Niyati Mehta
Nijee S. Luthra
Daniel M. Corcos
Giamila Fantuzzi- 1Department of Physical Therapy and Human Movement Sciences, Northwestern University, Chicago, IL, United States
- 2Movement Disorder and Neuromodulation Center, University of California, San Francisco, San Francisco, CA, United States
- 3Department of Kinesiology and Nutrition, College of Applied Health Science, University of Illinois at Chicago, Chicago, IL, United States
Parkinson’s disease (PD), a heterogeneous disease with no disease-modifying treatments available, is the fastest growing neurological disease worldwide. Currently, physical exercise is the most promising treatment to slow disease progression, with evidence suggesting it is neuroprotective in animal models. The onset, progression, and symptom severity of PD are associated with low grade, chronic inflammation which can be quantified by measuring inflammatory biomarkers. In this perspective, we argue that C-reactive protein (CRP) should be used as the primary biomarker for monitoring inflammation and therefore disease progression and severity, particularly in studies examining the impact of an intervention on the signs and symptoms of PD. CRP is the most studied biomarker of inflammation, and it can be detected using relatively well-standardized assays with a wide range of detection, allowing for comparability across studies while generating robust data. An additional advantage of CRP is its ability to detect inflammation irrespective of its origin and specific pathways, an advantageous characteristic when the cause of inflammation remains unknown, such as PD and other chronic, heterogeneous diseases.
Introduction
Physical exercise is a promising treatment to slow disease progression in various chronic, complex, heterogeneous diseases that share an inflammatory component, such as metabolic syndromes, type II diabetes, multiple sclerosis, Parkinson’s Disease (PD) and many others. Several ongoing intervention studies are assessing the effectiveness of multiple exercise modalities and intensities on disease progression (1–4). In this perspective, we will focus on PD.
PD is the fastest growing neurological disease worldwide and has no disease-modifying treatments. Despite the heterogeneity of its signs and symptoms, treatment of PD relies largely on dopaminergic medications to alleviate motor symptoms. However, over time, the effectiveness of these medications is challenged by continued disease progression and a rise in adverse effects (5, 6). A growing body of evidence supports the beneficial role of exercise in PD. In animal models of PD, exercise is neuroprotective (7) while in humans multiple exercise modalities reduce signs and symptoms of PD (8–10). However, the mechanisms by which exercise provides benefits in PD–as in many other diseases–remain unclear. Inflammation is an emerging component of PD pathogenesis that can be a target for neuroprotection and disease modification (11). Indeed, at least one study reports that chronic use of nonsteroidal anti-inflammatory drugs reduces the risk of PD by about 45%, suggesting that inflammation may play a pathogenic role in PD (12).
Several biomarkers, both individually and as multi-molecular panels, can be used to determine the presence of and quantify the severity of inflammation. Of these, the acute-phase protein C-reactive protein (CRP) is the most studied (13). Here, we elaborate on the reasons for selecting CRP as the biomarker of choice to monitor inflammation in response to exercise in PD and in studies examining the effect of exercise in other diseases with an inflammatory component (14).
C-reactive protein
Circulating levels of CRP increase rapidly during the acute-phase response, which can be initiated by infection, inflammation, or trauma (15). Inflammatory mediators such as the cytokine IL-6 induce transcription and translation of the CRP gene in hepatocytes (16), with other mediators and cell types also contributing to the rise in circulating levels of CRP (17–19). The biology and regulation of production of CRP have been extensively reviewed and we refer the reader to this vast literature for details (16, 20–24).
The designation of CRP as an acute-phase protein is misleading because levels of CRP (and of other positive acute-phase proteins) increase in virtually all conditions characterized by inflammation, irrespective of whether the course is acute or chronic. In response to an acute infection, CRP levels in peripheral blood can reach concentrations >1 g/L, i.e., thousands of folds up from the ≤1 mg/L observed in non-infected individuals (21). However, CRP levels increase more modestly, yet significantly and consistently, in a wide range of chronic, non-infectious conditions, such as cardiovascular disease (CVD), accelerated vascular aging, autoimmune diseases, obesity, Type 2 Diabetes, Alzheimer’s disease, and PD (14, 20, 25). In these conditions, CRP levels rarely reach the peak observed during acute infections, largely staying below 10 mg/L, but they signal the presence of low grade, chronic inflammation (26). Inflammaging, the presence of low-level chronic inflammation in older adults, is also associated with a modest but consistent elevation in CRP (27).
CRP in Parkinson’s Disease
Plasma and cerebrospinal fluid (CSF) CRP levels are associated with PD risk, prognosis, and symptom severity. A meta-analysis of 23 studies shows that individuals with PD have significantly higher CRP levels both in the peripheral circulation and in the CSF compared with matched healthy controls (13), indicating that either inflammation is a risk factor for PD or that PD leads to inflammation, and possibly both. Newly diagnosed PD patients have higher systemic CRP levels than people without PD, suggesting that inflammation is already present in the early stages of disease (28). Additionally, across the time course of the disease, patients with PD exhibit higher systemic and CSF CRP levels compared to healthy controls (13) and, independent of disease duration or symptom severity, baseline CRP levels in patients with PD are associated with risk of death and predicted life prognosis (29). CRP levels are also related to PD disease stage, as patients with higher Hoehn & Yahr scores, and therefore more severe motor symptoms, exhibit higher levels of systemic CRP (30, 31). One study found that CSF CRP concentrations correlate with motor symptom severity, measured using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor examination score (Part III), in male PD patients and with measures of cognitive performance in female patients, suggesting a possible sex dimorphism in CRP as a marker of inflammation in PD and/or in the pathogenic mechanisms of motor versus non-motor symptoms (32). Moreover, CSF CRP levels are higher in patients with PD-related dementia as compared to PD patients without dementia (33) and are also associated with severity of depression, anxiety, and fatigue in PD (33). Thus, despite the heterogeneous nature of PD, CRP–and therefore inflammation–is associated with many of its manifestations in terms of risk, progression, and symptom severity.
CRP: marker or maker?
There are many ways in which CRP may directly contribute to disease pathogenesis in PD, given its known role in the clearance of necrotic material, recruitment of the complement system, and more (34). However, epidemiological studies indicate that CRP is unlikely to play a major direct role in the pathogenesis of PD, similarly to what has been demonstrated in CVD. Genetic variants in the promoter of the CRP gene that modulate circulating levels of CRP have helped clarify the role of CRP in the pathogenesis of CVD. While elevated levels of CRP consistently predict adverse cardiovascular events, epidemiological studies demonstrated a lack of association between CRP genetic variants and CVD (30). That is, high CRP due to genetic variants without underlying inflammation does not increase the risk of CVD by itself, demonstrating that it is the underlying inflammation that contributes to disease risk, not CRP itself. Similarly, in PD, a large Genome-Wide Association Study failed to identify an association between CRP genetic variants and increased risk of PD (35). These studies indicate that while CRP predicts disease risk and progression, its participation in disease pathogenesis is questionable, at best. Thus, in PD, we should consider CRP as a marker rather than a maker, i.e., as a biomarker that detects the presence of inflammation and quantifies its severity rather than as a direct participant in disease pathogenesis.
CRP and physical exercise
In clinical studies, CRP is well established as a biomarker to monitor the effects of exercise on inflammation. Indeed, more than 400 randomized controlled trials in various populations and at least 80 systematic reviews or meta-analyses have evaluated the effect of different modalities and intensities of exercise on CRP levels. While there may be a short-lived increase in CRP levels after each exercise bout, since exercise can be an acute stressor, most studies indicate that over time physical exercise lowers CRP levels (7, 36), with aerobic exercise being the most beneficial, especially in older adults (36). Evidence suggests that physical exercise reduces CRP levels following a dose-response relationship, with higher intensity exercise causing a greater reduction in CRP over time compared to lower intensity exercise, and with longer interventions being more efficacious than those of shorter duration (37). Although no studies have yet examined the effect of exercise on CRP levels in PD, exercise, particularly aerobic interventions, counteract the increase in CRP that accompanies aging (27, 38). This is relevant to PD, as age is its primary risk factor (39–41), and can be described as a pre-PD state (39). Furthermore, exercise is a critical component in the prevention and management on Type 2 Diabetes, a condition that is associated with more severe symptoms and accelerated progression of PD and that shares inflammation as a pathogenic mechanism (14).
Discussion
There are several ongoing trials examining the effects of exercise interventions on PD (2, 4), including the Study in Parkinson’s disease of exercise phase 3 (SPARX3). SPARX3 is a Phase 3, multisite, randomized, two-arm (1:1 allocation), parallel group, evaluator-blinded, clinical trial to test the superiority hypothesis that high-intensity, endurance treadmill exercise slows the progression of the signs of PD compared to moderate-intensity endurance treadmill exercise (4). A change in the MDS-UPDRS Part III score is the primary outcome. Several biomarkers serve as secondary outcomes that might point to the mechanisms underlying the effects of exercise intensity in PD, including a potential reduction in inflammation (42).
In SPARX3, we could have chosen a variety of biomarkers to monitor inflammation in response to endurance exercise. Indeed, we plan to explore levels of cytokines and several other mediators in participants’ systemic circulation. However, several reasons led us to select CRP as the sole inflammation-related pre-specified outcome.
The fact that CRP is by far the most studied biomarker of inflammation, both in exercise and in PD as well as in many other diseases, will permit comparison between the findings of SPARX3 and those of hundreds of other studies. Moreover, compared to other mediators, CRP allows for better comparability across studies due to the higher standardization of the CRP assay compared to that of most cytokines and many other inflammatory mediators. Moreover, unlike most cytokines, levels of CRP can be reliably quantified even in the absence of inflammation, thus avoiding the clustering of values at the lower edge of the sensitivity curve that plagues most cytokine assays.
Lastly, and perhaps most importantly, CRP is nonspecific, meaning that it can detect the presence of inflammation, and quantify its changes, irrespective of the ultimate origin of the inflammatory response and of the mechanisms at play. This characteristic of CRP is very useful in PD, in which the cause and pathways of inflammation have not been identified. Similarly, because the mechanisms by which exercise reduces inflammation are also unidentified thus far, the lack of specificity of CRP becomes an asset. Studies that aim to investigate the location, triggers, and pathways of inflammation in PD, and the mechanisms by which exercise reduces inflammation, must quantify specific markers, such as individual cytokines. However, if the aim of a study is to determine whether inflammation is present and/or whether its severity can be altered through an intervention–as is the case in SPARX3–a nonspecific marker such as CRP is more appropriate, as its modulation is independent of the origin and characteristics of the inflammatory response. Thus, nonspecific is not always a dirty word, particularly when it comes to the interplay of PD, exercise, and inflammation. If SPARX3 demonstrates that endurance exercise is associated with reduced levels of CRP, as is our hypothesis, studies evaluating the mechanisms underlying this effect will be warranted.
For all the reasons outlined above, CRP should be utilized as the biomarker of choice for evaluating the response to exercise interventions in PD and other neurodegenerative diseases and chronic conditions. However, like any biomarker, there are limitations in the utility of CRP. First, CRP is sensitive to any form of inflammation, meaning that inflammation unrelated to PD, such as an infection, will increase CRP levels. This, however, is a challenge of nearly all inflammatory biomarkers, and not unique to CRP. Also, CRP levels are affected by genetics, and this will influence CRP levels irrespective of disease severity and exercise effectiveness. However, this can be overcome by averaging CRP levels across subjects to reduce the effect of genetic variations on CRP levels and/or by utilizing intra-subject longitudinal comparisons. Despite these limitations, we argue that CRP is the most effective biomarker for monitoring the effects of exercise interventions on the level of inflammation in PD and other conditions.
Conclusion
Researchers investigating the effects of physical exercise in PD and many other diseases are faced with lack of knowledge about the specific pathways in which inflammation is implicated both in disease pathogenesis and in the beneficial effects of the intervention. Here we argued that the current situation should not hamper progress in the field, that evaluating the effectiveness of exercise in PD and other conditions does not need to wait for mechanistic studies to elucidate such pathways. Indeed, choosing CRP as the biomarker of choice to monitor the state of inflammation during an intervention overcomes many of the limitations of current knowledge.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author contributions
NM – execution, writing, and editing of the final version of the manuscript. NL – writing and editing of the final version of the manuscript. DC – writing and editing of the final version of the manuscript. GF – execution, writing, and editing of the final version of the manuscript. All authors contributed to the article and approved the submitted version.
Funding
Author NL – Recipient of grant funding through K23NS123506. Author DC – Recipient of grant funding through U01NS113851.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. Corporation OHIR. Exercise training in patients with persistent or permanent atrial fibrillation (2019). Available at: https://ClinicalTrials.gov/show/NCT03397602.
2. Hospital SJs, Medical Center P. Exercise in advanced parkinson’s disease (PD) with deep brain stimulation (DBS) (2022). Available at: https://ClinicalTrials.gov/show/NCT05204680.
3. University IM. Comparison of the effects of green exercise programs on metabolic syndrome parameters in elderly individuals (2022). Available at: https://ClinicalTrials.gov/show/NCT05251597.
4. University N, Pittsburgh Uo, Group TPS. Study in Parkinson disease of exercise (2021). Available at: https://ClinicalTrials.gov/show/NCT04284436.
5. Bartus RT, Emerich D, Snodgrass-Belt P, Fu K, Salzberg-Brenhouse H, Lafreniere D, et al. A pulmonary formulation of l-dopa enhances its effectiveness in a rat model of parkinson’s disease. J Pharmacol Exp Ther (2004) 310(2):828–35. doi: 10.1124/jpet.103.064121
6. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA (2014) 311(16):1670–83. doi: 10.1001/jama.2014.3654
7. da Costa Daniele TM, de Bruin PFC, de Matos RS, de Bruin GS, Maia Chaves CJ, de Bruin VMS. Exercise effects on brain and behavior in healthy mice, alzheimer’s disease and parkinson’s disease model-a systematic review and meta-analysis. Behav Brain Res (2020) 383:112488. doi: 10.1016/j.bbr.2020.112488
8. Gamborg M, Hvid LG, Dalgas U, Langeskov-Christensen M. Parkinson’s disease and intensive exercise therapy - an updated systematic review and meta-analysis. Acta Neurol Scand (2022) 145(5):504–28. doi: 10.1111/ane.13579
9. Gollan R, Ernst M, Lieker E, Caro-Valenzuela J, Monsef I, Dresen A, et al. Effects of resistance training on motor- and non-motor symptoms in patients with parkinson’s disease: a systematic review and meta-analysis. J Parkinsons Dis (2022) 12(6):1783–806. doi: 10.3233/JPD-223252
10. Schenkman M, Moore CG, Kohrt WM, Hall DA, Delitto A, Cornella CL, et al. Effect of high-intensity treadmill exercise on motor symptoms in patients with De novo Parkinson disease a phase 2 randomized clinical trial. JAMA Neurol (2017) 75(2):219–26. doi: 10.1186/s13063-022-06703-0
11. Hirsch EC, Vyas S, Hunot S. Neuroinflammation in parkinson’s disease. Parkinsonism Relat Disord (2012) 18 Suppl 1:S210–2. doi: 10.1016/S1353-8020(11)70065-7
12. Chen H, Zhang S, Hernán MA, Schwarzschild MA, Willett WC, Colditz GA, et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurology. (2003) 60:1059–64. doi: 10.1001/archneur.60.8.1059
13. Qiu X, Xiao Y, Wu J, Gan L, Huang Y, Wang J. C-reactive protein and risk of parkinson’s disease: a systematic review and meta-analysis. Front Neurol (2019) 10:384. doi: 10.3389/fneur.2019.00384
14. Cullinane PW, de Pablo Fernandez E, Konig A, Outeiro TF, Jaunmuktane Z, Warner TT. Type 2 diabetes and parkinson’s disease: a focused review of current concepts. Mov Disord (2022) 2:162–77. doi: 10.1002/mds.29298
15. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem (2004) 279(47):48487–90. doi: 10.1074/jbc.R400025200
16. Volanakis JE. Human c-reactive protein: expression, structure, and function. Mol Immunol (2001) 38(2-3):189–97. doi: 10.1016/S0161-5890(01)00042-6
17. Agrawal A, Cha-Molstad H, Samols D, Kushner I. Overexpressed nuclear factor-kappaB can participate in endogenous c-reactive protein induction, and enhances the effects of C/EBPbeta and signal transducer and activator of transcription-3. Immunology (2003) 108(4):539–47. doi: 10.1046/j.1365-2567.2003.01608.x
18. Ganapathi MK, Rzewnicki D, Samols D, Jiang SL, Kushner I. Effect of combinations of cytokines and hormones on synthesis of serum amyloid a and c-reactive protein in hep 3B cells. J Immunol (1991) 147(4):1261–5. doi: 10.4049/jimmunol.147.4.1261
19. Ramadori G, Sipe JD, Dinarello CA, Mizel SB, Colten HR. Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1. J Exp Med (1985) 162(3):930–42. doi: 10.1084/jem.162.3.930
20. Banait T, Wanjari A, Danade V, Banait S, Jain J. Role of high-sensitivity c-reactive protein (Hs-CRP) in non-communicable diseases: a review. Cureus (2022) 14(10):e30225. doi: 10.7759/cureus.30225
21. Suffredini AF, Fantuzzi G, Badolato R, Oppenheim JJ, O’Grady NP. New insights into the biology of the acute phase response. J Clin Immunol (1999) 19(4):203–14. doi: 10.1023/A:1020563913045
22. Du Clos TW. Function of c-reactive protein. Ann Med (2009) 32:274–8. doi: 10.3109/07853890009011772
23. Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol (2005) 117(2):104–11. doi: 10.1016/j.clim.2005.08.004
24. Szalai AJ, van Ginkel FW, Wang Y, McGhee JR, Volanakis JE. Complement-dependent acute-phase expression of c-reactive protein and serum amyloid p-component. J Immunol (2000) 165(2):1030–5. doi: 10.4049/jimmunol.165.2.1030
25. Babcock MC, DuBose LE, Witten TL, Stauffer BL, Hildreth KL, Schwartz RS, et al. Oxidative stress and inflammation are associated with age-related endothelial dysfunction in men with low testosterone. J Clin Endocrinol Metab (2022) 107(2):e500–e14. doi: 10.1210/clinem/dgab715
26. Eklund CM. Proinflammatory cytokines in CRP baseline regulation. Adv Clin Chem (2009) 48:111–36. doi: 10.1016/S0065-2423(09)48005-3
27. Bautmans I, Salimans L, Njemini R, Beyer I, Lieten S, Liberman K. The effects of exercise interventions on the inflammatory profile of older adults: a systematic review of the recent literature. Exp Gerontol. (2021) 146:111236. doi: 10.1016/j.exger.2021.111236
28. Song IU, Chung SW, Kim JS, Lee KS. Association between high-sensitivity c-reactive protein and risk of early idiopathic parkinson’s disease. Neurological Sci (2011) 32:31–4. doi: 10.1007/s10072-010-0335-0
29. Sawada H, Oeda T, Umemura A, Tomita S, Kohsaka M, Park K, et al. Baseline c-reactive protein levels and life prognosis in Parkinson disease. PloS One (2015) 10(7):e0134118. doi: 10.1371/journal.pone.0134118
30. Luan YY, Yao YM. The clinical significance and potential role of c-reactive protein in chronic inflammatory and neurodegenerative diseases. Front Immunol (2018) 9:1302. doi: 10.3389/fimmu.2018.01302
31. Andican G, Konukoglu D, Bozluolcay M, Bayulkem K, Firtiina S, Burcak G. Plasma oxidative and inflammatory markers in patients with idiopathic parkinson’s disease. Acta Neurol Belg. (2012) 112(2):155–9. doi: 10.1007/s13760-012-0015-3
32. Moghaddam HS, Valitabar Z, Ashraf-Ganjouei A, Zadeh MM, Sherbaf FG, Aarabi MH. Cerebrospinal fluid c-reactive protein in parkinson’s disease: associations with motor and non-motor symptoms. NeuroMolecular Med (2018) 20:376–85. doi: 10.1007/s12017-018-8499-5
33. Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, et al. Cerebrospinal fluid inflammatory markers in parkinson’s disease–associations with depression, fatigue, and cognitive impairment. Brain Behav Immun (2013) 33:183–9. doi: 10.1016/j.bbi.2013.07.007
34. Michigan A, Johnson TV, Master VA. Review of the relationship between c-reactive protein and exercise. Mol Diagn Ther (2011) 15(5):265–75. doi: 10.1007/BF03256418
35. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-Scale meta-analysis of genome-wide association data identifies six new risk loci for parkinson’s disease. Nat Genet (2014) 46(9):989–93. doi: 10.1038/ng.3043
36. Kohut ML, McCann DA, Russell DW, Konopka DN, Cunnick JE, Franke WD, et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun (2006) 20(3):201–9. doi: 10.1016/j.bbi.2005.12.002
37. Rose GL, Skinner TL, Mielke GI, Schaumberg MA. The effect of exercise intensity on chronic inflammation: a systematic review and meta-analysis. J Sci Med Sport. (2021) 24(4):345–51. doi: 10.1016/j.jsams.2020.10.004
38. Khalafi M, Malandish A, Rosenkranz SK. The impact of exercise training on inflammatory markers in postmenopausal women: a systemic review and meta-analysis. Exp Gerontology. (2021) 150. doi: 10.1016/j.exger.2021.111398
39. Collier TJ, Kanaan NM, Kordower JH. Aging and parkinson’s disease: different sides of the same coin? Mov Disord (2017) 32(7):983–90. doi: 10.1002/mds.27037
40. Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med (1996) 334(2):71–6. doi: 10.1056/NEJM199601113340202
41. Tysnes OB, Storstein A. Epidemiology of parkinson’s disease. J Neural Transm (Vienna). (2017) 124(8):901–5. doi: 10.1007/s00702-017-1686-y
Keywords: C-reactive protein, Parkinson’s disease, inflammation, exercise, biomarker
Citation: Mehta N, Luthra NS, Corcos DM and Fantuzzi G (2023) C-reactive protein as the biomarker of choice to monitor the effects of exercise on inflammation in Parkinson’s disease. Front. Immunol. 14:1178448. doi: 10.3389/fimmu.2023.1178448
Received: 02 March 2023; Accepted: 02 May 2023;
Published: 12 May 2023.
Edited by:
Alok Agrawal, East Tennessee State University, United StatesReviewed by:
Valentino Racki, University of Rijeka, CroatiaCopyright © 2023 Mehta, Luthra, Corcos and Fantuzzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Niyati Mehta, niyati.mehta@northwestern.edu