Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder predominantly characterized by motor dysfunction (1, 2). The core pathological features include degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (3). Globally, the number of individuals with PD is projected to exceed 14 million by 2040, a trend particularly pronounced in developing countries (4). To date, no therapy exists to cure PD or halt its progression. The disease substantially impairs patients’ quality of life and reduces life expectancy, while also imposing a considerable socioeconomic burden. Although biomarkers from cerebrospinal fluid, blood, and peripheral tissues show promise for early detection, and advanced neuroimaging techniques, including positron emission tomography (PET), single-photon emission computed tomography (SPECT),and magnetic resonance imaging (MRI), enable detailed visualization of neurodegeneration and related cerebral changes (5), the widespread clinical adoption of these approaches remains constrained by high costs and invasive sampling requirements.

Neuroinflammation represents a well-established pathological component of PD (6–8). Chronic microglial activation contributes substantially to neuronal loss through the release of proinflammatory cytokines and reactive oxygen species, which subsequently disrupt blood–brain barrier (BBB) integrity and facilitate peripheral immune cell infiltration into the central nervous system. This cascade ultimately amplifies neurodegenerative processes (9). Peripheral inflammatory alterations in PD further involve neutrophil hyperactivation and enhanced lymphocyte migration across the compromised BBB (1, 10, 11). Recent attention has focused on composite inflammatory indices, particularly the systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) (12). By integrating neutrophil, platelet, and lymphocyte counts, SII provides a comprehensive assessment of immune-inflammatory balance. Elevated SII values have been correlated with unfavorable outcomes across various conditions, including solid tumors, thromboembolic events, cardiovascular diseases, and COVID-19 (13–16). Although emerging evidence highlights the potential significance of SII, its association with PD remains incompletely characterized. While one study identified serum SII as a determinant of motor performance in PD patients (17), and recent studies revealed a positive correlation between SII and PD incidence in U.S. adults (18, 19). However, the association between SII and PD remains contentious. Two studies reported no significant association between elevated SII levels and PD risk (20, 21). Thus, the role of SII in PD warrants further investigation. Similarly, SIRI has emerged as a novel marker of systemic inflammatory status, demonstrating prognostic utility in pneumonia, rheumatoid arthritis, acute pancreatitis (22–24), and cardiovascular events (25–28). Although one study documented a positive correlation between SIRI and anxiety symptoms in PD patients (29), the overall relationship between SIRI and PD remains undefined.

Given the established role of neuroinflammation in PD. Since the associations of the SII and SIRI with PD remain unclear, this study was designed to evaluate their potential clinical relevance as progression indicators.

Current diagnosis of PD primarily relies on core motor symptoms, yet the decades-long prodromal phase frequently leads to misdiagnosis in early stages (33). Compounding this challenge, substantial nigral dopaminergic neuron loss occurs before clinical manifestation (34), and advanced PD confers severe disability with significant socioeconomic burdens. These issues underscore the urgent need for reliable biomarkers enabling early detection. Growing evidence implicates inflammatory mechanisms in PD pathogenesis, prompting our investigation into the SII and SIRI as potential biomarkers. Our study yielded several key observations: PD patients demonstrated significantly elevated SII and SIRI levels compared to HCs, with both indices correlating with disease severity. Multivariable logistic regression confirmed their status as independent associated factors, while ROC analysis evidenced their discriminative capacity for PD identification. Furthermore, subgroup analyses revealed no significant interaction effects (all p > 0.05), indicating that the associations of the SII and SIRI with PD remained consistent across all predefined demographic and clinical strata. These results underscore the robustness and broad generalizability of our findings in diverse patient populations. Collectively, these findings establish elevated SII and SIRI as promising inflammatory biomarkers associated with PD.

The SII, integrating neutrophil, lymphocyte, and platelet counts, serves as a novel composite biomarker reflecting systemic inflammatory and immune status (35). Our study demonstrated significantly elevated SII levels in PD patients compared to HCs, with positive correlations between SII and UPDRS total and subscale scores, suggesting its potential utility in tracking PD progression-a finding consistent with prior reports (17). A binary logistic regression model demonstrated that the SII was an independent predictor of PD. Moreover, when the SII was employed as a categorical variable, after controlling for confounding variables, indicated that an elevated SII correlated with an increased likelihood of developing PD. While our results align with several previous studies (18, 19), the association between SII and PD remains controversial, as other groups have reported null findings (20, 21). Cohort characteristics may explain the discrepancies between the studies. For example, the work of Bissaco et al. (36) showed that SII is elevated in middle to advance disease compared to de novo. Therefore, future longitudinal studies should aim to recruit cohorts that stratify by important variables such disease stage and duration, motor subtype, cognitive impairment or neuropsychiatric comorbidities, sex, concomitant medication use, and co-existence of pro-inflammatory systemic conditions. Collectively, our work strengthens the evidence supporting SII as a clinically relevant inflammatory biomarker in PD.

The SIRI has emerged as an integrated inflammatory-immune biomarker with established prognostic value across multiple inflammatory conditions (22–24) and cardiovascular diseases (25–28). Although a recent study linked SIRI to anxiety symptoms in PD (29), its overall relationship with PD pathogenesis remains underexplored. Our study addresses this gap by demonstrating elevated SIRI levels in PD patients, correlations with clinical severity (UPDRS total and subscales), and independent predictive value for PD risk-assessed both as continuous and categorical variables. These findings broaden the potential role of SIRI in PD pathophysiology and highlight its possible utility in risk stratification. Nevertheless, given contradictory reports in the literature (20, 21), further validation through multicenter, large-scale studies is warranted to confirm these associations.

Our findings establish the elevated SII and SIRI are associated with the severity of PD and have potential utility as diagnostic biomarkers. However, the underlying pathophysiological mechanisms require further investigation. Several interconnected pathways may explain how elevated SII and SIRI contribute to PD pathogenesis. Firstly, neurovascular unit impairment represents a fundamental mechanism in PD progression. Evidence from clinical studies demonstrates increased BBB permeability in advanced PD stages (37, 38), facilitating the translocation of peripheral inflammatory mediators into the central nervous system. This pathological process is further supported by pharmacological evidence: non-steroidal anti-inflammatory drugs demonstrate potential neuroprotective effects through neutrophil count reduction (39). Our study demonstrated significantly elevated neutrophil counts in patients with PD compared to HCs, further supporting the involvement of neutrophils in PD pathogenesis. Secondly, the neuroimmune axis participates through coordinated cellular interactions. Th17-mediated immune responses orchestrate neutrophil recruitment to neural tissues, amplifying inflammatory cascades through degranulation processes (40). Central nervous system penetration of CD4⁺ and CD8⁺ T lymphocytes directly correlates with dopaminergic neurodegeneration (40, 41). Consistent with the findings of prior research (1, 42), we observed significantly lower plasma lymphocyte counts in patients with PD compared to HCs. While peripheral lymphopenia in PD patients may reflect compensatory trafficking of immune cells to cerebral compartments (43, 44). Thirdly, additional hematological components contribute to PD pathophysiology. Platelet-derived monoamine oxidase-B catalyzes the conversion of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) to neurotoxic 1-Methyl-4-phenylpyridinium (MPP⁺) compounds (45), while α-synuclein exhibits monocyte-activating properties that correlate with disease severity (46). In conclusion, our results corroborate the positive correlation between systemic inflammation and PD risk. As composite inflammatory indices derived from routine hematological parameters, SII and SIRI offer practical value for risk stratification in PD. However, definitive mechanistic insights into their pathological roles warrant further multidisciplinary investigation.

Uric acid (UA) is widely recognized as a natural antioxidant that exerts neuroprotective effects through free radical scavenging and antioxidant activity in neurological disorders (47). A study of blood alterations during the PD prodromal phase revealed significantly lower serum UA levels in individuals at high risk of developing PD (48). Reduced serum UA concentrations were associated with increased PD incidence, accelerated disease progression, and exacerbated motor and cognitive impairments in patients receiving long-term dopaminergic therapy (49). Additional clinical observations have established correlations between decreased serum UA levels and poorer sleep quality in PD patients, suggesting its potential utility as a biomarker for sleep disturbances in this population (50). A previous study have also linked lower serum UA levels with motor function deterioration (51), while both serum UA and UA/creatinine ratio showed negative correlations with Hoehn-Yahr staging and served as independent negative marks of PD incidence and progression (52). In contrast to these findings, our univariate and multivariate analyses did not identify significant associations between serum UA levels and motor performance in PD, consistent with some previous reports (2, 17). We propose that discrepancies observed across studies may be explained by methodological differences, such as variations in the ethnic composition of study cohorts, limitations in sample size, heterogeneity in medication regimens, and differences in the distribution of disease severity.

Given the substantial clinical and pathological heterogeneity of PD, reliable risk stratification and progression monitoring cannot depend on any single biomarker. The integration of complementary biomarkers is therefore essential for enhancing predictive accuracy. In the present study, we employed ROC analysis to evaluate the combined diagnostic performance of the SII and SIRI. Our results demonstrate that both indices effectively discriminated PD patients from HCs, with SII exhibiting superior discriminatory power (AUC = 0.750) relative to SIRI (AUC = 0.700). The combination of SII and SIRI yielded an AUC of 0.785, representing a statistically significant improvement over either biomarker alone. However, the ROC curves show only modest discriminative ability (AUC < 0.80). This indicates that they are not suitable for use as independent diagnostic tools but may have value in combination with other clinical parameters or for identifying high-risk populations.

This study has several limitations that should be considered when interpreting the results: (1) As a cross-sectional study conducted exclusively in a Chinese population and cannot directly infer causality. Thus, future large-scale longitudinal studies involving diverse ethnic cohorts are required to validate and generalize these findings; (2) the absence of complementary inflammatory biomarkers limited our ability to correlate SII and SIRI with broader inflammatory profiles, thereby constraining a comprehensive understanding of neuroimmune interactions in PD; (3) although key clinical variables were adjusted for, unmeasured confounder-such as genetic predisposition, neuroimaging features, environmental exposures, and substance use history-may influence the observed associations; (4) we did not collect vaccination history. Vaccination can temporarily elevate platelet count and other inflammatory markers (e.g., cytokines) which could impact the study results (53); (5) the multivariable analyses are under-adjusted. Key clinical variables such as on disease duration and LEDD are not included. Their omission reduces the strength of the claims regarding “independent” associations; and (6) while SII and SIRI reflect systemic inflammation, they lack specificity to neuroinflammatory pathways and can be affected by non-neurological conditions, complicating interpretation of their direct roles in PD pathogenesis.

In summary, our study demonstrates that elevated SII and SIRI are significantly associated with PD severity and represent promising composite biomarkers for clinical assessment. Importantly, the combination of these indices shows superior predictive value compared to individual markers, suggesting their potential utility in multidimensional evaluation approaches. Nevertheless, further validation through prospective multicenter studies and deeper investigation into their pathophysiological mechanisms are warranted to establish their definitive role in PD management.