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Association between neutrophil-to-lymphocyte ratio and motor subtypes in idiopathic Parkinson’s disease: a prospective observational study

BMC Neurology volume 24, Article number: 379 (2024) Cite this article

Abstract

Background

Peripheral immunity and neuroinflammation interact with each other and they play important roles in the pathophysiology of idiopathic Parkinson’s disease (IPD). There have been very few real-world reports on the relationship between peripheral immune inflammation and motor phenotypes of IPD. This study aimed to investigate the potential correlation between peripheral inflammatory indicators and motor subtypes in patients with IPD.

Methods

This observational, prospective case-control study examined patients with IPD and healthy controls (HC) matched for age and sex between September 2021 and July 2023 at the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University. The levels of peripheral inflammatory indicators were collected from each patient with IPD and HCs. Differences in the levels of peripheral inflammatory indicators among groups were compared. Binary logistic regression analysis was used to explore the inflammatory mechanism underlying the motor subtype of IPD.

Results

A total number of 94 patients with IPD were recruited at the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University between September 2021 and July 2023, including 49 males and 45 females, and 37 healthy volunteers matched for age and sex were also enrolled as the control group. Of the 94 patients with IPD, 42.6% performed as the TD motor subtype and 57.4% performed as the AR motor subtype. NLR and the plasma levels of IL-1βand TNF-α in the IPD group were higher than those in the HC group (P < 0.05). The disease duration, Hoehn and Yahr (H-Y) stage, NLR, and the levels of IL-1β in the AR group were higher than those in the TD group (P < 0.05). Additionally, IL-1β plasma levels and NLR were positively correlated with disease duration, H-Y stage, movement disorder society-Unified Parkinson’s Disease Rating Scale-III motor score, and AR subtype. The binary logistic regression model revealed that the plasma level of IL-1β was mildly associated with the AR motor subtype and NLR was strongly associated with the AR motor subtype. The combination of NLR and IL-1β showed better performance in identifying the AR motor subtype.

Conclusion

NLR is strongly associated with the AR motor subtype in IPD, and peripheral immunity is probably involved in the pathogenesis of AR motor subtype in IPD.

Peer Review reports

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its prevalence has been projected to double over the next generation. PD is strikingly heterogeneous regarding the age of onset, clinical presentation, rate of progression, and treatment response. Several clinical subtypes of PD have been proposed. Prevailing motor phenotype has been used for subtyping. Based on the motor symptoms, patients with PD can be categorized into two main subtypes: tremor-dominant (TD) and akinetic-rigid (AR). The AR subtype has been associated with faster progression, more cognitive decline, and increased risks of falls or disabilities compared to the TD subtype [1, 2]. However, 46% TD subtype can be converted into the AR subtype after five years [3, 4]. So far, the pathogenesis of idiopathic PD (IPD) has not been fully elucidated. Moreover, the pathogenesis of the motor phenotypes of PD remains poorly understood.

Accumulating evidence indicates that immune inflammation plays a key role in the pathological characteristics of IPD. Peripheral immunity and neuroinflammation interact with each other and they play important roles in the pathophysiology of IPD [5, 6]. In animal experiments, activated microglia promoted the activation of inflammatory corpuscles of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome and further induced the release of interleukin (IL)-1β, secretion of tumor necrosis factor (TNF)-α, and activation of T lymphocytes [7]. Autopsies of patients with IPD showed activation of glial cells in the substantia nigra, elevation of proinflammatory cytokines, and infiltration of T lymphocytes into the brain [8]. Actually, NLRP3 inflammasome is one of the main and most commonly studied inflammasome within the central nervous system [9]. Moreover, systemic NLRP3 inflammasome activation was confirmed by extensive research in IPD [10]. The neutrophil-to-lymphocyte ratio (NLR) is a biomarker of the peripheral inflammatory response. NLR is a prognostic factor for tumors, cardiovascular disease, and inflammatory diseases and is related to neurodegenerative diseases [11,12,13,14,15]. Patients with IPD have higher NLR levels than healthy controls, implying that peripheral immune inflammation is probably involved in the pathogenesis of IPD [12]. However, there are only a few reports on the relationship between peripheral immune inflammation and motor phenotypes of IPD [15].

Therefore, in the current study, we aimed to explore the associations of NLR and peripheral pro-inflammatory factors with motor phenotypes of IPD, in order to eventually understand the pathogenic mechanism underlying the motor phenotype of IPD.

Materials and methods

Study design

We conducted a single-center, observational, prospective case-control study. This study was approved by the Ethics Committee of the Huai’an No. 1 People’s Hospital of Nanjing Medical University (approval number: KY-2023-098-01). This study complied with the Declaration of Helsinki. A signed written informed consent was obtained from all participants.

Patient recruitment

IPD patients and healthy volunteers were recruited at the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University between September 2021 and July 2023.

The inclusion criteria of IPD patients were as follows: right-handed patients with IPD diagnosed with the criteria of the International Movement Disorders Association (MDS) in 2015 for PD were enrolled in the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University; and aged ≥ 18 years [16]. Patients were consecutively recruited from the outpatient clinic and ward of our hospital. The exclusion criteria were as follows: (1) diagnosis uncertain for PD or Parkinsonian plus syndromes, (2) diagnosis of chronic consumptive diseases such as cardiopulmonary and tumor diseases, (3) with acute and chronic inflammatory disorders, those taking anti-inflammatory drugs, (4) could not cooperate with the scale evaluation. According to the ratio of each patient’s Unified Parkinson’s Disease Rating Scale (UPDRS)-III tremor score to his/her mean UPDRS akinetic/rigid score, IPD patients were divided into subtypes using the method proposed by Kang et al. [17, 18].

The inclusion criteria of healthy controls were as follows: healthy controls (HC) were simultaneously recruited from the physical examination center of the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, matching the age and sex of PD patients. The exclusion criteria were as follows: (1) diagnosis of chronic consumptive diseases such as cardiopulmonary and tumor diseases, (2) with acute and chronic inflammatory disorders, those taking anti-inflammatory drugs, (3) could not cooperate with the scale evaluation.

Outcome measures

Clinical assessment

Two neurologists, including Dr. Liang and Dr. Yi, collected demographic data, disease duration, treatment regimen, and motor complications from patients with IPD through face-to-face personal standardized interviews. Dr. Yi also collected Clinical data regarding sex and age from HCs. Dr. Liang and Dr. Yi used the UPDRS and the Hoehn and Yahr (H-Y) stage to assess the motor symptom severity and each subject was evaluated in an “off” state (patients willing and able to withhold all PD medications for at least 12 h prior to assessment). Based on the UPDRS-III motor scores, patients with IPD were divided into TD and AR groups. Specifically, for each patient, the ratio was calculated between the average UPDRS-III tremor scores (the average of the component sub-items of items 20 and 21) and the average UPDRS akinetic-rigid scores (the average of the component sub-items of items 22–27 and 31). A patient was categorized as having the TD subtype when the ratio was > 1.0, the AR subtype when the ratio was 0.8, and the mixed subtype when the ratio was between 0.8 and 1 [17, 18]. According to the H-Y stage, patients were divided into early PD (H-Y ≤ 2.5) and advanced PD (H-Y > 2.5) groups. L-DOPA equivalent daily doses (LEDD) were evaluated according to the guidelines.

Measurement of neutrophil-to-lymphocyte ratio and plasma IL-1β and TNF-α

Two neurologists, including Dr. Xu and Dr. Li, collected peripheral blood samples from each patient with IPD and HCs while fasting in the morning. Two tubes containing EDTA were used to collect 5 ml of venous blood. One tube was centrifuged for 4 h at 3000 r/min for 15 min. After centrifugation, the supernatant was collected and frozen at -80℃ for later use. Serum neutrophil and lymphocyte levels were measured using a MEK-6400 C hematology analyzer (Nanjing Baden Medical Co., Ltd.), and the NLR was calculated. The plasma levels of IL-1β and TNF-α in peripheral blood were detected using ELX 800 automatic microparticle chemiluminescence immunoassay and ELISA.

Statistical analysis

This was a case-control study. PD patients made up the case group, whereas healthy participants made up the control group. The primary exposure factor was the concentration of inflammatory factors in peripheral blood. The pre-experimental results showed that the control group had an abnormally high change in peripheral blood inflammatory factors—roughly 30%. Considering α = 0.05, β = 0.10, and a case-to-control ratio of 3, the expected OR was 2. The overall number of N1 + N2 = 136 cases in the case group and the control group was determined using PASS 25 software. Considering that 10% of the clinical data may be missing, N1 + N2 = 151 cases were finally included, including N1 = 114 cases and N2 = 37 cases.

Data were analyzed with IBM SPSS 25 software with the significance level set at p < 0.05. Gender distribution and other binary or nominal variables between patient groups were compared with the Pearson chi-square or Fisher exact test when appropriate. Continuous, normally distributed data were compared between groups with an independent t-test. The Spearman correlation coefficient was used to evaluate correlations between different variables. We performed logistic binary regression to evaluate the strength of the association between different scale scores and motor phenotype. The study adhered to the STROBE statement [19].

Results

Peripheral inflammatory indicators in PD patients

A total number of 114 patients with IPD were recruited at the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University between September 2021 and July 2023, including 49 males and 45 females, and 37 healthy volunteers matched for age and sex were also enrolled as HCs. Among them, 4 IPD patients were excluded because of incomplete clinical data. We excluded 16 IPD patients who were categorized as having the mixed subtype.

This study actually included 94 IPD patients, including 49 males and 45 females, and 37 HCs, 25 males and 12 females included. The mean ages of 94 IPD patients and 37 HCs were 65.33 ± 10.17 years and 62.56 ± 6.02 years respectively.

The clinical characteristics of the PD and HC groups are shown in Table 1; Fig. 1A, B, and C. As shown in Table 1, the age in the PD group is higher than that in the HC group, and the female proportion is markedly higher in the PD group. However, there are no significant differences in sex (P = 0.109) and age (P = 1.119) between the HC and PD groups. Compared with the HC group, PD patients show higher NLR (P < 0.001) and plasma levels of IL-1β (P = 0.006), and TNF-α (P < 0.001).

Table 1 Comparison of clinical characteristics and inflammatory indicators between patients with IPD and healthy controls
Full size table
Fig. 1
figure 1

Neutrophil-to-lymphocyte ratio (NLR) and plasma levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) between health controls and PD patients; P < 0.05 was considered significant, **P < 0.01, ****P < 0.0001

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Comparison of inflammatory indicators between TD-PD and AR-PD groups

To further explore the underlying inflammatory mechanism in the pathogenesis of motor phenotype, we divided the PD patients into two groups, TD-PD and AR-PD group. Of the 94 patients with PD, 40 (42.6%) performed as the TD motor subtype and 54 (57.4%) performed as the AR motor subtype. As shown in Table 2, no significant differences are shown in age (P = 0.148), sex (P = 0.908), UPDRS- III score (P = 0.055), LEDD (P = 0.052), and TNF-α (P = 157) between the two groups. However, significant differences are shown in the disease duration (P = 0.023), H-Y stage (P = 0.004), tremor score (P < 0.001), akinetic-rigidity score (P < 0.001), NLR (P = 0.002), and the plasma levels of IL-1β (P = 0.003). Compared with the TD-PD group, the AR-PD group has a longer disease duration (P = 0.023) and a higher H-Y stage (P = 0.004). It should be noticed that the NLR (P = 0.002) and the plasma levels of IL-1β (P = 0.003) are higher in the AR group than those in the TD group (Fig. 2A, B, and C).

Table 2 Comparison of clinical characteristics and inflammatory indicators between patients with TD and patients with AR
Full size table
Fig. 2
figure 2

Neutrophil-to-lymphocyte ratio (NLR) and plasma levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) between two motor subtypes in PD; P < 0.05 was considered significant, **P < 0.01

Full size image

Associations between inflammatory indicators and clinical features

The correlations between peripheral inflammatory cytokines and the clinical features in the IPD patients are shown in Table 3. Higher plasma levels of IL-1β are positively associated with disease duration (r = 0.278, P < 0.05), H-Y stages (r = 0.261, P < 0.05), and UPDRS-III scores (r = 0.332, P < 0.05). Similarly, the NLR is positively correlated with disease duration, H-Y stages, and UPDRS-III scores (r = 0.277, P < 0.05; r = 0.367, P < 0.05; r = 0.363, P < 0.05). Whereas, TNF-α plasma levels are positively correlated with disease duration (r = 0.334, P < 0.05) and UPDRS-III scores (r = 0.276, P < 0.05) but not H-Y stages (P > 0.05).

Table 3 Correlations between inflammatory indicators and clinical characteristics in patients with IPD
Full size table

Logistic regression analysis between inflammatory indicators and the motor subtype

We performed the binary logistic regression analysis to explore the inflammatory mechanism underlying the motor subtype of IPD. As shown in Table 4, the multivariate binary logistic regression analysis in IPD patients with AR or TD as outcome, age, gender, disease duration, H-Y stage, UPDRS-III, LEDD, IL-1β, and NLR as covariates, reveals that the plasma level of IL-1β (Odds ratio [OR] = 1.01, 95% confidence interval [CI] = 1.00–1.02, P < 0.05) is mildly associated with the occurrence of AR motor subtype and the NLR (OR = 2.28, 95%CI = 1.01–5.17, P < 0.05) is strongly associated with the occurrence of AR motor subtype.

Table 4 Binary logistical regression between variables with AR motor subtype in IPD
Full size table

Discussion

The findings of this study indicate that the plasma level of IL-1β was mildly associated with the AR motor subtype and NLR was strongly associated with the AR motor subtype. The combination of NLR and IL-1β performed better in identifying the AR motor subtype. Peripheral immunity appears to be involved in the pathogenesis of the AR motor subtype in IPD.

Existing evidence indicates that neuroinflammation plays a key role in the pathogenesis of IPD and that the interactions between the central and peripheral inflammatory responses contribute to the development of IPD [20]. Under long-term injury stimulation, microglial cells are activated, which stimulates the activation of the inflammatory corpuscles of NLRP3, releases cytokines such as IL-1β, and promotes the release of TNF-α [21]. The disruption of the blood-brain barrier allows peripheral immune cells to enter the central nervous system, triggering the production of inflammatory cytokines and leading to a neuroinflammatory reaction [22, 23]. Our results showed that the patients with IPD had higher plasma levels of IL-1β, TNF-α, and NLR than health controls. The levels of IL-1β in the AR group were remarkably higher than those in the TD group. Moreover, higher plasm levels of IL-1β were positively correlated with the occurrence of the AR subtype. Notably, some studies found that the cascade reaction of microglia and neuroinflammation can lead to oxidative stress and mitochondrial dysfunction, cause α-syn aggregation, and damage DA neurons [24,25,26]. Therefore, our study further confirmed that the pro-inflammatory response is probably involved in the pathogenesis of different motor subtypes of IPD.

NLR is regarded as a biological marker of peripheral immunity in the diagnosis of IPD and indicates the fusion of active inflammation (neutrophils) and immunoregulation process (lymphocytes) [15, 18, 27]. Our results demonstrated that the NLR in the AR group was not only significantly higher than that in the TD group but also positively correlated with the AR subtype. To our knowledge, this is the first time to confirm the relationship between NLR and motor subtypes in patients with IPD.

As a recognized indicator of chronic inflammation, the NLR integrates information from lymphocytes and neutrophils and reflects two complementary immune pathways: neutrophils are related to chronic inflammation, and lymphocytes are related to immune regulation [15]. This accurately reflects the inflammatory state of the body. An imbalance of specific T lymphocyte subsets with regulatory functions may cause insufficient inhibition of the pro-inflammatory response, which may lead to the loss of dopaminergic neurons [28, 29]. Therefore, we could speculate that the interplay between peripheral immunity and central neuroinflammation is probably involved in the occurrence and progression of the motor subtypes. Currently, there are only a few studies on inflammatory cytokines and motor subtypes in IPD. Further large-scale investigations are required to confirm this hypothesis.

Actually, remarkable peripheral inflammatory reactions were observed in the two most common IPD model animals induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and rotenone. Furthermore, both model animals exhibited AR symptoms behaviorally [30]. Therefore, according to the hypothesis of “Body-First” or “Brain-First”, we could speculate that the IPD of the AR subtype may be “Body-First” [31]. More importantly, we found that NLR was strongly associated with the AR subtype. Moreover, our previous clinical research on fecal microbiota transplantation for the treatment of patients with IPD showed that both motor symptoms and non-motor symptoms were improved significantly. Additionally, Wu et al. discovered that the altered microbiota seen in patients with IPD could be associated with systemic inflammatory responses that contribute to the development of IPD [32].

However, the relationship between peripheral inflammation and motor function severity has not been established [33]. In the previous study, Rathnayake et al. found that the plasma levels of IL-10 were correlated with disease severity and motor function and that TNF-α-mediated neurotoxicity could occur early in IPD [34]. We found that the IL-1β plasma levels and NLR were positively correlated with UPDRS-III scores, which was consistent with the results of Munoz et al. [35]. In our present case-control study, we also found a positive correlation between IL-1β plasma levels and the H-Y stage in patients with IPD. Additionally, NLR was positively correlated with disease duration and H-Y stage, which is consistent with the cohort study by Grillo et al. [36].

The BioFINDER study, conducting a 5-year follow-up on patients with IPD, found that motor subtypes were not fixed but changed following the progress and treatment of the disease, and the improvement of tremors could change as AR motor subtype [37]. Our results showed that the AR subtype accounted for a higher proportion and had a longer disease duration and higher H-Y stage than the TD subtype. Although the difference was not statistically significant, patients with the AR subtype showed higher UPDRS-III scores and higher LEDD doses than those with the TD subtype. In accordance with the findings of Eisinger et al., our investigation revealed that patients with long-duration and severe IPD primarily manifested the AR subtype [4].

Collectively, our results showed that IL-1β plasma levels and NLR were not only significantly increased in patients with IPD but were also positively associated with the severity in IPD. Most importantly, NLR was strongly associated with the AR motor subtype in IPD. Furthermore, peripheral immunity probably contributes to the pathogenesis of AR motor subtype in IPD. To our knowledge, this is the first study to investigate the relationship between NLR and IL-1β plasm levels with the motor subtype in IPD.

Peripheral immunity and central neuroinflammation may influence the occurrence of motor subtypes in IPD. Peripheral immunity is probably involved in the pathogenesis of the AR motor subtype in IPD, which provides a new way to clarify the potential pathogenesis of motor subtypes in IPD.

However, this study had certain limitations. First, the research scale was relatively small, and selection bias occurred to a certain extent. Second, our study only examined peripheral cell classification and inflammatory cytokines. Prospective cohort study and further autopsy studies will help elucidate the relationship between inflammatory cytokines and classification with motor subtypes.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank the patient and the patient’s parents for their trust and openness.

Funding

This study was supported by grants from National Natural Science Foundation of China (No. 81600981), Natural science foundation of Jiangsu Province(BK20191212), Jiangsu commission of health (M2022082).

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Author notes

  1. Hongyan Yi, Xiaojing Liang contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Neurology, the Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China

    Hongyan Yi, Xiaojing Liang, Fugui Xu, Tiantian Li, Xiu Yang, Ming Wei, Zhou Ou, Lijun Wang & Qiang Tong

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  1. Hongyan Yi
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  2. Xiaojing Liang
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  3. Fugui Xu
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  8. Lijun Wang
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Contributions

Q. Tong and L.J. Wang conceived and designed the experiments. H.Y. Yi and X.J. Liang collected demographic data, disease duration, treatment regimen, and motor complications from patients with IPD through face-to-face personal standardized interviews. H.Y. Yi also collected Clinical data regarding sex and age from HCs. H.Y. Yi and X.J. Liang assessed the motor symptom severity. F.G. Xu and T.T. Li collected peripheral blood samples. M. Wei and X. Yang performed the data analyses. Z. Ou helped to perform the analysis with constructive discussions. H.Y. Yi wrote the manuscript. Q. Tong revised the manuscript.

Corresponding authors

Correspondence to Lijun Wang or Qiang Tong.

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Ethical Compliance Statement

The experimental procedures were all in accordance with the guidelines of the Huai’an No. 1 People’s Hospital of Nanjing Medical University and were approved by the Huai’an No. 1 People’s Hospital of Nanjing Medical University (approval number: KY-2023-098-01). This study complied with the Declaration of Helsinki. A signed written informed consent was obtained from all participants. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

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The authors declare no competing interests.

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Yi, H., Liang, X., Xu, F. et al. Association between neutrophil-to-lymphocyte ratio and motor subtypes in idiopathic Parkinson’s disease: a prospective observational study. BMC Neurol 24, 379 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-024-03887-7

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-024-03887-7

Keywords

BMC Neurology

ISSN: 1471-2377

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