Inflammation-associated peripheral blood cells and serum lipid levels are associated with Parkinson's disease.

Abstract

To the Editor: Parkinson's disease (PD) is one of the most common neurodegenerative disorders and the most common movement disorder worldwide. PD pathogenesis has been demonstrated to be associated with neuroinflammation and intestinal inflammation. Increased C-reactive protein (CRP) levels were related to freezing of gait and rapid PD progression, particularly in elderly patients. Recent research indicates that immune cells in peripheral blood might also contribute to PD pathogenesis, providing further insight into the relationship between inflammation and PD.[1] Additionally, peripheral blood lipid levels were also associated with PD development, with recent studies showing that high serum low-density lipoprotein (LDL) and total cholesterol were associated with decreased PD risk in healthy individuals, and changes in lipid levels or their chemical properties induce the aggregation of α-synuclein, further contributing to PD pathogenesis. Moreover, concurrent lipid changes were observed in dopaminergic neurons and other nearby glial cells, such as microglia and astrocytes, in the brains of PD patients.[2] Given these pieces of evidence, we further analyzed the levels of peripheral inflammatory factors and lipids in the peripheral blood of PD patients and healthy age-matched controls to validate if these factors jointly impacted PD onset. Our findings may encourage more in-depth explorations of the role of inflammation and lipid metabolism in PD pathogenesis and predict the risk of PD. One hundred and eighty-two Han PD patients with an average age of (67 ± 10) years and 176 age-matched healthy controls with an average age of (66 ± 9) years were included in our study. All PD patients were diagnosed according to the current clinical diagnostic criteria of the Movement Disorders Society[3] by at least two experienced neurologists. All the participants were selected with systemic exclusion criteria, including diabetes mellitus, hypothyroidism, infection, severe hepatic or renal failure, dyslipidemia, myocardial infarction, surgery within the last 3 months, and inflammatory, autoimmune, or neoplastic disease. A comparison of baseline data did not reveal significant differences in the proportion of patients’ age (P = 0.815) and gender distribution (P = 0.766) between the two groups. Patients’ blood samples were obtained from each PD patient and healthy controls’ antecubital vein in the morning without food intake. All the samples were then centrifuged for 30 min at 2500 × g at 4°C for 10 min. Leukocytes, monocytes, neutrophils, lymphocytes, and high-sensitivity C-reactive protein (CRP) were quantitated with a BC-6800 automatic hematology analyzer (Mindray, China). Serum LDL, High-density lipoprotein, total cholesterol, and triglycerides were analyzed enzymatically on an Olympus AU5400 automatic biochemical analyzer (First Chemical Co., Ltd, Japan) using commercial reagents according to the manufacturer's instructions. All patients signed informed consent before inclusion. The study was approved by the Medical Ethics Committee of The Second Affiliated Hospital of Soochow University (No. JD-LK-2018-061-03). After comparing the peripheral blood levels of inflammatory factors and lipids between the two groups, it was found that the peripheral blood levels of monocytes (P < 0.001), neutrophils (P = 0.009), and CRP (P < 0.001) were significantly higher in PD patients than in the control group. In contrast, the lymphocyte counts (P < 0.001), LDL (P < 0.001), total cholesterol (P < 0.001), and triglyceride (P < 0.001) were significantly lower than that in the control group [Table 1]. The logistic regression analysis revealed that peripheral blood levels of monocytes (P < 0.001) and CRP (P < 0.001) were independent risk factors for PD pathogenesis, while lymphocyte counts (P = 0.001) and triglyceride levels (P = 0.020) were protective factors for PD onset. The area under the curve value of the recipient operating characteristic curve for predicting the accuracy of the model (combining monocyte, lymphocyte, CRP, and triglyceride levels) for PD development reached 0.825 [Supplementary Figure 1, https://links.lww.com/CM9/B198], suggesting a combined effect of peripheral inflammatory cells and serum lipid on PD onset. Table 1 - Comparison of peripheral blood cells and serum lipids in PD patients and healthy controls. Univariate Multivariate Indices PD (n = 182) Control (n = 176) Wilcoxon P-value OR SE P value OR SE P value Age (years) 67 66 0.815 Monocyte (×109/L) 0.40 0.30 <0.001 202.57 0.92 <0.001 98.10 1.223 <0.001 Lymphocyte (×109/L) 1.60 1.90 <0.001 0.51 0.19 <0.001 0.45 0.239 0.001 Neutrophil (×109/L) 3.50 3.20 0.009 1.29 0.09 0.004 1.09 0.122 0.494 Leukocyte (×109/L) 5.60 5.85 0.245 0.96 0.07 0.504 CRP (mg/L) 5.50 4.90 <0.001 6.92 0.27 <0.001 6.21 0.314 <0.001 LDL (mmol/L) 2.60 2.89 <0.001 0.62 0.13 <0.001 1.03 0.36 0.933 HDL (mmol/L) 1.30 1.26 0.087 1.25 0.27 0.410 Total cholesterol (mmol/L) 4.41 4.93 <0.001 0.65 0.12 <0.001 0.72 0.319 0.302 Triglyceride (mmol/L) 0.90 1.29 <0.001 0.61 0.14 <0.001 0.68 0.170 0.020 Values of variables in PD and control groups were shown as median. OR: Odds ratio; SE: Standard error; CRP: C-reactive protein; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; PD: Parkinson's disease. Emerging evidence suggests that chronic inflammation, particularly in the central nervous system (CNS), is associated with PD pathogenesis and that peripheral immune cell counts, including monocytes, are potentially associated with PD development.[4] Inflammatory proteins, including CRP, have also been elevated before PD onset. Peripheral monocyte, a typical inflammation-related cell, has been demonstrated to infiltrate into the nervous system and activate resident microglia, producing inflammatory factors leading to impaired dopaminergic neurogenesis and ultimately contributing to the development of PD. Monocytes in PD patients, but not healthy controls, were also reported to secrete more inflammatory cytokines, inducing and exacerbating CNS inflammation. The study of changes in peripheral blood components such as monocytes, CRP, and plasma lipid levels in patients with PD has been well discussed in numerous previous reports.[2] However, studies combining these factors in a multi-metric diagnostic model in PD have not been reported. In the present study, we explored the factors associated with PD by logistic regression on multiple peripheral blood components. Our results emphasized the significance of monocytes, CRP levels, lymphocyte, and triglyceride levels in PD patients. Moreover, the diagnostic model based on these peripheral factors accurately diagnosed PD patients. These results suggest that under a systemic inflammatory response in PD, the levels of various inflammatory cells and lipids in peripheral blood can reflect the PD status. In addition, our correlation analysis of symptom scores with peripheral blood lipids and inflammatory factors in PD patients revealed that protective inflammatory factors, such as lymphocytes, were negatively correlated with The Unified Parkinson's Disease Rating Scale II (UPDRS II) and UPDRS III scores, while peripheral blood lipid levels, including cholesterol and triglyceride, were negatively correlated with UPDRS I scores, suggesting that these protective factors for the onset of PD also play a role in the severity of PD symptoms [Supplementary Table 1, https://links.lww.com/CM9/B199]. However, our results were limited by our sample size and single-center retrospective analysis, and the accuracy of the results remains to be confirmed by further large-sample, multicenter randomized controlled studies with longitudinal levels of peripheral blood factors and serum lipids. Further, our analysis needs to include other neuroinflammatory diseases, such as multiple sclerosis and cerebrovascular disease, as disease controls to better illustrate the role of peripheral blood inflammatory factors and serum lipids in PD. In conclusion, our research revealed the adverse effects of peripheral blood CRP and monocytes in PD and the protective effects of lymphocytes and triglyceride on the development of PD. The diagnostic model combining these peripheral blood lipids and inflammatory factors has good accuracy in diagnosing PD. Further studies on peripheral blood inflammatory factors and lipid levels can help explore the pathogenesis of PD and potential therapeutic targets of PD, providing reliable information for the precise treatment of PD. Funding The present study was supported by the social development projects in Jiangsu Province (No. BE2018658), the Jiangsu Provincial Medical Key Discipline Project (No. ZDXKB2016022), the Suzhou Science and Technology Development Program (No. SYS2020131), the Discipline Construction Program of The Second Affiliated Hospital of Soochow University (No. XKTJ-XK202001), and The Second Hospital of Soochow University Young Staff Pre-Research Fund Project (No. SDFEYQN1807). Conflicts of interest None.