As a common neurodegenerative disease, studies have shown that the prevalence of Parkinson’s disease is about 1–2% in people over 60 years of age (Bloem et al., 2021; Cabreira and Massano, 2019). Patients with Parkinson’s disease can exhibit a wide range of motor and non-motor symptoms, resulting in disruption of daily life and increased socio-medical burden. The focus of Parkinson’s disease research has been on motor symptoms, while non-motor symptoms are under-recognized and under-intervened clinically due to the insidious nature of the symptoms (Kumar et al., 2022). Fatigue is one of the common non-motor symptoms in Parkinson’s patients (Friedman and Friedman, 1993). Relevant studies have found that about half of Parkinson’s patients present with symptoms of fatigue, as evidenced by the presence of significantly reduced energy levels almost every day of the month or for most of the day, or by exhibiting fatigue that is disproportionate to the level of activity (Barone et al., 2009; Siciliano et al., 2018). In Parkinson’s patients fatigue often occurs insidiously and develops before the onset of motor symptoms and may be a major cause of disability (Friedman et al., 2007). The fatigue experienced by patients with Parkinson’s Disease, excluding other causes, is called Parkinson’s Disease-Related Fatigue (PDRF). PDRF is a feeling of exhaustion and weakness without a clear cause that is disproportionate to physical activity, which is chronic and unpredictable (Bruno and Sethares, 2015; Friedman et al., 2016). PDRF can have adverse effects on patients’ exercise capacity, cardiorespiratory fitness, quality of life, and social participation. PDRF can directly affect the aerobic capacity and exercise endurance of Parkinson’s patients, leading to a decline in motor function. In addition, one study showed that PDRF may further exacerbate neuropsychiatric symptoms such as apathy, depression, and anxiety, thus affecting patients’ quality of life (Béreau et al., 2022). Further studies have found that PDRF shows a gradual worsening trend with the progression of the disease (Ongre et al., 2021; Herlofson and Larsen, 2002). A longitudinal cohort study showed that patients with PDRF had a longer duration of illness, higher doses of levodopa medication, and more significant progression of motor symptoms as well as sleep, mood, cognitive, and autonomic dysfunction (Zhou et al., 2023). Moreover, PDRF increases in severity as the disease progresses and can interact with sleep disorders, pain, and psychosomatic problems, thus further decreasing patients’ quality of life (Diaconu et al., 2024). In some ways, the PDRF may be even more destructive due to the above adverse effects. Therefore, early identification and active intervention of PDRF are significant in improving the quality of life and the prognosis of patients with Parkinson’s disease (Heimrich et al., 2023; Mantri et al., 2021).

PDRF is not easy to draw attention to because of its insidious symptoms and the fact that it is mainly based on the patient’s subjective feelings. The diagnosis of PDRF is based on the simultaneous fulfillment of the following conditions: a confirmed diagnosis of Parkinson’s disease, the presence of fatigue and related symptoms, and the exclusion of other causes of fatigue (Kluger et al., 2016). PDRF is primarily assessed using questionnaires. The Fatigue Severity Scale (FSS) and The Multidimensional Fatigue Inventory (MFI) are commonly used clinical scales to assess fatigue in patients with Parkinson’s disease. The FSS focuses on assessing the extent and frequency of fatigue and its impact on daily life. The scale consists of nine items, each rated 0–7, and the total score is finally tallied. The total score reflects the fatigue status, the higher the score the greater the fatigue and the greater the impact on life. The MFI consists of 20 items, each rated on a scale of 1–7, and assesses fatigue on various dimensions, including physical, mental, and activity status. One study found that an FSS score of ≥37 and an MFI score of ≥60 had significant diagnostic value for Parkinson’s disease-related fatigue (Huether et al., 2023). PDRF should be distinguished from lethargy, emotional apathy, and depression in Parkinson’s patients. Characterized by energy deficiency and increased effort required for daily activities, PDRF has a different pathomechanism and treatment than other co-morbid symptoms in Parkinson’s patients. Indeed, PDRF is a multidimensional symptom encompassing physical sensations, emotional components, and cognitive involvement (Mantri et al., 2020). Currently, the diagnosis of PDRF relies on scale scores, and further research is needed to confirm the diagnosis of PDRF through relevant objective neurologic tests or markers (Sarmento et al., 2024).

The basic pathomechanism of Parkinson’s disease is the death of dopaminergic neurons in the substantia nigra and decreased secretion of neurotransmitters such as dopamine. A double-blind, placebo-controlled crossover study found that levodopa improved physical fatigue in patients with Parkinson’s disease, suggesting that PDRF is associated with reduced dopamine secretion (Lou et al., 2003). Some scholars agree that other non-motor symptoms of Parkinson’s disease such as sleep disorders, depression and anxiety, and affective and cognitive disorders may contribute to PDRF (Nassif and Pereira, 2018; Lin et al., 2024). According to the analysis of relevant research results, Pathological changes in brain networks, neuroinflammation, and autonomic dysfunction are possible causes of PDRF in patients. Pathological changes in brain networks are important clinical features. A clinical study found abnormal functional connectivity of the sensorimotor network system and bilateral precuneus associated with PDRF. Further, it looked to the left posterior central gyrus as a potential target of action for Parkinson’s Disease-Related Fatigue (Shan et al., 2023). Moreover, some scholars believe that the functional defects of the striatal-cerebellar-cerebral cortical network are involved in the pathological process of PDRF (Hou et al., 2022). In addition, abnormal alterations in functional brain regions related to psycho-cognition may also be a potential mechanism for PDRF. A clinical study found a significant correlation between reduced frontal perfusion and fatigue in Parkinson’s disease patients by SPECT (Abe et al., 2000). Further studies revealed that the altered connectivity of the default mode network in the frontal lobe and posterior cingulate cortex may be an important pathologic mechanism for patients with PDRF (Tessitore et al., 2016). Another study suggested that the frontoparietal attention network may mediate PDRF (Liu et al., 2022). Parkinson’s disease is closely related to the dysregulation of neuroimmune and inflammatory responses (Cohen et al., 2024). One study found that elevated levels of inflammatory components in the serum of PD patients may mediate the development of PDRF (Nikitina et al., 2024). A study on the relationship between plasma inflammatory cytokines and fatigue in Parkinson’s disease showed that plasma levels of inflammatory cytokines, such as IL-1β, IL-18, TNF-α, and phosphorylated α-syn, were significantly increased in patients with Parkinson’s disease accompanied by fatigue compared to those without associated symptoms (Wang et al., 2023). Abnormal aggregation of alpha-synuclein in Parkinson’s patients activates toll-like receptor 4, releasing pro-inflammatory cytokines. The binding of pro-inflammatory cytokines to the endothelial cells of the blood–brain barrier can disrupt the blood–brain barrier, and a large amount of pro-inflammatory cytokines enter the brain and inhibit the reuptake of glutamate by astrocytes, which may be a possible mechanism of Parkinson’s disease-associated fatigue (Wang et al., 2021). In addition to the above causes, autonomic dysfunction is associated with PDRF (Bansal et al., 2022; Zhao et al., 2021). Elevated serum homocysteine levels in Parkinson’s patients treated with levodopa can activate the sympathetic nervous system and lead to autonomic-related blood flow disorders (Mendes et al., 2014). In addition, abnormal vasodilation and contraction due to autonomic dysfunction can affect blood pressure and blood distribution, resulting in decreased muscle function and fatigue (Nakamura et al., 2011). Low-intensity resistance training with blood flow restriction can improve autonomic dysfunction and may be an effective form of exercise for PDRF (Bane et al., 2024).

In recent years, the understanding and treatment of PDRF have attracted increasing attention, but related progress remains slow. Currently, the treatment of PDRF can be categorized into pharmacological and non-pharmacological treatments, with the former including medications such as levodopa, dopamine agonists, rasagiline, and antidepressants, and the latter including non-invasive brain stimulation techniques, exercise therapy, acupuncture, and yoga. Since the efficacy of pharmacologic treatments is not conclusive, scholars are now turning to nonpharmacologic therapies as important interventions (Figure 1).

Neuroplasticity is a fundamental characteristic of the brain. As a self-adjustment mechanism of the human body to cope with changes in the internal and external environments, neuroplasticity is of great significance for neural development and injury repair (Johansson et al., 2020). As a fundamental property of the human brain to adapt to internal pathological damage and external environmental changes, neuroplasticity changes involve different molecular, cellular, and cortical tissue reorganization levels. The essence of neuroplasticity is the self-regulatory mechanism of the brain through structural and functional changes in response to chronic stress, injury, etc. (Zhang et al., 2018). Neuroplasticity is fundamental in neurodegenerative diseases such as Parkinson’s. In the face of the death of related neurons, how the surviving neurons adapt to this change, and compensate the neural network by adding new connections or accelerating neurotransmitter transmission, is significant for delaying the progression of the disease, and improving the related symptoms (Chen and Zhang, 2023). Non-invasive brain stimulation technology and exercise therapy are important therapies for regulating neuroplasticity. Among the non-invasive brain stimulation techniques, tDCS is mostly applied to PDRF treatment, and its specific action targets and parameters, etc. need to be continued to be researched to realize precise rehabilitation. Currently, the theory of exercise-induced neuroplasticity is attracting the attention of scholars. Summarizing the current relevant studies, exercise-induced neuroplasticity may be an important mechanism for the improvement of PDRF in patients.

As one of the common non-motor symptoms of Parkinson’s disease, PDRF has many adverse effects on patients. A related study found that more than half of PD patients in Turkey had problems with sleep, fatigue, mood, cognition, and urinary tract (Onder and Comoglu, 2024). PDRF is a multidimensional clinical condition associated with factors such as physical sensations, emotional changes, and cognition, and patients present with subjective high levels of distress. PDRF significantly impacts patients’ daily lives, and exploring its underlying pathophysiological mechanisms for targeted interventions is a direction for future research (Tinazzi et al., 2025). The specific etiology and pathogenesis are still in the exploratory stage, but it is imperative to understand PDRF based on biological, psychological, and social models (Weis, 2024). In recent years, studies on PDRF have attracted increasing attention from scholars. In the early recognition and diagnosis of PDRF, there are many problems with the current subjective scale assessment, and exploring possible biomarkers has become a hot research topic (Stocchi et al., 2024; Popescu et al., 2024). Mass spectrometry imaging (MSI), a novel molecular imaging technique that visualizes the distribution and content of molecular compounds, may be an early screening tool for non-motor symptoms in PD patients (Lai et al., 2024). In addition, exploring changes in serum biomarker levels with the help of relevant techniques may provide clinical implications for the early diagnosis of PDRF. It has been suggested that serum insulin-like growth factor 1 is correlated with non-motor symptoms in patients with Parkinson’s disease and may be a potential biomarker for PDRF (Gu et al., 2025). Treatment for PDRF is another topic of current research. Pharmacologic therapy is based on levodopa, dopamine agonists, rasagiline, and antidepressants, and the efficacy is not exact. Non-pharmacologic therapies have some potential to improve PDRF and deserve further in-depth study. From the current study, modulating functional cortical excitability and inducing changes in neuroplasticity may be important therapeutic concepts for PDRF (Andica and Kamagata, 2024; Jahan et al., 2024). In the future, in addition to continuing to study the pathomechanisms of PDRF, targeted development of non-pharmacological therapies that target neuroplasticity and functional cortex from the center may be the key to improving PDRF (Popescu et al., 2024; Sharbafshaaer et al., 2024).