CSF proenkephalin sechiratidzo chechirwere cheHuntington chisati chatanga

Pepa iri rine musoro unoti, Cerebral Spinal Fluid Proenkephalin Inofanotaura Kupera Kwesimba Kwemusana Kwemasvondo Makumi Emakore Pamberi Pekuongororwa Kwemotokari MuHuntington's Disease. Mena, [00:01:00] makorokoto nepepa renyu, uye tinokutendai zvikuru nekubatana nesu nhasi.

Dr. Mena Farag: Ndatenda nekundikoka uye nekundigamuchira paMovement Disorder Society Podcast, Eduardo.

Dr. Eduardo de Pablo-Fernandez: Saka tisati tanyatsoongorora munyaya yako chii chinonzi proenkephalin uye izvozvo zvine chekuita sei nechirwere cheHuntington?

Dr. Mena Farag: Saka tinoziva kuti chirwere cheHuntington chinoratidzwa nezvirwere zvakasiyana-siyana zvinokanganisa mashandiro emuviri, kudzikira kwepfungwa, uye kukanganiswa kwepfungwa nepfungwa panguva yekukwegura, kazhinji pakati pekukura. Kunyangwe paine kusiyana kukuru pakati pevanhu uye padanho repfungwa, chirwere cheHuntington chinotsanangurwa nekutanga kwekusagadzikana kwetsinga dzeropa munzvimbo dzakasiyana.

Maneuron e striatum ne medium spiny anomiririra huwandu hwema neuron ari panjodzi huru. Uye striatal Atrophy ndeimwe yemamwe ekutanga ekufungidzira uye kuwanikwa kwe post-mortem muchirwere ichi. Uye mukati meiyi striatum neurons yenzira isina kunanga inonyanya kubatwa. Maneuron aya [00:02:00] anozivikanwa kwete chete neGABAergic phenotype yavo, asiwo nekutaura kwe enkephalin derived neuropeptides.

Saka proenkephalin, kana kuti PENK, ndiyo inotangira enkephalins uye ine zvakawanda zvakapfuma munzira isina kunanga, ichiratidza ku globus pallidus ye striatum, uye data rezvinyorwa zvemhuka nevanhu rinoratidza kuti PENK expression iri mukati me basal ganglia uye inotsigira biological specificity ku striatal circuitry. Uye zvisati zvaitika zvidzidzo zve post-mortem neHuntington zvakaratidza kudzikira kwe enkephalin mu basal ganglion nuclide, izvo zvinoratidza kuti panogona kunge paine kurasikirwa kwekutanga kwe enkephalin expressing neurons. Uye izvi zvakawanikwa zvinopa chikonzero chakasimba chePENK sechiratidzo che striatal vulnerability mu HD.

Mumakore mashanu apfuura kwave neongororo dzakaratidza kuti PENK inogona kuverengwa zvakavimbika mu cerebral spinal fluid uye ndiyo CSF. [00:03:00] Kuwanda kwePENK kunoderera nguva dzose muHuntington's disease, uye kudzikira uku kwave kuchidzokororwa muma cohorts akazvimiririra, izvo zvinotsigira basa rayo sechiratidzo chechirwere chakakodzera.

Uye zvisina kucherechedzwa mu neurology uye zvichienzaniswa nezvimwe zvirwere zvinokanganisa mashandiro etsinga, huwandu hweCSF PENK hwakanga hwakaderera muvanhu vane chirwere cheHuntington kana tichienzanisa kwete chete nevanochengetedza, asiwo nedzimwe zvirwere zvinokanganisa mashandiro etsinga, kusanganisira Parkinson's, Alzheimer's, uye ALS. Uye zvakakosha, huwandu uhwu hwakaderera hwePENK hwakaratidzwa kuti hune chekuita nemutoro wezvirwere uye zvinofambisa shanduko, izvo zvinotsigirawo kukosha kwayo muhunhu hweHD.

Dr. Eduardo de Pablo-Fernandez: Saka zvinoita sekunge une humbowo hwezvinonzwika se biomarker chaiyo. Zvakanyatsojeka, zvine chekuita nebiology. Zvinochinja nekufamba kwenguva. Zvinoenderana nekuchinja kwekiriniki uye ndizvo zvinoedza kuitwa neongororo yako kuratidza kana ichi chiri biomarker chaiyo.

Uye mukudzidza kwako fungidziro yako ndeyekuti inogona kunge iri [00:04:00] yakananga kupfuura zvimwe zviratidzo zvekuora kwetsinga zvakamboshandiswa kare, muvanhu vane Huntington's kana zvakanyanya muoora kwetsinga, senge neurofilament light chain. Uye zvakare unoenzanisa izvozvo nekufambira mberi paMRI uye kufambira mberi padanho rehupenyu rechirwere cheHuntington.

Mungatiudze zvimwe nezvefungidziro yacho uye zvakabuda muchidzidzo ichi here?

Dr. Mena Farag: Saka pasinei nechiratidzo chekuti izvozvo zvave zvichivimbisa muzvidzidzo kusvika pari zvino, pave nemikana yakakosha. Zvidzidzo zvekare zvaive zvakasiyana-siyana. Zvaive nemapoka madiki kana kuti akaonekwa zvakanyanya mukurapa, uye hazvina kutaura kana CSF PENK ichichinja kwenguva refu kana kuti ine chekuita nekushomeka kweuropi munzvimbo. Uye kunyanya hunhu hweCSF PENK sechiratidzo chekuora kwetsinga dzemudumbu hwakanga husati hwaedzwa. Saka chinangwa chechidzidzo ichi chaive chekuongorora CSF proenkephalin se biomarker ine ruzivo rwezvehupenyu hwekutanga [00:05:00] HD ichinyanya kutarisa pane boka rekudzidza revechidiki veHD risati ratanga.

Saka chinangwa chedu ndechekuongorora hukama hwepakati pezvikamu zviviri uye hwenguva refu pakati pehuwandu hwekutanga hweCSF hwePENK uye kuora kwetsinga dzenharaunda tichishandisa MRI yechimiro. Saka fungidziro yedu huru yaive yekuti huwandu hwakaderera hweCSF PENK hwaizobatanidzwa nekuderera kweuropi kunotevera kunyanya mu striatum.

Uye sezvamakataura, takaedzawo kuenzanisa maitiro enzvimbo dzekubatana kwePENK neaya akacherechedzwa kune mamwe ma biofluid biomarkers akaratidza kusiyana kwemapoka ane chekuita nezvirwere, kunyanya neurofilament light, yatinoziva inoratidza kukuvara kwe neuro axonal kwepasi rose uye kwakajairika.

Uye tinotaura nezvekurongwa kwematanho uye mukana wekuti basa iri rive nekwaniso, kupatsanurwa kwematanho uye dhizaini yekuyedzwa kwekiriniki. Saka iyi ingave pfungwa yakanaka yekusuma HD Integrated Staging System kana HD ISS, [00:06:00] inova ndiyo hurongwa hwakakosha hunosimbisa kukosha kwebasa iri.

Kuongororwa kweHD kwagara kuripo kubva muzviratidzo zvekiriniki, zvichisiyanisa pakati pechirwere che pre manifest nechirwere che manifest. Uye kunyangwe izvi zvichibatsira mukurapa, nzira iyi hainyatso ratidza kufambira mberi kwezvipenyu kunotanga zviratidzo zvakatanga. Saka HD ISS yakagadzirwa kugadzirisa dambudziko iri nekupa humbowo hwakabatana hunotsigira nhoroondo yechisikigo yeHD muchikamu chose. Saka kune matanho mana muHD ISS uye basa riri mupepa iri rinosanganisira vatori vechikamu kubva kuHD Young Adult Study vari padanho re zero, kusanganisira. Vatori vechikamu vaive vatakuri vemajini ekuwedzera vane penetrance yakazara, asi vasina mhando yeshanduko dzezvipenyu dzinoonekwa.

Danho rekutanga rinonyatsotsanangurwa neuchapupu hwe biomarker hwechirwere, uye rakarongwa zvakananga nechiyero che MRI chezuva rinonzi IAM [00:07:00] atrophy uye danho rechipiri rinobata kubuda kwezviratidzo zve subtle motor uye clinical, zviratidzo zve cognitive uye danho rechitatu rinoratidza kudzikira kwebasa. Uye miedzo yakawanda yekiriniki parizvino inonyoresa vatori vechikamu vari muHD ISS danho rechipiri nerechitatu.

Uye chirwere chinoratidza zviratidzo zvekutanga. Uye zvakawanda zvebasa iri uye zvakawanda zvekudzidza kwevechidiki veHD, chinangwa chikuru ndechekutevera shanduko dzekutanga dzezvemuviri mumakondi ekutanga dzinogona kushandiswa kudzidzisa dhizaini yekuedza kudzivirira.

Dr. Eduardo de Pablo-Fernandez: Ipfupiso yakanaka kwazvo, uye zvinonakidza kuti chidzidzo chako chiri kutarisa mapoka aya anonakidza zvikuru pakutanga kwechirwere. Mungatiudze zvimwe nezvemapoka ekudzidza uye nzira dzamakashandisa muchidzidzo ichi here?

Dr. Mena Farag: Ehe, chidzidzo cheHD Young Adult iboka revechidiki vane gene reHuntington's disease [00:08:00] rinoonekwa kwenguva refu uye paavhareji vanenge makore makumi maviri kubva pakuongororwa kwezvirwere zvemuviri. Uye vakaenzaniswa pamwe chete nevasina kukanganiswa, vakaenzana zvakanyanya maererano nezera, murume kana mukadzi, uye dzidzo.

Saka chidzidzo ichi chakatangwa uye chakatungamirwa naPurofesa Sarah Tabrizi uye chakatanga muna 2017. Uye kusvika pari zvino, kwave nenguva mbiri. Tapedza nguva yechitatu munguva pfupi yapfuura. Uye nguva iri pakati pekushanya kwekutanga nekushanya kwechipiri yaive makore angangoita mana nehafu.

Saka boka revanhu rakanyatso tsanangurwa zvakadzama. Saka zvaisanganisira kuongororwa kwemhando dzakasiyana-siyana kunosanganisira biofluid, kutora mifananidzo yeropa neropa remusana. Saka neTesla nhatu, kuongororwa kweMRI, kuongororwa kwepfungwa uye kuongororwa kwepfungwa. Uye mumakore mana nehafu, takava nevanhu 103 vakadzoka kuzotevera, uye takatorawo vanhu vatsva 23. Uye maererano nenzira, kunyanya mupepa rino [00:09:00] inonyanya kushandiswa kuongorora biofluid. Saka kuti tiongorore chimiro cheuropi, takashandisa whole brain voxel based morph geometry, inozivikanwa seVBM.

Saka izvi ndizvo chaizvo, saka pane kusarudza nzvimbo dzatinofarira, nzira iyi inotibvumira kuongorora huwandu hwezvinhu zvichena nezvichena muuropi hwese nenzira isina rusaruro. Uye inosanganisira kupatsanura uropi kuita zvinhu zvichena, zvinhu zvichena uye mvura yemusana. Uye tinoshandisa nzira dzakagara dziripo, nzira dzeEBM kuti tione kana zvinhu zvichichinja nekufamba kwenguva muuropi.

Uye padanho revoxel, zvinotibvumira kuona mamepu ekuwedzera kwenyama yemuno kana kudzikira pakati penguva yekutanga nenzvimbo yechipiri kuti tione kuti neurodegeneration iri kuitika riini uye kuti ingani. Uye zvatakaita ndezvekuti takaedza huwandu hwemvura hweproenkephalin muCSF uye muplasma neCSF NfL. Uye tinoshandisa izvozvo [00:10:00] kufanotaura, kwakawanikwa patani yenzvimbo uye hukuru hweatrophy. Uye takagadzirisa izvi kuti tizive nezvezera, nguva iri pakati pemaskeni uye mutoro wechirwere. Saka chinhu chikuru ndechekuti hatisi kungobvunza kuti mapoka aya akasiyana papi panguva imwe chete, asi tiri kubvunza kuti kurasikirwa kwenyaya yeuropi kuri kuitika kupi nekufamba kwenguva uye kana ma biomarkers e biofluid ekutanga anogona kufanotaura patani yenzvimbo uye hukuru hwekurasikirwa ikoko.

Dr. Eduardo de Pablo-Fernandez: Uye zuva iro ma biomarker aya akaratidza patani, patani yemaumbirwo e atrophy paMRI.

Dr. Mena Farag: Saka chikuru chakawanikwa muongororo iyi ndechekuti baseline CSF PENK yakafanotaura zvakasimba kuti brain atrophy ine striatal pattern kana spatial pattern yakanyanya kuderera, kunyanya baseline CSF PENK concentrations, yakabatana nekurasikirwa kukuru kwe grey matter mu core date uye putamen kumativi ese maviri nekuchinja kwakafanana mu white matter mu adjoining peri striatal white matter. Uye hukama uhwu hunoramba hwakakosha [00:11:00] kunyangwe mushure mekugadzirisa mutoro wechirwere, izvo zvinoratidza kuti PENK inopa ruzivo rwunopfuura zera uye CAG repeat length chete, izvo zvatinoziva kuti ndizvo zvinotungamira kufambira mberi muHuntington's.

Kunyange zvazvo NfL yakaratidza chimiro chakasiyana chenzvimbo, CSF yepamusoro-soro, kuwanda kwechiedza cheNeurofilament kwairatidza zvakanyanya kuchinja kwe g lobal uye kwakapararira kwezvinhu zvichena uye kuchinja kwe cortical grey zvinhu. Izvi zvinonyatsoenderana nezvatinoziva nezve NfL.

Nekuti tinoziva kuti NfL ipuroteni ye axonal inoratidza kukuvara kwe neuro axonal pasi rose, nepo PENK ichiita seyakabatana zvakanyanya ne striatal pathology. Chimwe chaive chinonakidza ndechekuti takaona misiyano pakati peCSF ne plasma NfL muzvikamu izvi zvekutanga zvechirwere.

Uye maererano neongororo, rudzi rwekutanga rweplasma NfL rwakabatana nemaitiro akaganhurirwa [00:12:00] ekurasikirwa kwehuwandu hwehuropi, kwakaganhurirwa kumaboka madiki mu cortical grey matter izvo zvaive zvakasiyana zvikuru kana tichienzanisa nezvatinoona neCSF NfL. Uye izvi zvakawanikwa zvinoratidza kuti pamwe plasma NfL inogona kunge isina kugadzikana kupfuura CSF NfL pakuona shanduko dzekutanga dze neurodegenerative mune idzi dziri kure nekutanga kwe cohorts.

Asi zvakadaro, kuchine kushanda uye kushandiswa muNfL mune izvi.

Dr. Eduardo de Pablo-Fernandez: Saka sezvamataura, iwo ma biomarker ane maitiro akasiyana zvishoma. Imwe nzira chaiyo, imwe nzira yekubatanidza ne striatal neurons. Imwe nzira yakajairika, inongoratidza kukuvara kwe neuro axonal. Ma biomarker aya anogona sei kuzivisa nezve pathophysiology uye maitiro e neurodegenerative pakutanga.

Tinofanira kunamatira kuproenkephalin here? Tinofanira kushandisa zvese zviri zviviri kuti tive neruzivo rwakawedzerwa here? Munofungei nezvekushandiswa kwe biomarkers dzese dziri mbiri?

Dr. Mena Farag: Ndiwo mubvunzo wakanaka chaizvo, uye pane kuvafunga se [00:13:00] sema biomarkers anokwikwidzana. Ndinofunga kuti vanoratidza maitiro ezvirwere zvekuwedzera. Saka PENK chiratidzo chekusagadzikana kwe striatal specific neuronal, nepo NfL inobata kukuvara kwakakura kwe neuronal axonal. Uye patakanyatsotarisa kurongwa kwechirwere, saka ndakataura nezvekuti cohort yaive sei chikamu che zero mune imwe isati yasvika sainzi yekiriniki patakaita ma curve e receiver operator kuti tione kunzwisisika kwePENK. Taienzanisa kuti tione kana CSF PENK yakafanana kana kuti inogona kupfuura NfL mukusiyanisa pakati pezvikamu zviviri izvi. Uye tinoziva kuti chikamu chekutanga chinotsanangurwa neuchapupu hwe striatal kana kubatanidzwa, kuronga kurasikirwa kwe putamen atrophy.

Saka zvaizova nyore kunzwisisa kuti ma biomarker akapfuma sePENK anogona kukodzera shanduko iyi. Uye kunyange zvazvo patakazviita, takaratidza kuti PENK yaive nani kupfuura NfL mukusiyanisa danho rekutanga kubva padanho rezero. Uye [00:14:00] pawakabatanidza ma biomarker ese ari maviri, pakava nekuvandudzika kudiki mukuita uku kwekusarura.

Saka ndinofunga kuti zvakazara, ndinofunga kuti chimwe chezvinetso zvikuru muHD ndechekuti, panguva iyo zviratidzo zvekufamba kwemuviri zvinoonekwa, panogona kunge paine kurasikirwa kukuru kwetsinga dzemuviri, uye kana pasina zviratidzo zvekiriniki, semuenzaniso, padanho re zero nerekutanga, kutarisa chirwere kunoenderana nematanho ekuongorora emuviri chaiwo.

Ndipo panopinda ma biomarkers e biological ne neuroimaging. PENK ine mukana wakanyanya panyaya iyi nekuti inoratidza striatal neuronal integrity uye inogona kufanotaura remangwana striatal atrophy. Ndinofunga kuti NfL nePENK pamwe chete zvinopa mhando yehunhu uye mufananidzo we biologically wekuchinja uku kwekutanga kwechirwere cheHuntington kuri kudzoka.

Dr. Eduardo de Pablo-Fernandez: Izvi zvinotisvitsa kumubvunzo wangu unotevera. Saka ndinonzwisisa kuti nzira yekuongorora masero yeHuntington's, kufambira mberi pakati pedanho re zero kana pasina kuonekwa kwe [00:15:00] neurodegeneration uye danho rekutanga kana pasina zviratidzo asi humbowo hwekuora kwemasero, uku ndiko kushandiswa kwakaratidzwa kazhinji neMRI uye kunzwisisa kwangu ndekwekuti hazvisi izvo biomarkers zvinosanganisirwa muhurongwa uhwu hwekuongorora masero. Saka maererano nemiedzo yekiriniki yeramangwana, unofunga sei mhedzisiro yekudzidza kwako uye mune biomarkers dzakawanda paNfL neproenkephalin nedzimwe biomarkers dzinogona kunge dzakanyorova, unofunga kuti dzichabatsira sei pakugadzirwa kwemiedzo yekiriniki? Unoona sei kuti mhedzisiro yako ichashandiswa munguva pfupi iri kutevera?

Dr. Mena Farag: Mubvunzo wakanaka chaizvo. Kubva pakuronga dhizaini yekuedza kwekiriniki yekudzivirira mune ramangwana uye sezvamunotaura, zvinodiwa zveHD ISS zviripo hazvisanganisire ma biomarkers emvura. Saka ndinofunga kuti pamwe mukana wekuwedzera zvinodiwa zveHD ISS zvedanho re zero uye rimwe kusvika patingangosanganisira.

Zvishandiso zveWet biomarkers zvakaita sePENK neNfL kuti zviwedzere kupatsanura nekupatsanura danho zero [00:16:00] zvinogona kubatsira. Uye kubva pakugadzira bvunzo yekudzivirira ine mitemo yakagadziriswa uye

Neruzivo rwakawanda rwezvibodzwa izvi, tinogona kunge tiine ruzivo rwakakura mumatanho ekuongorora izvo zvinogona kubatsira pakutsvaga vanhu vanoedza mishonga yekiriniki. 

Dr. Eduardo de Pablo-Fernandez: Zvakanaka kwazvo. Ehe. Uye ndinofunga munguva pfupi yapfuura nhau dzasvika kwavari. Ini nevezvenhau vazhinji tinofunga kuti chirwere cheHuntington maererano nekudzivirira uye izvi zviri kugadzirisa miedzo yekiriniki pamwe zviri pamberi pezvimwe zvezvirwere zvekufamba kwetsinga zvine maitiro ekurapa majini nezvimwe zvidzidzo zvakaburitswa kusvika pari zvino. Mubvunzo wangu chete, unofunga kuti ramangwana remiedzo yekiriniki muchirwere cheHuntington riri kuenda kupi? Uye unoona sei mhedzisiro yako ichizivisa izvi? Uye unofunga kuti chii chichava chinhu chinotevera chinokosha mukurapa kweHuntington?

Dr. Mena Farag: Ehe, chirwere cheHuntington, nzira dzekurapa dzakawedzera zvakanyanya mumakore mashanu kusvika gumi apfuura. Nzira dzakasiyana siyana. Saka kunze kweHuntington kuderedza, kune ma splicing modulators. Kune kurapa kwemajini ehutachiona, uye zvimwe, munguva pfupi yapfuura somatic CAG repeat expansion iri chinangwa chekurapa kwezvirwere sezvazviri kuitwa.

Ndinofunga kuti kunyangwe miedzo yekiriniki iripo iri muchikamu chechipiri, mimwe iri muchikamu chekutanga, ndinofunga kuti chinangwa netariro zvichave zvekuti mapurogiramu aya awedzere kusvika muchikamu chechitatu chemiedzo zvichienda mberi. Uye ndinotarisira kuti miedzo inochinja chirwere ichi iwane mvumo kuburikidza nemasangano anotonga. Asi ndinofunga kuti kunyangwe zvese zviri kuitika kufunga nezvekugadzira miedzo yekudzivirira mune ramangwana zvakakosha.

Kana tichida kuedza kudzivirira kana kuderedza kufambira mberi kwechirwere mumapoka asina zviratidzo uye asati aratidza zviratidzo, sevanhu vari muchikamu cheHD ISS zero ne1. Uye ndinofunga kuti tiite matanho ekuita izvozvo. Ndipo pakakosha zvidzidzo zvekutarisa zvenguva refu [00:18:00], sekudzidza kwevechidiki nekuti kuitira kuti masangano anotonga agamuchire zviratidzo zvebiomarkers senzvimbo dzekupedzisira dzinofanirwa kuonekwa sedzinogona kufanotaura zvakanakira zvekiriniki.

Uye. Paunofunga nezvematanho ekutanga aya, magumo ekiriniki echinyakare akadai se, composite UHDRS, iyo iri kushandiswa parizvino semagumo. Mumiedzo yekiriniki yedanho rechipiri nerechitatu miedzo iyoyo haisi iyo magumo ayo haana basa padanho re zero nerekutanga kana pasina zviratidzo zvekiriniki.

Saka ndipo panonyanya kukosha zviratidzo zve biomarker zvakaita se biofluid, biomarkers uye neuroimaging markers. 

Dr. Eduardo de Pablo-Fernandez: Ndatenda zvikuru. Ndinofunga kuti inzvimbo yakanaka kwazvo yekutsvaga chirwere cheHuntington mumakore anotevera. Ndatenda zvikuru Mena nenguva yako nhasi, ndaive naMena Farag kubva kuUCL queen Square Institute of Neurology muHuntington's Disease Center.

Ndinovimba muchawana podcast iyi inonakidza uye ndinokurudzira vaverengi vese [00:19:00] kuti vaverenge bepa rese rakaburitswa muMovement Disorders Journal. Sarai zvakanaka izvozvi.

Dr. Mena Farag: Ndatenda. [00:20:00]