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Li J, Zhang M, Yu CQ, Xue M, Hu PP. Early diagnosis of Parkinson's disease: biomarker study. Front Aging Neurosci 2025; 17:1495769. [PMID: 40416739 PMCID: PMC12098601 DOI: 10.3389/fnagi.2025.1495769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 03/28/2025] [Indexed: 05/27/2025] Open
Abstract
Parkinson's disease (PD) is a common chronic degenerative disease with age-dependent increasing prevalence in the elderly. Non-motor symptoms include sensory deficiencies, autonomic dysfunction, psychological and cognitive abnormalities; while motor symptoms are bradykinesia, myotonia, resting tremor, and postural balance difficulties. The clinical diagnosis of PD depends mainly on patients' medical history and physical examination. It is highly important to realize early detection of PD, and biomarkers are a valuable tool in this regard. The present study reviewed the findings of researches from the last few years, involving the advancements in the study of PD biomarkers in blood, cerebrospinal fluid, saliva, urine, tears, imaging, and pathology.
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Affiliation(s)
- Jing Li
- Department of Neurology, The First Hospital of Anhui University of Science and Technology (Huainan First People’s Hospital), Huainan, China
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mei Zhang
- Department of Neurology, The First Hospital of Anhui University of Science and Technology (Huainan First People’s Hospital), Huainan, China
| | - Chuan-Qing Yu
- Department of Neurology, The First Hospital of Anhui University of Science and Technology (Huainan First People’s Hospital), Huainan, China
| | - Min Xue
- Department of Neurology, The First Hospital of Anhui University of Science and Technology (Huainan First People’s Hospital), Huainan, China
| | - Pan-Pan Hu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Jing Y, Zhu H, Yao P, Chen Y, Lai X, He Q, Yu L, Lin Y, Kang D. IgD-CD38-B Cell Partially Mediates the Protective Effect of Higher Serum Triacylglycerol (53:4) Levels Against Parkinson's Disease. J Neurochem 2025; 169:e70067. [PMID: 40302204 DOI: 10.1111/jnc.70067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 02/17/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025]
Abstract
Emerging evidence suggests that dysregulated lipid metabolism contributes to Parkinson's disease (PD) risk, with chronic inflammation in the central nervous system (CNS) also playing a pivotal role. Although correlations between inflammatory responses, serum lipid metabolism, and PD risk are established, a causal relationship remains unclear. Building on previous findings linking higher serum triacylglycerol (51:4) levels to reduced PD risk, this study explores the potential causal associations between 38 triacylglycerol isoforms and PD risk using Mendelian randomization (MR). We utilized summary-level data from genome-wide association studies (GWAS) on PD, circulating immune cells, inflammatory proteins, and serum lipidomes-including 38 triacylglycerol isoforms, 15 sterol ester isoforms, and 46 phosphatidylcholine isoforms-to assess the relationship between serum lipid profiles and PD. Our analysis revealed that higher levels of serum triacylglycerol (51:4) and triacylglycerol (53:4) were associated with a reduced PD risk, whereas lower levels of phosphatidylcholine (17:0_18:1) and sterol ester (27:1/20:2) were linked to higher PD risk. Notably, multivariable MR analysis confirmed a robust causal association between increased serum triacylglycerol (53:4) and a 24% reduction in PD risk (1 SD higher triacylglycerol (53:4) leading to a 24% [95% CI, 0.54-0.97] risk reduction, p = 0.005). Mediation analysis suggested that circulating immune cells, rather than inflammatory proteins, may mediate the relationship between triacylglycerol (53:4) levels and PD risk. These findings establish a causal link between triacylglycerol (53:4) and PD risk, highlighting the potential role of immune modulation in PD pathogenesis.
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Affiliation(s)
- Yajun Jing
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Honglin Zhu
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Peisen Yao
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yiming Chen
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Xuemiao Lai
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qiu He
- Department of Immunology, Northwestern University, Evanston, Illinois, USA
| | - Lianghong Yu
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
| | - Yuanxiang Lin
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Dezhi Kang
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Koros C, Simitsi AM, Papagiannakis N, Antonelou R, Bougea A, Papadimitriou D, Pachi I, Beratis I, Kontaxopoulou D, Fragkiadaki S, Sfikas E, Alefanti I, Chrysovitsanou C, Angelopoulou E, Bregianni M, Lourentzos K, Constantinides VC, Velonakis G, Prassopoulos V, Bonakis A, Papageorgiou SG, Potagas C, Picillo M, Barone P, Stamelou M, Stefanis L. Peripheral Immune pattern in a genetic cohort of p.A53T alpha-synuclein carriers. Parkinsonism Relat Disord 2025; 135:107853. [PMID: 40328209 DOI: 10.1016/j.parkreldis.2025.107853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 03/30/2025] [Accepted: 04/26/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Previous research has shown that inflammatory immune biomarkers including peripheral white blood cell subpopulations differ between Parkinson's disease (PD) patients and healthy controls (HC), with PD exhibiting higher neutrophil to lymphocyte ratio (NLR). The aim of the present report was to assess the peripheral immune profile in patients or asymptomatic carriers harboring the p.A53T alpha-synuclein (SNCA) mutation. METHODS Data regarding 31 p.A53T SNCA PD patients, 9 asymptomatic mutation carriers and 194 HCs were obtained from the database of the Parkinson's Progression Markers Initiative (PPMI). Focus was placed on peripheral immune blood cells subpopulations and clinical/imaging parameters at baseline. RESULTS NLR, Absolute Neutrophil cell count and Neutrophils to total Leukocytes ratio were increased in the p.A53T SNCA PD group as compared to HCs [2.77 vs 2.18 (p < 0.001), 4.32 × 10^3 cells/μL vs 3.67 × 10^3 cells/μL (p = 0.001), 65.67 % vs 59.55 % (p < 0.001)]. Differences in NLR were mainly driven by the male patient subgroup. Lymphocytes to total Leukocytes and Monocytes to total Leukocytes ratio were lower in the p.A53T SNCA cohort as compared to HC [(p = 0.001) and (p = 0.002)]. Finally, we observed a positive correlation between the absolute Lymphocyte count and the mean putamen DATSCAN signal. Asymptomatic carriers did not differ statistically from either group. DISCUSSION Our current study provides evidence of a specific pattern of peripheral immune response in the p.A53T SNCA PD group which aligns well with literature data in idiopathic and GBA-PD. Whether this peripheral immune activation represents a contributing cause or an effect of the neurodegenerative process will require further study.
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Affiliation(s)
- Christos Koros
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Athina-Maria Simitsi
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Papagiannakis
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Roubina Antonelou
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Bougea
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Ioanna Pachi
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2nd Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, Greece
| | - Ion Beratis
- Deree, The American College in Greece, Athens, Greece
| | - Dionysia Kontaxopoulou
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Stella Fragkiadaki
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Sfikas
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioanna Alefanti
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Chrysa Chrysovitsanou
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthalia Angelopoulou
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Marianna Bregianni
- 2nd Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, Greece
| | - Konstantinos Lourentzos
- 2nd Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, Greece
| | - Vasilios C Constantinides
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Velonakis
- 2nd Department of Radiology, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Anastasios Bonakis
- 2nd Department of Neurology, Attikon Hospital, National and Kapodistrian University of Athens, Greece
| | - Sokratis G Papageorgiou
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Constantin Potagas
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Marina Picillo
- Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Italy
| | - Paolo Barone
- Center for Neurodegenerative Diseases (CEMAND), Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Italy
| | | | - Leonidas Stefanis
- 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Lin R, Cai G, Chen Y, Zheng J, Wang S, Xiao H, Ye Q, Xue Y, Jiang R. Association of glymphatic system function with peripheral inflammation and motor symptoms in Parkinson's disease. NPJ Parkinsons Dis 2025; 11:62. [PMID: 40155401 PMCID: PMC11953377 DOI: 10.1038/s41531-025-00909-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 03/06/2025] [Indexed: 04/01/2025] Open
Abstract
Growing evidence highlights the roles of glymphatic system and peripheral inflammation in Parkinson's disease (PD). We evaluated their interrelationship and potential mechanisms contributing to motor symptoms using DTI-ALPS and inflammatory markers (leukocyte, lymphocyte, neutrophil counts, neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR]) in 134 PD patients (52 tremor-dominant [TD], 62 postural instability and gait difficulty [PIGD]) and 81 healthy controls (HC, 33 with inflammatory markers). PD exhibited lower DTI-ALPS than HC (1.43 ± 0.19 vs. 1.52 ± 0.21, p = 0.001). DTI-ALPS was negatively correlated with NLR, PLR, and neutrophils in PD (all p < 0.05) and with neutrophils in PIGD (β = -0.043, p = 0.048), and positively correlated with lymphocytes in TD (β = 0.105, p = 0.034). DTI-ALPS mediated the relationship between peripheral inflammation (NLR and neutrophils) and MDS-UPDRS III score in PD. Overall, glymphatic dysfunction correlates with peripheral inflammation and may mediate effects of inflammation on motor symptoms in PD, with distinct inflammation profiles between TD and PIGD.
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Affiliation(s)
- Ruolan Lin
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Guoen Cai
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China
- Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Ying Chen
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China
- Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Jinmei Zheng
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shu Wang
- School of Mechanical Engineering and Automation, Fuzhou University, Fuzhou, China
| | - Huinan Xiao
- Department of Radiotherapy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Qinyong Ye
- Department of Neurology, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China.
- Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
| | - Yunjing Xue
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, China.
| | - Rifeng Jiang
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, China.
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Zhang CG, Zhang Y, Xu K, Wang S, Bai Y. Correlation of inflammatory markers with depression and sleep disorders accompanying the prodromal stage of Parkinson's disease. World J Psychiatry 2025; 15:99901. [PMID: 40109997 PMCID: PMC11886346 DOI: 10.5498/wjp.v15.i3.99901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/20/2024] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
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.
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Affiliation(s)
- Cheng-Guang Zhang
- Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Yu Zhang
- Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Ke Xu
- Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Shun Wang
- Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Yan Bai
- Department of Acupuncture and Moxibustion, Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
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Carbajal C, Rodriguez M, Owens F, Stone N, Veeragoni D, Fan RZ, Tieu K, El-Hage N. Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson's Disease. Pharmaceutics 2025; 17:365. [PMID: 40143028 PMCID: PMC11944340 DOI: 10.3390/pharmaceutics17030365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Parkinson's disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or "mitophagy") links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug's inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD.
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Affiliation(s)
- Candy Carbajal
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
| | - Myosotys Rodriguez
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
| | - Florida Owens
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
| | - Nicole Stone
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
| | - Dileepkumar Veeragoni
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
| | - Rebecca Z. Fan
- Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, USA; (R.Z.F.); (K.T.)
| | - Kim Tieu
- Department of Environmental Health Sciences, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, USA; (R.Z.F.); (K.T.)
| | - Nazira El-Hage
- Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (C.C.); (M.R.); (F.O.); (N.S.); (D.V.)
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Qiao CM, Ma XY, Tan LL, Xia YM, Li T, Wu J, Cui C, Zhao WJ, Shen YQ. Indoleamine 2, 3-dioxygenase 1 inhibition mediates the therapeutic effects in Parkinson's disease mice by modulating inflammation and neurogenesis in a gut microbiota dependent manner. Exp Neurol 2025; 385:115142. [PMID: 39793693 DOI: 10.1016/j.expneurol.2025.115142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/27/2024] [Accepted: 01/06/2025] [Indexed: 01/13/2025]
Abstract
Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX+) cells and SOX2+ cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.
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Affiliation(s)
- Chen-Meng Qiao
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xiao-Yu Ma
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Lu-Lu Tan
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yi-Meng Xia
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Ting Li
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jian Wu
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Chun Cui
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Wei-Jiang Zhao
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yan-Qin Shen
- Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
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Liu F, Ran Q, Zhang H, Chen J. The Systemic Immune-Inflammation Index and the Risk of Parkinson's Disease in the U.S.: A Cross-Sectional Study. J Clin Med 2025; 14:403. [PMID: 39860410 PMCID: PMC11765590 DOI: 10.3390/jcm14020403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/29/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Inflammation is reportedly related to Parkinson's disease (PD). However, the relationship between the systemic immune-inflammation index (SII) and PD remains unexplored. This study aimed to explore the potential relationship between the SII and PD. Methods: This retrospective cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES) covering the years 2003 to 2020. We analyzed patients over 40 years of age after excluding those with missing SII, PD and covariate data. Logistic regression, subgroup analysis, and restricted cubic spline models were subsequently conducted to evaluate the associations between the SII and PD. Results: Finally, 30,638 participants were included in this study, of whom 416 (1.36%) were identified as having PD. Weighted multivariate regression analysis, adjusted for all covariates, revealed that participants with elevated in-transform (SII) values had a higher likelihood of PD [OR 1.39; 95% CI (1.02, 1.91), p = 0.039] compared to those with lower SII values. The fully adjusted restricted cubic spline curve revealed that the SII/100 was positively and linearly associated with the incidence of PD (p for nonlinearity > 0.05). Additionally, subgroup analysis revealed a stronger correlation between the SII and PD in female participants [OR = 1.06, 95% CI (1.03, 1.08)] compared to male participants [OR = 1.02, 95% CI (1.00, 1.03)] (p for interaction = 0.01). Conclusions: The SII showed a positive correlation with the incidence of PD, particularly in females. Further large-scale prospective studies are necessary to confirm these findings and explore the causal factors that may contribute to the early prevention of PD.
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Affiliation(s)
- Fujun Liu
- State Key Laboratory of Biotherapy Center, West China Hospital, Sichuan University, Chengdu 610041, China; (F.L.); (H.Z.)
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qibo Ran
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huajin Zhang
- State Key Laboratory of Biotherapy Center, West China Hospital, Sichuan University, Chengdu 610041, China; (F.L.); (H.Z.)
| | - Jing Chen
- Department of Neurosurgery and Neuromodulation Center, West China Hospital, Sichuan University, Chengdu 610041, China
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9
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Zhu S, Li H, Huang Z, Zeng Y, Huang J, Li G, Yang S, Zhou H, Chang Z, Xie Z, Que R, Wei X, Li M, Liang Y, Xian W, Li M, Pan Y, Huang F, Shi L, Yang C, Deng C, Batzu L, Poplawska-Domaszewicz K, Chen S, Chan LL, Ray Chaudhuri K, Tan EK, Wang Q. Plasma fibronectin is a prognostic biomarker of disability in Parkinson's disease: a prospective, multicenter cohort study. NPJ Parkinsons Dis 2025; 11:1. [PMID: 39747089 PMCID: PMC11697031 DOI: 10.1038/s41531-024-00865-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/13/2024] [Indexed: 01/04/2025] Open
Abstract
In a prospective longitudinal study with 218 Parkinson's disease (PD) patients in the discovery cohort and 84 in the validation cohort, we aimed to identify novel blood biomarkers predicting disability milestones in PD. Through Least Absolute Shrinkage and Selection Operator-Cox (Lasso-Cox) regression, developed nomogram predictive model and Linear mixed-effects models, we identified low level of plasma fibronectin (pFN) as one of the best-performing risk markers in predicting disability milestones. A low level of pFN was associated with a short milestone-free survival period in PD. Longitudinal analysis showed an annual decline in the rate of pFN was significantly associated with the annual elevation rate in the Hoehn-Yahr stage. Moreover, pFN level was negatively correlated with phosphorylated α-synuclein, and a low level of pFN was associated with BBB disruption in the striatum on neuroimaging, providing evidence for pFN's role in PD progression. We finally identified pFN as a novel blood biomarker that predicted first-milestone disability in PD.
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Affiliation(s)
- Shuzhen Zhu
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Hualin Li
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Zifeng Huang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Yiheng Zeng
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Jianmin Huang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Guixia Li
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Shujuan Yang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Hang Zhou
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Zihan Chang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Zhenchao Xie
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Rongfang Que
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Xiaobo Wei
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Minzi Li
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Yanran Liang
- Department of Neurology, Sun Yat-Sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Wenbiao Xian
- Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Mengyan Li
- Department of Neurology, Guangzhou First People's Hospital of South China University of Technology, Guangzhou, Guangdong, People's Republic of China
| | - Ying Pan
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Fanheng Huang
- Department of Radiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China
| | - Lin Shi
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, People's Republic of China
| | - Chengwu Yang
- Division of Biostatistics and Health Services Research, Department of MassachusettPopulation and Quantitative Health Sciences, T.H. Chan School of Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA
| | - Chao Deng
- School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia
| | - Lucia Batzu
- Parkinson Foundation International Centre of Excellence at King's College Hospital, and Kings College, Denmark Hill, London, SE5 9RS, UK
| | - Karolina Poplawska-Domaszewicz
- Parkinson Foundation International Centre of Excellence at King's College Hospital, and Kings College, Denmark Hill, London, SE5 9RS, UK
| | - Shuhan Chen
- Guangdong Experimental High School, Guangzhou, Guangdong, 51000, People's Republic of China
| | - Ling-Ling Chan
- Department of Neurology, Singapore General Hospital, Singapore, Singapore
- Duke-National University of Singapore Medical School, Singapore, Singapore
| | - K Ray Chaudhuri
- Parkinson Foundation International Centre of Excellence at King's College Hospital, and Kings College, Denmark Hill, London, SE5 9RS, UK.
| | - Eng-King Tan
- Department of Neurology, Singapore General Hospital, Singapore, Singapore.
- Duke-National University of Singapore Medical School, Singapore, Singapore.
| | - Qing Wang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510282, People's Republic of China.
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10
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Jacob G, Milan BA, Antonieto LR, Levi Y, Ribeiro MC, Nassar R, de Sousa-Neto MD, Mazzi-Chaves JF, Messora MR, Furlaneto FAC, Nascimento GC, Del-Bel E. Experimental Periodontitis Worsens Dopaminergic Neuronal Degeneration. J Clin Periodontol 2025; 52:159-170. [PMID: 39223037 DOI: 10.1111/jcpe.14065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/09/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
AIM To investigate the hypothesis supporting the link between periodontitis and dopaminergic neuron degeneration. MATERIALS AND METHODS Adult male Wistar rats were used to induce dopaminergic neuronal injury with 6-hydroxydopamine (6-OHDA) neurotoxin and experimental periodontitis via ligature placement. Motor function assessments were conducted before and after periodontitis induction in controls and 6-OHDA-injury-induced rats. Tissue samples from the striatum, jaw and blood were collected for molecular analyses, encompassing immunohistochemistry of tyrosine hydroxylase, microglia and astrocyte, as well as micro-computed tomography, to assess alveolar bone loss and for the analysis of striatal oxidative stress and plasma inflammatory markers. RESULTS The results indicated motor impairment in 6-OHDA-injury-induced rats exacerbated by periodontitis, worsening dopaminergic striatal degeneration. Periodontitis alone or in combination with 6-OHDA-induced lesion was able to increase striatal microglia, while astrocytes were increased by the combination only. Periodontitis increased striatal reactive oxygen species levels and plasma tumour necrosis factor-alpha levels in rats with 6-OHDA-induced lesions and decreased the anti-inflammatory interleukin-10. CONCLUSIONS This study provides original insights into the association between periodontitis and a neurodegenerative condition. The increased inflammatory pathway associated with both 6-OHDA-induced dopaminergic neuron lesion and periodontal inflammatory processes corroborates that the periodontitis-induced systemic inflammation may aggravate neuroinflammation in Parkinson's-like disease, potentially hastening disease progression.
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Affiliation(s)
- Gabrielle Jacob
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Bruna A Milan
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Livia Rodrigues Antonieto
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Yara Levi
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Marcela Costa Ribeiro
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Raquel Nassar
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Manoel Damião de Sousa-Neto
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Jardel Francisco Mazzi-Chaves
- Department of Restorative Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Michel Reis Messora
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Flavia Aparecida Chaves Furlaneto
- Department of Oral and Maxillofacial Surgery and Periodontology, School of Dentistry of Ribeirão Preto, University of São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Glauce C Nascimento
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Elaine Del-Bel
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil
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11
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Bellini G, Rettura F, Palermo G, Ippolito C, Segnani C, Pierucci C, Fontanelli L, Frosini D, Nardini V, Lambiase C, Bernardini N, Pellegrini C, Ceravolo R. Prokineticin-2 Is Highly Expressed in Colonic Mucosa of Early Parkinson's Disease Patients. Mov Disord 2024; 39:2091-2097. [PMID: 39051733 DOI: 10.1002/mds.29937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/20/2024] [Accepted: 07/01/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Elevated levels of prokineticin-2 (PK2), regarded as a protein involved in modulating immune/inflammatory responses, have been detected in the substantia nigra, serum, and olfactory neurons of Parkinson's disease (PD) patients. Of note, emerging evidence suggests that gut alterations, including dysbiosis and enteric inflammation, play a role in PD via the gut-brain axis. OBJECTIVES Our goal was to investigate the expression of PK2 in colonic biopsies of PD patients. METHODS Mucosal biopsies from the descending colon were obtained in 11 PD patients and five asymptomatic subjects. Biopsy samples were processed for PK2 immunofluorescence and western blot. RESULTS We revealed an increased PK2 expression in colonic mucosa from PD patients in the early stages compared to controls. In addition, we found that PK2 was expressed by activated enteric glial cells and macrophages. CONCLUSIONS PK2 is highly expressed within neurogenic/inflammatory cells of colonic mucosa from early PD patients, suggesting a potential role of PK2 in gut inflammation, especially in the early stages of PD. © 2024 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Gabriele Bellini
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Department of Neurology, the Marlene and Paolo Fresco Institute for Parkinson's Disease and Movement Disorders, New York University Langone Health, New York, New York, USA
| | - Francesco Rettura
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Giovanni Palermo
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Clarissa Pierucci
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Lorenzo Fontanelli
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Daniela Frosini
- Neurology Unit, Department of Medical Specialties, AOUP, Pisa, Italy
| | - Vincenzo Nardini
- Anatomia Patologica 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Christian Lambiase
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Neurology Unit, Department of Medical Specialties, AOUP, Pisa, Italy
- Anatomia Patologica 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Carolina Pellegrini
- Unit of Histology and Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Roberto Ceravolo
- Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Center for Neurodegenerative Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Yi H, Liang X, Xu F, Li T, Yang X, Wei M, Ou Z, Wang L, Tong Q. Association between neutrophil-to-lymphocyte ratio and motor subtypes in idiopathic Parkinson's disease: a prospective observational study. BMC Neurol 2024; 24:379. [PMID: 39379829 PMCID: PMC11460115 DOI: 10.1186/s12883-024-03887-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 09/27/2024] [Indexed: 10/10/2024] Open
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.
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Affiliation(s)
- Hongyan Yi
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Xiaojing Liang
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Fugui Xu
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Tiantian Li
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Xiu Yang
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Ming Wei
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Zhou Ou
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China
| | - Lijun Wang
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China.
| | - Qiang Tong
- Department of Neurology, the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, 1 Huanghe Road West, Huaian, 223300, Jiangsu, China.
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13
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Roodveldt C, Bernardino L, Oztop-Cakmak O, Dragic M, Fladmark KE, Ertan S, Aktas B, Pita C, Ciglar L, Garraux G, Williams-Gray C, Pacheco R, Romero-Ramos M. The immune system in Parkinson's disease: what we know so far. Brain 2024; 147:3306-3324. [PMID: 38833182 PMCID: PMC11449148 DOI: 10.1093/brain/awae177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/02/2024] [Accepted: 05/13/2024] [Indexed: 06/06/2024] Open
Abstract
Parkinson's disease is characterized neuropathologically by the degeneration of dopaminergic neurons in the ventral midbrain, the accumulation of α-synuclein (α-syn) aggregates in neurons and chronic neuroinflammation. In the past two decades, in vitro, ex vivo and in vivo studies have consistently shown the involvement of inflammatory responses mediated by microglia and astrocytes, which may be elicited by pathological α-syn or signals from affected neurons and other cell types, and are directly linked to neurodegeneration and disease development. Apart from the prominent immune alterations seen in the CNS, including the infiltration of T cells into the brain, more recent studies have demonstrated important changes in the peripheral immune profile within both the innate and adaptive compartments, particularly involving monocytes, CD4+ and CD8+ T cells. This review aims to integrate the consolidated understanding of immune-related processes underlying the pathogenesis of Parkinson's disease, focusing on both central and peripheral immune cells, neuron-glia crosstalk as well as the central-peripheral immune interaction during the development of Parkinson's disease. Our analysis seeks to provide a comprehensive view of the emerging knowledge of the mechanisms of immunity in Parkinson's disease and the implications of this for better understanding the overall pathogenesis of this disease.
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Affiliation(s)
- Cintia Roodveldt
- Centre for Molecular Biology and Regenerative Medicine-CABIMER, University of Seville-CSIC, Seville 41092, Spain
- Department of Medical Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Seville, Seville 41009, Spain
| | - Liliana Bernardino
- Health Sciences Research Center (CICS-UBI), Faculty of Health Sciences, University of Beira Interior, 6200-506, Covilhã, Portugal
| | - Ozgur Oztop-Cakmak
- Department of Neurology, Faculty of Medicine, Koç University, Istanbul 34010, Turkey
| | - Milorad Dragic
- Laboratory for Neurobiology, Department of General Physiology and Biophysics, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia
- Department of Molecular Biology and Endocrinology, ‘VINČA’ Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Kari E Fladmark
- Department of Biological Science, University of Bergen, 5006 Bergen, Norway
| | - Sibel Ertan
- Department of Neurology, Faculty of Medicine, Koç University, Istanbul 34010, Turkey
| | - Busra Aktas
- Department of Molecular Biology and Genetics, Burdur Mehmet Akif Ersoy University, Burdur 15200, Turkey
| | - Carlos Pita
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal
| | - Lucia Ciglar
- Center Health & Bioresources, Competence Unit Molecular Diagnostics, AIT Austrian Institute of Technology GmbH, 1210 Vienna, Austria
| | - Gaetan Garraux
- Movere Group, Faculty of Medicine, GIGA Institute, University of Liège, Liège 4000, Belgium
| | | | - Rodrigo Pacheco
- Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580702, Santiago, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia 7510156, Santiago, Chile
| | - Marina Romero-Ramos
- Department of Biomedicine & The Danish Research Institute of Translational Neuroscience—DANDRITE, Aarhus University, DK-8000 Aarhus C, Denmark
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14
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Marques D, Moura-Louro D, Silva IP, Matos S, Santos CND, Figueira I. Unlocking the potential of low-molecular-weight (Poly)phenol metabolites: Protectors at the blood-brain barrier frontier. Neurochem Int 2024; 179:105836. [PMID: 39151552 DOI: 10.1016/j.neuint.2024.105836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/05/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide. The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression. Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB. In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites' ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.
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Affiliation(s)
- Daniela Marques
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
| | - Diogo Moura-Louro
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
| | - Inês P Silva
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
| | - Sara Matos
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal
| | - Cláudia Nunes Dos Santos
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade NOVA de Lisboa, Avenida da República, Oeiras, Portugal; iBET, Instituto de Biologia Experimental e Tecnológica, Avenida da República, Apartado 12, Oeiras, Portugal
| | - Inês Figueira
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.
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15
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Woo KA, Kim HJ, Lee CY, Shin JH, Sun C, Im H, An H, Lim J, Choi SY, Koh Y, Jeon B. Parkinson's disease is associated with clonal hematopoiesis with TET2 mutation. NPJ Parkinsons Dis 2024; 10:168. [PMID: 39242596 PMCID: PMC11379878 DOI: 10.1038/s41531-024-00784-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 08/27/2024] [Indexed: 09/09/2024] Open
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson's disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11-2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.
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Affiliation(s)
- Kyung Ah Woo
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Han-Joon Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Chan Young Lee
- Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Jung Hwan Shin
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Hogune Im
- NOBO Medicine Inc, Seoul, Republic of Korea
| | - Hongyul An
- NOBO Medicine Inc, Seoul, Republic of Korea
| | - Jiwoo Lim
- NOBO Medicine Inc, Seoul, Republic of Korea
| | - Su-Yeon Choi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Youngil Koh
- NOBO Medicine Inc, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Beomseok Jeon
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Umehara T, Mimori M, Kokubu T, Ozawa M, Shiraishi T, Sato T, Onda A, Matsuno H, Omoto S, Sengoku R, Murakami H, Oka H, Iguchi Y. Peripheral immune profile in drug-naïve dementia with Lewy bodies. J Neurol 2024; 271:4146-4157. [PMID: 38581545 DOI: 10.1007/s00415-024-12336-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 03/17/2024] [Accepted: 03/18/2024] [Indexed: 04/08/2024]
Abstract
BACKGROUND Accumulating evidence suggests that peripheral inflammation is associated with the pathogenesis of Parkinson's disease (PD). We examined peripheral immune profiles and their association with clinical characteristics in patients with DLB and compared these with values in patients with PD. METHODS We analyzed peripheral blood from 93 participants (drug-naïve DLB, 31; drug-naïve PD, 31; controls, 31). Absolute leukocyte counts, absolute counts of leukocyte subpopulations, and peripheral blood inflammatory indices such as neutrophil-to-lymphocyte ratio were examined. Associations with clinical characteristics, cardiac sympathetic denervation, and striatal 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) binding were also examined. RESULTS Patients with DLB had lower absolute lymphocyte and basophil counts than did age-matched controls (both; p < 0.005). Higher basophil counts were marginally associated with higher global cognition (p = 0.054) and were significantly associated with milder motor severity (p = 0.020) and higher striatal 123I-FP-CIT binding (p = 0.038). By contrast, higher basophil counts were associated with more advanced PD characterized by decreased global cognition and severe cardiac sympathetic denervation. Although lower lymphocyte counts had relevance to more advanced PD, they had little relevance to clinical characteristics in patients with DLB. Higher peripheral blood inflammatory indices were associated with lower body mass index in both DLB and PD. CONCLUSIONS As in patients with PD, the peripheral immune profile is altered in patients with DLB. Some peripheral immune cell counts and inflammatory indices reflect the degree of disease progression. These findings may deepen our knowledge on the role of peripheral inflammation in the pathogenesis of DLB.
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Affiliation(s)
- Tadashi Umehara
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan.
| | - Masahiro Mimori
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Tatsushi Kokubu
- Department of Neurology, Katsushika Medical Center, The Jikei University School of Medicine, Tokyo, Japan
| | - Masakazu Ozawa
- Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomotaka Shiraishi
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Takeo Sato
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Asako Onda
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Hiromasa Matsuno
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Shusaku Omoto
- Department of Neurology, Katsushika Medical Center, The Jikei University School of Medicine, Tokyo, Japan
| | - Renpei Sengoku
- Department of Neurology, Daisan Hospital, The Jikei University School of Medicine, Tokyo, Japan
| | - Hidetomo Murakami
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
- Department of Neurology, Showa University School of Medicine, Tokyo, Japan
| | - Hisayoshi Oka
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
| | - Yasuyuki Iguchi
- Department of Neurology, The Jikei University School of Medicine, 3-19-18, Tokyo, 105-8471, Japan
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Zhang F, Chen B, Ren W, Yan Y, Zheng X, Jin S, Chang Y. Association analysis of dopaminergic degeneration and the neutrophil-to-lymphocyte ratio in Parkinson's disease. Front Aging Neurosci 2024; 16:1377994. [PMID: 38650864 PMCID: PMC11033456 DOI: 10.3389/fnagi.2024.1377994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 03/28/2024] [Indexed: 04/25/2024] Open
Abstract
Introduction Peripheral inflammatory responses are suggested to play a major role in the pathophysiology of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a new recognized biomarker, can reflect peripheral inflammation in PD. However, the association between the NLR and dopaminergic degeneration in PD remains unclear. Methods In this retrospective study, 101 enrolled PD patients were categorized into early-stage and advanced-stage PD based on the Hoehn and Yahr (HY) scale. We evaluated the clinical characteristics, peripheral immune profile, and 11C-CFT striatal dopamine transporter (DAT) binding levels. Linear regression analyses were employed to assess the associations between NLR and striatal DAT levels at different stages in PD patients. Results Covariate-controlled regression analysis revealed that higher NLR was significantly associated with lower DAT levels in the caudate (β = -0.27, p = 0.003) and the putamen (β = -0.27, p = 0.011). Moreover, in the early-stage PD subgroup, a similar association was observed (caudate: β = -0.37, p = 0.013; putamen: β = -0.45, p = 0.005). The lymphocytes count was correlated positively with the striatal DAT levels in the Spearman correlation analysis whether in total patients (caudate: ρ = 0.25, p = 0.013; putamen: ρ = 0.22, p = 0.026) or in the early-stage subgroup (caudate: ρ = 0.31, p = 0.023, putamen: ρ = 0.34, p = 0.011). Conclusion Dopaminergic degeneration is associated with peripheral inflammation in PD. The NLR, a widely used inflammatory marker, may have the potential to reflect the degree of dopaminergic degeneration in individuals with early-stage PD.
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Affiliation(s)
- Fengjiao Zhang
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Bin Chen
- Departments of Nuclear Medicine, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Wenhua Ren
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yayun Yan
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xiaoqi Zheng
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Shuxian Jin
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Ying Chang
- Departments of Neurology, China-Japan Union Hospital, Jilin University, Changchun, China
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18
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Li F, Weng G, Zhou H, Zhang W, Deng B, Luo Y, Tao X, Deng M, Guo H, Zhu S, Wang Q. The neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and neutrophil-to-high-density-lipoprotein ratio are correlated with the severity of Parkinson's disease. Front Neurol 2024; 15:1322228. [PMID: 38322584 PMCID: PMC10844449 DOI: 10.3389/fneur.2024.1322228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
BACKGROUND Inflammation plays a pivotal role in the pathogenesis of Parkinson's disease (PD). However, the correlation between peripheral inflammatory markers and the severity of PD remains unclear. METHODS The following items in plasma were collected for assessment among patients with PD (n = 303) and healthy controls (HCs; n = 303) were assessed for the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-high-density-lipoprotein ratio (NHR) in plasma, and neuropsychological assessments were performed for all patients with PD. Spearman rank or Pearson correlation was used to evaluate the correlation between the NLR, the LMR and the NHR and the severity of PD. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of the NLR, LMR and NHR for PD. RESULTS The plasma NLR and NHR were substantially higher in patients with PD than in HCs, while the plasma LMR was substantially lower. The plasma NLR was positively correlated with Hoehn and Yahr staging scale (H&Y), Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS-I, UPDRS-II, and UPDRS-III scores. Conversely, it exhibited a negative relationship with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. Furthermore, the plasma NHR was positively correlated with H&Y, UPDRS, UPDRS-I, UPDRS-II and UPDRS-III scores. Moreover, negative associations were established between the plasma LMR and H&Y, UPDRS, UPDRS-I, UPDRS-II, and UPDRS-III scores. Finally, based on the ROC curve analysis, the NLR, LMR and NHR exhibited respectable PD discriminating power. CONCLUSION Our research indicates that a higher NLR and NHR and a lower LMR may be relevant for assessing the severity of PD and appear to be promising disease-state biomarker candidates.
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Affiliation(s)
- Fangyi Li
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
- Department of Neurology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China
| | - Guomei Weng
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
- Department of Neurology, The First People’s Hospital of Zhaoqing, Zhaoqing, China
| | - Hang Zhou
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Wenjie Zhang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Bin Deng
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Yuqi Luo
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xi Tao
- Department of Neurological Rehabilitation, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Mingzhu Deng
- Department of Neurology, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha, China
| | - Haiqiang Guo
- Department of Neurology, Dafeng Hospital of Chaoyang District in Shantou City, Shantou, China
| | - Shuzhen Zhu
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Qing Wang
- Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
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Ratan Y, Rajput A, Pareek A, Pareek A, Jain V, Sonia S, Farooqui Z, Kaur R, Singh G. Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson's Disease. Biomolecules 2024; 14:73. [PMID: 38254673 PMCID: PMC10813470 DOI: 10.3390/biom14010073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/15/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative movement disorder worldwide, which is primarily characterized by motor impairments. Even though multiple hypotheses have been proposed over the decades that explain the pathogenesis of PD, presently, there are no cures or promising preventive therapies for PD. This could be attributed to the intricate pathophysiology of PD and the poorly understood molecular mechanism. To address these challenges comprehensively, a thorough disease model is imperative for a nuanced understanding of PD's underlying pathogenic mechanisms. This review offers a detailed analysis of the current state of knowledge regarding the molecular mechanisms underlying the pathogenesis of PD, with a particular emphasis on the roles played by gene-based factors in the disease's development and progression. This study includes an extensive discussion of the proteins and mutations of primary genes that are linked to PD, including α-synuclein, GBA1, LRRK2, VPS35, PINK1, DJ-1, and Parkin. Further, this review explores plausible mechanisms for DAergic neural loss, non-motor and non-dopaminergic pathologies, and the risk factors associated with PD. The present study will encourage the related research fields to understand better and analyze the current status of the biochemical mechanisms of PD, which might contribute to the design and development of efficacious and safe treatment strategies for PD in future endeavors.
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Affiliation(s)
- Yashumati Ratan
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aishwarya Rajput
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Ashutosh Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Aaushi Pareek
- Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India; (A.R.); (A.P.); (A.P.)
| | - Vivek Jain
- Department of Pharmaceutical Sciences, Mohan Lal Sukhadia University, Udaipur 313001, Rajasthan, India;
| | - Sonia Sonia
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India;
| | - Zeba Farooqui
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA;
| | - Ranjeet Kaur
- Adesh Institute of Dental Sciences and Research, Bathinda 151101, Punjab, India;
| | - Gurjit Singh
- Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60607, USA;
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20
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Patel B, Greenland JC, Williams-Gray CH. Clinical Trial Highlights: Anti-Inflammatory and Immunomodulatory Agents. JOURNAL OF PARKINSON'S DISEASE 2024; 14:1283-1300. [PMID: 39331111 PMCID: PMC11492043 DOI: 10.3233/jpd-240353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/28/2024]
Abstract
Inflammation and immune dysregulation have been linked to the pathogenesis and progression of Parkinson's disease (PD), and represent an attractive target for therapeutic intervention, given the potential for repurposing of existing anti-inflammatory and immunomodulatory agents. Despite the fact that initial studies of drugs with secondary anti-inflammatory effects did not yield positive results, agents specifically targeting immune and inflammatory pathways may hold more promise. This article will briefly review the evidence base for targeting the immune system and neuroinflammation in PD, and discuss in detail the recently completed and currently active trials of primary anti-inflammatory/immunomodulatory drugs in PD.
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Affiliation(s)
- Bina Patel
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Julia C. Greenland
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
| | - Caroline H. Williams-Gray
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
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21
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Vijiaratnam N, Foltynie T. How should we be using biomarkers in trials of disease modification in Parkinson's disease? Brain 2023; 146:4845-4869. [PMID: 37536279 PMCID: PMC10690028 DOI: 10.1093/brain/awad265] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/18/2023] [Accepted: 07/22/2023] [Indexed: 08/05/2023] Open
Abstract
The recent validation of the α-synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson's disease has formed the backbone for a proposed staging system for incorporation in Parkinson's disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson's disease patients into trials (as distinct from patients with non-Parkinson's disease parkinsonism or non-Parkinson's disease tremors). There remain, however, further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson's disease, namely: optimizing the distinction between different α-synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; a sensitive means of confirming target engagement; and the early prediction of longer-term clinical benefit. For example, levels of CSF proteins such as the lysosomal enzyme β-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer's disease-like pathology (detectable through CSF levels of amyloid-β42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline in Parkinson's disease even in its later stages. The exploitation of additional biomarkers to the α-synuclein seed amplification assay will, therefore, greatly add to our ability to plan trials and assess the disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson's disease. However, correlation with clinical progression does not necessarily equate to causation, and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson's disease.
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Affiliation(s)
- Nirosen Vijiaratnam
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Thomas Foltynie
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
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Hosseini S, Shafiabadi N, Khanzadeh M, Ghaedi A, Ghorbanzadeh R, Azarhomayoun A, Bazrgar A, Pezeshki J, Bazrafshan H, Khanzadeh S. Neutrophil to lymphocyte ratio in parkinson's disease: a systematic review and meta-analysis. BMC Neurol 2023; 23:333. [PMID: 37735638 PMCID: PMC10512499 DOI: 10.1186/s12883-023-03380-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND The goal of this research was to explore the role of Neutrophil to lymphocyte ratio (NLR) in Parkinson's disease (PD). METHODS From inception to 4 June 2023, PubMed, Web of Science, and ProQuest were searched for papers comparing NLR in PD to healthy individuals. Standardized mean difference (SMD) with a confidence interval (CI) of 95% were calculated. RESULTS A random-effect model revealed that PD patients had elevated NLR values compared to healthy individuals (SMD = 0.81, 95% CI = 0.47 to 1.14, P < 0.001). The results of subgroup analysis were as follows: (1) study design: We observed that patients with PD had higher levels of NLR than healthy controls in either retrospective (SMD = 1.12, 95% CI = 0.58 to 1.66, P < 0.001) or prospective (SMD = 0.43, 95% CI = 0.18 to 0.68, P = 0.001) studies. (2) Ethnicity: We noticed that individuals with PD had higher levels of NLR than healthy controls, whether they were East Asian (SMD = 0.93, 95% CI = 0.22 to 1.63, P = 0.010) or Caucasian (SMD = 0.75, 95% CI = 0.40 to 1.10, P < 0.001).The pooled sensitivity of NLR in the prediction of PD was 0.67 (95% CI = 0.61-0.73), and the pooled specificity was 0.66 (95% CI, 0.61-0.70). CONCLUSIONS Increased levels of NLR is highly related with the presence of PD. Further research is needed to determine the potential clinical benefits of this simple and low-cost biomarker in the PD diagnosis.
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Affiliation(s)
- Samaneh Hosseini
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Monireh Khanzadeh
- Geriatric & Gerontology Department, Medical School, Tehran University of medical and health sciences, Tehran, Iran
| | - Arshin Ghaedi
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Raziyeh Ghorbanzadeh
- Department of Psychiatry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Azarhomayoun
- Sina trauma and surgery research center, Tehran University of medical sciences, Tehran, Iran
| | - Aida Bazrgar
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Hanieh Bazrafshan
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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