Correlation of inflammatory markers with depression and sleep disorders accompanying the prodromal stage of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder with increasing incidence and disability rates globally, placing a heavy burden on patients and their families. In the prodromal phase of PD, nonmotor symptoms, particularly depression and sleep disorders, are frequent, with profound effects on disease progression and patient quality of life. Emerging research highlights the critical role of inflammatory markers-including interleukins and tumor necrosis factor-in the pathogenesis of prodromal PD. These inflammatory mediators participate in neurodegenerative processes and may induce or exacerbate depressive symptoms and sleep disorders by disrupting the function of the hypothalamic-pituitary-adrenal axis and affecting neurotransmitter, including serotonin, metabolism. Understanding their correlations with nonmotor symptoms in prodromal PD remains incomplete, limiting our ability to develop targeted interventions. This comprehensive review aims to investigate the specific correlations between inflammatory markers and nonmotor symptoms-particularly depression and sleep disorders-in prodromal PD. The findings could have important practical applications, potentially leading to the development of new diagnostic tools and therapeutic strategies for managing PD. By identifying and understanding these correlations, healthcare providers may better predict disease progression and implement more effective treatments for nonmotor symptoms in PD.

Key Words: Parkinson's disease; Prodromal Parkinson's disease; Inflammatory markers; Depression; Sleep disorders

Core Tip: This review highlights the critical role of inflammatory markers such as interleukins and tumor necrosis factor in the prodromal phase of Parkinson’s disease. It explores their connection to nonmotor symptoms, particularly depression and sleep disorders, by disrupting the hypothalamic–pituitary–adrenal axis and neurotransmitter metabolism. By addressing considerable knowledge gaps, the review underscores the potential of these markers as predictive indicators of symptom severity and progression. The findings aim to inspire the design of new diagnostic tools and therapeutic strategies, ultimately improving disease management and patient outcomes.

INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms. Inflammation plays a critical role in the pathogenesis of PD, potentially contributing to both neurodegeneration and the progression of nonmotor symptoms. The expression of inflammatory biomarkers such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 is significantly altered in patients with PD, reflecting the complex process of neuroinflammation[1-4]. These inflammatory mediators accelerate disease progression by activating microglia, promoting oxidative stress, and inducing neuronal damage. Data indicate that the global prevalence of PD increased by 74% between 1990 and 2016[5]. This dramatic increase underscores the importance of understanding the complex mechanisms underlying the disease development and progression. Currently, PD diagnosis is based on clinical criteria, which require the presence of bradykinesia along with at least one additional motor symptom, such as tremor, stiffness, or postural instability[6]. The incubation period for nonmotor symptoms before meeting the current diagnostic criteria for PD, known as the prodromal phase, can vary between 5 and 20 years. During this prolonged prodromal phase, subtle changes in neurological and immunological processes begin to manifest, presenting a crucial window for potential early intervention.

Depression is a common nonmotor symptom during this phase. Depressive symptoms can affect the quality of life of patients with PD by aggravating motor symptoms, accelerating disease progression, and impairing cognitive function. At the neurobiological level, depression in PD is associated with complex interactions between neurotransmitter dysregulation, neuroinflammatory processes, and structural brain changes. Studies have found that elevated levels of proinflammatory cytokines, such as IL-6 and TNF-α, are positively correlated with the severity of depression. These inflammatory mediators can cross the blood-brain barrier, affecting neurotransmitter balance and triggering neuroendocrine abnormalities[7-9]. Therefore, early recognition of these nonmotor symptoms is crucial, as it can potentially slow disease progression and improve patient outcomes through targeted interventions.

Sleep disorders are the most common nonmotor symptoms in patients with PD, with an overall incidence ranging from 47.66% to 89.10%[5,10] and increasing annually with disease progression. These sleep disturbances represent more than just a secondary symptom, serving as potential early biomarkers of neurological dysfunction. Common sleep disorders in PD include excessive daytime sleepiness (EDS), rapid eye movement sleep behavior disorder (RBD), periodic limb movements in sleep, restless legs syndrome (RLS), and sleep-disordered breathing (SDB). Studies have found that sleep disturbances are closely associated with neuroinflammation. Inflammatory cytokines such as IL-1β and TNF-α can directly affect sleep-regulating regions of the brain, disrupting melatonin secretion and interfering with the hypothalamic-pituitary-adrenal (HPA) axis. This disruption in the HPA axis can, in turn, influence sleep patterns, contributing to the sleep disorders commonly observed in conditions such as PD[11-13]. Each of these sleep disorders reflects underlying neurological changes and may be linked to inflammatory processes that precede motor symptom manifestation. In addition to diminishing the quality of life, sleep disorders in PD are associated with complications, such as depression, psychosis, autonomic dysfunction, increased motor disability, fatigue, and neuroinflammation.

The interconnected nature of these symptoms suggests a complex pathological mechanism involving neuroinflammatory processes, neurotransmitter disruption, and neurodegeneration. Inflammation plays a multifaceted and pivotal role in this process by disrupting the blood-brain barrier, increasing the release of inflammatory cytokines, and accelerating the death of dopaminergic neurons. These mechanisms collectively contribute to the progression of PD, exacerbating both motor and nonmotor symptoms[14]. This comprehensive review aims to elucidate the intricate relationships between inflammatory markers, depression, and sleep disorders in the prodromal stage of PD, exploring potential mechanisms and implications for early diagnosis and intervention.

PATHOLOGICAL MECHANISMS OF PD

The pathogenesis of PD primarily involves basal ganglia dysfunction, particularly the loss of dopaminergic neurons in the midbrain substantia nigra and reduced dopamine levels in the striatum. Additionally, the formation of Lewy bodies, primarily caused by pathological α-synuclein aggregation, is a key factor (Figure 1)[15].

Figure 1 Schematic diagram of the pathogenic mechanism of Parkinson's disease. Increased oxidative stress due to mitochondrial dysfunction is a key initiator of Parkinson's disease and not only damages cellular structures but also triggers an inflammatory response. Together, oxidative stress and inflammation promote abnormal aggregation of α-synuclein, which further exacerbates nerve cell damage. In addition, excitotoxicity exacerbates mitochondrial damage and cell death by increasing the activity of neurotransmitters such as glutamate, leading to intra-neuronal calcium overload. MTPT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, PINK1: PTEN-induced kinase 1.

In the prodromal stage of PD, patients exhibit neurodegenerative signs or symptoms that do not yet meet the current diagnostic criteria. Consequently, this phase is often overlooked or misdiagnosed. However, it presents an opportunity for early diagnosis, pathophysiologic studies, and disease-modifying treatments that may slow or prevent the onset of motor symptoms. Table 1 summarizes the neurotransmitters or sources associated with PD, and the clinical stages, symptoms, and affected brain regions. Mood and cognitive disorders are associated with acetylcholine in the basal forebrain, orexin in the posterior hypothalamus, histamine in the nucleus accumbens, and γ-aminobutyric acid in the ventral preoptic area[16], while sleep disorders are associated with neurotransmitters in the brainstem[17].

Table 1 Time course and stages of Parkinson's disease.

Phase	Potential neurotransmitters/source	Symptoms	Location
Advanced (late nonmotor and motor symptoms)	Ach/basal forebrain orexin/posterior hypothalamus histamine/TMNGABA/ventrolateral preoptic area	Emotional and cognitive disturbances	Cortex
Symptomatic (motor and nonmotor manifestations)	Dopamine/substantia nigra parscompactaSerotonin/dorsal and ventralraphe nuclei	Dyskinesia motor fluctuation movement problems	Substantia nigra
Prodromal (early nonmotor symptoms)	Ach/ventral tegmental area GABA/ventral tegmental area epinephrine/locus coeruleus glutamate/sub-coeruleus area	Hyposmia	Olfactory bulb
		Sleep disorders	Brain stem
		Autonomic dysfunction	Vagus nerve
		Constipation	Enteric nervous plexuses of the foregut

Ach: Acetylcholine; TMN: Tuberomammillary nucleus; GABA: Gamma-aminobutyric acid; Vagus nerve: Vagus nerve (cranial nerve X); Raphe nuclei: Dorsal and ventral raphe nuclei.

INFLAMMATORY MARKERS IN THE PRODROMAL STAGE OF PD

Neuroinflammation in the central nervous system (CNS) involves the activation of microglia and astrocytes, which produce various inflammatory factors and chemokines. These disrupt the blood-brain barrier and promote the degeneration of dopaminergic neurons[18]. Besides motor and nonmotor symptoms, body fluids are often considered potential biomarkers in the early stages of PD. Therefore, biomarkers associated with α-synuclein aggregation may help diagnose early PD. The aggregation of α-synuclein protein can be detected in peripheral tissues and body fluids, including the cerebrospinal fluid, blood, the gastrointestinal tract, and skin. Proinflammatory cytokines, such as TNF-α[1], IL-1 β[3], and IL-6[2,4] play key roles in the inflammatory response. Anti-inflammatory cytokines such as IL-10[19] and transforming growth factor-β help reduce inflammation. The monocyte chemoattractant protein-1 (MCP-1) is a chemokine involved in monocyte recruitment and inflammatory spread[20]. Chitinase-3-like-1 (YKL-40) is a glycoprotein predominantly expressed in microglia and astrocytes[21]. While there is insufficient evidence to establish the significance of these molecules for the early diagnosis of PD, they may serve as indicators of disease progression or cognitive decline.

Markers of neuroinflammation include the detection of translocator protein (TSPO), also known as the 18 kDa translocator protein or peripheral benzodiazepine receptor, using imaging agents such as 18F-DPA-714 and 18F-GE-180. TSPO is primarily expressed on the outer mitochondrial membrane of activated microglia and macrophages. Microglia are immune cells in the CNS that play a crucial role in neuroinflammation. Therefore, TSPO is considered a marker of neuroinflammation and a key regulator of microglia activity[22]. In patients with PD, increased TSPO signals have been observed in the substantia nigra, pons, basal ganglia, and frontal and temporal cortices[22]. However, while positron emission tomography imaging targeting neuroinflammation can reveal these signals, it is insufficient for the specific diagnosis of early PD, and its clinical significance requires further investigation.

DEPRESSION AND PRODROMAL STAGE OF PD

Depression in PD often peaks in the early stages of the disease. Clinical manifestations include persistent low mood, difficulty concentrating, and reduced interest in work and daily activities. Long-term depression can exacerbate motor symptoms in PD, creating a vicious cycle that markedly affects the patients’ quality of life. The pathogenesis of depression in PD is multifactorial and involves endogenous biological factors and exogenous psychosocial factors. On the one hand, as with primary depression, neurotransmitter disorders are important, but for depression in PD, dopamine and norepinephrine play a more substantial role than serotonin. On the other hand, the psychogenic response to the disease itself also contributes, as patients may struggle to accept changes in their abilities and living conditions, leading to emotional disorders[23,24]. Statistics show that depression affects up to 40% of patients with PD[16], often appearing up to 20 years before a PD diagnosis and increasing in incidence 3-6 years before diagnosis. Emerging evidence suggests that inflammation may be an early driver of PD and plays a considerable role in depression during the preclinical phase of the disease[25].

CORRELATION BETWEEN DEPRESSION AND LEVELS OF INFLAMMATORY MARKERS

Proinflammatory cytokines activate microglia and astrocytes, inducing the kynurenine pathway and affecting the volume and thickness of the prefrontal cortex, amygdala, and hippocampus[7]. Simultaneously, the HPA axis responds to stress by releasing corticotropin-releasing hormone and arginine vasopressin, which stimulate the adrenal cortex to release cortisol[9]. Elevated cortisol levels exert inhibitory feedback through receptors in the CNS and systemic tissues to maintain homeostasis. However, when this balance is disrupted, hypercortisolism activates 2,3-indoleamine dioxygenase (IDO), reducing tryptophan metabolism, impairing serotonin synthesis, and potentially generating reactive oxygen and nitrogen radicals[8]. Additionally, high levels of kynurenine activate the glutamatergic system, leading to tissue damage and inflammatory responses. Peripheral proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, and IFN, released by fibroblasts, endothelial cells, and epithelial cells exacerbate inflammatory reactions[26]. Stimulation of the vagus nerve modulates peripheral proinflammatory interleukin levels by releasing acetylcholine, which inhibits inflammatory cytokine release as part of the sympathetic-cholinergic anti-inflammatory pathway[7]. Ultimately, sustained cortisol elevation and the release of inflammatory cytokines create a vicious cycle of neuroinflammation, which further exacerbates depression symptoms and brain structural damage.

Research has shown that inflammatory markers are widespread in patients with depression. A genome-wide association study identified genetic and epigenetic networks related to inflammation in depression[27], involving genetic variations in various cytokines and inflammatory mediators, such as IL-1β, TNF-α, C-C motif chemokine ligand 2, and C-reactive protein (CRP), which correlate with depression severity[28]. Kofod et al[28] found that patients with depression with high blood levels of IL-6 had lower levels of IL-6 methylation. A systematic review of the literature, however, reveals inconsistent findings regarding the levels of CRP, IL-10, TNF-α, MCP-1, and IL-6 in PD-related depression. Potential explanations for these discrepancies include variations in the study design (e.g., cross-sectional vs cohort studies), sample size, patient selection bias, as well as differences in the timing and methods of inflammatory biomarker measurement[24].

SLEEP DISORDERS AND PRODROMAL PHASE OF PD

Sleep disorders often worsen as PD progresses. These disorders include insomnia, EDS, SDB, disturbances in the sleep-wake cycle, and movement disorders such as RLS and periodic limb movement disorder. Specifically, RBD has been found in up to 50% of patients with PD[10]. RBD has garnered special attention because it can appear more than 10 years before the onset of PD. According to Braak’s model of pathological progression, structural changes in the brainstem and midbrain occur during the prodromal phase of PD, suggesting that sleep disorders may manifest early in the disease[17]. In patients with prodromal PD, the incidence of EDS, insomnia, and potentially RBD gradually increases, while fewer cases report multiple sleep disorders, indicating a distinct pathogenesis[29]. Additionally, the incidence of EDS rises within five years before a PD diagnosis and correlates with disease progression[29].

CORRELATION BETWEEN SLEEP DISORDERS AND INFLAMMATORY MARKERS

Inflammatory factors can disrupt neurotransmitter balance and affect the sleep-wake cycle through various mechanisms. For example, inflammatory factors, such as TNF-α and IL-1β can directly affect the brain, altering sleep structure and duration[30]. Furthermore, inflammation can interfere with sleep by increasing stress responses and altering the levels of hormones such as cortisol, leading to long-term alterations in sleep patterns and circadian rhythms. Conversely, sleep disorders can increase brain inflammation, potentially accelerating the progression of neurodegenerative diseases through oxidative stress and neuronal damage[31].

INTERPLAY BETWEEN INFLAMMATORY MARKERS, DEPRESSION, AND SLEEP DISORDERS

Yin et al[32] examined pairwise associations between the neutrophil-to-lymphocyte ratio (NLR), CRP, sleep disorders, and depressive symptoms in the National Health and Nutrition Examination Survey population (n = 32749) from 2005 to 2018. Their results showed that individuals with depression or sleep disorders had increased levels of inflammatory markers compared to those without these conditions. Even after adjusting for confounding factors, such as age, sex, and body mass index, a positive correlation remained between sleep disorders, inflammatory markers, and depressive symptoms. The relationship between inflammatory markers and depressive symptoms is nonlinear and remains positively correlated after treatment. Sex differences are evident, with women showing a stronger positive correlation between sleep disorders and depressive symptoms than men. In men, elevated levels of inflammatory markers are associated with sleep disorders and depressive symptoms and act as mediators between the two. However, this mediating effect was not observed in women.

Reduction in dopamine neurotransmission and dysfunction in the noradrenergic and serotonergic systems is associated with prodromal PD, accompanied by depression and sleep disorders. Proinflammatory cytokines, such as TNF-α and IL-1β, exert toxic effects on noradrenergic neurons, decreasing norepinephrine levels. Norepinephrine, an anti-inflammatory and neuroprotective neurotransmitter, reduces inflammation primarily by decreasing NF-κB activity through β-adrenergic receptor activation[33]. In the prodromal phase of PD, inflammatory factors may exert effects on the noradrenergic system, reducing norepinephrine levels and associated dysfunction. Ma et al[14] found that microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission. Additionally, TNF-α and IL-1β increase the activity and expression of the serotonin transporter, promoting serotonin reuptake and decreasing serotonin levels. These cytokines may also stimulate the expression of IDO, leading to tryptophan depletion, thereby affecting serotonin synthesis[31]. Systemic inflammation-induced oxidative stress, neurotoxicity, and the interaction between inflammation and the CNS may also affect serotonin metabolism[34].

Sleep disorders are closely related to the disruption of neurotransmitter systems in the brain, especially the serotonergic, cholinergic, dopaminergic, and glutamatergic systems[35]. PD primarily features loss of dopaminergic neurons, leading to decreased dopamine levels[36]. This decrease in dopamine levels and imbalances in other neurotransmitters, such as acetylcholine, have been shown to affect sleep patterns. These neurotransmitter systems are crucial in regulating the sleep-wake cycle[37]. Moreover, an increase in the expression of inflammatory factors may worsen sleep disorders by altering the levels of the neurotransmitter mentioned above[13]. These inflammatory responses may further damage neuronal function, reducing sleep quality and disrupting sleep structure[12,13]. In the prodromal phase, the levels of inflammatory factors such as TNF-α and IL-10 are significantly higher in patients with isolated RBD, while the levels of IL-1β, IL-2, IL-4, IL-6, and IFN-γ do not show significant changes[11]. Wang et al[13] explored the association between peripheral blood inflammatory cytokines and RBD in PD through clinical studies. Their findings revealed that patients with PD-RBD exhibited higher CRP levels and lower lymphocyte-to-monocyte ratios (LMR). These findings align with those by Ugalde-Muñiz et al[9] who used animal models to show how systemic inflammation exacerbates neurotoxicity in PD, particularly affecting the levels of serotonin and dopamine, two key neurotransmitters.

POTENTIAL ROLE OF INFLAMMATORY MARKERS IN DEPRESSION AND SLEEP DISORDERS DURING THE PRODROMAL PHASE OF PD

Systemic inflammation adversely affects the availability of neurotransmitters such as serotonin and dopamine by activating microglia and stimulating the release of inflammatory factors. In particular, the increased levels of these inflammatory markers are closely related to serotonergic pathway dysfunction, which may exacerbate depression symptoms and the progression of sleep disorders.

Cytokines are crucial for immune regulation and inflammatory responses. The levels of IL-1β and IL-6 in the cerebrospinal fluid and brain tissue of patients with PD are elevated[3]. High levels of IL-6 are associated with the severity and rapid progression of PD[4]. Additionally, high levels of the anti-inflammatory cytokine IL-10 in patients with PD are positively correlated with the severity of autonomic symptoms[19]. IL-17, a cytokine involved in autoimmune and inflammatory responses, may affect the progression of PD by promoting the infiltration and activation of inflammatory cells and affecting neuronal survival and death[38].

Lymphocyte counts generally decline in patients with PD, with this reduction being potentially observable 10-20 years before diagnosis[39,40]. Therefore, lower lymphocyte counts may be associated with an increased risk of PD[18]. Conversely, the number of neutrophils in patients with PD tends to increase[40-42]. In lipopolysaccharide-induced PD models, a significant systemic inflammatory response is observed, characterized by an increase in NLR, derived NLR, platelet-to-lymphocyte ratio (PLR), and systemic immunoinflammation index (SII)[43]. In patients with PD, there is an enhanced immune response against α-synuclein aggregates, involving the activation of T cells, B cells, and other lymphocytes[25]. Patients with prodromal PD, especially those at high risk of early dementia, have significantly lower B cell counts[25]. Additionally, an elevated NLR is significantly correlated with low dopamine transporter (DAT) levels in the caudate nucleus and putamen[44]. The decrease in DAT levels or function typically indicates the degeneration or dysfunction of dopaminergic neurons. These findings indicate a link between systemic inflammation and the degeneration of dopaminergic neurons in patients with PD, with neutrophil and lymphocyte counts playing a key role. A case-control study found that NLR increased in patients with PD compared to healthy controls, confirmed by a subsequent meta-analysis of nine studies[45]. Compared to early-onset PD, late-onset PD is associated with a higher NLR[46]. Additionally, NLR showed a negative association with the striatal binding ratio in DaTScan analysis, a surrogate parameter for nigrostriatal degeneration, and a positive association with movement disorders. These findings indicate that NLR is a potential biomarker for disease progression[45,47].

A study by Büyükkoyuncu Pekel[48] showed that PLR is positively and significantly correlated with disease duration (r = 0.780, P < 0.001). A notable correlation exists between PLR and Hoehn-Yahr staging, indicating that disease duration and severity increase as the disease progresses, leading to higher PLR values. This observation suggests that PLR plays a crucial role in the onset and progression of PD. A study by Liu et al[49] found that the neutrophil-to-high-density lipoprotein ratio (NHR) and NLR are risk factors for PD. NHR negatively correlates with disease duration, indicating that its value decreases as the disease progresses. Li et al[50] demonstrated that a high NLR and NHR and low LMR positively correlate with PD severity, indicating that these peripheral inflammatory markers may be associated with disease severity and could serve as biomarkers.

In neurological disorders, changes in CRP levels may be associated with neuroinflammation and cognitive decline. A study using United Kingdom Biobank data found that high baseline CRP levels are associated with a low PD risk, indicating a negative correlation between systemic inflammation and PD risk[2]. However, this finding was not replicated in the Finn Gen cohort, indicating that the relationship between CRP levels and PD risk may vary across populations. Furthermore, the United Kingdom Biobank data may not fully represent the broader European population, due to potential selection bias among its participants. A multicenter cohort study involving 206 Asian patients with PD, which integrated clinical features, genetic markers, and blood biochemical markers, classified PD into three clinical subtypes: A (severe), B (moderate), and C (mild)[51]. In the study, CRP emerged as a biomarker for the severe subtype of PD, offering new insights into the pathophysiology of the disease.

In PD, TNF-α levels are typically elevated and correlate with disease severity[52]. Preclinical model studies of PD have shown that blocking TNF-α activity has neuroprotective effects, and TNF-α inhibitors used for inflammatory bowel disease can reduce the risk of developing PD[53]. While the source of TNF-α in PD remains unclear, some studies suggest that TNF-α levels in the cerebrospinal fluid may serve as a risk biomarker for the prodromal phase of PD[54]. Furthermore, using dominant-negative TNF inhibitors to suppress soluble TNF signaling has protective effects to approximately 50% of dopaminergic neurons in several preclinical PD models[55], offering a new approach for future PD treatment.

In summary, inflammation plays a key role in the progression of depression and sleep disorders during the prodromal phase of PD, particularly in terms of dopaminergic neuron degeneration. Elevated levels of inflammatory factors such as IL-1β, IL-6, and IL-17 are associated with the severity and rapid progression of prodromal symptoms. Conversely, the anti-inflammatory cytokine IL-10 Level positively correlates with the severity of autonomic symptoms. Additionally, peripheral inflammatory markers, such as NLR, PLR, CRP, and TNF-α are positively correlated with the course and severity of PD, indicating their potential as biomarkers for disease progression. Therefore, monitoring of these inflammatory markers may provide new strategies for the early diagnosis, prevention, and treatment of PD.

CONCLUSION

Inflammatory markers play a critical and multifaceted role in the complex interactions between comorbid depression, sleep disorders, and the prodromal phase of PD. Elevated levels of interleukins (IL-1β and IL-6), TNF-α, and CRP in patients with PD correlate with the severity of the disease. These inflammatory markers exacerbate considerably depressive symptoms by comprehensively disrupting neurotransmitter systems, particularly serotonin and dopamine pathways, which are critical for maintaining neurological and psychological homeostasis. Moreover, the relationship between inflammatory responses and sleep disorders is profoundly intricate and encompasses extensive disruptions in neurotransmitter systems; increased physiological and neurological stress; marked interference with circadian rhythms; and progressive deterioration of sleep quality and neurological structure. Critically, this relationship is bidirectional: Sleep disorders can simultaneously exacerbate inflammatory responses, creating a complex and potentially self-perpetuating pathological cycle. Elevated SII levels indicate high production of peripheral inflammatory mediators that can potentially penetrate the blood-brain barrier, thereby directly compromising the brain's microenvironment and accelerating neuropathological changes characteristic of PD. Consequently, inflammatory markers represent a pivotal component in understanding PD pathology, offering unprecedented potential as comprehensive biomarkers for early diagnosis, prognostic assessment, and targeted therapeutic interventions. While existing studies demonstrate increased neutrophil counts in patients with PD, the current research landscape reveals a critical gap in understanding the nuanced changes and functional dynamics related to neutrophils during the prodromal phase of PD. Future research must leverage advanced techniques such as multiparameter flow cytometry and single-cell RNA sequencing, and sophisticated immunohistochemical methods to comprehensively characterize neutrophil phenotypes; evaluate neutrophil functional heterogeneity; map the intricate interactions between neutrophils and microglia; and develop mechanistic models of the neuroinflammatory processes. Despite the promising potential of inflammatory markers as early diagnostic tools, their broad clinical utility during the prodromal phase of PD remains largely underexplored and requires rigorous and systematic investigation. Imperative future research directions include large-scale, multicenter prospective studies, advanced statistical modeling, the development of robust predictive algorithms, and rigorous assessment of marker sensitivity, specificity, and positive and negative predictive values. Furthermore, sophisticated, interdisciplinary research is critically needed to elucidate the complex multidimensional mechanisms by which neuroinflammation systematically disrupts neurotransmitter systems and circadian rhythms, ultimately manifesting as sleep disorders.