in the off-medication state, subjects were asked to refrain from taking their PD medications after 8 pm the night before.

A blinded rater completed the Unified Parkinson’s disease Rating Scale (UPDRS) motor examination, a standardized test that assesses motor function in individuals with PD.

2.3. Experimental Design

Following baseline testing, individuals were randomized into one of the following groups: (1) FE Cycling (FE), (2) Voluntary Exercise Cycling (VE), and (3) Nonexercise control group. Randomization was performed by having participants draw an envelope from a nonreplenished box. Of note, olfaction testing was added to the study testing protocol of an ongoing aerobic exercise study due to subjects’ self-report of improved smell; thus the sample sizes were not evenly distributed.

2.4. Exercise Intervention

Participants in the VE and FE groups attended exercise sessions in the Neural Control Laboratory of the Cleveland Clinic, three times per week for a total of eight weeks. Participants were asked to take their PD medication as prescribed by their neurologist on the day of each exercise session. During exercise session, participants in the VE groups performed a 10-minute warm-up, 40- minute exercise set, and a 10-minute cool-down on a semirecumbent bike at a self-selected pace. Participants were encouraged to maintain a target heart rate zone of 60–80% based on heart rate reserve (HRR) method using results from individual maximal CPX test.

铁集团行使相同的时期time and target heart rate zone on a semirecumbent stationary exercise cycle custom engineered with a motor and accompanying control algorithm designed to augment the individual’s torque production during pedaling, thus resulting in a steady, high-rate cadence. It is important to note that the FE approach required active participation from the participant and that cycling was not passive. The motor assisted the individual in achieving a pedaling rate 30% greater than their preferred voluntary rate as determined during CPX testing, a percentage increase that resulted in global motor improvements in our previous work with PD [22,27]。For both exercise groups, cadence in revolutions per minute (rpm) and heart rate were recorded for each session.

The control group received no exercise intervention and was asked to continue their current level of physical activity.

2.5. Statistical Analysis

The primary outcome was the change in UPSIT scores from (1) baseline to EOT and (2) baseline to EOT+4. Shapiro-Wilk test was used to determine normality of the variables considered in the study. A 3 × 3 analysis of variance (ANOVA) model was used to examine UPSIT score changes at three time points (baseline, EOT, and EOT+4) for three groups (FE, VE, and nonexercise) and the interaction between the time and group variables. A two-sample-test was performed to determine the influence of exercise performance variables, cadence and HRR, between the two exercise groups. An analysis of covariance (ANCOVA) model was used to determine the association between the UPSIT and the exercise performance variables, HRR and cadence. All hypothesis testing was completed at 5% level of significance.

3. Results

Using UPSIT score as the dependent variable in the ANOVA model, neither group (F_2,105= 0.09，), time (F_2,105= 0.30,），或基团和时间（之间的相互作用F₄₁₀₅= 0.24,）是显著。尽管趋势是本为VE组到以更大的强度由测量HRR来锻炼，有运动强度之间没有差异显著为VE并与57.9手段和，分别HRR的48.9％的FE基（)。从ANCOVA结果，使用HRR作为因变量，揭示HRR和变化之间的VE和FE之间UPSIT分数（不显着的交互作用at EOT;at EOT+4). There was a significant difference in cadence between the VE and FE groups, with means of 69.7 and 82.9 rpms, respectively (）;然而，一个ANCOVA模型，使用韵律作为因变量，显示节奏和变化之间没有显着的相互作用在UPSIT评分组之间（at EOT;at EOT+4). Due to the similarities in exercise performance variables, data were collapsed across exercise groups for comparison to the nonexercise control group. Baseline demographics, provided in Table1, were similar between the exercise and the nonexercise groups.

Table2图1provide summary statistics for the exercise and control groups. A-test指示在运动和nonexercise组之间UPSIT得分显著差从基线到EOT（) and from baseline to EOT+4 ()。Figure2是一个图形化描述个人的响应es from each the groups from baseline to EOT. At EOT, no participants in the nonexercise group demonstrated an improvement on the UPSIT with a mean decrease of 2.9 (2.3) points. In contrast, 12 out of 23 individuals in the exercise group demonstrated an improvement in UPSIT scores; overall there was a mean decrease of 0.5 (3.3) points. From baseline to EOT+4, the nonexercise group had a decrease of 2.7 (3.4) points in UPSIT score while the exercise group exhibited a slight improvement of 0.2 (3.5) points.

但没有关系nders (those who improved their UPSIT score) and nonresponders (those who stayed the same or got worse in their UPSIT score) and the demographic variables listed in Table1。

4. Discussion

Based on the UPSIT data, PD patients who did not exercise demonstrated a worsening of olfaction throughout the 8-week study and 4-week follow-up period, while those participating in aerobic exercise were spared from further worsening of olfaction function. The significant difference in UPSIT scores between the exercise and nonexercise groups suggests that aerobic exercise may be altering neurophysiological pathways or neurotransmitter function that regulate the physiologic or cognitive processes controlling olfaction [19,20]。While we are not able to determine the exact mechanism underlying a sparring of olfaction, it is plausible, based on results from animal exercise studies, that the physiological changes (i.e., increased neurotrophins, neurotransmitters, and improved functional connectivity) and increases in cerebral blood flow associated with intensive aerobic exercise may have facilitated function of the olfaction system centrally or improved the higher level cognitive processes associated with odor detection [21,28,29]。虽然我们以前的成像数据载体改变激活的CNS图案初级运动皮质，辅助运动区，丘脑，苍白球和壳核[24,25], there is still much unknown about the role that aerobic exercise plays in modifying the structural and functional role of the CNS.

Although debated, olfaction function may worsen with disease duration [三十], which is consistent with the nonexercise group demonstrating a decline in UPSIT scores over time. The wide range of change in UPSIT scores from the exercise group gives rise to the possibility that there is an individualized neurophysiological response to exercise ([28,31,32]). Individualized responses are reported with pharmacological interventions to PD, where some individuals exhibit a strong favorable response to levodopa therapy and others experience modest benefits [33]。Since our previous research revealed acute bouts of FE that resulted in CNS changes similar to those seen with Parkinson’s disease medications [24,25),它是可能的,类似的药物,印第安纳州ividuals experience varying responses to aerobic exercise. The genetic response to exercise continues to be evaluated; Bath and colleagues reported impaired odor discrimination associated with brain derived neurotrophic factor (BDNF) val66met polymorphism in mice and propose a mechanism of decreased neurogenesis in the olfactory bulb as a result of the polymorphism [34]。While we are unable to speculate if genetics played a role in our results, the role of genetics in response to exercise in individuals with PD is an area for future study.

There are limitations to the current study. First, the sample was a relatively small group of individuals with mild to moderate Parkinson’s disease; thus the data should be interpreted within this context. A larger scale () clinical trial is currently testing a similar cycling protocol that includes a variety of motor and nonmotor outcomes, including the UPSIT. Second, we did not screen for individuals who may have had preexisting nasal disease or olfactory dysfunction. Third, although the UPSIT is a well-studied test, the minimal clinical important difference is unknown; thus we are not able to determine if a change in the score is meaningful to the participant. Additionally, although the UPSIT is an odor identification test that is easily administered in a clinical setting, odor detection and threshold are not measured by this test. Notably, there was no difference in UPSIT scores between the FE and VE groups; thus it appears that the mode of cycling was less important than the aerobic nature of the exercise. In the future it will be important to determine the relationship between mode, frequency, duration, and intensity of aerobic exercise and olfaction dysfunction in PD.

These findings, although preliminary, have potential to impact quality of life in individuals with PD. Hyposmia is one of the top five symptoms in individuals diagnosed with PD ≤6 years in duration [35], and individuals with olfactory dysfunction are more likely to report difficulties with activities of daily living and to rely on community resources [36]。A meaningful implication of halting the progression of anosmia with aerobic exercise is the potential that exercise may modify the disease progression. The difference in UPSIT scores exhibited by the exercise group supports previous findings that intensive aerobic exercise is linked to global changes in PD function [22,23]。This work may have significant implications regarding the relationship between exercise and brain function and the potential to modify the course of this progressive neurological disorder through exercise.

5. Conclusion

在这项研究中，由UPSIT测量，而谁没有演习展示个人UPSIT得分恶化与PD谁参加有氧运动，24次个人保持他们的嗅觉功能。虽然这些结果提供了有前途的初步证据表明运动可以改变疾病进程，还需要进一步系统的测试。

Disclosure

The content is solely the responsibility of the authors and does not necessarily represent the views of the funding sources.

利益争夺

Jay L. Alberts has authored intellectual property associated with the algorithm used in the control of the forced-exercise cycle. The remaining authors declare no competing interests.

Acknowledgments

The authors would like to thank Amanda M. Penko and A. Elizabeth Jansen for their assistance with subject recruitment, protocol implementation, and data collection. This study was made possible by support from the National Institute of Health under Award no. R21HD056316 and B6678R VA Merit Review and the Davis Phinney Foundation.

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Copyright

Copyright © 2016 Anson B. Rosenfeldt et al. This is an open access article distributed under theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.