Aerobic exercise-induced changes in fluid biomarkers in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms that progressively deteriorate and for which there is no disease-modifying pharmacological treatment. Exercise is widely recommended for individuals with PD due to its potential neuroprotective benefits. However, the mechanisms underlying these exercise-induced effects in PD remain poorly understood. Analyzing fluid biomarkers responsive to exercise could offer valuable insights into the mechanisms by which exercise impacts PD and aid in optimizing exercise prescriptions for individuals with PD. This review explores exercise-responsive biomarkers categorized into three key groups-neurotrophic, inflammatory, and neuroendocrine markers. It highlights both well-validated biomarkers and candidates with promising potential. We also highlight key biomarkers linked to PD pathology, such as α-synuclein, and their potential connection to exercise based on current evidence. Comprehensive characterization of these biomarkers will advance our understanding of the biological effects of exercise in PD, enabling mechanism-based and objective measures to evaluate exercise response in future clinical trials and its impact on PD signs and symptoms.

Fig. 1. Proposed Model for Exercise-Induced Changes in Biomarkers and their Mechanisms in PD.

Chronic aerobic exercise leads to liberation of neurotrophic factors, modulation of inflammatory factors, and modulation of neuroendocrine factors. Downstream mechanisms may include enhanced neuronal synthesis, structural and behavior adaptations. Adapted from Paillard et al. 2023. BDNF brain-derived neurotrophic factor, GDNF glial cell line-derived neurotrophic factor, IGF-1 insulin-like growth factor 1, VEGF vascular endothelial growth factor, GPLD1, glycosylphosphatidylinositol-specific phospholipase D1, TNF tumor necrosis factor, IL-6 interleukin-6, CRP C-reactive protein.

Fig. 2. Exercise-Induced Changes in Neurotrophic/Neuroprotective Factors.

Chronic aerobic exercise stimulates elevations in multiple neurotrophins, with a most robust response in BDNF, VEGF, and IGF-1 in the periphery and in the CNS. Irisin, GPLD1, SIRT3, and lactate are involved in tissue-brain crosstalk to mediate positive benefits of exercise, with one mechanism being an increase in neurotrophins such as BDNF by GPLD1. Elevation in neurotrophic factors has been linked to pathways that counter neurodegeneration and synaptic plasticity. BDNF brain-derived neurotrophic factor, GDNF glial cell line-derived neurotrophic factor, IGF-1 insulin-like growth factor 1, VEGF vascular endothelial growth factor, GPLD1 glycosylphosphatidylinositol-specific phospholipase D, SIRT3 sirtuin-3. Created in BioRender. Mehta, N. (2025) https://BioRender.com/a05k823.

Fig. 3. Expected exercise-induced changes in inflammatory markers.

There are chronic increases in inflammatory markers in both central nervous system and periphery in PD. There is increased permeability of the BBB in PD, and many inflammatory markers including IL-6, TNF, IL-1β, and clusterin can cross the BBB, while others such as CRP and CX3CL1 modulate the permeability of the BBB in PD. Chronic aerobic exercise may be effective at reducing levels of inflammatory markers in both the central nervous system and periphery. PD Parkinson’s disease, BBB blood brain barrier, IL-6 interleukin-6, TNF tumor necrosis factor, IL-1β interleukin-1 beta, CRP c-reactive protein, CX3CL1, fractalkine. Created in BioRender. Mehta, N. (2025) https://BioRender.com/d17z951.

Fig. 4. Exercise-induced changes in neuroendocrine markers.

In PD, there is persistent elevation of stress hormone cortisol, increased insulin resistance, and reduction in klotho levels. These abnormalities have been linked to increased neuroinflammation, oxidative stress, neurodegeneration, and aging. Chronic aerobic exercise can help lower blood cortisol levels, reduce insulin resistance, and increase blood klotho levels, which may counter these pathological pathways. While cortisol and insulin can cross the BBB, klotho cannot cross the BBB and has two distinct pools (CNS and periphery). PD Parkinson’s disease, BBB blood brain barrier, CNS central nervous system. Created in BioRender. Mehta, N. (2025) https://BioRender.com/j77o278.

Fig. 5. Potential interactions between exercise and markers of PD pathology.

Exercise may induce increases in irisin, clusterin, and SIRT3, markers that have been shown to reduce conversion of misfolded α- synuclein to pathological α-synuclein. Pathological α-synuclein aggregate formation in PD can lead to oxidative stress, mitochondrial dysfunction, pro-inflammatory cytokine release, and neuronal degeneration. Insulin resistance also associates with increased α-synuclein aggregate formation, but exercise may decrease insulin resistance and thus reduce aggregated protein. Axonal injury in PD releases NfL with preliminary evidence suggesting exercise may lower circulating NfL levels. α-syn, α-synuclein; SIRT3 sirtuin-3, NfL neurofilament light chain. Created in BioRender. Mehta, N. (2025) https://BioRender.com/h90y253.