Insights into Neuroinflammation in Parkinson’s Disease: From … · (AD),multiplesystematrophy(MSA)patients,andhealthy controls:totaltau,phosphorylatedtau,amyloidbetapeptide 1–42

Review ArticleInsights into Neuroinflammation in Parkinsonrsquos DiseaseFrom Biomarkers to Anti-Inflammatory Based Therapies

Nataacutelia Pessoa Rocha Aline Silva de Miranda and Antocircnio Luacutecio Teixeira

Laboratorio Interdisciplinar de Investigacao Medica Faculdade de Medicina Universidade Federal de Minas GeraisAvenida Professor Alfredo Balena 190 Sala 281 30130-100 Belo Horizonte MG Brazil

Correspondence should be addressed to Natalia Pessoa Rocha npessoarochagmailcom

Received 5 December 2014 Revised 27 January 2015 Accepted 2 February 2015

Academic Editor Magda Santos

Copyright copy 2015 Natalia Pessoa Rocha et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Parkinsonrsquos disease (PD) is the secondmost commonneurodegenerative disorderworldwide being characterized by the progressiveloss of dopaminergic neurons in the substantia nigra pars compacta Among several putative factors that may contribute to PDpathogenesis inflammatory mechanisms may play a pivotal role The involvement of microglial activation as well as of brain andperipheral immune mediators in PD pathophysiology has been reported by clinical and experimental studies These inflammatorybiomarkers evaluated by imaging techniques andor by biological sample analysis have become valuable tools for PD diagnosis andprognosis Regardless of the significant increase in the number of people suffering from PD there are still no established disease-modifying or neuroprotective therapies for it There is growing evidence of protective effect of anti-inflammatory drugs on PDdevelopment Herein we reviewed the current literature regarding the central nervous system and peripheral immune biomarkersin PD and advances in diagnostic and prognostic tools as well as the neuroprotective effects of anti-inflammatory therapies

1 Introduction

Parkinsonrsquos disease (PD) is the second most common neu-rodegenerative disorder worldwide The major pathologi-cal findings in PD are the progressive loss of dopamin-ergic neurons in the substantia nigra pars compacta andthe presence of intraneuronal inclusions of the protein 120572-synuclein (known as Lewy bodies) [1] Neuronal death in thesubstantia nigra results in dopamine deficit at the striatumand as an outcome the clinical hallmarks of Parkinsonismbradykinesia rigidity resting tremor and postural instabilityPD diagnosis which is essentially clinical is based on thediagnosis of Parkinsonian syndrome and the exclusion ofother causes of Parkinsonism [2] Good response to levodopaand asymmetry of motor symptoms support the diagnosisAlthough PD is traditionally regarded as a movement disor-der motor symptoms may be heralded or accompanied byseveral nonmotor symptoms such as hyposmia constipationneuropsychiatric and sleep disorders [3]

PD was first described in 1817 [4] and despite the well-characterized pathological features the cause of neuronaldeath in PD remains a matter of debate Among several

putative factors that may contribute to PD pathogenesisinflammatory mechanisms may play an important role Forinstance microglial activation is associated with dopamin-ergic neuronal loss which suggests that neuroinflammatoryreaction may contribute to the progressive degenerativeprocess Moreover it has been reported that the protein120572-synuclein has an important role in the initiation andmaintenance of inflammation in PD (see Figure 1) [5]

A recent meta-analysis revealed an overall prevalence ofPD of 315 per 100000 individuals Prevalence of PD increasessteadily with age raising from 428 per 100000 in individualsfor the age group of 60 to 69 years to 1903 per 100000individuals for the group of 80 years or older [6] Overallworldwide incidence of PD is estimated in 365 per 100000person-years for females and 655 per 100000 person-years among males [7] Most countries are facing markeddemographic changes with progressively larger proportion oftheir populations entering old age PD affects predominantlythe elderly being a disease worthy of concern since thecauses are still unknown and the treatment is palliative andmerely symptomatic Levodopa the first breakthrough inthe treatment of PD is still the most effective drug for

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 628192 12 pageshttpdxdoiorg1011552015628192

2 BioMed Research International

RamifiedmicrogliaActivated

microglia

Neuron

Dying neuron

InfectioninjuryAging

genetic factorsCytokines

CytokinesROS

CNS

BBB

Periphery

120572-synucleinGenetic factors

aging

Debrisclearance

Figure 1 Inflammatory pathways in Parkinsonrsquos disease An acute insult to CNS (eg 120572-synuclein aggregates) triggers the activationof microglia with changes in their morphofunctional characteristics increased proliferation and release of inflammatory mediators (egcytokines and ROS) Inflammatory molecules can induce the recruitment of peripheral leukocytes into the CNS This neuroinflammatoryprocess can be regarded as beneficial for neuronal tissue since it promotes clearance of cell debris Conversely inflammatory mediators donot modulate only immune cells but also act on neurons contributing to neurodegeneration Neuronal death further activates inflammatorymechanisms resulting in a vicious cycle of inflammation and neuronal death Systemic inflammation due to infection or peripheral injurycan exacerbate symptoms and promote neuronal damage in PD Leukocytes secrete proinflammatory cytokines which can affect the brain byseveral routes including action on endothelial cells and leakage throughdamagedBBBThese cytokines induce self-synthesis and the synthesisof other cytokines which can then stimulate microglia to secrete chronically inflammatory mediators maintaining neuroinflammation andas a consequence slow and progressive neuronal death Genetic and aging factors might contribute to this process BBB blood-brain barrierCNS central nervous system PD Parkinsonrsquos disease ROS reactive oxygen species

themotor symptoms of the disease In certain instances othermedications such as monoamine oxidase type B inhibitorsanticholinergics and dopamine agonists may be initiatedfirst to prevent levodopa-related motor complications [8]Although the number of people suffering from PD risessignificantly year by year there are no established disease-modifying or neuroprotective therapies for PD In this sce-nario in the present review we discuss current evidenceregarding the contribution of immune dysfunction andorinflammation in PD advances in recent image techniquesas valuable tolls for PD diagnosis and progression and theperspectives of anti-inflammatory based therapies (data aresummarized in Table 1)

2 Neuroinflammation in PD Lessons fromPost-Mortem and Neuroimaging Studies

21 Microglial Activation Role in PD The first evidence ofinflammation involvement in PD was derived from JamesParkinsonrsquos report on the first clinical and pathological

description of the disease in the early nineteenth century[4] More direct evidence was provided much later in thetwentieth century from systematic post-mortem analysis ofthe brain of PD patients [9] Based onmorphological featuresand immunohistochemical staining againstHLA-DR humanglycoprotein of theMHC-II group expressed on the surface ofimmunocompetent cells a significant increase in the numberof reactive microglia was found in the substantia nigra of PDpatients Interestingly reactive microglia was also found tobe enhanced in the hippocampus of PD patients who alsopresented dementia [9]

Neuronal death in PDprecedes the development ofmotorsymptoms by many years The mechanisms underlying theprogressive neurodegeneration in PD are still elusive and thediscovery of the active or main driving force is of paramountimportance in the search of effective therapeutic strategiesNeuroinflammation has been proposed to actively participatein PD onset and progression An acute insult to the centralnervous system (CNS) triggers microglial activation leadingto a series of changes inmicroglia notably in shape increased

BioMed Research International 3

Table 1 Evidence regarding the contribution of immune dysfunction andor inflammation in Parkinsonrsquos disease

Evidence Source Results Reference

CNS inflammationHuman brain

Significant increase in the numberof reactive microglia in thesubstantia nigra of PD patients

[9 12]

Coexistence of 120572-synuclein andactivated microglia [15]

Higher expressionincreased levelsof inflammatory mediators in PDbrains

[13 16ndash18]

Human CSF samplesIncreased levels of IL-1120573 IL-2 IL-4IL-6 TGF-120572 free TGF-1205731 and totalTGF-1205732 in the CSF of PD patients

[30ndash32]

Peripheral inflammation

Serumplasma samplesIncreased levels of IFN-120574 IL-1120573IL-2 IL-3 IL-10 MIF TNF-120572 andits soluble receptors sTNFR1 andsTNFR2 in PD patients samples

[48ndash58]

Supernatants from cell culturesMCP-1 MIP-1120572 IL-8 IFN-120574 IL-1120573and TNF-120572 levels were significantlyhigher in PD patients

[65]

Blood leukocytes

PD patients exhibited lower totallymphocyte counts decrease in thepercentage of T (CD3+) and B(CD19+) cells and reduction in Thelper (Th CD4+) lymphocyteshigher percentage of NK cells

[52 61 71ndash74 77]

Genetic evidence DNA extracted from brain blood or buccal samples Enhancement in IL-1120573 511 IL-6 andTNF-120572 polymorphisms [21ndash24]

Epidemiological evidence Clinical and population-based studies

NSAIDs use was associated with alower risk for PD [91 92 94 95 104]

IFN-120572-induced Parkinsonism inchronic hepatitis [67ndash69] [67ndash69]

The relationship between PD andsystemic infections (severeinfluenza)

[70]

CSF cerebrospinal fluid CNS central nervous system IFN interferon IL interleukin MIF migration inhibitory factor MCP monocyte chemotactic proteinMIP macrophage inflammatory protein NSAIDs nonsteroidal anti-inflammatory drugs PD Parkinsonrsquos disease TGF transforming growth factor TNFtumor necrosis factor sTNFR TNF soluble receptor

proliferation and production of inflammatorymediators thatcan stimulate the recruitment of peripheral leukocytes to theCNSThis inflammatory process can be regarded as beneficialfor neuronal tissue since it promotes clearance of cell debrisand secretion of neurotrophic factors Conversely inflam-matory mediators do not only modulate immune cells butalso act on neurons and contributing to neurodegenerationNeuronal death further activates inflammatory mechanismsresulting in a vicious cycle of inflammation and neuronaldeathTherefore inflammatory responses although essentialfor tissue homeostasis can contribute to neuronal injurywhen it is not controlled andor chronic (Figure 1) As neuraltissues have a restricted cell renewal and regenerative capac-ity CNS is extremely vulnerable to uncontrolled immune andinflammatory processes [10] Dopaminergic neurons fromsubstantia nigra are particularly vulnerable to microglial-mediated neurotoxicity [11]

Banati et al demonstrated higher microglial activationin the substantia nigra of patients with PD as indicated

by increased expression of CR343 and EBM11 markers foractivated microglia [12] The number of activated microglia(MHC-II ICAM-1 and LFA-1 positive cells) in the substantianigra and putamen of PD patients also increased in parallelwith neuronal degeneration in those regions Moreovermicroglial activation persisted regardless of the presence orabsence of Lewy bodies and was frequently associated withdamaged neurons and neuritis [13] The lack of reactiveastrocytes in autopsies of the substantia nigra and putamenfrom PD patients contrasts with the response (with reactiveastrocytes and microglia) typically found in other neurologi-cal disorders (eg seizures) supporting the hypothesis thatthe inflammatory process in PD is a unique phenomenon[14] Autopsy brain tissue acquired from substantia nigra andbasal ganglia of PD patients demonstrated that 120572-synucleinis present in regions of brain where microglial activation isknown to be also present Furthermore an in vitro stimu-lation of murine microglia with aggregated and nitrated 120572-synuclein shift microglial morphology to an amoeboid shape


and elicited dopaminergic neurotoxicity The mechanismby which 120572-synuclein activates and alters the function ofmicroglia in PD is not yet clear although evidence fromgenomic and proteomic assays has supported a role for thetranscript factor nuclear factor-kappa B [15] Taken togetherthese studies provide evidence supporting CNS immuneresident cells role in PD Whether microglia activation is asecondary event following the ongoing neurodegeneration ora primary inducer of the disease remains to be defined

22 Central Nervous System Inflammatory Mediators in PDOver the past decades apart from microglia activation agrowing body of clinical and experimental research hasbeen supporting a role for oxidative stress and inflamma-tory mediators (cytokines and chemokines) events poten-tially associated with microglial reaction in PD [13 16ndash18]For instance higher expression of the chemokine receptorCXCR4 and of its natural ligand CXCL12 was found indopaminergic neurons of the substantia nigra of patients withPD and this was associated with an increase in microglialactivation [18] CXCL12CXCR4 signaling can induce neu-rotoxic events including activation of caspase-3 leadingto neuronal death by apoptosis Negative effects on theCNS mediated by CXCL12 could be induced through adirect action on dopaminergic neurons expressing CXCR4or the release of cytokines from microglia [18 19] Adirect link between CXCL12CXCR4 upregulation and lossof dopaminergic neurons was provided in an animal modelof degeneration of the nigrostriatal system following 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP) admin-istration a well-recognized model of PD [18] The pres-ence of activated microglia expressing the inflammatorycytokines interleukin- (IL-) 6 and tumor necrosis factor-(TNF-) 120572 as well as enzymes associated with inflamma-tion such as inducible isoform of nitric oxide synthase(iNOS) and cyclooxygenase-2 (COX-2) was also evidencedby immunohistochemistry assays in post-mortem brain tissuefrom PD patients [13 16 20] A previous study demonstratedan enhancement in the inflammatory cytokine IL-1120573 511polymorphism from DNA extracted from brain tissues ofPD patients [21] Similar findings were reported for IL-6 andTNF-120572 using peripheral tissue samples (ie blood or buccalsamples) indicating polymorphisms in these cytokines asrisk factors of PD [22ndash24]

Upregulation of inflammatory mediators involved inapoptotic cell death through TNF-120572-induced signaling path-way including caspase-1 caspase-3 and TNF receptor R1(TNF-R1 or p55) was identified in the substantia nigrafrom Parkinsonian patients indicating the occurrence ofa proapoptotic environment in PD [25] Neutralizationof soluble TNF signaling in vivo with dominant-negativeTNF inhibitor XENP345 (a PEGylated version of the TNFvariant A145RI97T) abrogated in 50 the dopaminergicneuronal degeneration in an experimental model of PDinduced by striatal injection of the oxidative neurotoxin6-hydroxydopamine (6-OHDA) [17] A more recent studydemonstrated that long-lasting TNF-120572 expression inducedby the injection of an adenovector expressing soluble mouseTNF-120572 (AdTNF120572) directly in the substantia nigra of adult

rats leads to dopaminergic neuronal death motor symptomsand microglia activation associated with recruitment ofperipheral monocytes [26] Similar findings were reportedfollowing chronic expression of IL-1120573 induced by 60 daysadministration of a recombinant adenovirus expressing IL-1120573 in the substantia nigra of adult rats [27] Interestinglyalterations in mRNA expression of mediators of the immuneresponse during PD including members of the complementsystem colony stimulating factors Toll family and cytokinesseem to occur in a brain region-dependent manner Forinstance a downregulation in themRNA expression of tumornecrosis factor related protein 7 (C1QTNF7) a member ofthe complement system was found in the substantia nigrawhereas an upregulation was observed in the putamen of PDpatients at the same stage of the disease Immunohistochem-istry also reveals the expression of cytokines including IL-6and TNF-120572 by microglia and neurons in the PD substantianigra and frontal cortex [28] Active NF120581B is localized inthe nucleus of subpopulations of neurons and glial cellsmainly in substantia nigra and less frequently in putamenand cerebral cortex [28] Altogether these studies suggestan involvement of inflammation in particular related toCNS resident immune cells activation in the degeneration ofdopaminergic neurons associated with PD

Cerebrospinal fluid (CSF) mirrors metabolic and patho-logical states of the CNS more directly than any other bodyfluidTherefore CSF is a good source for neuroinflammationevaluation and PD biomarker discovery since it is moreaccessible than brain tissue and less costly than imaging [29]In this regard studies have evaluated levels of inflammatorymarkers in the CSF of PD patients Increased levels of IL-1120573 and IL-6 were found in the CSF of PD patients [30]Corroborating these findings concentrations of IL-2 and IL-6 were higher in ventricular CSF from PD patients in com-parison with control subjects In addition concentrations ofIL-1120573 IL-2 IL-4 and transforming growth factor- (TGF-)120572 in ventricular CSF were higher in juvenile PD patients(PD manifesting clinically bellow the age of 40) than thosein controls [31] Free TGF-1205731 and total TGF-1205732 levels wereelevated in post-mortem ventricular CSF of patients withPD in comparison with age and gender-matched controls[32] However one study failed to find significant differ-ences in CSF levels of the inflammatory markers C-reactiveprotein (CRP) IL-6 TNF-120572 eotaxin interferon gamma-induced protein 10 (IP-10) monocyte chemotactic protein1 (MCP-1) and macrophage inflammatory protein- (MIP-)1120573 from PD patients in comparison with a reference group[33]

Using a highly sensitive Luminex assay one studyassessed a series of CSF molecules in PD Alzheimerrsquos disease(AD) multiple system atrophy (MSA) patients and healthycontrols total tau phosphorylated tau amyloid beta peptide1ndash42 [A120573(1ndash42)] Flt3 ligand and fractalkine CSF levelsof Flt3 clearly differentiated PD from MSA a disease thatclinically overlaps with PD with excellent sensitivity (99)and specificity (95) In addition CSF fractalkineA120573(1ndash42) ratio positively correlated with PD severity and PDprogression Flt3 ligand and fractalkine are inflammatorymarkers possibly related to PD [29]


23 Insights from the Genetic Leucine-Rich Repeat Kinase 2(LRRK2) Model of Neuroinflammation Associated with PDAnimal models of PD have become valuable tools to theunderstanding of its pathophysiology regardless of theirlimitations in mimicking all features of the human diseaseNeurotoxin-based animal models (6-OHDA and MPTP)referred to as pathogenic models have largely been usedto induce selective neuronal death in both in vitro and invivo studies Currently genetic-based models (or etiologicmodels) such as those related to mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have opened new direc-tions of investigation of molecular and cellular mechanismsunderlying PD pathogenesis [34 35]

Fine-mapping gene expression and splicing analysisfrom human post-mortem brain tissues have supported arole for LRRK2 gene in PD There is convincing evidencefor a common variant PD association located outside of theLRRK2 protein coding region (rs117762348) [36] In thisscenario it has been shown that activated myeloid lineagecells including macrophages and microglia presented highlevels of LRRK2 suggesting an involvement of this gene in theneuroinflammation associated with PD [37 38] An elegantstudy demonstrated that 120572-synuclein overexpression in ratsrsquosubstantia nigra induced LRRK2 expression in activatedmicroglial cells and this correlated with a high expression ofiNOS known to be involved in PD [39] LRRK2 knockout ratsare protected from dopaminergic neurodegeneration elicitedby 120572-synuclein overexpression or intracranial administrationof lipopolysaccharide (LPS)Neuroprotection observed in theabsence of LRRK2 was associated with reduction in proin-flammatory CD68-positive myeloid cells in the substantianigra indicating an involvement of LRRK2 in conditionswhere neuroinflammation may underlie neuronal dysfunc-tion and degeneration such as PD [39]

24 Positron Emission Tomography (PET) as a DiagnosticTool for Neuroinflammation Related to PD Positron emissiontomography (PET) is a noninvasive functional imaging tech-nique that detects gamma rays emitted by a positron-emittingradionuclide (tracer) which is introduced into the body on abiologically active molecule [40]

The isoquinoline carboxamide PK11195 is currently themost widely used ligand for the translocator protein 18 kDa(TSPO also known as peripheral benzodiazepine receptor)TSPO is a marker of microglial activation and has been usedto assess and quantify the dynamics of activated microgliain neurodegenerative diseases including PD [11C]PK11195is used in PET studies for imaging brain inflammationin vivo [41] PET studies using [11C]PK11195 demonstratedincreased binding potential values (parameter that mixesreceptor density with ligand affinity) in the midbrain aswell as in the pons basal ganglia and frontal and temporalcortices in PD indicating an anatomically widespread dis-tribution of microglial activation possibly associated withthe pathological process of PD [42 43] Longitudinal anal-ysis of these patients revealed stable [11C]PK11195 bindingpotential values indicative of early activation of microgliain PD pathogenesis [43] However [11C]PK11195 tracer can-not distinguish between microglial protective or damaging

profile To overcome this a PET tracer for the dopamine-transporter (DAT) [11C]CFT has been used in conjunctionwith [11C]PK11195 in order to further investigate microglialactivation in parallel with the viability of the presynap-tic dopaminergic neurons Midbrain [11C]PK11195 bindingpotential levels were inversely correlated with [11C]CFTbinding potential values in the putamen and positivelycorrelated with the severity of motor symptoms suggestingthat neuroinflammation associatedwithmicroglial activationmight contribute to the progression of the disease [44]PET imaging has also been employed to investigate invivo potential therapeutic strategies for PD For instance[11C]PK11195 PET was used to evaluate the ability of COX-2 inhibition with celecoxib to reduce neuroinflammation inPD patients Patients showed higher putamen and midbrainbinding potential in comparison with controls but consider-able overlap was seen between groups and differences werenot statistically significantThis prevented reliable assessmentof the changes in the [11C]PK11195 uptake by celecoxibtreatment [45] In a rat model of PD induced by intrastriataladministration of 6-OHDA PET imaging revealed that theCOX-2 inhibitor celecoxib decreased microglial activationand prevented dopaminergic neuron degeneration [46] Astudy conducted by Edison et al demonstrated by PETanalysis that both PD patients with or without dementiapresented significant microglial activation in cortical brainregions suggesting that neuroinflammation could be an earlyphenomenon in PD persisting as the disease progress [47]

3 Peripheral Immune Response in PD

31 Peripheral Immune Biomarkers A great body of evidenceregarding peripheral inflammatoryimmune markers hassupported the hypothesis of inflammation involvement inPD Studies of cytokines in serum or plasma have revealedincreased levels of proinflammatory cytokines such as TNF-120572 [48 49] and its soluble receptors sTNFR1 [50 51] andsTNFR2 [51] and IL-1120573 [52] in PD patients in comparisonwithmatched controls Increased serum levels ofmacrophagemigration inhibitory factor (MIF) were found in PD patientsin comparison with healthy subjects [53] Also the levels ofIL-2 [54 55] interferon (IFN)-120574 [54] IL-6 [49 54 56 57]and the anti-inflammatory cytokine IL-10 were described tobe increased in PD [54 58] IL-6 plasma concentration wasprospectively associated with an increased risk of developingPD [58] In contrast some authors failed to show significantalterations in cytokine levels in PD Peripheral levels of thecytokines IL1-120572 IL-6 TNF-120572 [50 52 59 60] IFN-120574 IL-2IL-4 IL-10 [61] and IL-12 [62] were similar in PD patientsand age- and gender-matched controls Circulating levels ofthe chemokines MIP-1120572 IL-8 [63] eotaxin eotaxin-2 IP-10[63 64] and MCP-1 [64] did not differ between PD patientsand controlsThese controversial findings could be explainedat least in part by methodological differences among thestudies including heterogeneous PD samples and differenttechniques to measure the molecules

Apart from serumplasma studies the concentration ofcytokines produced by peripheral cells in vitro has been


assessed in PD Both basal production and LPS-inducedproduction of MCP-1 MIP-1120572 IL-8 IFN-120574 IL-1120573 and TNF-120572 were significantly higher in PD patients compared withcontrol subjects [65] Conversely the secretion of IL-2 byperipheral blood mononuclear cells (PBMC) after mitogenicstimulation was decreased in PD patients in comparison withcontrols whereas IL-6 IFN-120572 IFN-120574 and sIL-2R levels werecomparable in both groups [66]

Several case reports of IFN-120572-induced Parkinsonism inchronic hepatitis patients further corroborate the hypothesisof the role played by peripheral inflammation in PD patho-genesis [67ndash69] The relationship between PD and systemicinfections also supports this hypothesis For instance in apopulation-based case-control study in British ColumbiaCanada severe influenza infection was associated with PDalthough this effect was attenuatedwhen cases were restrictedto those occurring ten or more years before diagnosis(Figure 1) [70]

32 Peripheral Immune Cells Studies have also describedchanges in the percentage of peripheral blood immune cellsin PD such as lower total lymphocyte counts in comparisonwith controls [71ndash73] Reduction in the total number oflymphocytes may result from the decrease in the percentageof T (CD3+) and B (CD19+) cells in PD patients Changesin CD3+ cells were associated with a reduction in T helper(Th CD4+) lymphocytes while T cytotoxic (CD8+) cellsincreased or remained unchanged [71ndash74] Lower number ofCD4+ cells could be explained by the fact that in PD thesecells presented both increased spontaneous apoptosis andactivation-induced apoptosis [75]

Not only the percentage of circulating immune cells butalso their activation profile must be taken into account whenevaluating immune parameters One study showed that thenumber of ldquonaıverdquo (CD4+CD45RA+) and memory helper(CD4+CD29+) T cells was decreased while the number ofactivated (CD4+CD25+) T cells was increased in PD [71]In addition impaired ability of regulatory T cells (Treg)to suppress effector T cell function has been described inPD patients [73] Increased oxidative stress may also beassociated with changes in lymphocyte profile in PD sinceboth whole cell and mitochondrial reactive oxygen species(ROS) in peripheral blood mononuclear cells are increasedin PD [76]

Some studies have reported similar percentages of CD3+lymphocytes in PD patients and control subjects [52 72] Thelper lymphocytes (CD4+) were decreased while CD8+ cellcounting increased in PD [72]

There is evidence of higher percentage of natural killer(NK) cells in peripheral blood of PD patients compared tocontrols and this increase has been associated with diseaseseverity and progression [52 61 77] Despite increased num-ber of NK cells in PD their activity seems to be unchanged inPD [61 77]

33 The Concomitant Effect of Inflammaging PD is unequiv-ocally an age-related disorder Aging is a complex processaccompanied by many physiological changes notably in theimmune system Aging results in an increase in systemic

levels of inflammatory markers indicating the presenceof subtle chronic inflammation a phenomenon known asinflammaging Chronic inflammation damages cells of thebrain heart arterial walls and other body structures con-tributing to the onset and progression of a broad spectrumof degenerative diseases of aging including heart diseaserheumatoid arthritis AD and PD Inflammation generatesoxidative stress which might contribute to neuronal deathin diseases such as AD PD and amyotrophic lateral sclerosis(ALS) (Figure 1) [78]

4 GWAS Studies Further Evidence for a Roleof Inflammation in PD

Genome-wide association studies (GWAS) have also identi-fied genetic markers that link PD and inflammation Hamzaet al detected an association between PD and the humanleukocyte antigen (HLA) region (chromosome 6p213) find-ing replicated in two datasets with Caucasians (North-American of European ancestry) Associations were partic-ularly strong for individuals with sporadic and late-onset PDand men The variant most strongly associated with PD wasrs3129882 in intron 1 of HLA-DRA [79] The protein chainsare encoded by the closely linked HLA-DRA and HLA-DRBform the class II HLA-DR antigens that are expressed byantigen-presenting cells includingmicroglia in the brain andinteract with T-cell receptors [79] This result is in line withPD specific overexpression ofHLA-DR antigens in substantianigra [9] One study has also confirmed HLA region as PDrisk locus among the Dutch population [80]

One GWAS was conducted to identify common geneticvariants associated with motor and cognitive outcomes inPD The single nucleotide polymorphisms (SNP) rs10958605(C8orf4 gene) and rs6482992 (CLRN3 gene) were associ-ated with motor and cognitive outcomes respectively Theencoded protein by C8orf4 genemay play a role in the NF-120581Band ERK12 signaling pathways highlighting inflammationas a possible pathogenesis mechanism for progression in PD[81]

A recent meta-analysis has identified four loci includingthe HLA region that contain a secondary independent riskvariant for PD that exerts an effect independently of theprimary risk allele [82]

Genetic factors may also be essential in determiningan individualrsquos susceptibility to inflammation-induced nigraldopaminergic neuronal cell death (Figure 1) [83]

5 Immune Changes Induced byAntiparkinsonian Drugs

Long-term treatment with antiparkinsonian drugsmay resultin changes in immune system For example treatment withamantadine originally established as an antiviral drug wasassociatedwith an increase of theCD4 CD8 ratio [84] Treat-ment with amantadine has been described to increase IL-2levels [85 86] The same was not observed in patients in useof levodopa as monotherapy [85] Levodopa therapy inducedchanges in T lymphocytes proteome [87] Levodopa-treated


patients showed significantly higher IL-15 and RANTEScirculating levels in comparison with healthy controls andhigher but not statistically significant levels with respect tountreated patients [88]

In order to evaluate a putative immunomodulatory roleof levodopa PBMC of PD patients and controls were incu-bated in vitro with the drug Levodopa caused an inhibitionof mitogen-induced proliferation stimulation of IL-6 andTNF-120572 production whereas the secretion of IL-1120573 and IL-2was not affected in both groups [89]

6 Nonsteroidal Anti-Inflammatory Drugs(NSAIDs) Use and Risk of PD

Based on the hypothesis that neuroinflammation is involvedin PD pathophysiology epidemiological studies have eval-uated nonsteroidal anti-inflammatory drugs (NSAIDs) useand risk of PD The first study conducted with this purposewas a prospective cohort in which the regular use of NSAIDsbut not aspirin was associated with a delay or preventionof PD onset [90] The same research group later investigatedwhether NSAIDs use was associated with a lower risk for PDin a large cohort with more detailed information on differenttypes of NSAIDs They found no association between theuse of aspirin other NSAIDs or acetaminophen and PDrisk Interestingly PD risk was lower among ibuprofenusers than nonusers suggesting that ibuprofen use maydelay or prevent the onset of PD [91] In line with theseresults a prospective study revealed that ibuprofen usershad a significantly lower PD risk than nonusers even whenadjusting for age smoking caffeine consumption and othercovariates The same effect was not observed for aspirinother NSAIDs or acetaminophen [92] Since only the useof ibuprofen but not other NSAIDs was associated withlower PD risk some specific effects of ibuprofen may beimportant In fact an earlier study examined the effects ofNSAIDs drugs on cultured primary rat embryonic neuronsfrom mesencephalon the area primarily affected in PDIbuprofen protected both dopaminergic neurons and otherneurons against glutamate toxicity In addition ibuprofenalone increased the relative number of dopaminergic neuronsby 47 [93]

In contrast with the above mentioned studies apopulation-based study described a decreased risk of PDamong regular aspirin users A stronger protective effectwas observed for regular nonaspirin NSAIDs users Itis noteworthy that the aspirin effect differed by gendershowing a protective effect only in women especiallyamong long-term regular users [94] The most recent studysupporting the association between NSAIDs and reducedPD risk was conducted in 2008 NSAIDs use was describedto significantly reduce PD risk in 20 to 30 The effectof the combination of NSAIDs use and smoking and coffeeconsumption was also evaluated People who were at thehighest exposure to smoking and coffee and used NSAIDshad an estimated 87 reduction in PD risk As properlystated by the authors whether this finding reflects truebiological protection needs to be further investigated [95]

There are studies that failed to show any associationbetweenNSAIDs use and PD [96ndash102]The discrepant resultsmay be due to different methods used to conduct the investi-gations especially how authors collected data about NSAIDuse (medical records self-report pharmacy databases etc)and the evaluated population

Several case-control studies have been performed toexamine the association between NSAIDs use and PD riskGiven the discrepancy in results meta-analysis is of greatvalue to better define this association A meta-analysis withthis purpose concluded that NSAIDs do not seem to mod-ify the risk of PD However ibuprofen may have a mildprotective effect in lowering the risk of PD [103] Anothermeta-analysis estimated an overall reduction in 15 in PDincidence among users of nonaspirin NSAIDS with a similareffect observed for ibuprofen use The protective effect ofnonaspirin NSAIDs was more pronounced among regularand long-term users No protective effect was observedfor aspirin or acetaminophen [104] In conclusion there isevidence for a protective effect of nonaspirin NSAIDs use inrelation to PD which is consistent with the neuroinflamma-tory hypothesis for PD pathogenesis

In this scenario among several studies evaluating anti-inflammatory strategies in animal models of PD one isnoteworthy The nitric oxide (NO)-NSAID HCT1026 [2-fluoro-120572-methyl(111015840-biphenyl)-4-acetic-4-(nitrooxy)butylester] NO-donating flurbiprofen is an anti-inflammatoryagent obtained by derivatization of conventional NSAIDswith a NO-donating moiety which strongly reduces theiruntoward side effects without altering the anti-inflammatoryeffectiveness Oral treatment with HCT1026 showed a safeprofile and a significant efficacy in counteracting MPTP-induced dopaminergic neurotoxicity motor impairmentand microglia activation in aging mice [105] providing apromising approach towards the development of effectivepharmacological neuroprotective strategies against PD

7 Autoimmunity and Immune-BasedTherapies in PD

PD has been associated with autoimmunity Juvenile Parkin-sonism has been reported as a manifestation of systemiclupus erythematosus [106] Anecdotal reports tried to estab-lish an association between PD and rheumatoid arthritis[107 108] Antibodies against dopaminergic neurons weredemonstrated in the serum of a patient with a complexautoimmune disorder and rapidly progressing PD [109] Onestudy reported significantly higher antibody levels towardsmonomeric 120572-synuclein in the sera of PD patients comparedto controls and their levels decreased with PD progressionAccording to these authors this possibly indicates a protec-tive role of autoimmunity in maintaining body homeostasisand clearing protein species whose imbalance may lead tomisfolded protein aggregation [110]

All currently available treatments for PD are of onlysymptomatic benefit and a pharmacological strategy withdisease-modifying effect is highly needed In this con-text immune-based therapies have been proposed for PD


treatment The first strategy was based on immunotherapyagainst aggregated forms of 120572-synuclein Transgenic micedisplaying abnormal accumulation of human 120572-synucleinand120572-synuclein-immunoreactive inclusion-like structures inthe brain were vaccinated with human 120572-synuclein Therewas decreased accumulation of aggregated 120572-synuclein inneuronal cell bodies and synapses and as a consequencereduced neurodegeneration Similar effects were observedwith an exogenously applied FITC-tagged 120572-synuclein anti-body [111] The same work group showed that passive immu-nization with a monoclonal 120572-synuclein antibody (9E4)against the C-terminus 120572-synuclein reduced the accumula-tion of calpain-cleaved 120572-synuclein in axons and synapses inthe 120572-synuclein transgenic mice In addition 9E4 was ableto cross the blood brain barrier into the CNS to bind tocells displaying 120572-synuclein accumulation and to promote 120572-synuclein clearance via the lysosomal pathway [112]

Studies on AD have provided valuable informationabout immunotherapy in neurodegenerative disordersImmunotherapy against the 120573-amyloid peptide in ADshowed that approaches targeting cerebral proteins can beapplied to humans with relative safety Neuropathologicalexamination showed the clearance of amyloid plaques inbrains of AN1792-vaccinated AD patients Nonethelessrelevant issues must be considered For instance T cellresponses specific for cerebral antigens need to be avoidedAnother important issue is to define which patient should bevaccinated Disease-modifying approaches are more effectivewhen applied in the early stage of the disease when diagnosisis not established yet [113]

AFFITOPE PD01 the most promising vaccine developedfor PD so far entered clinical trials and therefore representsthe first PD vaccine to be tested clinically AFFITOPE PD01has been developed to induce antibodies recognizing 120572-synuclein but sparing the family member 120573-synuclein whichhas neuroprotective properties [113]

Immune stimulation in the periphery may also providea new strategy to halt PD progression In addition to studieson immunotherapy against aggregated forms of 120572-synucleinone study described the neuroprotective effects of BacillusCalmette-Guerin (BCG) vaccination in the MPTP mousemodel of PD BCG vaccination had a significant beneficialeffect on both striatal dopamine content and DAT ligandbinding levels BCG vaccination prevented the increase in thenumber of activatedmicroglia in the substantia nigra inducedby the MPTP suggesting that general immune stimulation inthe periphery can limit CNSmicroglia response to a neuronalinsult [114]

8 Conclusion

We reviewed the evidence regarding the contribution ofimmune dysfunction andor inflammation in PD includingmicroglial activation and brain and peripheral levels ofimmune mediators Assessment of these biomarkers maycontribute to the development of diagnostic and prognostictools in PD In addition the protective role ofNSAIDs furthersupports the neuroinflammation hypothesis in PD

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Natalia Pessoa Rocha andAline Silva deMiranda contributedequally to the study

Acknowledgments

This research was supported by FAPEMIG CNPq andCAPES

References

[1] A Samii J G Nutt and B R Ransom ldquoParkinsonrsquos diseaserdquoThe Lancet vol 363 no 9423 pp 1783ndash1793 2004

[2] A J Hughes S E Daniel L Kilford and A J Lees ldquoAccuracyof clinical diagnosis of idiopathic Parkinsonrsquos disease a clinico-pathological study of 100 casesrdquo Journal of Neurology Neuro-surgery and Psychiatry vol 55 no 3 pp 181ndash184 1992

[3] M B Stern A Lang and W Poewe ldquoToward a redefinition ofParkinsonrsquos diseaserdquoMovement Disorders vol 27 no 1 pp 54ndash60 2012

[4] J Parkinson ldquoAn essay on the shaking palsyrdquo The Journal ofNeuropsychiatry and Clinical Neurosciences vol 14 no 2 pp223ndash236 2002

[5] K A Jellinger ldquoNeuropathology of sporadic Parkinsonrsquos dis-ease evaluation and changes of conceptsrdquoMovement Disordersvol 27 no 1 pp 8ndash30 2012

[6] T Pringsheim N Jette A Frolkis and T D L Steeves ldquoTheprevalence of Parkinsonrsquos disease a systematic review andmeta-analysisrdquo Movement Disorders vol 29 no 13 pp 1583ndash15902014

[7] T Pringsheim K Fiest and N Jette ldquoThe international inci-dence and prevalence of neurologic conditions how commonare theyrdquo Neurology vol 83 no 18 pp 1661ndash1664 2014

[8] B S Connolly and A E Lang ldquoPharmacological treatment ofParkinson disease a reviewrdquo Journal of the American MedicalAssociation vol 311 no 16 pp 1670ndash1683 2014

[9] P LMcGeer S Itagaki B E Boyes and EGMcGeer ldquoReactivemicroglia are positive for HLA-DR in the substantia nigra ofParkinsonrsquos and Alzheimerrsquos disease brainsrdquo Neurology vol 38no 8 pp 1285ndash1291 1988

[10] H-M Gao and J-S Hong ldquoWhy neurodegenerative diseasesare progressive uncontrolled inflammation drives disease pro-gressionrdquo Trends in Immunology vol 29 no 8 pp 357ndash3652008

[11] L M Collins A Toulouse T J Connor and Y M NolanldquoContributions of central and systemic inflammation to thepathophysiology of Parkinsonrsquos diseaserdquo Neuropharmacologyvol 62 no 7 pp 2154ndash2168 2012

[12] R B Banati S E Daniel and S B Blunt ldquoGlial pathologybut absence of apoptotic nigral neurons in long-standingParkinsonrsquos diseaserdquoMovement Disorders vol 13 no 2 pp 221ndash227 1998

[13] K Imamura N Hishikawa M Sawada T Nagatsu M Yoshidaand Y Hashizume ldquoDistribution of major histocompatibility


complex class II-positive microglia and cytokine profile ofParkinsonrsquos disease brainsrdquo Acta Neuropathologica vol 106 no6 pp 518ndash526 2003

[14] B Mirza H Hadberg P Thomsen and T Moos ldquoThe absenceof reactive astrocytosis is indicative of a unique inflammatoryprocess in Parkinsonrsquos diseaserdquo Neuroscience vol 95 no 2 pp425ndash432 1999

[15] A D Reynolds J G Glanzer I Kadiu et al ldquoNitrated alpha-synuclein-activatedmicroglial profiling for Parkinsonrsquos diseaserdquoJournal of Neurochemistry vol 104 no 6 pp 1504ndash1525 2008

[16] C Knott G Stern and G P Wilkin ldquoInflammatoryregulators in Parkinsonrsquos disease iNOS lipocortin-1 andcyclooxygenases-1 and -2rdquoMolecular and Cellular Neurosciencevol 16 no 6 pp 724ndash739 2000

[17] M K McCoy T N Martinez K A Ruhn et al ldquoBlockingsoluble tumor necrosis factor signaling with dominant-negativetumor necrosis factor inhibitor attenuates loss of dopaminergicneurons in models of Parkinsonrsquos diseaserdquo Journal of Neuro-science vol 26 no 37 pp 9365ndash9375 2006

[18] M Shimoji F Pagan E B Healton and I Mocchetti ldquoCXCR4and CXCL12 expression is increased in the nigro-striatal systemof Parkinsonrsquos diseaserdquoNeurotoxicity Research vol 16 no 3 pp318ndash328 2009

[19] A Bachis S A Aden R L Nosheny P M Andrews andI Mocchetti ldquoAxonal transport of human immunodeficiencyvirus type 1 envelope protein glycoprotein 120 is found inassociation with neuronal apoptosisrdquo Journal of Neurosciencevol 26 no 25 pp 6771ndash6780 2006

[20] S Hunot F Boissiere B Faucheux et al ldquoNitric oxide synthaseand neuronal vulnerability in Parkinsonrsquos diseaserdquo Neuro-science vol 72 no 2 pp 355ndash363 1996

[21] P L McGeer K Yasojima and E G McGeer ldquoAssociationof interleukin-1120573 polymorphisms with idiopathic Parkinsonrsquosdiseaserdquo Neuroscience Letters vol 326 no 1 pp 67ndash69 2002

[22] R Kruger C Hardt F Tschentscher et al ldquoGenetic analysisof immunomodulating factors in sporadic Parkinsonrsquos diseaserdquoJournal of Neural Transmission vol 107 no 5 pp 553ndash562 2000

[23] A Hakansson L Westberg S Nilsson et al ldquoInteractionof polymorphisms in the genes encoding interleukin-6 andestrogen receptor beta on the susceptibility to Parkinsonrsquosdiseaserdquo The American Journal of Medical Genetics Part BNeuropsychiatric Genetics vol 133 no 1 pp 88ndash92 2005

[24] A D Wahner J S Sinsheimer J M Bronstein and B RitzldquoInflammatory cytokine gene polymorphisms and increasedrisk of Parkinson diseaserdquo Archives of Neurology vol 64 no 6pp 836ndash840 2007

[25] M Mogi A Togari T Kondo et al ldquoCaspase activities andtumor necrosis factor receptor R1 (p55) level are elevated inthe substantia nigra fromParkinsonian brainrdquo Journal of NeuralTransmission vol 107 no 3 pp 335ndash341 2000

[26] A L D L Ezcurra M Chertoff C Ferrari M Graciarena andF Pitossi ldquoChronic expression of low levels of tumor necrosisfactor-120572 in the substantia nigra elicits progressive neurodegen-eration delayed motor symptoms and microgliamacrophageactivationrdquo Neurobiology of Disease vol 37 no 3 pp 630ndash6402010

[27] C C Ferrari M C Pott Godoy R Tarelli M Chertoff A MDepino and F J Pitossi ldquoProgressive neurodegeneration andmotor disabilities induced by chronic expression of IL-1120573 in thesubstantia nigrardquoNeurobiology of Disease vol 24 no 1 pp 183ndash193 2006

[28] P Garcia-Esparcia F Llorens M Carmona and I FerrerldquoComplex deregulation and expression of cytokines and medi-ators of the immune response in parkinsonrsquos disease brain isregion dependentrdquo Brain Pathology vol 24 no 6 pp 584ndash5982014

[29] M Shi J Bradner A M Hancock et al ldquoCerebrospinal fluidbiomarkers for Parkinson disease diagnosis and progressionrdquoAnnals of Neurology vol 69 no 3 pp 570ndash580 2011

[30] D Blum-Degena T Muller W Kuhn M Gerlach H Przuntekand P Riederer ldquoInterleukin-1120573 and interleukin-6 are elevatedin the cerebrospinal fluid of Alzheimerrsquos and de novo Parkin-sonrsquos disease patientsrdquoNeuroscience Letters vol 202 no 1-2 pp17ndash20 1995

[31] M Mogi M Harada H Narabayashi H Inagaki M Minamiand T Nagatsu ldquoInterleukin (IL)-1120573 IL-2 IL-4 IL-6 andtransforming growth factor-120572 levels are elevated in ventricularcerebrospinal fluid in juvenile parkinsonism and Parkinsonrsquosdiseaserdquo Neuroscience Letters vol 211 no 1 pp 13ndash16 1996

[32] M P Vawter O Dillon-Carter W W Tourtellotte P CarveyandW J Freed ldquoTGF1205731 andTGF1205732 concentrations are elevatedin Parkinsonrsquos disease in ventricular cerebrospinal fluidrdquo Exper-imental Neurology vol 142 no 2 pp 313ndash322 1996

[33] D Lindqvist S Hall Y Surova et al ldquoCerebrospinal fluidinflammatory markers in Parkinsonrsquos diseasemdashassociationswith depression fatigue and cognitive impairmentrdquo BrainBehavior and Immunity vol 33 pp 183ndash189 2013

[34] E Bezard Z Yue D Kirik and M G Spillantini ldquoAnimalmodels of Parkinsonrsquos disease limits and relevance to neuropro-tection studiesrdquo Movement Disorders vol 28 no 1 pp 61ndash702013

[35] F M Ribeiro E R D S Camargos L C de Souza and AL Teixeira ldquoAnimal models of neurodegenerative diseasesrdquoRevista Brasileira de Psiquiatria vol 35 supplement 2 pp S82ndashS91 2013

[36] D Trabzuni M Ryten W Emmett et al ldquoFine-mappinggene expression and splicing analysis of the disease associatedLRRK2 locusrdquo PLoS ONE vol 8 no 8 Article ID e70724 2013

[37] J Thevenet R Gobert R H van Huijsduijnen C Wiessnerand Y J Sagot ldquoRegulation of LRRK2 expression points to afunctional role in human monocyte maturationrdquo PLoS ONEvol 6 no 6 Article ID e21519 2011

[38] M S Moehle P J Webber T Tse et al ldquoLRRK2 inhibitionattenuates microglial inflammatory responsesrdquo The Journal ofNeuroscience vol 32 no 5 pp 1602ndash1611 2012

[39] J P Daher L A Volpicelli-Daley J P Blackburn M S MoehleandA BWest ldquoAbrogation of 120572-synuclein-mediated dopamin-ergic neurodegeneration in LRRK2-deficient ratsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 111 no 25 pp 9289ndash9294 2014

[40] R B Banati J Newcombe R N Gunn et al ldquoThe peripheralbenzodiazepine binding site in the brain in multiple sclerosisquantitative in vivo imaging ofmicroglia as ameasure of diseaseactivityrdquo Brain vol 123 no 11 pp 2321ndash2337 2000

[41] F Dolle C Luus A Reynolds and M Kassiou ldquoRadiolabelledmolecules for imaging the translocator protein (18 kDa) usingpositron emission tomographyrdquo Current Medicinal Chemistryvol 16 no 22 pp 2899ndash2923 2009

[42] Y Ouchi E Yoshikawa Y Sekine et al ldquoMicroglial activationanddopamine terminal loss in early Parkinsonrsquos diseaserdquoAnnalsof Neurology vol 57 no 2 pp 168ndash175 2005

[43] A Gerhard N Pavese G Hotton et al ldquoIn vivo imaging ofmicroglial activation with [11C](R)-PK11195 PET in idiopathic


Parkinsonrsquos diseaserdquo Neurobiology of Disease vol 21 no 2 pp404ndash412 2006

[44] Y Ouchi S Yagi M Yokokura and M Sakamoto ldquoNeu-roinflammation in the living brain of Parkinsonrsquos diseaserdquoParkinsonism and Related Disorders vol 15 supplement 3 ppS200ndashS204 2009

[45] A L Bartels A T M Willemsen J Doorduin E F J deVries R A Dierckx and K L Leenders ldquo[11C]-PK11195 PETquantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinsonrsquos diseaserdquo Parkinsonismand Related Disorders vol 16 no 1 pp 57ndash59 2010

[46] R Sanchez-Pernaute A Ferree O Cooper M Yu A-LBrownell and O Isacson ldquoSelective COX-2 inhibition preventsprogressive dopamine neuron degeneration in a rat model ofParkinsonrsquos diseaserdquo Journal of Neuroinflammation vol 1 article6 2004

[47] P Edison I Ahmed Z Fan et al ldquoMicroglia amyloid andglucose metabolism in Parkinsonrsquos disease with and withoutdementiardquo Neuropsychopharmacology vol 38 no 6 pp 938ndash949 2013

[48] D Koziorowski R Tomasiuk S Szlufik and A FriedmanldquoInflammatory cytokines and NT-proCNP in Parkinsonrsquos dis-ease patientsrdquo Cytokine vol 60 no 3 pp 762ndash766 2012

[49] R J Dobbs A Charlett A G Purkiss S M Dobbs C Wellerand DW Peterson ldquoAssociation of circulating TNF-120572 and IL-6with ageing and parkinsonismrdquo Acta Neurologica Scandinavicavol 100 no 1 pp 34ndash41 1999

[50] P Scalzo A Kummer F Cardoso and A L Teixeira ldquoIncreasedserum levels of soluble tumor necrosis factor-120572 receptor-1 inpatients with Parkinsonrsquos diseaserdquo Journal of Neuroimmunologyvol 216 no 1-2 pp 122ndash125 2009

[51] N P Rocha A L Teixeira P L Scalzo et al ldquoPlasma levelsof soluble tumor necrosis factor receptors are associated withcognitive performance in Parkinsonrsquos diseaserdquo Movement Dis-orders vol 29 no 4 pp 527ndash531 2014

[52] Z Katsarou S Bostantjopoulou O Hatzizisi E Giza A Soler-Cardona and G Kyriazis ldquoImmune factors or depressionFatigue correlates in Parkinsonrsquos diseaserdquo Revista de Neurologiavol 45 no 12 pp 725ndash728 2007

[53] A Nicoletti P Fagone G Donzuso et al ldquoParkinsonrsquos diseaseis associated with increased serum levels of macrophage migra-tion inhibitory factorrdquo Cytokine vol 55 no 2 pp 165ndash167 2011

[54] B Brodacki J Staszewski B Toczyłowska et al ldquoSeruminterleukin (IL-2 IL-10 IL-6 IL-4) TNF120572 and INF120574 concen-trations are elevated in patients with atypical and idiopathicparkinsonismrdquoNeuroscience Letters vol 441 no 2 pp 158ndash1622008

[55] G Stypuła J Kunert-Radek H Stępien K Zylinska andM Pawlikowski ldquoEvaluation of interleukins ACTH cortisoland prolactin concentrations in the blood of patients withParkinsonrsquos diseaserdquo NeuroImmunoModulation vol 3 no 2-3pp 131ndash134 1996

[56] D Lindqvist E Kaufman L Brundin S Hall Y Surova and OHansson ldquoNon-motor symptoms in patients with Parkinsonrsquosdiseasemdashcorrelations with inflammatory cytokines in serumrdquoPLoS ONE vol 7 no 10 Article ID e47387 2012

[57] P Scalzo A Kummer F Cardoso and A L Teixeira ldquoSerumlevels of interleukin-6 are elevated in patients with Parkinsonrsquosdisease and correlate with physical performancerdquo NeuroscienceLetters vol 468 no 1 pp 56ndash58 2010

[58] H Chen E J OrsquoReilly M A Schwarzschild and A AscherioldquoPeripheral inflammatory biomarkers and risk of Parkinsonrsquos

diseaserdquo American Journal of Epidemiology vol 167 no 1 pp90ndash95 2008

[59] K W Hofmann A F S Schuh J Saute et al ldquoInterleukin-6serum levels in patients with parkinsonrsquos diseaserdquo Neurochemi-cal Research vol 34 no 8 pp 1401ndash1404 2009

[60] M Dufek M Hamanova J Lokaj et al ldquoSerum inflammatorybiomarkers in Parkinsonrsquos diseaserdquo Parkinsonism and RelatedDisorders vol 15 no 4 pp 318ndash320 2009

[61] T Mihara M Nakashima A Kuroiwa et al ldquoNatural killercells of Parkinsonrsquos disease patients are set up for activation apossible role for innate immunity in the pathogenesis of thisdiseaserdquo Parkinsonism and Related Disorders vol 14 no 1 pp46ndash51 2008

[62] M Rentzos C Nikolaou E Andreadou et al ldquoCirculatinginterleukin-10 and interleukin-12 in Parkinsonrsquos diseaserdquo ActaNeurologica Scandinavica vol 119 no 5 pp 332ndash337 2009

[63] P Scalzo A S De Miranda D C Guerra Amaral M DeCarvalho Vilela F Cardoso and A L Teixeira ldquoSerum levels ofchemokines in Parkinsonrsquos diseaserdquo NeuroImmunoModulationvol 18 no 4 pp 240ndash244 2011

[64] N P Rocha P L Scalzo I G Barbosa et al ldquoCognitive statuscorrelates with CXCL10IP-10 levels in Parkinsonrsquos diseaserdquoParkinsonrsquos Disease vol 2014 Article ID 903796 7 pages 2014

[65] M Reale C Iarlori A Thomas et al ldquoPeripheral cytokinesprofile in Parkinsonrsquos diseaserdquo Brain Behavior and Immunityvol 23 no 1 pp 55ndash63 2009

[66] H Kluter P Vieregge H Stolze and H Kirchner ldquoDefectiveproduction of interleukin-2 in patients with idiopathic Parkin-sonrsquos diseaserdquo Journal of the Neurological Sciences vol 133 no1-2 pp 134ndash139 1995

[67] M Malaguarnera A Laurino I di Fazio et al ldquoNeuropsychi-atric effects and type of IFN-120572 in chronic hepatitis Crdquo Journal ofInterferon amp Cytokine Research vol 21 no 5 pp 273ndash278 2001

[68] N Atasoy Y Ustundag N Konuk and L Atik ldquoAcute dystoniaduring pegylated interferon alpha therapy in a case with chronichepatitis B infectionrdquoClinical Neuropharmacology vol 27 no 3pp 105ndash107 2004

[69] M Kajihara S Montagnese P Khanna et al ldquoParkinsonism inpatients with chronic hepatitis C treated with interferon-1205722b areport of two casesrdquo European Journal of Gastroenterology andHepatology vol 22 no 5 pp 628ndash631 2010

[70] M A Harris J K Tsui S A Marion H Shen and K TeschkeldquoAssociation of Parkinsonrsquos disease with infections and occupa-tional exposure to possible vectorsrdquo Movement Disorders vol27 no 9 pp 1111ndash1117 2012

[71] J Bas M Calopa M Mestre et al ldquoLymphocyte populations inParkinsonrsquos disease and in rat models of parkinsonismrdquo Journalof Neuroimmunology vol 113 no 1 pp 146ndash152 2001

[72] Y Baba A Kuroiwa R J Uitti Z K Wszolek and T YamadaldquoAlterations of T-lymphocyte populations in Parkinson diseaserdquoParkinsonism and Related Disorders vol 11 no 8 pp 493ndash4982005

[73] J A H Saunders K A Estes L M Kosloski et al ldquoCD4+regulatory and effectormemory T cell subsets profile motordysfunction in Parkinsonrsquos diseaserdquo Journal of NeuroimmunePharmacology vol 7 no 4 pp 927ndash938 2012

[74] C H Stevens D Rowe M-C Morel-Kopp et al ldquoReduced Thelper and B lymphocytes in Parkinsonrsquos diseaserdquo Journal ofNeuroimmunology vol 252 no 1-2 pp 95ndash99 2012

[75] M Calopa J Bas A Callen and M Mestre ldquoApoptosis ofperipheral blood lymphocytes in Parkinson patientsrdquo Neurobi-ology of Disease vol 38 no 1 pp 1ndash7 2010


[76] A Prigione I U Isaias A Galbussera et al ldquoIncreased oxida-tive stress in lymphocytes from untreated Parkinsonrsquos diseasepatientsrdquo Parkinsonism and Related Disorders vol 15 no 4 pp327ndash328 2009

[77] F Niwa N Kuriyama M Nakagawa and J Imanishi ldquoEffectsof peripheral lymphocyte subpopulations and the clinical cor-relation with Parkinsonrsquos diseaserdquo Geriatrics and GerontologyInternational vol 12 no 1 pp 102ndash107 2012

[78] P L McGeer and E G McGeer ldquoInflammation and thedegenerative diseases of agingrdquoAnnals of theNewYorkAcademyof Sciences vol 1035 pp 104ndash116 2004

[79] T H Hamza C P Zabetian A Tenesa et al ldquoCommongenetic variation in theHLA region is associated with late-onsetsporadic Parkinsonrsquos diseaserdquoNature Genetics vol 42 no 9 pp781ndash785 2010

[80] J Simon-Sanchez J J van Hilten B van de Warrenburg et alldquoGenome-wide association study confirms extant PD risk lociamong the Dutchrdquo European Journal of Human Genetics vol19 no 6 pp 655ndash661 2011

[81] S J Chung S M Armasu J M Biernacka et al ldquoGenomicdeterminants of motor and cognitive outcomes in Parkinsonrsquosdiseaserdquo Parkinsonism and Related Disorders vol 18 no 7 pp881ndash886 2012

[82] M A Nalls N Pankratz C M Lill et al ldquoLarge-scale meta-analysis of genome-wide association data identifies six new riskloci for Parkinsonrsquos diseaserdquo Nature Genetics vol 46 no 9 pp989ndash993 2014

[83] E K Tan ldquoGenetic marker linking inflammation with sporadicParkinsonrsquos diseaserdquo Annals of the Academy of Medicine Singa-pore vol 40 no 2 pp 111ndash112 2011

[84] G G Tribl C Wober V Schonborn T Brucke L Deeckeand S Panzer ldquoAmantadine in Parkinsonrsquos disease lymphocytesubsets and IL-2 secreting T cell precursor frequenciesrdquo Exper-imental Gerontology vol 36 no 10 pp 1761ndash1771 2001


[86] K P Wandinger J M Hagenah H Kluter M RothermundtM Peters and P Vieregge ldquoEffects of amantadine treatment onin vitro production of interleukin-2 in de-novo patients withidiopathic Parkinsonrsquos diseaserdquo Journal of Neuroimmunologyvol 98 no 2 pp 214ndash220 1999

[87] T Alberio A C Pippione C Comi et al ldquoDopaminergictherapies modulate the T-CELL proteome of patients withParkinsonrsquos diseaserdquo IUBMB Life vol 64 no 10 pp 846ndash8522012

[88] S Gangemi G Basile R A Merendino et al ldquoEffect oflevodopa on interleukin-15 and RANTES circulating levels inpatients affected by Parkinsonrsquos diseaserdquoMediators of Inflamma-tion vol 12 no 4 pp 251ndash253 2003

[89] H Bessler R Djaldetti H Salman M Bergman and MDjaldetti ldquoIL-1120573 IL-2 IL-6 and TNF-120572 production by periph-eral blood mononuclear cells from patients with Parkinsonrsquosdiseaserdquo Biomedicine and Pharmacotherapy vol 53 no 3 pp141ndash145 1999

[90] H Chen S M Zhang M A Hernan et al ldquoNonsteroidal anti-inflammatory drugs and the risk of Parkinson diseaserdquoArchivesof Neurology vol 60 no 8 pp 1059ndash1064 2003

[91] H Chen E Jacobs M A Schwarzschild et al ldquoNonsteroidalantiinflammatory drug use and the risk for Parkinsonrsquos diseaserdquoAnnals of Neurology vol 58 no 6 pp 963ndash967 2005

[92] X Gao H Chen M A Schwarzschild and A Ascherio ldquoUseof ibuprofen and risk of Parkinson diseaserdquo Neurology vol 76no 10 pp 863ndash869 2011

[93] D Casper U Yaparpalvi N Rempel and P Werner ldquoIbuprofenprotects dopaminergic neurons against glutamate toxicity invitrordquo Neuroscience Letters vol 289 no 3 pp 201ndash204 2000

[94] A D Wahner J M Bronstein Y M Bordelon and B RitzldquoNonsteroidal anti-inflammatory drugs may protect againstParkinson diseaserdquo Neurology vol 69 no 19 pp 1836ndash18422007

[95] K M Powers D M Kay S A Factor et al ldquoCombined effectsof smoking coffee and NSAIDs on Parkinsonrsquos disease riskrdquoMovement Disorders vol 23 no 1 pp 88ndash95 2008

[96] T G Ton S R Heckbert W T Longstreth Jr et al ldquoNons-teroidal anti-inflammatory drugs and risk of Parkinsonrsquos dis-easerdquoMovement Disorders vol 21 no 7 pp 964ndash969 2006

[97] D B Hancock E R Martin J M Stajich et al ldquoSmokingcaffeine and nonsteroidal anti-inflammatory drugs in familieswith Parkinson diseaserdquoArchives of Neurology vol 64 no 4 pp576ndash580 2007

[98] M Bornebroek L M L De Lau M D M Haag et al ldquoNon-steroidal anti-inflammatory drugs and the risk of Parkinsondiseaserdquo Neuroepidemiology vol 28 no 4 pp 193ndash196 2007

[99] M Etminan B C Carleton and A Samii ldquoNon-steroidal anti-inflammatory drug use and the risk of Parkinson disease aretrospective cohort studyrdquo Journal of Clinical Neuroscience vol15 no 5 pp 576ndash577 2008

[100] J A Driver G Logroscino L Lu J M Gaziano and T KurthldquoUse of non-steroidal anti-inflammatory drugs and risk ofParkinsonrsquos disease nested case-control studyrdquo British MedicalJournal vol 342 no 7791 article d198 p 270 2011

[101] A D Manthripragada E S Schernhammer J Qiu et al ldquoNon-steroidal anti-inflammatory drug use and the risk of Parkinsonrsquosdiseaserdquo Neuroepidemiology vol 36 no 3 pp 155ndash161 2011

[102] C Becker S S Jick and C R Meier ldquoNSAID use and riskof Parkinson disease a population-based case-control studyrdquoEuropean Journal of Neurology vol 18 no 11 pp 1336ndash13422011

[103] A Samii M Etminan M O Wiens and S Jafari ldquoNSAID useand the risk of parkinsons disease systematic review and meta-analysis of observational studiesrdquo Drugs and Aging vol 26 no9 pp 769ndash779 2009

[104] J J Gagne andM C Power ldquoAnti-inflammatory drugs and riskof Parkinson disease ameta-analysisrdquoNeurology vol 74 no 12pp 995ndash1002 2010

[105] F LrsquoEpiscopo C Tirolo S Caniglia et al ldquoCombining nitricoxide release with anti-inflammatory activity preserves nigros-triatal dopaminergic innervation and prevents motor impair-ment in a 1-methyl-4-phenyl-1236-tetrahydropyridine modelof Parkinsonrsquos diseaserdquo Journal of Neuroinflammation vol 7article 83 2010

[106] JMGarcıa-Moreno and J Chacon ldquoJuvenile parkinsonism as amanifestation of systemic lupus erythematosus case report andreview of the literaturerdquo Movement Disorders vol 17 no 6 pp1329ndash1335 2002

[107] M A Melikoglu I Sezer and C Kacar ldquoRheumatoid-likehand deformities in Parkinson diseaserdquo Journal of ClinicalRheumatology vol 13 no 4 pp 236ndash237 2007

[108] T Kogure T Tatsumi Y Kaneko and K Okamoto ldquoRheuma-toid arthritis accompanied by Parkinson diseaserdquo Journal ofClinical Rheumatology vol 14 no 3 pp 192ndash193 2008


[109] R C Kunas A McRae J Kesselring and P M VilligerldquoAntidopaminergic antibodies in a patient with a complexautoimmune disorder and rapidly progressing Parkinsonrsquos dis-easerdquo Journal of Allergy and Clinical Immunology vol 96 no 5part 1 pp 688ndash690 1995

[110] K Yanamandra M A Gruden V Casaite R Meskys LForsgren and L A Morozova-Roche ldquo120572-synuclein reactiveantibodies as diagnostic biomarkers in blood sera of parkinsonrsquosdisease patientsrdquoPLoSONE vol 6 no 4 Article ID e18513 2011

[111] E Masliah E Rockenstein A Adame et al ldquoEffects of 120572-synuclein immunization in a mouse model of Parkinsonrsquosdiseaserdquo Neuron vol 46 no 6 pp 857ndash868 2005

[112] E Masliah E Rockenstein M Mante et al ldquoPassive immu-nization reduces behavioral andneuropathological deficits in analpha-synuclein transgenic model of Lewy body diseaserdquo PLoSONE vol 6 no 4 Article ID e19338 2011

[113] A Schneeberger M Mandler F Mattner and W SchmidtldquoVaccination for Parkinsonrsquos diseaserdquo Parkinsonism and RelatedDisorders vol 18 supplement 1 pp S11ndashS13 2012

[114] J Yong G Lacan H Dang et al ldquoBCG vaccine-inducedneuroprotection in amousemodel of ParkinsonrsquosDiseaserdquoPLoSONE vol 6 no 1 Article ID e16610 2011


RamifiedmicrogliaActivated

microglia

Neuron

Dying neuron

InfectioninjuryAging

genetic factorsCytokines

CytokinesROS

CNS

BBB

Periphery

120572-synucleinGenetic factors

aging

Debrisclearance

Figure 1 Inflammatory pathways in Parkinsonrsquos disease An acute insult to CNS (eg 120572-synuclein aggregates) triggers the activationof microglia with changes in their morphofunctional characteristics increased proliferation and release of inflammatory mediators (egcytokines and ROS) Inflammatory molecules can induce the recruitment of peripheral leukocytes into the CNS This neuroinflammatoryprocess can be regarded as beneficial for neuronal tissue since it promotes clearance of cell debris Conversely inflammatory mediators donot modulate only immune cells but also act on neurons contributing to neurodegeneration Neuronal death further activates inflammatorymechanisms resulting in a vicious cycle of inflammation and neuronal death Systemic inflammation due to infection or peripheral injurycan exacerbate symptoms and promote neuronal damage in PD Leukocytes secrete proinflammatory cytokines which can affect the brain byseveral routes including action on endothelial cells and leakage throughdamagedBBBThese cytokines induce self-synthesis and the synthesisof other cytokines which can then stimulate microglia to secrete chronically inflammatory mediators maintaining neuroinflammation andas a consequence slow and progressive neuronal death Genetic and aging factors might contribute to this process BBB blood-brain barrierCNS central nervous system PD Parkinsonrsquos disease ROS reactive oxygen species

themotor symptoms of the disease In certain instances othermedications such as monoamine oxidase type B inhibitorsanticholinergics and dopamine agonists may be initiatedfirst to prevent levodopa-related motor complications [8]Although the number of people suffering from PD risessignificantly year by year there are no established disease-modifying or neuroprotective therapies for PD In this sce-nario in the present review we discuss current evidenceregarding the contribution of immune dysfunction andorinflammation in PD advances in recent image techniquesas valuable tolls for PD diagnosis and progression and theperspectives of anti-inflammatory based therapies (data aresummarized in Table 1)

2 Neuroinflammation in PD Lessons fromPost-Mortem and Neuroimaging Studies

21 Microglial Activation Role in PD The first evidence ofinflammation involvement in PD was derived from JamesParkinsonrsquos report on the first clinical and pathological

description of the disease in the early nineteenth century[4] More direct evidence was provided much later in thetwentieth century from systematic post-mortem analysis ofthe brain of PD patients [9] Based onmorphological featuresand immunohistochemical staining againstHLA-DR humanglycoprotein of theMHC-II group expressed on the surface ofimmunocompetent cells a significant increase in the numberof reactive microglia was found in the substantia nigra of PDpatients Interestingly reactive microglia was also found tobe enhanced in the hippocampus of PD patients who alsopresented dementia [9]

Neuronal death in PDprecedes the development ofmotorsymptoms by many years The mechanisms underlying theprogressive neurodegeneration in PD are still elusive and thediscovery of the active or main driving force is of paramountimportance in the search of effective therapeutic strategiesNeuroinflammation has been proposed to actively participatein PD onset and progression An acute insult to the centralnervous system (CNS) triggers microglial activation leadingto a series of changes inmicroglia notably in shape increased






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Documents

Insights into Neuroinflammation in Parkinson’s Disease: From … · (AD),multiplesystematrophy(MSA)patients,andhealthy controls:totaltau,phosphorylatedtau,amyloidbetapeptide 1–42