Neutrophil to lymphocyte ratio in parkinson’s disease: a systematic review and meta-analysis

Parkinson’s disease (PD) is the second most common neurological illness after Alzheimer’s disease, affecting approximately 7 to 10 million individuals globally [1, 2]. The disease’s most apparent symptoms are related to movement, such as rigidity, movement slowness, tremor, and postural instability [3, 4]. Despite the fact that PD is identified by the appearance of intraneuronal proteinacious cytoplasmic inclusions defined as Lewy bodies and a considerable decrease of dopaminergic neurons in the substantia nigra pars compacta, the illness’s origin remains unknown [5‐7]. The antiparkinson medicines, including dopamine agonists and levodopa are often used to treat PD, and they are clinically beneficial in the early stages of disease. However, as the condition worsens, these treatments become ineffective and have adverse side effects [8, 9]. As a result, there is an urgent need to comprehend the etiology of PD and create innovative medicines to prevent or halt disease development.

Inflammation appears to play a prominent role in the pathologic characteristics and symptoms of PD, according to growing research [10‐15]. Interleukins and tumor necrosis factors (TNFs) are crucial immune activation signaling molecules that affect both the brain and the periphery [16]. In vivo findings of positron emission tomography and postmortem in PD patients revealed elevated inflammatory reactions, such as microglial activation [17, 18], and higher levels of immunological markers in the brain [18‐20].

In addition, several studies have compared inflammatory biomarkers in individuals with PD to healthy controls in an effort to better understand the origin of the condition and identify potential biomarkers for it [21‐24].

Neutrophil to lymphocyte ratio (NLR) is a biomarker based on Complete blood count (CBC), and it shows the balance between immunity and systemic inflammation. Although several new studies found links between PD and NLR, the findings were contradictory [25‐43]. A meta-analysis on this topic is needed to resolve clinical evidence discrepancies. As far as we know, this is the first systematic review and meta-analysis on this matter.

We undertook meta-analysis of 20 studies to evaluate the correlation of NLR with PD. It was discovered that PD patients had higher levels of NLR than healthy controls.

PD is a progressive neurodegenerative illness defined pathologically by emergence of lewy bodies and dopaminergic neuron loss in the substantia nigra. Neuroinflammation has a critical role in lewy body formation and substania nigra cell loss. Both the adaptive and innate immune systems are significantly altered in PD [48]. Inflammation is silent in the brain. The response relies on the production of inflammatory components by microglia in the brain. Microglia produce inflammatory cytokines that appear to play significant roles [49]. Interleukin-1 (IL-1), IL-6, and Tumor necrosis factor-alpha (TNF) are examples of inflammatory cytokines that amplify and sustain immune responses and inflammation. It is interesting that PD patients’ CSF basal ganglia contain elevated levels of TNFα, IL-6, and IL-1b [50]. The BBB’s integrity may be lost as a result of the release of pro-inflammatory cytokines by microglia and also upregulation of adhesive molecules (VCAM and ICAM), which cause infiltration of peripheral immune cell in brain [51]. The NLR is a low-cost, simple-to-use indicator of peripheral inflammation [52, 53]. Increased NLR has been shown in many CNS conditions [54]. Several studies evaluated association of increased NLR with PD and our meta-analysis confirmed this association. This may show important role of inflammation and it may exist several years before clinical manifestation of PD and the immune system involvement is promising for therapeutic targeting. In addition to diagnostic utilities, NLR can be used as a prognostic factor in PD. For example, in 2022, Muñoz-Delgado et al. conducted a retrospective cohort study on 211 PD patients as primary-cohort. For replication goals, they also included 344 separate patients with PD in Parkinson’s Progression Markers Initiative group as PPMI-cohort. They showed that NLR is associated with nigrostriatal dopaminergic system degeneration, assessed using striatal dopamine transporter (DAT) density. Patients with higher levels of NLR had significantly lower DAT levels in the putamen (primary-cohort: P = 0.02; PPMI-cohort: P = 0.02) and the caudate (primary-cohort: P < 0.001; PPMI-cohort: P = 0.05) [55]. In addition, Song et al. prospectively followed up 26,210 participants for 21 years. During the follow-up, 486 incidences of PD were reported. The results showed that NLR (HR = 1.09; 95% CI: 1.00- 1.19), was related to an increased risk of PD [56].

Although the role of chronic inflammation is confirmed in PD, it is unclear whether inflammation is the root cause of neurodegeneration or whether it develops as a consequence of cell degeneration and selective damage process [57]. Also the trigger factor for inflammation such as viral infection or autoimmunity remain to be elucidated. The role of inflammation may be different in various subtypes of PD. Use of anti-inflammatory, anti-viral drug and immune-modulating (immunotherapy)for PD treatment and even preventing of PD can be a new era for management of neurodegenerative disease [51, 58].

Due to the extensive evidence that inflammation and immune activation are characteristics of PD, it is not strange that immune-targeting interventions and anti-inflammatory drugs have progressed in the treatments for PD, as they have in other neurodegenerative illnesses such as amyotrophic lateral sclerosis and Alzheimer’s disease [59, 60]. Trials on anti-inflammatory medication in PD have been profoundly unsatisfactory, as they have been in other neurodegenerative illnesses, and such trials need adjusting the strategy [52]. The incorporation of immune-related end points might be a significant therapeutic factor that influences the design of future, possibly more effective trials that use combination medicines that target many processes, like immunological responses [52, 61].

As the neurodegenerative field grows, it is becoming more important to investigate the role of peripheral and central inflammation in the progression and pathogenesis of PD, one of the key obstacles is the creation of innovative methods, including advanced patient-derived models, machine learning, or single-cell multi-omics that will empower the field to thoroughly examine how immune cells predispose or protect neuron injury, whether or not inflammation and the immune system are significant elements of the disease, and at which stages immune processes play crucial roles and are prognostic of illness course [62, 63]. Therefore, further research in these areas is required. Better knowledge and identification of the immunological processes behind the initial indications of PD may result in innovative medicines, and physicians may one day be able to successfully intervene with repurposed or novel immunomodulatory and anti-inflammatory medications to postpone or slow progression of the illness from the periphery to the CNS [64].

There were several limitations to this study. First, only summary data, rather than individual patient data, can be utilized. Second, we only considered studies that reported mean and SD. Third, there was a significant publication bias in our results. Forth, we could not perform trial sequential analysis (TSA), because it can be applied to analyses on dichotomous data like odds ratio (OR) and hazard ratio (HR), but not on SMD, which was reported in our meta-analysis. We tried to extract dichotomous data like OR from included studies and conduct a new meta-analysis and then, perform TAS; however, except to one study [33], no study had reported OR, so further studies reporting TSA results are needed. Finally, neutrophil and lymphocyte counts are nonspecific measures that might be affected by other circumstances such as infections, inflammation, and medicines. These contemporaneous variables may affect how NLR is measured in some of the included studies since they were not specifically controlled.

In conclusion, high NLR can be regarded as an indicator of inflammation in PD. Still, it needs more investigations to study its diagnostic value, association with the stage and progression of the disease, and therapeutic value. Our results expanded immunological information from Parkinson’s disease patients to build better preclinical models, with the long-term objective of allowing early detection of at-risk people to postpone, and treat the illness more properly.