Role of Neuroinflammation in Parkinson Disease: The Enigma Continues
2016; Elsevier BV; Volume: 91; Issue: 10 Linguagem: Inglês
10.1016/j.mayocp.2016.08.010
ISSN1942-5546
AutoresShyamal H. Mehta, Caroline M. Tanner,
Tópico(s)Neuroinflammation and Neurodegeneration Mechanisms
ResumoParkinson disease (PD) is a progressive neurodegenerative disorder characterized by selective neuronal loss and α-synuclein deposition in specific central and peripheral nervous system regions, including nigro-striatal dopaminergic neurons.1Beach T.G. Adler C.H. Sue L.I. et al.Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program.Neuropathology. 2015; 35: 354-389Crossref PubMed Scopus (219) Google Scholar The central feature of the clinical syndrome is slowed musculoskeletal movement, accompanied by progressive deterioration of gait and balance, rigidity, tremor at rest, and a variable panoply of cognitive, psychiatric, and autonomic nervous system features. Parkinson disease is predominantly a disease of later life, rare before age 50 years, and more common in men. Although we do not understand the inciting event, etiology is believed to be heterogeneous, involving both genetic and environmental factors. Inflammatory mechanisms increasingly appear to be a unifying pathophysiologic feature in PD, irrespective of etiology. Epidemiologic, pathologic, and laboratory studies have suggested a role for neuroinflammatory processes in the pathogenesis of this disease. In the current issue of Mayo Clinic Proceedings, Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar investigate the role of inflammation in PD by studying the link between rheumatoid arthritis (RA), disease-modifying antirheumatic drugs (DMARDs), and the risk for PD. Since McGeer et al3McGeer P.L. Itagaki S. Boyes B.E. McGeer E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains.Neurology. 1988; 38: 1285-1291Crossref PubMed Google Scholar first reported neuroinflammation in the form of microglial activation in the context of PD, evidence has steadily accumulated that the immune system plays a role in the pathogenesis and progression of PD.4Benkler M. Agmon-Levin N. Hassin-Baer S. et al.Immunology, autoimmunity, and autoantibodies in Parkinson's disease.Clin Rev Allergy Immunol. 2012; 42: 164-171Crossref PubMed Scopus (32) Google Scholar, 5Kannarkat G.T. Boss J.M. Tansey M.G. The role of innate and adaptive immunity in Parkinson's disease.J Parkinsons Dis. 2013; 3: 493-514PubMed Google Scholar In the brains of patients with PD, densities of CD8+ and CD4+ T cells in proximity to dopaminergic neurons are high when compared with those in healthy individuals.6Hirsch E.C. Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection?.Lancet Neurol. 2009; 8: 382-397Abstract Full Text Full Text PDF PubMed Scopus (1399) Google Scholar This anatomic selectivity suggests that the lymphocytic infiltration is a response to neuronal damage in PD. Elevated levels of cytokines and other inflammatory biomarkers including tumor necrosis factor α (TNF-α), β2-microglobulin, epidermal growth factor, transforming growth factor α, transforming growth factor-β1, and IL-1β, IL-6, and IL-2 may be present in the blood, cerebrospinal fluid, and brains of patients with PD, pointing toward the role of inflammatory mechanisms in PD progression.6Hirsch E.C. Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection?.Lancet Neurol. 2009; 8: 382-397Abstract Full Text Full Text PDF PubMed Scopus (1399) Google Scholar Studies of the role of human leukocyte antigen (HLA) genes—first reported in the late 1970s and recently confirmed in genomewide association studies—have provided more evidence that immune mechanisms are important in the pathogenesis of PD.7Hamza T.H. Zabetian C.P. Tenesa A. et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.Nat Genet. 2010; 42: 781-785Crossref PubMed Scopus (585) Google Scholar, 8Ahmed I. Tamouza R. Delord M. et al.Association between Parkinson's disease and the HLA-DRB1 locus.Mov Disord. 2012; 27: 1104-1110Crossref PubMed Scopus (92) Google Scholar Single-nucleotide polymorphism-imputed HLA analysis recorded positive associations with the HLA-B*07:02, DRB1*15:01, and DQB1*06:02 haplotypes, but risk was inversely correlated with DRB1*04:04.9Wissemann W.T. Hill-Burns E.M. Zabetian C.P. et al.Association of Parkinson disease with structural and regulatory variants in the HLA region.Am J Hum Genet. 2013; 93: 984-993Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar A recent genomewide association study meta-analysis including 13,708 cases and 95,282 controls identified 26 loci as genomewide significant. These and 6 additional previously reported loci were tested in an independent set of 5353 cases and 5551 controls. Their analysis found loci within the HLA-containing secondary independent risk variants.10Nalls M.A. Pankratz N. Lill C.M. et al.Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.Nat Genet. 2014; 46: 989-993Crossref PubMed Scopus (1269) Google Scholar However, this still does not answer the question of causation: specifically, is activation of the immune system an inciting event or a concomitant, downstream occurrence along the cascade of progression of PD? Recent observations in PD due to mutations in the leucine-rich repeat kinase-2 (LRRK2) gene may provide insights. Phenotypically, patients with LRRK2 mutations bear close resemblance to late-onset idiopathic PD. In a recent study, inflammatory marker profiles were similar in idiopathic and LRRK2-associated PD, but LRRK2 mutation carriers without manifest parkinsonism (but who still had PD prodromal features) had profiles similar to controls.11Brockmann K. Apel A. Schulte C. et al.Inflammatory profile in LRRK2-associated prodromal and clinical PD.J Neuroinflammation. 2016; 13: 122Crossref PubMed Scopus (44) Google Scholar This research suggests that inflammation may not be a triggering event, but may contribute to PD progression. Such an interpretation is supported by a prospective study of early PD, where serum inflammatory marker profiles predicted motor and cognitive decline.12Williams-Gray C.H. Wijeyekoon R. Yarnall A.J. et al.ICICLE-PD study groupSerum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD).Mov Disord. 2016; 31: 995-1003Crossref PubMed Scopus (139) Google Scholar Although many epidemiologic studies have investigated the role of immune mechanisms by studying anti-inflammatory drugs (see below), Rugbjerg et al13Rugbjerg K. Friis S. Ritz B. Schernhammer E.S. Korbo L. Olsen J.H. Autoimmune disease and risk for Parkinson disease: a population-based case-control study.Neurology. 2009; 73: 1462-1468Crossref PubMed Scopus (94) Google Scholar performed the only previous investigation of autoimmune disorders and PD, by conducting a population-based case-control study in Denmark, comparing each of nearly 13,700 patients with PD diagnosed between 1986 and 2006 to 5 matched controls. They found a 30% reduced risk of PD in the 519 patients with RA, but no risk reduction in the other autoimmune disorders studied, similar to the report of Sung et al.2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Although this association may be a result of clinical misdiagnosis (because the symptoms of RA can mimic the slowed movements of PD), they limited analyses to cases of RA with demonstrated antibodies diagnosed at least 5 years before PD onset (or an analogous index date) to minimize diagnostic misclassification. In fact, the inverse association was even stronger—a 50% reduction in PD risk—in those with RA diagnosed 10 to 14 years before the index date. An alternative explanation for this inverse association is that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) by those with RA had an anti-inflammatory effect that reduced the risk of PD. This explanation has considerable intrigue for the development of new therapies to slow PD progression. The possibility that the use of anti-inflammatory drugs may reduce PD risk has been investigated in numerous observational studies. In a meta-analysis of 14 studies, exposure to nonaspirin NSAIDs was associated with a 13% risk reduction for developing PD (effect estimate, 0.87; 95% CI, 0.73-1.04; random-effects model), but this result did not achieve statistical significance.14Rees K. Stowe R. Patel S. et al.Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies.Cochrane Database Syst Rev. 2011; : CD008454PubMed Google Scholar In the analysis of 4 observational studies of ibuprofen alone, the risk for developing PD was reduced by 27% (effect estimate, 0.73; 95% CI, 0.63-0.85).14Rees K. Stowe R. Patel S. et al.Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies.Cochrane Database Syst Rev. 2011; : CD008454PubMed Google Scholar Of note, data analysis in studies of this design may be problematic because many anti-inflammatory drugs are available as over-the-counter medications, and self-reported use or use derived from prescription databases may have reduced accuracy. The Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar research in this issue of the Proceedings may provide additional insight into the possible relationship between treatment with anti-inflammatory agents and PD risk. In the RA cohort, NSAID use was associated with a modestly reduced hazard of PD although, as noted above, overall NSAID use may have been underreported because only prescription use was considered. The authors report that the hazard of PD was decreased by approximately 35% in patients with RA treated with DMARDs (95% CI, 0.58-0.73). Many of the drugs studied in the Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar research may have potent and specific effects on inflammatory cytokines, such as TNF-α, lending additional indirect support for the role of inflammation in PD. The significant reduction in the hazard ratio of patients with RA treated with DMARDs may suggest therapeutic potential for these drugs in limiting the progression of PD. Although the Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar results are exciting, limitations of their research must also be mentioned. Most remarkable is the very high incidence of PD reported—about 10 times the PD incidence reported in other studies,15Twelves D. Perkins K.S. Counsell C. Systematic review of incidence studies of Parkinson's disease.Mov Disord. 2003; 18: 19-31Crossref PubMed Scopus (406) Google Scholar including the recent report by Liu et al16Liu C.-C. Li C.-Y. Lee P.-C. Sun Y. Variations in incidence and prevalence of Parkinson's disease in Taiwan: a population-based nationwide study.Parkinsons Dis. 2016; 2016: 8756359PubMed Google Scholar using the same Taiwan National Health Insurance Registry database. Liu et al16Liu C.-C. Li C.-Y. Lee P.-C. Sun Y. Variations in incidence and prevalence of Parkinson's disease in Taiwan: a population-based nationwide study.Parkinsons Dis. 2016; 2016: 8756359PubMed Google Scholar reported that PD incidence was approximately 35/100,000 person-years for the entire population in the years 2002 to 2009, a number similar to other published incidence statistics and contrasting to the 267/100,000 person-years reported by Sung et al.2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar This high PD incidence in the Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar report is even more remarkable in view of the relatively young age (39% were younger than 49 years) and female preponderance (77.6%) of the patients with RA, contrasting to the typically older age and male predominance of PD. The very high PD incidence reported by Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar may reflect diagnostic misclassification, which can be common in claims databases. Importantly, the authors do not provide the criteria they used to reduce misclassification although scientific criteria for such studies have been described.15Twelves D. Perkins K.S. Counsell C. Systematic review of incidence studies of Parkinson's disease.Mov Disord. 2003; 18: 19-31Crossref PubMed Scopus (406) Google Scholar The authors report using International Classification of Diseases, Ninth Revision, Clinical Modification code 332 to identify PD cases. This broad category includes both PD (332.0) and secondary parkinsonism (332.1), suggesting that the unusually high incidence of PD in this article could be due to the inclusion of secondary forms, such as parkinsonism due to drugs. Finally, the actual difference of 2.42% in PD incidence between the RA group and the non-RA group is relatively small. Although statistically significant, this small difference may not be clinically meaningful. In conclusion, there are several points that we would like to highlight. This is the second study to report the association between RA and lower risk for developing PD. Secondary analyses in each report (Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and Rugbjerg et al13Rugbjerg K. Friis S. Ritz B. Schernhammer E.S. Korbo L. Olsen J.H. Autoimmune disease and risk for Parkinson disease: a population-based case-control study.Neurology. 2009; 73: 1462-1468Crossref PubMed Scopus (94) Google Scholar) suggest that this effect could be due to anti-inflammatory drug use. The present study by Sung et al2Sung Y.-F. Liu F.-C. Lin C.-C. et al.Reduced risk of Parkinson disease in patients with rheumatoid arthritis: a nationwide population-based study.Mayo Clin Proc. 2016; 91: 1346-1353Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar showed that anti-inflammatory agents that directly target TNF-α or other inflammatory cytokines may have an even stronger effect than do NSAIDs. These findings indirectly support the hypothesis that inflammation plays a role in PD progression, irrespective of the etiologic trigger. Such an inference may have important therapeutic implications: anti-inflammatory drugs may alter the progression of PD. For chronic treatment, choice of an agent with a safe side-effect profile will be desirable. A safer way to achieve anti-inflammatory effects may be through lifestyle interventions. For example, physical activity and exercise positively impact molecular mechanisms implicated in the pathophysiology of PD—by reducing oxidative stress, inflammation, and mitochondrial dysfunction, as well as upregulation of favorable growth factors such as brain-derived neurotropic factor and glial-derived neurotropic factor.17Ahlskog J.E. Does vigorous exercise have a neuroprotective effect in Parkinson disease?.Neurology. 2011; 77: 288-294Crossref PubMed Scopus (305) Google Scholar, 18Scalzo P. Kummer A. Bretas T.L. Cardoso F. Teixeira A.L. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson's disease.J Neurol. 2010; 257: 540-545Crossref PubMed Scopus (193) Google Scholar, 19Tanner C.M. Comella C.L. When brawn benefits brain: physical activity and Parkinson's disease risk.Brain. 2015; 138: 238-239Crossref PubMed Scopus (8) Google Scholar There is a growing body of literature on the positive effects of physical exercise in PD.17Ahlskog J.E. Does vigorous exercise have a neuroprotective effect in Parkinson disease?.Neurology. 2011; 77: 288-294Crossref PubMed Scopus (305) Google Scholar Finally, to gain a better understanding of these issues, continued investigation is needed, including laboratory studies to characterize the role of inflammation in PD, plus well-designed observational and, ultimately, interventional studies of anti-inflammatory drugs. In the interim, there seems little reason not to recommend lifestyle alterations that have anti-inflammatory benefits. Reduced Risk of Parkinson Disease in Patients With Rheumatoid Arthritis: A Nationwide Population-Based StudyMayo Clinic ProceedingsVol. 91Issue 10PreviewTo investigate the association between rheumatoid arthritis (RA) and the risk of developing Parkinson disease (PD). Full-Text PDF
Referência(s)