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RESEARCHOpenAccessBrain-derivedneurotrophicfactor(Val66Met)polymorphismandolfactoryabilityinyoungadultsAlessandroTonacci,AndreaBorghini*,AntonellaMercuri,GiovanniPioggiaandMariaGraziaAndreassiAbstractBackground:Brain-derivedneurotrophicfactor(BDNF)islinkedtoneurodegenerativediseases(e.
g.
AlzheimerdiseaseandParkinsondisease)whichareoftencharacterizedbyolfactoryimpairment.
AspecificsinglenucleotidepolymorphismoftheBDNFgene,theVal66Met,modulatesintracellulartraffickingandactivity-dependentsecretionofBDNFprotein.
Theaimofthisstudywastoinvestigateapossibleassociationbetweenbrain-derivedneurotrophicfactorVal66Metpolymorphismandolfactoryfunction,awell-knownbiomarkerforneurodegeneration,inhealthyyoungadults.
Atotalof101subjects(45males,age38.
7±9.
4years)wereassessedusingtheSniffin'SticksExtendedTest,ahighlyreliablecommercialolfactorytestcomposedofthreesub-parts,calculatingolfactorythreshold(sensitivity),odordiscriminationandodoridentification.
TheVal66Metpolymorphismwasdeterminedbypolymerasechainreaction-restrictionfragmentlengthpolymorphism(PCR-RFLP)analysis.
Results:AnimpairedfunctioninMetcarrierswasfound,especiallywhencomparedtosubjectswithVal/Valgenotype,inthethreshold(5.
5±2.
0vs6.
5±1.
8,p=0.
009),discrimination(10.
3±2.
5vs11.
9±2.
2,p=0.
002),andidentificationtask(13.
3±1.
6vs14.
1±1.
3,p=0.
007),aswellasintheoverallTDIScore(29.
1±4.
5vs32.
6±3.
9,p<0.
001).
Conclusions:Thesefindingsappeartohaveimplicationsfortheevaluationofolfactoryfunctionandtherelationofitsimpairmenttocognitivedeclineandneurodegenerativedisease.
Keywords:Olfactoryfunction,Brain-derivedneurotrophicfactor,Val66MetpolymorphismBackgroundOlfactoryfunctionisawell-knownbiomarkerforneu-rodegeneration.
Thelossofolfactionis,infact,oftenasso-ciatedwithmanyneurodegenerativeconditions,suchasParkinson's(PD)andAlzheimer's(AD)diseases[1,2].
Adecreaseinolfactoryfunctioncouldbeanearlyalarmwarningforsuchconditions,sinceitsonsetoccurspriortothefirstclinicalsignsofpathologyby4–5years.
Manyfactorsareknowntoinfluenceolfactoryability,includinggeneticvariability[3,4].
Moreover,anincreasingnumberofanimalstudies,aswellasclinicalstudies,confirmtheimportantroleofthebrain-derivedneurotrophicfactor(BDNF)inneurodegenerativediseases[5-9].
Inparticular,BDNF,amemberoftheneurotrophinfamily,playsanim-portantroleinthedevelopmentandmaintenanceofneuronsandneuronalconnectionsinthecentralandper-ipheralnervoussystem[10].
AcommonfunctionalsinglenucleotidepolymorphismoftheBDNFgene,theVal66Met,modulatesintracellulartraffickingandactivity-dependentsecretionofBDNFprotein,andimpairstheabilityofBDNFtoundergoactivity-dependentrelease,butnotgeneralsecretion[11-14].
TheVal66Metislocatedatnucleotide196(G/A)inthepro-proteinofBDNFandpro-ducesanaminoacidsubstitution,valinetomethionine.
TheMetalleleinhibitstheintracellulartraffickingandtheregulatedsecretionoftheBDNFproteinatsynapses[11].
PublisheddatasupportaroleforBDNFgenevariantinsomeneuropsychiatricdisorders.
Guerinietal.
showedacorrelationbetweenBDNFVal66MetpolymorphismandcognitiveimpairmentinItalianpatientswithParkinson'sdisease[15].
BDNFVal66Metisalsoreportedtobeassoci-atedwithADand/orschizophrenia,aswellasotherpsychoses[16,17],butthefindingsarestillcontradictory[18,19].
Furthermore,evidencesuggestedthatBDNFmightberelevantforolfactoryprocessing[20].
Infact,BDNFinducestheproliferationandsurvivalofneuronalprecursorcells/immatureneuronsintheolfactorysysteminvivoandinvitrousingmicewithtargeteddeletionof*Correspondence:aborghini@ifc.
cnr.
itEqualcontributorsInstituteofClinicalPhysiology,NationalResearchCouncil(IFC-CNR),Pisa,Italy2013Tonaccietal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Tonaccietal.
JournalofBiomedicalScience2013,20:57http://www.
jbiomedsci.
com/content/20/1/57thegeneforBDNFandanolfactoryepitheliumculturesystem,respectively[20].
Arecentworkfoundanassoci-ationbetweenmatureBDNFlevelsandincreasingofmi-tralcell,pyramidal-likeneurons,excitabilityolfactorybulblevelinthemice[21].
Furthermore,anexperimentalstudyshowedthatBDNFplayapivotalroleintheolfactoryneurogenesis,contributinginolfactoryepitheliumtotheearlystageofregenerationandinolfactorybulbinthelatestageofregenerationofolfactoryreceptorneurons[22].
Additionally,thereareexperimentalstudiesinanimalslinkingthegeneticvarianttoolfactoryfunction[23],but,todate,littleisknownaboutthisassociationinhumans,exceptforarecentpopulation-basedstudythatshowedalinkbetweenage-relatedolfactorydeclineandBDNFVal66Metpolymorphismintheolderagecohort(70–90years)[24].
InordertobetterdefinetheinfluenceofBDNFVal66Metpolymorphismontheolfactoryfunction,thepurposeofthisstudywastoassessapossibleassoci-ationbetweenBDNFVal66Metpolymorphismandolfac-toryabilityinhealthyyoungadults,populationlesssubjectedtocomorbiditiespossiblyassociatedwithanol-factorydysfunctionifcomparedwithelderlypeople.
MethodsEthicsThepresentstudywasapprovedbytheEthicsCommit-teeforclinicaltrialswithmedicines-PisaHospital,Italy,withprotocolnumber36169.
StudypopulationAtotalof101volunteers(45males,age38.
7±9.
4years)wereenrolledforthestudy.
Writteninformedconsentwasobtainedfromallsubjects.
Thevolunteerswerechosenfromamongyoungadults,asthispopulationislesssubjecttodiseasesaffectingolfactoryfunction.
Aclinicalquestion-nairewasfilledoutbythevolunteersandcollected.
Manyexclusioncriteriawereappliedtoobtainacleanpopulation,withabsenceofpathologicalconditionspossiblyaffectingthesenseofsmell.
Inparticular,subjectshavingnasalprob-lems,suchasflu,rhinitis,sinusitis,allergies,wereexcludedfromtheanalysis,togetherwithsubjectshavingusedmedi-cationssuchasnasaldecongestants,antidepressantsandanxiolyticsinthe2-monthperiodbeforeadministrationoftheolfactorytest.
Familiarhistoryofneurodegenerationwasalsoconsidered,andsubjectswithparentsorfirstde-greerelativeswithconditionssuchasAlzheimer'sdisease,Parkinson'sdisease,AmyotrophicLateralSclerosis,Lewybodydisease,Huntington'schoreaorschizophreniawereexcludedfromthestudy.
Amongnormalsubjectsmatchingthesecriteria,peoplewithnormalgeneralcognitivefunc-tionevaluatedwithstandardizedneuropsychologicaltestbatteriesbyaprofessionalneuropsychologistwereincluded,whilesubjectswithsub-normalscoreswerenotconsideredintheanalysis.
OlfactoryassessmentOlfactoryfunctionwasassessedusingtheSniffin'SticksExtendedTest[25,26],anolfactorytestcommerciallydis-tributedbyBurghart,Medizintechnik,GmbH(Wedel,Germany).
Itconsistsofthreedifferentsub-tests,assessingtheolfactorysensitivity(threshold),discriminationandidentification,typicaltasksoftheolfactorysystem.
Inthisversionofthetest,theolfactorysensitivityton-butanolwasemployed.
Theolfactorythresholdisconsideredastheminimumconcentrationofanodorant(n-butanol)thatcanbedetectedbyasubject.
N-butanolwaspre-sentedin16differentdilutionsinfelttippens.
Foreachtrialtheblindfoldedsubjectwassubjectedtothreediffer-entstimuli,oneconsistingofagivenconcentrationofn-butanol,andtheothertwowithblankstimuli.
Thesubjectwasaskedwhichofthethreestimulicontainedthen-butanol(or,equivalently,whichofthethreestimuliwasthestrongest).
Dependinguponthecorrectandwrongan-swersgiven,theconcentrationofthestimuluswaschangedandthetrialwasrepeateduptosevenstaircasereversals.
Thethresholdscorewascalculatedbyper-formingameanofthevaluesoffourlastreversals.
Theol-factorydiscrimination'saimwastoassessthesubject'sabilitytodiscriminatebetweendifferentodorants.
Eveninthiscasethesubjectwasblindfoldedand16differenttrip-letsofodorantswerepresented.
Foreachtriplet,twofelttippenscontainedthesameodorant,whilethethirdoneheldadifferentsubstance.
Thesubjectwasaskedwhichofthethreepenscontainedthedifferentodorant.
Theolfac-toryidentificationtestaimedtoevaluatethesubject'sabil-itytocorrectlyidentifyanodorant.
Thesubjectwaspresentedwith16differentodorantsandaskedtoidentifythembychoosingbetweenfourpossibleodorsforeachtrial.
Inthisfinaltest,thesubjectwasnotblindfolded.
Eachofthesetestsyieldedascore,andthetotalsumofthethreesub-scoreswascalled"TDI(ThresholdDiscrim-inationIdentification)Score",relatingtoolfactoryfunc-tion.
Wechosetoemployabilateraltesting,inordertoavoidpossiblefalseresultsduetothecongestionofoneofthetwonostrils,eventhoughthepresenceoffluand/ornasalproblemswasincludedintheexclusioncriteriaofthesurvey.
Thetestwasperformedonceforeachpartici-pant,giventhehightest-retestreliabilityofthemethodemployed(r=0.
80forOdorDiscrimination,r=0.
88forOdorIdentification,r=0.
92forOdorThreshold)[25,27].
Thereliabilitydataobtainedinpreviouspilotstudiesareinagreementwithdataabovementioned.
DNAextractionandgenotypingGenomicDNAwasextractedfromperipheralbloodleukocytes.
TheBDNFVal66MetpolymorphismwasTonaccietal.
JournalofBiomedicalScience2013,20:57Page2of5http://www.
jbiomedsci.
com/content/20/1/57genotypedbypolymerasechainreactionamplificationandrestrictionenzymedigestion,aspreviouslydescribed[28].
Briefly,a274bpDNAsegmentincludingthepoly-morphicsitewasamplifiedbyPCRusingasetofoligo-nucleotideprimers:5'-AAAGAAGCAAACATCCGAGGACAAG-3'and5'-ATTCCTCCAGCAGAAAGAGAAGAG-3',senseandantisenseprimersrespectively.
ThePCRproductwasdigestedwithNlaIIIrestrictionendonuclease,resultingintwofragmentsof57and217bpfortheGalleleandinthreefragmentsof57,77,140bpfortheAallele.
Theproductswereseparatedby2%agarosegelstainedwithethidiumbromide.
Genotyperesultswereregularlyconfirmedbyrandomrepetitionofthesampleswithnodiscrepancies.
StatisticalmethodsStatisticalanalysisofthedatawasperformedwiththeStatViewstatisticalpackage,version5.
0.
1(AbacusCon-cepts,Berkeley,CA,USA).
Dataareexpressedasmean±SD.
Student'sT-testwasusedtoexaminedemographicdataandtocompareindividual'sgenotypeswitholfactorytestscalled"ThresholdTest","DiscriminationTest"and"IdentificationTest",aswellaswiththeoverall"TDIScore".
Fisher'sexactTtestwasusedforpost-hoctests.
Thelevelofsignificancewassetatp<0.
05forallstatis-ticalanalyses.
Assumingafrequencyof23%fortheriskal-lele,thesizeofthestudypopulationallowstodetecta15%differenceormoreinolfactoryparametersinthehet-erozygouscarriersofMetvariantthewithapowerofβ=80%bymeansofatwo-sidedt-testwithα=5%.
ResultsWeinvestigatedapossibleassociationofBDNFVal66Metpolymorphismwitholfactoryfunctioninagroupofyoungadults.
Duetothelowpopulationfre-quencyoftheMet/Metgenotype(<5%),participantsweredividedintotwogroups,eitherhomozygousfortheTable1DemographiccharacteristicsofstudypopulationVal/Valn=60Metcarriersn=41Age(mean±SD)(years)38.
1±8.
539.
7±10.
7Gender,malesn(%)24(40)21(51)Smokinghabit,n(%)17(28)12(29)Figure1ImpactoftheBDNFVal66Metpolymorphismonolfactoryability.
BDNFVal66Metpolymorphismandtheolfactorythreshold(topleft),discrimination(topright),identification(bottomleft)andtheoverallTDIScore(bottomright).
Tonaccietal.
JournalofBiomedicalScience2013,20:57Page3of5http://www.
jbiomedsci.
com/content/20/1/57Valallele(Val/Val)orhomozygousandheterozygousfortheMetallele(Met/Met,Val/Met),respectively.
ThedemographiccharacteristicsofthestudypopulationarereportedinTable1.
Therewasnosignificantdifferenceinage,genderandsmokinghabitsbetweengroups.
Thegenotype'sdistributionofVal66Metpolymorphismob-servedinbothpatientsandcontrolssatisfiedtheHardy-WeinbergequilibriumandwerecomparablewiththatpreviouslyobservedinCaucasiansubjects[11].
TherewassignificantevidencefortheimpactoftheBDNFVal66Metpolymorphismonolfactoryability.
Inparticu-lar,MetcarriersshowedimpairedolfactoryfunctioncomparedwithVal/Valcarriersinallthreesub-tests,aswellasintheoverallTDIScore.
Theimpairmentwasmarkedinalltasks,inthecaseofOlfactoryThreshold(5.
5±2.
0vs6.
5±1.
8,p=0.
009),OlfactoryDiscrimin-ation(10.
3±2.
5vs11.
9±2.
2,p=0.
002),andIdentifica-tion(13.
3±1.
6vs14.
1±1.
3,p=0.
007),aswellasintheTDIScore(29.
1±4.
5vs32.
6±3.
9,p<0.
001),suggestingacleareffectoftheVal/Metvariantonolfactoryfunc-tion,asdisplayedinFigure1.
DiscussionThestudyaimedtodiscovertheinfluenceofbrain-derivedneurotrophicfactor(BDNF)singlenucleotidepolymorph-ism(SNP)Val66Metonolfactoryfunction.
Brain-derivedneurotrophicfactor(BDNF)iswidelyexpressedintheadulthippocampusandneocortex[29].
Itisconsideredanimportantneurotrophicfactorforneuronaldifferentiationandlife-longplasticityandrepair[30].
BDNFVal66Metpolymorphismimpairsactivity-dependentBDNFexcretionandhasbeenassociatedwithchangesincorticalandsub-corticalanatomy[31,32].
BDNFVal66Metpolymorphismisstrictlyrelatedtocognitivefunction.
Inparticular,Metcarriersshowimpairedabilityindeclarativememorytasks,aswellasadecreaseinengagementofparticularareas,suchasthehippocampus,duringencodingandretrieval[33],althoughcurrentfindingsarestillcontradictory[34,35],andarecentmeta-analysisreportednosignificantcorrelationbetweenVal66MetSNPandthecognitivephe-notypes[36].
BDNFalsoappearstoinfluencetheolfactoryfunction,sincethemodulationofproliferationandsurvivalofolfactoryreceptorsisoneofitskey-roles,accordingtoSimpsonetal.
[20].
TheexpressionofBDNFVal66MetSNPisrelevantinparticularareas,involvedinolfactoryprocessingandpartoftheolfactorypathway,suchasintheolfactorybulb,whoseneurogenesisdisruptionisstrictlyrelatedtotheBDNFVal66Metvariant.
Todate,onlyoneworkhasbeenpublishedshowinganassociationbetweenolfactoryfunction(identificationtask)andBDNFVal66MetSNPinhumans[24],buttheeffectofthisSNPinyoungadultswasnotinvestigated,norwasitseffectonotherimportanttasks,suchasolfactorydiscrimination.
Furthermore,wechosetoemploythecompleteSniffin'SticksExtendedTestinordertoevaluateeventualvaria-tionsoccurringatdifferentlevelsoftheolfactorypathway.
Inparticular,aclearimpairmentforMetcarrierswasfoundinalltasks,suggestingtheprofoundinfluenceofthisgeneticvariantonthegoodfunctioningoftheolfactorypathway.
Severalkeylimitationsneedtobeacknowledged.
First,althoughthepresentstudyseemstobesufficientlypowered,oursamplesizeisrelativelysmall,thusmakingstatisticalestimationslessrobust.
Second,thefrequenciesoftheValandMetallelesofBDNFVal66Metvarybyeth-nicity;about80%oftheEuropeanpopulation,butonly50%oftheAsianpopulation,carryit[16].
Anotherlimita-tionofourstudyisthelackofamorecomprehensivegen-eticanalysisofpolymorphismspotentiallyassociatedwitholfactoryfunction[37].
ConclusionsDespitetheselimitations,wewereabletoshowarelevantinfluenceofBDNFVal66Metpolymorphismonolfactoryfunction.
Thesefindingscouldhaveimplicationsfortheevaluationofolfactoryfunctionandforrelatingitsimpair-menttocognitivedeclineandneurodegenerativediseases.
Furtherinvestigationareneededtosubstantiatethisrela-tionshipinlargersubgroupsofpopulationsofdifferentethnicbackgrounds.
CompetinginterestsTheauthorsdeclarenopotentialconflictofinterests.
Authors'contributionsAT,ABandAMcarriedoutthemajorexperiments.
AT,ABandMGAcontributedtotheexperimentaldesignandwrotethemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsTheauthorsthankallyoungvolunteersofInstituteofClinicalPhysiology-NationalResearchCouncil(Pisa,Italy)fortheirparticipationtothestudy.
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doi:10.
1186/1423-0127-20-57Citethisarticleas:Tonaccietal.
:Brain-derivedneurotrophicfactor(Val66Met)polymorphismandolfactoryabilityinyoungadults.
JournalofBiomedicalScience201320:57.
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