Possible inflammatory mechanisms and predictors of Parkinson's disease patients with fatigue (Brief Review).

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra and the abnormal cytoplasmic accumulation of proteinaceous aggregates called Lewy bodies (LBs), mainly composed of α-synuclein (α-syn). In recent years, it has been gradually recognized that fatigue is one of the most common and disabling symptoms in PD patients, with a prevalence of approximately 50%. Although neuroinflammation, a pathological hallmark of PD, is closely associated with fatigue, present mechanisms of fatigue in PD patients have not yet been systematically summarized, with their inflammatory predictors remaining controversial. Therefore, the aim of this brief review is to fill in the gaps in our understanding on the inflammatory factors involved in the pathophysiological mechanisms of fatigue and predicting its occurrence in PD patients. The determination of fatigue is mainly assessed using the Parkinson Fatigue Scale 16 (PFS-16) and Fatigue Severity Scale 9 (FSS-9). Several studies have reported that inflammatory marker levels, such as interleukin-6 (IL-6), and other inflammatory predictors closely associated with fatigue, such as soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), and red blood cell distribution width (RDW), may help detect fatigue. Moreover, the following inflammatory mechanisms may be involved. (1) Abnormal aggregation of α-syn undergoes a conformational change, which then activates toll-like receptor 4 (TLR4) to release a large number of proinflammatory cytokines, causing fatigue symptoms. (2) Chronic peripheral inflammation and immune activation responses induce elevated levels of proinflammatory cytokines in PD patients, which enter the brain mainly through the traditional endocrine route or via direct vagus nerve transmission. The rising levels of proinflammatory cytokines cause the destruction of the blood-brain barrier (BBB) by combining with BBB endothelial cells, allowing many proinflammatory cytokines to cross the destroyed BBB and enter the brain, preventing astrocytes from reuptaking glutamate and laying foundations for the occurrence of fatigue. Furthermore, studies have suggested that fatigue symptoms in PD patients often represent a poor prognosis. Nevertheless, if the aforementioned inflammatory markers can effectively predict the occurrence of fatigue and allow early intervention, the prognosis of PD patients could be significantly improved. At present, its management mainly includes medical treatment (levodopa, dopamine receptor agonists, rasagiline, and antidepressants) and non-medical treatment (acupuncture and yoga). Thus, it is of great significance to be able to practice early detection and intervention in fatigue and improve the prognosis of patients with PD.