Tšoaro ea kotsi ea ho becha le ea patholo ea lefu la Huntington (2014)

Carla Kalkhoven¹, Cor Sennef¹, Meetso ea Ard¹ 'me Ruud van den Bos^2*

• ¹Chardon Pharma, Herpen, Netherlands
• ²Lefapha la Fisiks ea Liphoofolo ka Tlhaho, Lefapha la Saense, Radboud University Nijmegen, Nijmegen, Netherlands

Lefu la Huntington (HD) ke lefu la tlhaho, le amanang le lefu la neurodegenerative, le amang ka ho toba methapo ea methapo ea kutlo e sa lebelloang, e bakang ho fokotseha ho tsoelang pele ha tšebelisano ea mesifa le tahlehelo ea taolo ea maikutlo le kelello. Ho khahlisang, ho tseba esale pele ho ts'oaroa hoa marang-rang le litheko tse ling ho kenyelletsa pherekano makaleng a tšoanang a cortico a amanang le HD, 'me a bonts'a matšoao a amanang le disinhibition, ho kenyelletsa le maikutlo a fetotsoeng a likotlo le meputso, ho hloka matla le ho se nahane ka melemo ea nako e telele. mabapi le meputso ea nako e khuts'oane. Ka bobeli bakuli ba HD le ba betšang ba pathological le bona ba bonts'a bofokoli bo ts'oanang ba ts'ebetso mesebetsing e kotsi e nkang liqeto, joalo ka Iowa Gossip Task (IGT). Lintho tsena tse tšoanang li fana ka maikutlo a hore bakuli ba HD ke sehlopha se ka bang kotsing ea ho becha. Leha ho le joalo, mathata a joalo a bile teng ka tšohanyetso ho bakuli ba HD. Thutong ena, re ikemiselitse ho supa kotsi ea ho becha ha methapo ea methapo ho HD, le mekhoa e ka tlas'a methapo ea kutlo. Haholo-holo ka ho phahama ha hona joale ha menyetla ea ho becha ea inthanete e fumanehang habonolo, ho bohlokoa ho utloisisa likotsi tsena le ho fana ka tšehetso e loketseng ea mokuli ka ho loketseng. Ho latela sephetho sa neuropathological le boits'oaro, re fana ka tlhahiso ea hore bakuli ba HD ba kanna ba se be le tloaelo e eketsehileng ea ho batla likotsi mme ba qale ho becha, empa hore ba na le monyetla o moholo oa ho lemalla hang ha ba kenella liketsong tsa papali ea papali ea chelete. Ka hona, tsoelo-pele ea hona joale le ea nako e tlang ea menyetla ea papali ea chelete ea inthanete le bokhoba bo amanang le eona e lokela ho tsotelloa ka tlhokomelo, haholo-holo bakeng sa lihlopha tse tlokotsing tse kang bakuli ba HD.

Selelekela

Lefu la Huntington (HD) ke lefu le amanang le lefutso, le futsitsoeng ka mokhoa o atileng oa Autosomal. Lefu lena le tšoauoa ke matšoao a motor a tsoetseng pele, a boloi le a boitšoaro, a atisang ho bonahala lipakeng tsa lilemo tsa 30 le 50, 'me a lebisa lefung la pele ho nako lilemong tsa 10-20 kamora ho qala ha lefu. HD e bakoa ke phetoho ea mofuta oa Huntingtin (HTT), e lebisang ho ho eketseheng ha liprotheine, ho hlakoloa ha lits'ebetso tse 'maloa tsa sele, mme qetellong lefu la sele. Neuronal degeneration qalong e hlaha ka mokhoa o ikhethileng ho striatum (caudate nucleus le putamen), moo e amang litsela tsa cortico-striatal tse sebeletsang ho laola mesebetsi ea makoloi le ea kelello (Reiner et al., 2011; Vonsattel et al., 2011). Boemong ba makoloi, ts'ebetso ena e mpefatsang e hlahisoa e le mekhatlo e sa hlophisehang (chorea), le ha ba le maemong a kelello bakuli ba bontša "dysfunction syndrome", e kenyelletsa har'a ho se ts'oanehe, tlhahlobo e mpe ea kotsi le ho se khone ho emisa tsela e fosahetseng ea ketso (Hamilton et al., 2003; Duff et al., 2010b). Matšoao a tšoanang a boits'oaro le a kelello a bonoa ho boitšoaro bo lemalloang bo amanang le lintho kapa liketso (Newman, 1987; Rosenblatt, 2007; Iacono et al., 2008). Ka hona, ho ka lebelloa hore bakuli ba HD ba kotsing ea ho lemalla. Liphapang tsa ho etsa liqeto maemong a laboratori li hlile tsa khothaletsa bofokoli ba ho etsa liqeto tse kotsi ho bakuli ba HD ba tsoetseng pele (mohlala, Stout et al., 2001), mme papali ea chelete ea ho becha e 'nile ea bonoa ka tšohanyetso sehlopheng sena sa bakuli (De Marchi et al., 1998). Leha ho le joalo, liphumano tsena li fumaneha seoelo, 'me ho makatsang ke hore ke lithuto tse' maloa tse ileng tsa hlahloba matšoao le litlamorao tsa mohlala.

Thutong ena re tla pheha khang ea hore bakuli ba HD e ka ba sehlopha se kotsing ea ho theha papali ea chelete. Taba ea pele, papali ea chelete e nang le mathata e tšoauoa ka ho sitoa ha lithuto ho emisa ho becha le ha ho na le mathata a lichelete, a motho kapa a litsebi. Ho ipapisitse le likhathatso tsa methapo ea kutlo le matšoao a boits'oaro matla a ho emisa boitšoaro ba papali ea chelete a bonahala a fokotsehile kapa a le sieo ho bakuli ba HD. Taba ea bobeli, ka lebaka la maikutlo a lokolohileng mabapi le papali ea papali ea chelete ea ho becha le menyetla e eketsehang ea papali ea chelete ea molao le e seng molaong (bona mohlala ,. Griffiths, 2003), re ka lebella hore ho hlaha ha mathata a papali ea chelete ho tla eketseha lilemong tse tlang. Ho fihlella ho eketsehileng ho ka beha kotsi ho lihlopha tse tlokotsing, tse kang bakuli ba HD, tse sa kang tsa pepesetsoa likotsi tse joalo.

Ka kakaretso, ho fetola maemo a kantle le mekhoa ea kalafo e ka ba le litlamorao tse sa lebelloang le tse sa rateheng ho boitšoaro ba mokuli, haholoholo mafu a rarahaneng a methapo. Litholoana tse joalo li lahleheloa habonolo ha matšoao a boitšoaro a sa hlakoloe khafetsa. Sena se ka tšoantšoa hantle ke lefu la Parkinson, moo ho qalisoa ha kalafo ea lithethefatsi ka li-dopamine agonists ho lebisitseng ho tsitsipano ea taolo joalo ka papali ea chelete e khothalletsoang ea ho becha, ho ea mabenkeleng, ho ja, le khatello e matla ea maikutlo, e bakoang ke ho fetella hoa tsamaiso ea mesolimbic dopaminergic (Dodd et al., 2005; Witjas et al., 2012; Weintraub et al., 2013). Leha ho le joalo, litla-morao tsena ha lia ka tsa amoheloa ho fihlela lilemo kamora ho hlahisoa ha kalafo ea dopamine agonist hammoho le liphetoho tsa sechaba tse amanang le (ho fumaneha ha) mabenkele, tšebeliso ea lijo, thobalano, inthanete le papali ea chelete. Mohlala ona o bontša hore netefatso ea mabaka a kotsi e bohlokoa ho khona ho fana ka kalafo e sebetsang le tataiso ho bakuli ha ba le tikolohong e fetohang.

Mona, re tla hlahloba boemo ba lefu la HD mabapi le bokhoba, mathata a papali ea chelete, le bofokoli ba ho etsa liqeto. Karolong HD: Neuropathology, Matšoao le Tsoelo-pele, tsoelo-pele ea matšoao a HD e tla tšohloa mabapi le ho ferekana ho lipotoloho tsa cortico-striatal tse kenyelletsoang ho ithuteng mesebetsi, kutloisiso ea kotlo, le taolo ea kelello / tšusumetso. Karolong Ho nka menyetla ea ho beha kotsi le ho bapala papali ea kotsi ka HD, boemo ba neurobiological ba bakuli ba HD bo tla tšohloa maemong a papali ea papali ea chelete le liteko tse nkang likotsi le ho nka liqeto, joalo ka Iowa Gossip Task (IGT) le mosebetsi oa papali ea chelete ea Cambridge (CGT). Karolong Puisano, re tla tšohla kamoo tšobotsi ea likotsi tsa papali ea chelete e ka lebisang ho likeletso bakeng sa bakuli ba HD le bahlokomeli ba bona mabapi le mokhoa oa ho sebetsana le bothata bona le hore na ke maemo afe a ka thibeloang hamolemo. Re ikemiselitse hape ho tseba lipotso tse e-so arabe, tse ka bang mohato oa ho qala lipatlisiso tsa nako e tlang mabapi le ho hlaha le likotsi tsa mathata a papali ea chelete ho bakuli ba HD.

HD: Neuropathology, Matšoao le Tsoelo-pele

Mechanisms ea Maloetse a Mafu a Neurobiological

HD e bakoa ke phetoho e sa tsitsang ea CAG (trinucleotide; cytosine-adenine-guanine) seterekeng sa coding sa mofuta oa HTT, se lebisang tlhahiso ea protheine ea hutantin (Htt) e atolositsoeng ea polyglutamine (polyQ) e atolositsoeng (MacDonald et al., 1993). Palo ea makhetlo a phetisetso ea trinucleotide e amana hantle le lilemo tsa ho qala ha lefu (Snell et al., 1993; Stine et al., 1993). Boholo ba bakuli ba HD bo na le pheta-pheta ea 40-55 e bakang khatello e tloaelehileng ea ho qala ha batho ba baholo, ha ho phetoa ho hongata ho feta ha 70 ho lebisa bothateng ba ho qala ho ba mocha. Batho ba nang le lipalo tse ka tlase ho 35 CAG ka mofuta oa HTT ba ke ke ba nts'etsapele HD. Leha lits'ebetso tse nepahetseng tsa pathogenesis ea HD li lula li sa tsejoe ebile li sa khone ho tšohloa mona ka botlalo, li kenyelletsa ho etsoa ha liprotheine tse kopantsoeng le polyQ e atolositsoeng HT, hammoho le tšebelisano ea phetoho ea phetoho ea phetoho ea liprotheine tse ngata tse nang le protheine ea matla, protheine le vesicle lipalangwang, le molaoana oa tlhaiso ea liphatsa tsa lefutso (Li le Li, 2004; Jones le Hughes, 2011). Phapang e bakoang ke ts'ebetso ea methapo ena ea cellular qetellong e lebisa ho senyeha ha neuronal ka mekhoa e amang thabo le apoptosis.

Neuronal degeneration e qalile e lekanyelitsoe ho basal ganglia, moo li-neurons tse mahareng tsa "spinyatum" ("caudate nucleus" le "putamen") li amehang ka kotloloho (Vonsattel le DiFiglia, 1998; Kassubek et al., 2004). Striatum e fumana tlhahiso ea eona ea mantlha ea thabo (glutamatergic) e tsoang libakeng tsa cortical, ha e ntse e fumana dopaminergic ea eona e tsoang ho substantia nigra. Striatum e na le liphetho tse peli tsa mantlha tsa thibelo (GABA-ergic): tsela e tobileng le e sa tobang (Setšoantšo. 1A). Li-neuron tsa "striatal neurons" tsa projeke ea tseleng e eang ka kotloloho ho ea ka hare ho globus pallidus (GPi), eo le eona e nang le moelelo oa thibelo ho thalamus. The thalamus e etsa hore ho be le mohopolo o ka sehloohong oa thabo. Kahoo, ts'ebetso ea ts'ebetso ea "striatal pathway" e sitisang ts'ebetso ea GPi, e tla sitisa ts'ebetso ea thalamocortical, ka ho etsa joalo e tsamaise motsamao le mesebetsi e hlokolosi. Tsela e sa tobang ea ka kotloloho, ka lehlakoreng le leng, e qala ho GP (GPe), eo ka nako e 'ngoe e romellang merero ea inhibitory ho subthalamic nucleus (STN). STN e romela likhakanyo tsa thabo ho GPi. Ka hona, ts'ebetso ea tsela e sa tobang ea litoro ka tsela ena e hlakola STN, e e lumella ho kenya tšebetsong GPi, eo ka nako e emisang ts'ebetso ea thalamocortical, e hatellang motsamao le mesebetsi ea kelello. Boitšoaro bo feteletseng bo hlaha ho latela (tekeniki) ea ts'ebetso tseleng e ka kotloloho le e sa tobang. Pathology tseleng e sa etsoang ka kotloloho ke senotlolo ho HD mme e sitisa botsitso tsamaisong ea striatal e lebisang ho tahlehelo ea taolo ea thibelo mabapi le ts'ebetso ea motor le boits'oaro (Setšoantšo. 1B; Albin le al., 1989; Alexander le Crutcher, 1990).

 

Setšoantšo sa 1. (A) Morero o hlophisitsoeng oa mokhatlo o hlophisitsoeng oa marang-rang a cortico-basal ganglia (libaka tsa cortical, striatal, pallidal le thalamic) tse bonts'ang litsela tse otlolohileng le tse sa tobang ka bokong bo tloaelehileng. (B) Ho hlepha ha tsela e sa tobang (X) ho HD ho lebisa ho fokotseheng ha taolo ea inhibitory holim'a mesebetsi ea cortical. GPe: globus pallidus ea ka ntle; GPi: globus pallidus ea ka hare; STN: subthalamic nucleus. Red: inhibitory (GABA) tsela, Blue: litsela tsa thabo (glutamate).

Li-circuits tsa Cortico-basal ganglia, likhokahanyo tse akaretsang pakeng tsa libaka tsa cortical, libaka tse nang le mapheo, libaka tsa pallidal le libaka tsa thalamic, li hlophisitsoe ka mokhoa o ts'oanang oa ho tšehetsa mesebetsi e fapaneng mokhatlong oa boitšoaro. Ha ho buuoa ka litlhahlobo tse ngata tse ntle holima boiphihlelo le tšebetso ea lipotoloho tsena (mohlala, Alexander et al., 1986, 1990; Alexander le Crutcher, 1990; Yin le Knowlton, 2006; Verny et al., 2007; Yin et al., 2008; Haber le Knutson, 2010; Sesack le Grace, 2010), re totobatsa lintlha tse 'maloa feela tse loketseng tlhahlobo ea rona. Taba ea pele, ho buuoa ka mokhoa o hlakileng oa ho etsa hore batho ba hlophisehe ka libaka tse fumanehang libakeng tse haufi. Kahoo, libaka tse ka pele tsa dorsal li amahanngoa le libaka tse qabolang tsa dorsal ha libaka tse tlang pele li kenella kahare ho libaka tse amanang le sebaka sa bolulo (ho kenyeletsoa le li-nucleus accumbens). Taba ea bobeli, ho ka hlalosoa ka ho pharaletseng mekotla e meraro e fapaneng. Potoloho ea sensorimotor e akaretsa sensorimotor striatum (putamen) le li-cortices tsa sensorimotor tse amanang le ho bolaoa hoa boitšoaro ba makoloi. Potoloho ea taolo ea "Associative / cognitive control" e kenyeletsa "cortex" ea dorsolateral pele, cterex ea anterior le cortex e amanang le eona. Potoloho ena e bohlokoa haholo ts'ebetsong ea botsamaisi, ke hore, e kenella taolong ea kelello, ho rera le ho hopola mohopolo. Ntle le moo e kenyelletsa ho ntšetsapele boitšoaro ba nako e telele bo feto-fetohang ka ho tiisa kapa ho emisa (ho otla) boitšoaro ba sebapali, ke ho re, tatelano ea liketso tsa boits'oaro, e ithutoang ka ho sebelisana le tikoloho (Kravitz et al., 2012; Paton le Louie, 2012). Potoloho ea limbic e kenyelletsa cortex ea orbitof Pambal, cortex ea ventromedial prefrontal, amygdala, le limbic striatum (nucleus accumbens). Potoloho ena e bohlokoa haholo ho hlahloba boleng bo amanang le tšusumetso, ho supa moputso kapa kotlo e lebelletsoeng ea khothatso e tlang, khetho kapa ketsahalo, taolo ea maikutlo, le ho ithuta ka maikutlo (maikutlo) (O'Doherty et al., 2001; Rushworth et al., 2007; van den Bos et al., 2013b, 2014).

Pathology ka HD e bonoa ho mothong o mong oa putamen le caudate (Vonsattel le DiFiglia, 1998; Kassubek et al., 2004; Vonsattel, 2008; Vonsattel et al., 2011; Hadzi et al., 2012). Ntle le moo, atrophy ea mekhahlelo ena ka bobeli e latela mokhoa oa sebopeho, ho qala libakeng tsa kahare le tsa mahoatata le ho leba libakeng tse kenang kahare le tsa lefu lena ha lefu le ntse le tsoela pele (Vonsattel le DiFiglia, 1998; Kassubek et al., 2004; Vonsattel, 2008). Leha ho le joalo atrophy ea pele ho nako e boetse e bonoa ho li-nucleus accumbens le globus pallidus lithutong tse ling (van den Bogaard et al., 2011; Sánchez-Castañeda et al., 2013). Ha likhathatso potolohong ea sensorimotor (putamen) li kanna tsa amana le matšoao a koloi, likhathatso tse tsamaeang le "cquitive control circ" (caudate nucleus) li ka amana le ho se sebetse hantle, 'me tsa baka khaello ho mohlala, ho hopola memori ho bakuli ba pele ba HD (Lawrence et al., 1996; Bonelli le Cummings, 2007; Wolf le al., 2007). Mathata a ho potoloha hoa litho tsa 'mele, joalo ka ha a qalile ka nako ea bokhoni ba nyutlelie, a ka amana le ho hloka thahasello le khatello ea maikutlo (Bonelli le Cummings, 2007; Unschuld et al., 2012). Ho atoloha ho tsoelang pele ha striatum ho ka lebisa ho se sebetse hantle hoa lipotoloho tsa cortico-striatal. Mohlala, khubu ea "ventral caudate" le eona ke karolo ea potoloho ea orbitofrontal, e amehang ha bokuli bo ntse bo tsoela pele. Ho se sebetse hantle ha potoloho ena ho amana le boitšoaro bo sa sebetseng (Bonelli le Cummings, 2007). Qetellong, bofokoli bo ka fetela libakeng tse ling tsa boko, ho kenyelletsa le likarolo tse ling tsa basal ganglia (libaka tsa pallidal le thalamus), hippocampus, amygdala le cortical maemong a morao a lefu lena.

Ka kakaretso, HD e tšoauoa ka bofokoli bo khethehileng ba methapo ea kutlo e tsamaeang tseleng e sa tsejoeng. Ha lefu lena le ntse le tsoela pele, atrophy ea striatum e ntse e phahama hammoho le mahlaseli a potoloho ea cudico-drial le dorsal-ventral. Tahlehelo ea taolo ea inhibitory makaleng ana e amana ka kotlolloho le matšoao a boloi, a kelello le a boits'oaro ho HD, joalo ka ha ho hlalositsoe ka tlase.

Matšoao a HD

HD e tšoauoa ka matšoao a fapaneng a tsoetseng pele a koloi, tlhalohanyo le boits'oaro. Matšoao a pele hangata a hlaha lilemong tse mahareng, ka nako ea ho qala ea 40, leha palo e nyane ea bakuli e na le lefu la HD le sa qalang, le qalang pele ho lilemo tsa 20. Ha matšoao le tsoelo-pele ea HD ea bongoana li fapane ka tsela e fapaneng le lefu la ho qala ho ba batho ba baholo, re tla tsepamisa maikutlo ho sehlopha sa morao-rao sa bakuli litekong tsena. E 'ngoe ea matšoao a pele a ho totobala ho HD ke chorea (ho hloka boikhathatso ho sisinyeha ha mokokotlo),' me tlhahlobo ea bongaka hangata e etsoa kamora ho qala ha mahlaba a pelehi (Shannon, 2011). Leha ho le joalo, lithuto tse ling li tlaleha liphetoho tse poteletseng le tse nang le maikutlo pele ho matšoao a koloi, 'me tatellano ea tatellano ea liketsahalo le HD e ntse e tsoela pele. Leha ho le joalo, litlhahlobo tse 'maloa tse phethahetseng tsa lipontšo tsa kliniki tsa HD li fumaneha (Roos, 2010; Anderson, 2011; Shannon, 2011).

Matšoao a koloi

Matšoao a koloi a qala ho totobala methating ea pele ea HD, 'me hangata ke matšoao a pele a lokelang ho bonoa maemong a laboratori le ke beng ka motho oa pele oa bakuli ba HD (de Boo et al., 1997; Kirkwood et al., 1999, 2001). Ho ferekana ha koloi ho bonahala ho qala e le ho se sebetse ka taolo ea phoso ea karabo (Smith le al., 2000), e tsamaellanang le karolo ea potoloho ea makoloi ea cortico-striatal ho ithuta le taolo ea sensorimotor (Graybiel et al., 1994). Matšoao a pele a tlhekefetso ea makoloi hangata ke metsamao e poteletseng ea mohlala, mesifa ea sefahleho, menoana le menoana ("ho choachoha"), hyperreflexia, le metsamao e feteletseng ea boithaopo (Young le al., 1986; Shannon, 2011), e lebisang ponahalong e akaretsang ea ho hloka botsitso le ho ts'oareha ho bakuli ba pele ba HD. Ts'ebetso ena e sa sebetseng e ea utloahala ebile hangata ha e hlokomeloe qalong, empa butle-butle ea mpefala le ho fetela ho mesifa e meng kaofela ha nako e ntse e tsamaea. Matšoao a mang a koloi ea pele e kenyelletsa ho sisinyeha ha mahlo ha a lieha kapa a lieha ho tsamaea.Peltsch et al., 2008) le dysarthria (Ramig, 1986; Young le al., 1986). Dysarthria, bothata ba puo, bo etsa hore ho be thata ho bua ka ho hlaka le ho tsitsisa ha mantsoe, e leng ho etsang hore ho be thata haholo ho utloisisa puo. Dysphagia (mathata a ho koenya) e bonoa ho bakuli ba bangata ba nang le ho qala ha methapo ea mafu a mahareng, 'me butle-butle e mpefala ho fihlela bakuli ba se ba sa khone ho ja ba sa elelloe' me hangata ba hloka lesapo la phepelo ka morao ho sethala sa HD (Heemskerk le Roos, 2011). Matšoao a mang ao e seng a choreic motor a atisang ho bonahala hangata ho lefu la methapo e kholo a kenyelletsa ho rarahana ho rarahaneng, ho se tsitse ha pelo, le dystonia.Koller le Trimble, 1985; Tian et al., 1992; Louis et al., 1999; Grimbergen et al., 2008). Rigidity le bradykinesia (ho lieha ho sisinyeha le ho sisinyeha) ka linako tse ling li bonoa, empa li na le meeli feela ho linyeoe tsa ho qala ha bana ba HD (Bittenbender le Quadfasel, 1962; Hansotia et al., 1968). Matšoao ana a motor a tsamaisana le ho se sebetse ha sensorimotor (le Associative / cognitive control) li-circuits tsa cortico-striatal tse atisang ho ameha ho HD.

Matšoao a boitšoaro le a kelello

Mathata a amanang le boitšoaro ho HD a ka ba thata mme a thatafalloa ho a khetholla, mme ketsahalo ea bona le ho qala ha bona li fapana haholo pakeng tsa batho. Ho feta moo, ka linako tse ling ho ka ba thata ho khetholla mathata a boitšoaro ho fapana le ho sebetsana ka katleho le lefu le sithabetsang (Caine le Shoulson, 1983). Palo ea lithuto tse bonts'itseng matšoao a boitšoaro ho HD e lekanyelitsoe, 'me ka lebaka leo, ha ho na kutlwisiso e ngata ho ateng ha bona ho lefu lena (van Duijn et al., 2007). Matšoao a tloaelo le a tlalehiloeng khafetsa a hlahang khafetsa ho HD ke ho hloka kutloelo-bohloko, ho hloka thahasello le khatello ea maikutlo, tse bang teng ka bongata ba hoo e ka bang 50% (Caine le Shoulson, 1983; Folstein le Folstein, 1983; Craufurd et al., 2001; Kirkwood et al., 2001; van Duijn et al., 2007, 2014; Tabrizi et al., 2009). Ka linako tse ling ho khopisa le ho hloka thahasello ka linako tse ling ho bonoa ho bakuli ba HD ba hlahileng pele (HD).Tabrizi et al., 2009; van Duijn et al., 2014), hape le khatello ea maikutlo e tlalehiloe mehatong ea kliniki ea pele (Shiwach, 1994; Julien et al., 2007; Epping et al., 2013). Matšoao ana a amanang ke a mang a matšoao a pele a seng koloi ho bonoa ke ba lelapa la pele.Kirkwood et al., 2001). Matšoao a amanang le ho hloka thahasello a tloaelo, ao butle-butle a mpefang nakong ea lefu lena, a kenyelletsa ho hloka matla, ho susumetsa le ho nka khato, ho fokotsa mamello le boleng ba mosebetsi, kahlolo e fosahetseng, ho itlhokomela le ho se amehe maikutlong (Craufurd et al., 2001; Kirkwood et al., 2001). Matšoao a sithabetsang a amana le ts'ebetso e eketsehileng ea cortex ea ventromedial prefrontal cortex (Unschuld et al., 2012). Ho teneha ho amana le ho se sebetse hantle ha potoloho ea potoloho, e lebisang taolong e fokotsehileng ea likarabo tsa maikutlo ho amygdala (Klöppel et al., 2010).

Tse ling, matšoao a kelello le mathata a sa tsotelleng a HD ke matšoenyeho, ho se sebetse hantle, khatello ea kelello, matšoao a kelello a amanang le kelello, a kang paranoia, hallucinations le ho qhekella (Caine le Shoulson, 1983; Folstein le Folstein, 1983; Craufurd et al., 2001; Kirkwood et al., 2001; van Duijn et al., 2007). Hangata matšoao ana ha a etsahale ho fihlela mekhahlelo ea mafu a mahareng kapa ea morao, leha ho le joalo ho tlalehiloe hore e etsahala ho bakuli ba HD ba sa lebelloang (Duff et al., 2007). Boloetse bo qobellehang bo fetelletseng bo amahanngoa le tšenyo ea orbitofrontal cortex le anterior cingrate cortex, ha schizophrenia, bokuli bo kenyelletsang khaello ea ho hlophisa, ho rera le ho ela hloko, bo amana le dorsolateral prefrontal cortex dysfunction (Tekin le Cummings, 2002).

Ho khothalletsoa hore matšoao a kelello a HD hangata ke karolo ea "frontal lobe syndrome" kapa "dysfunction syndrome", e kenyeletsang matšoao a kang ho hloka thahasello, ho se tsikinyehe, ho hlaka, ho hloka matla, ho tsila-tsila, le ho tiisetsa (Lyketsos et al., 2004; Rosenblatt, 2007), tseo kaofela li bonoang hangata ho bakuli ba HD (Hamilton et al., 2003; Duff et al., 2010b). Ha ho tsamaisoa hammoho, lingoliloeng li bonts'a hore ho qaleha le ho eketseha hoa matšoao a boitšoaro ho HD ho bohlokoa haholo, ka mathata a amanang le mathata a hlahang khafetsa le ka ho qaleha ha nako, athe ho tšoenyeha, pherekano e fokolisang mahlo le matšoao a kelello ha a sa tloaeleha mme hangata a hlaha hamorao ho lefu lena. . Matšoao ana a kelello a amahanngoa le ho se sebetse hantle ha lipotoloho tsa maoto le tsa "cortitive" tse tsamaeang le methapo.

Matšoao a kelello

Ho fokotseha hoa kelello ke karolo e 'ngoe ea bohlokoa ea lefu lena la HD. Boithuto bo bongata bo shebile ka kotloloho ho hlaha hoa matšoao a ho lemoha maemong a pele le a pele a kliniki a HD, ka tšepo ea ho fumana li-biomarkers tsa bongaka tsa lefu lena (tse hlahliloeng ho Papp et al., 2011; Dumas et al., 2013). Ka kakaretso, liphetho li fana ka maikutlo a hore liphetoho tse hlakileng tsa kelello li ka bonoa ho fihlela lilemo tsa 5-10 pele ho matšoao a koloi ka mekhoa e hlokolosi e lekaneng. Phuputso e 'ngoe e bile ea fumana hore, maemong a HD a kalafo ea pele le e potlakileng ea HD, hoo e ka bang 40% ea bakuli ba se ba ntse ba fihlella mokhoa oa ho senyeha hoa kelello (bothata bo amanang le tahlehelo e fokolang ea mohopolo, ba sa fihlelleng litekanyetso tsa ho fumana lefu la' dementia '; Duff et al., 2010a). Leha ho le joalo, ha se lithuto tsohle tse tšehetsang liphetho tsena (Blackmore et al., 1995; Giordani et al., 1995; de Boo et al., 1997; Kirkwood et al., 2001). Ka kakaretso, lingoliloeng li lumela hore ts'ebetso ea tlhahisoleseling le lebelo la psychomotor li ameha haholo sethaleng sena sa pele (Rothlind et al., 1993; Kirkwood et al., 1999; Verny et al., 2007; Paulsen et al., 2008). Lits'oaetso tse ling tse atileng ho bonoa hangata tsa ts'ebetso ea kelello li kenyelletsa mathata a tlhokomelo, (ho sebetsa) memori, le ts'ebetso ea pono (Jason et al., 1988; Rothlind et al., 1993; Foroud et al., 1995; Lawrence et al., 1996; Hahn-Barma et al., 1998; Verny et al., 2007; Paulsen et al., 2008; Tabrizi et al., 2009; Papp et al., 2011; Stout et al., 2011). Ho feto-fetoha ha kelello ho hlokometse ho bakuli ba mafu a pele (Jason et al., 1988), eo maemo a fetohang ka mokhoa o fetelletseng a senyehileng ka kotloloho, athe thuto e khutlisetsang morao e ntse e eme hantle (Lawrence et al., 1996). Ka hona, bakuli ba ntse ba khona ho lekola boleng ba ntlafatso hape ba ithuta maemo a macha a meputso a khothatsang ka mokhoa o tšoanang (mohlala, sebopeho kapa mmala), empa ba na le mathata a ho lebisa tlhokomelo ea bona boemong bo fapaneng (mohlala, ho tloha ho 'mala ho ea sebopeho) joalo ka ha ho hlokahala ka molao o mocha oa ho fumana moputso. Mehatong ea morao ea lefu lena, ho ba le tsebo ea kelello ea ho feto-fetoha le maemo le mamello le tsona li baka ho feto-fetoha ha maikutlo ho pheta-pheta ho bakuli ba HD (Josiassen et al., 1983; Lange et al., 1995). Tsoelo-pele ena ea matšoao e lumellana le ho se sebetse hantle ha potoloho ea methapo ea methapo pele ho lefu lena, hobane ho feto-fetoha ha boemo bo fetelletseng ho hokahanngoa le cortex ea dorsolateral pele, ha ho ithuta ka morao-rao ho tsamaisana le orbitofrontal cortex (Dias et al., 1996; McAlonan le brown, 2003). Lits'oaetso tse ling tsa pele li kenyelletsa boitšoaro bo sa hlophisehang, moralo o sa senyeheng, kahlolo e mpe, le boitšoaro bo fokotsehileng boits'oarong le maikutlong (Watkins et al., 2000; Paradiso et al., 2008; Duff et al., 2010b). Disinhibition e bonoe ho bakuli ba pele ba HD, bao ts'ebetso ea bona e sitisoang ke mesebetsi e hlokang ho sitisoa ha likarabo tse matla empa tse sa lokang (Holl et al., 2013). Kamora nako, liphuputso tse 'maloa li fumane hore bakuli ba HD ba sa tsotelleng ba haelloa ke ts'ebeliso ea maikutlo a mabe a kang bohale, manyala, tšabo le masoabi. Boemo ba maikutlo bo fokotseha hanyane ka hanyane, 'me bo ka fetela ho mathata le maikutlo a sa jeleng paate methating ea kliniki ea lefu lena (Johnson et al., 2007; Tabrizi et al., 2009; Labuschagne et al., 2013). Mokhoa ona oa phenotype o amana le ho se sebetse hantle ha orbitofrontal cortex, e amehang ho sebetsanang le tlhahisoleseling ea maikutlo le moputso (Henley et al., 2008; Ille et al., 2011).

Boithuto bo nang le mefuta ea liphoofolo tsa HD bo bonts'a ho senyeha ho tšoanang hoa kelello ho ba hlokometsoeng ho bakuli ba batho. Leha e se lithuto tsohle tse fumanang bofokoli bo matla ba kelello (Masimong et al., 2012), liphetho tsa mofuta oa rat le "mouse" li kenyelletsa ho tšoenyeha, ho arabela ka mokhoa o nyarosang oa maikutlo a mabe le ho senyeha ha ho ithuta hape le ho fetoha hoa leano (Faure et al., 2011; Abada et al., 2013). Phuputso e 'ngoe e fumane bofokoli bo khethehileng ba ho ithuta ka morao-rao pele matšoao a koloi a qala ho mofuta oa litekanyetso tsa HD (Fink et al., 2012). Ho khahlisang, liphoofolo tsa HD li bonahala li e-na le karabelo e eketsehang maikutlong a fosahetseng, ha bakuli ba batho ba bonts'a ho fokotseha ha maikutlo a mabe. Hajoale ha ho hlake hore na sena se bontša phapang ea tšebetso e etsoang (ho lemoha maikutlo khahlano karabelo ea boits'oaro ho tshusumetso e tsosang), phapang e amanang le mefuta ea liphoofolo sephethong sa pathology kapa phapang ea mantlha lipakeng tsa mohlala oa rat le boemo ba motho. Ka kakaretso, liphuputso tse entsoeng ho bakuli ba batho le mefuta ea liphoofolo tsa HD li bonts'a hore mefuta e mengata ea ts'ebeliso ea kelello e se e ka senyeha ho pele ho HD. Boitšoaro ba pelehi bo kenyeletsa ho haella ha kelello, ho hopola, ho fetoha le maemo, le ho amohela maikutlo. Mothating ona oa pele, hangata bakuli ba na le tsebo e fokolang ea bokhoni ba bona ba ho fokotseha (ho theoha)Hoth et al., 2007). Ha nako e ntse e tsamaea, matšoao a boloi a ntse a mpefala le ho feta, a qetella a lebisa ho ho fokola ha kelello 'meleng maemong a morao a lefu lena. Le ha ho ba teng hoa matšoao hangata ho tsamaisana le ho senyeha hoa taolo ea li-circuits tsa "Associative / ccinitive control" le "limbic cortico-striatal circuits", ka ho tšoanang, mesebetsi e ikhethileng e amanang le potoloho ea maoto le eona e ka se ameha qalong-mohato oa HD.

fihlela qeto e

Matšoao a motor, boits'oaro le boits'oaro ho HD a ithutoe haholo nakong e fetileng, mme a tsoela pele ho ba sehlooho sa lithahasello ka lebaka la phapang e fapaneng le phapang ea ho hlaha le matšoao a tsona ho bakuli. Ka kakaretso, matšoao a boits'oaro le a kelello a amana le likarolo tse tharo tsa boitsoaro bo ka pele: ho hloka thahasello, ho se sebetse hantle, le ts'oaetso. Ho kopanya matšoao ana ka linako tse ling ho thoe ke "dysfunction syndrome". Matšoao ana kaofela a amana le bofokoli mokokotlong oa cortico-striatal o kenyang orbitof Pambal cortex, dorsolateral prefrontal cortex le anterior cingrate cortex. Joalokaha ho tšohliloe ka holimo, lithuto tsa neuropathological li hlokometse ho theoha butle butle ha boemo ba methapo ho leba kahare ho bakuli ba HD. Leha litlhahlobo tsa boits'oaro le tlhaiso-leseling li lumellana le ho senyeha ho tsoelang pele ha lipotoloho tsa cortico, matšoao a phello a bonahala a ferekanya haholo ho feta kamoo ho lebelletsoeng ho ipapisitse le tlhahlobo ea methapo ea kutlo. Ts'ebetso le tsoelo-pele ea matšoao a boits'oaro le a kelello ho HD li na le mathata a mangata, e leng se bonts'a hore tšenyo e bakoang ke litereke e ka fetoha ka ho fetesisa le ho atoloha mehatong ea pele ea HD ho feta kamoo ho neng ho hopotsoe pele. Pono ena e tšehetsoa ke bopaki bo tsoang lipatlisong tse 'maloa tsa ho nahana ka sebopeho (Thieben et al., 2002; Rosas et al., 2005; van den Bogaard et al., 2011).

Ho nka menyetla ea ho beha kotsi le ho bapala papali ea kotsi ka HD

Papali ea Tlhaho

Le ha batho ba bangata ba khona ho becha ka boithabiso, e ka ba bothata bo boholo ho ba bang, ha ba ntse ba nts'etsapele mekhoa ea boitšoaro ena. Ho becha ka tsela ea tlhaho ho tsebahala ka takatso e fetelletseng ea ho becha le ha ho e-na le litlamorao tse hlakileng tse mpe tsa lichelete, tsa motho le tsa botsebi. Haufinyane e thathamisitsoe e le tšibollo ho DSM-V, kaha e tšoana hantle le mathata a tlhekefetso ea lithethefatsi maemong ohle a tlhahlobo le neuropathology (van Holst et al., 2010; Clark le Goudriaan, 2012). Ho becha ka tsela ea tlhaho e tla ba “tšibollo ea boitšoaro” e amoheloang sehlopheng sa "Bokhoba ba Bokhoba le Mathata a amanang ”. Leha ho le joalo, ho lokela ho hlokomeloa hore ho na le phapang pakeng tsa ho lemalla lintho tse ling tsa kelello le ho lemalla papali ea chelete. Taba ea pele, takatso e khotsofatsang ea lintho tse ferekanyang kelello e holim'a ho ja ntho eo phello e tsejoang ka eona, ha e khotsofatsa takatso ea papali ea chelete ea ho becha e ka ba le sephetho se sa tsitsang kaha chelete e ka hloloa kapa che, ntle le haeba ke ketso ea papali ea chelete. e le ketsahalo e khahlisang. Ka hona, papali ea chelete ea ho becha e ka ba e holika ntlheng ena le sephetho se sa tsitsang ho feta tlhekefetso ea lithethefatsi. Re lokela ho hlokomela hore ho fapana ha sephetho, ho kenyelletsa mathata le tahlehelo ka bobeli, ho ka ba bohlokoa ho nts'etsopele ea temallo ea papali ea chelete, hobane e fana ka mokhoa o fapaneng oa tšebeliso, e leng mokhoa o matlahali oa ho sebetsa ka mokhoa oa sehlohlolo / oa maemo a mantlha (Sharpe, 2002; Fiorillo et al., 2003). Taba ea bobeli, lintho tse fanang ka kelello li ka fetola ts'ebetso bokong le ts'ebetsong ea methapo ea kutlo ho feta papali ea chelete, ka lebaka la ts'ebetso ea bona e otlolohileng ea pharmacological lits'ebetsong tse 'maloa tsa methapo ea kutlo, e potlakisa ts'ebetso ea litheko, e etsa hore tlhekefetso ea lithethefatsi e be mokhoa o matla haholo oa ho lemalla.

Mekhoa ea methapo ea kutlo ea ho becha e rarahane ebile e ama likarolo tse ngata tse fapaneng tsa boko le li-neurotransmitter system (tse lekiloeng ho Raylu le Oei, 2002; Goudriaan et al., 2004; Potenza, 2013). Predisposition ea ho lemalla e amana le boemo bo fokotsehileng ba li-receptor tsa dopamine D2 ho striatum, e sebetsang ho loop ea tlhahiso ho thibela ts'ebetso e eketsehileng ea dopamine. Boitšoaro bo matla ba dopaminergic pathways bo eketsa ho ts'oenyeha ho putsa, ho susumetsa le ho matlafatsa ts'ebetso ea boits'ebetso bo lematsang (Volkow et al., 2002; Di Chiara le Bassareo, 2007). Liphetoho tse ikhethileng tse bang teng ha papali ea chelete ea ho becha e hlaha e kenyelletsa sepheo se eketsehileng sa ho becha (van Holst et al., 2012) le tlhokomelo e ntlafalitsoeng ho susumetso e amanang le ho becha (Li-brows et al., 2011a,b). Ntle le moo, basomi ba methapo ea kutlo ba fokotse taolo ea kelello holima boitšoaro ka kakaretso, joalo ka mohlala oa ho fokotseha hoa ts'ebetso mesebetsing ea thibelo, karabelo e matla, le khethollo bakeng sa meputso e liehang ho feta mesebetsing ea li-neurocognitive (Goudriaan et al., 2004; Li-brows et al., 2012a; van den Bos et al., 2013a).

Batho ba tsubang ka thobalano ba etsa hampe ha ba bapisoa le lits'ebetso tse amanang le ho etsa liqeto tse amanang le meputso e amanang le moputso (mohlala, Cavedini et al., 2002; Brand et al., 2005; Li-brows et al., 2012b; tlhahlobo: Li-brows et al., 2013). Ts'ebetso ena e mpe e ikemetse ntle le hore na mesebetsi e na le melao e hlakileng le e tsitsitseng bakeng sa ho hlolang le tahlehelo joalo ka Game of Dice Task (Brand et al., 2005) kapa hore na lithuto li tlameha ho ithuta ka teko-le-phoso tseo likhetho li nang le molemo kamora nako e telele, joalo ka IGT (Cavedini et al., 2002; Li-brows et al., 2012b; sheba Karolo Ho Etsa Qeto ka Kotsi ka Ho Etsa Bakuli ba HD ka Mesebetsi ea Laboraro bakeng sa lintlha tsa mosebetsi ona). Leha ho le joalo, botebo ba papali ea chelete ea papali ea chelete bo ne bo hokahane le ts'ebetso ea ho etsa liqeto tseo ho tsona qeto e sa tsejoeng (IGT) ho fapana le mesebetsi e nang le melao e hlakileng (Li-brows et al., 2012b). Pono ena e ea khahlisa hobane ho lithuto tse tloaelehileng halofo ea bobeli ea IGT ha lithuto li ithutile maemo a ts'ohanyetso e tšoana le mesebetsi e nang le melao e hlakileng. Ka kopanelo, lintlha tsena li fana ka maikutlo a hore ho senyeha hoa ts'ebetso ea papali ea chelete ea ho becha ha motho ho etseng liqeto ho ka hlaha ho tsoa taolong e fokotsehileng ea botsamaisi, e amanang le melao e hlakileng, le ts'ebetso e hlokofatsang ea kotlo (maikutlo) e amanang le teko-le-. phoso ea ho ithuta ho lekola boleng ba khetho ea nako e telele (van den Bos et al., 2013a, 2014). Ntle le moo, e fana ka maikutlo a hore likhathatso tsa ho qetela e ka ba sesosa sa ho eketseha hoa boitšoaro ba papali ea chelete.

Ho tsoa lithutong tsena ho hlakile hore tšebeliso ea methapo ea kutlo bakeng sa ho ntšetsa pele ts'ebetso ea papali ea papali ea methapo e kenyelletsa pherekano ho potoloho ea taolo ea "Associative"van den Bos et al., 2013a). Ka lebaka leo, libapali tsa 'mele tsa basomi li bontša taolo e fokotsehileng ea kelello, ho eketseha ha maikutlo, le kutloelo-bohloko e eketsehileng ea ho putsa, tseo kaofela e leng likarolo tsa boits'oaro bo senolang boitšoaro (Iacono et al., 2008). Monyetla oa hore motho a be le temallo bophelong ba hae, leha ho le joalo, o boetse o itšetleha ka lintlha tse ling tse ngata, joalo ka liphihlelo tsa bophelo ba pele le likotsi tsa tikoloho.

Ho becha ka tsela ea tlhaho ho HD: Bopaki ba lefu la ho bola

Ka palo e ntseng e eketseha ea menyetla e fanoang ke inthanete, ho boetse ho na le keketseho ea menyetla ea ho becha ea molao le e seng molaong ea inthanete lilemong tsa morao tjena. Ts'ebetso tsena tse fumanehang habonolo ebile hangata li sa laoloe li ka baka kotsi ho mang kapa mang ea nang le monyetla oa ho lemalla ho becha, empa ho seng joalo a ka se kopanele mesebetsing e joalo (Griffiths, 2003). Bakuli ba HD ke se seng sa lihlopha tseo ho becha Inthaneteng ho ka behang motho kotsing joalo, hobane boitšoaro bo tšoaetsanoang — e leng tšobotsi e tloaelehileng ho lefu lena — ke karolo ea bohlokoa kholisong ea bokhoba ba tahi (Iacono et al., 2008). Kannete, joalo ka ha ho boletsoe kaholimo, bakuli ba HD ba bonts'a matšoao a 'maloa a tšoaetso, a joalo ka ho teneha, ho sitisoa ha karabelo, le ho fokola tlhokomelong ea maikutlo, qalong ea lefu lena. Matšoao a mang a hlokometsoeng ho HD, mme a ka susumetsa bokhoni ba bakuli ba ho etsa liqeto tse hlakileng, ke ho se khonehe ho utloisisa maemo, ho phehella, ho hloka kahlolo e molemo, le ho se itlhomphe. Ntle le lits'oants'o tsena tsa matšoao lipakeng tsa bakuli ba HD le bats'oari ba methapo ea methapo, lihlopha tsena ka bobeli li bonts'a tlhekefetso e sebetsang le e sebetsang lipotolohong tse tšoanang tsa cortico-striatal.

Ka lebaka la ho ts'oana hona lipakeng tsa bakuli ba marang-rang le bakuli ba HD, re ka lebella hore ts'oaetso ea mathata a papali ea chelete e eketsehe har'a bakuli ba HD ha ho bapisoa le sechaba se tloaelehileng. Leha ho le joalo, ke phuputso e le 'ngoe feela ho tla fihlela joale e tlalehileng linyeoe tsa ho becha ha methapo ka bongata lelapeng la Mataliana le HD (De Marchi et al., 1998). Lelapeng lena, ho fumanoe hore batho ba babeli ba tšoeroe ke ho becha ka methapo ho tloha lilemong tsa 18, hantle pele ho matšoao a HD a bongaka. Boithuto bo bong ba lefu la seoa ha bo tlalehe ka bothata bona, leha ho nka liqeto tse sa sitisang ho nka qeto, ho nka likotsi le ho ahloloa hampe ho beha kotsi ho bakuli ba HD ba etsang liqeto tsa bohlokoa tsa bophelo le litaba tsa lichelete (Klitzman et al., 2007; Shannon, 2011). Ka mokhoa o ts'oanang, litlaleho tse mabapi le litaba tse amanang le tlhekefetso ea lithethefatsi le ho lemalla ts'ebeliso ea inthanete ha li fumanehe mangolong a hajoale ka lefu la HD. Nakong ena, ha ho hlake hore na ho ba sieo ha litlaleho tsa mathata a ho becha ka har'a lingoliloeng tsa HD ho bakoa ke ho se tsotelle ketsahalo ena, kapa hore na kannete ha ho na leqhubu le lengata la ho becha ha lipilisi har'a bakuli ba HD. Mabaka a 'maloa a ka hlalosa hore na ke hobane'ng ha mathata a joalo a sa tlaleheloa khafetsa. Taba ea mantlha, le haeba menyetla ea ho becha ea pathological e eketsehile ka HD, hona ho kanna ha ama bakuli ba fokolang feela. Ho kopantsoe le taba ea hore sechaba se anngoeng ke HD ka botsona se lekane ka palo, hona ho ka baka mathata a papali ea chelete hore a se ke a bonoa e le bothata bo ikhethang sehlopheng sena sa bakuli. Taba ea bobeli, ho haella ha mathata a ho becha ho HD ho ka amana le ho se khonehe kapa ho se rate ha bakuli ho tsoa ka tlung ka lebaka la mathata a koloi le ho bona matšoao a ho hloka thahasello le khatello ea maikutlo khafetsa. Pele ho qaleho ea papali ea chelete ea inthanete, sena se kanna sa thibela bakuli ba HD ho etela libakeng tsa ho becha tsa sechaba joalo ka casino. Kamora nako ea bocha e bonahala e le nako e tebileng ea ho ba le mathata a ho becha (van den Bos et al., 2013a), ha bakuli ba bangata ba HD ba sa qale ho bonts'a matšoao a amanang le disinhibition ho fihlela hamorao bophelong. Leha ho le joalo, ka ho phahama ha mesebetsi e amanang le inthanete ea bacha, ba ka ba le mekhoa ea boithabiso e joalo ka papali ea chelete ea inthaneteng, e fetoha bothata ha matšoao a HD a bonahala hamorao bophelong. Kahoo, leha tikoloho eo ho eona bakuli ba ts'oaroang ke papali ea HD ba iphumanang ba sa khothaletse boitšoaro bo joalo nakong e fetileng, ho hlakile hore ho ba teng ha menyetla ea papali ea chelete ka lapeng ho ka fetola ho ata ha mathata a amanang le ona ho baahi ba HD. .

Ho Etsa Qeto ka Kotsi ka Ho Etsa Bakuli ba HD ka Mesebetsi ea Laboraro

Mesebetsi ea laboratori e tloaetse ho sebelisoa ho lekola likotsi tsa kelello le boits'oaro mathateng a methapo ea kutlo. Ho fumana temohisiso mabapi le lits'ebetso le lits'enyehelo tse kentsoeng tšebetsong ea ho nka liqeto le ho nka likotsi, ho hlahisitsoe mesebetsi e 'maloa, ho kenyelletsa IGT (Bechara et al., 1994) le CGT (Roger et al., 1999). Ho IGT, barupeluoa ba fuoa likarete tse 'ne tsa likarete. Ba laetsoe ho khetha likarete ho litekete tsena, tseo ka tsona ba ka hlolang kapa ba lahleheloa ke chelete; sepheo sa mosebetsi ke ho hapa chelete e ngata kamoo ho ka khonehang. Li-decks li fapana ho tse ling khafetsa le ka bongata le moputso le tahlehelo. Tse peli tsa tsona ke litsi "tse mpe", tse lebisang ho tahlehelo e kholo kamora nako, 'me tse peli ke litsi "tse ntle", tse lebisang ho leruo ka kakaretso. Barupeluoa ha ba fuoe tlhaiso-leseling ena, leha ho le joalo, 'me ba hloka ho fumana hore na ke li-desks life tse sebetsang hantle haholo nakong ea liteko. Ba tloaelehileng, ba phetseng hantle, barupeluoa ba ithuta ka katleho melao ea mosebetsi ka mor'a ho fumana sampole e itseng, 'me qetellong ba qala ho khetha litekanyetso tse peli "tse ntle". Leha ho le joalo, ho na le phapang e kholo ea ts'ebetsong esita le har'a barupeluoa ba phetseng hantle, ho kenyelletsa le mehlala e hlakileng ea thobalano (van den Bos et al., 2013b). Ho CGT, barupeluoa ba fuoa letoto la mabokose a 10 a mebala e 'meli e fapaneng,' me ba hloka ho etsa qeto ea hore na lebokose la mebala le patiloe hakae. Ba tlameha ho becha lintlha tsa mokoloto ka tšepo ea bona ho qeto ena. Mosebetsing ona, tlhaiso-leseling eohle e nepahetseng e hlahisoa ho morupeluoa nakong ea teko, 'me liteko li ikemetse, ka hona li fokotsa mohopolo oa ho sebetsa le litlhoko tsa ho ithuta. Mesebetsi ea bobeli ea papali ea chelete e tiisitsoe hantle, 'me IGT e amoheloa e le tšibollo e nepahetseng ea ho etsa liqeto tsa nnete (Buelow le Suhr, 2009), leha CGT e le bohlokoa haholo ha ho ithutoa ho etsa liqeto kantle ho mohopolo.

Bakuli ba HD ba lekoa ho Iowa le Cambridge Gask Task. Phuputsong le bakuli ba mahareng a mahareng, Stout et al. (2001) e fumane hore ts'ebetso ho IGT e fokotsehile ha e bapisoa le lithuto tse tloaelehileng. Phapang ea ts'ebetso e ile ea totobala karolong ea bobeli ea mosebetsi; moo ka tloaelo lithuto li qalang ho bontša ho rata li-desks tse ntle, bakuli ba HD ba ile ba tsoela pele ho khetha khafetsa ho tsoa litlelakeng tse mpe. Sena se fana ka maikutlo a hore bakuli ba HD mohlomong ha baa ka ba ithuta hore na ke li-desks life tse neng li le molemo, kapa ba tsoela pele ho khetha likarete ho tsoa literekeng tse mpe leha ho na le tsebo ena. Bangoli ba hlokometse hore barupeluoa ba 'maloa ba HD ba bonts'itse ho tseba hore li-desks tse ling li ne li le kotsi, empa ba ntse ba tsoela pele ho khetha likarete ho liteki tseo, ba fana ka maikutlo a hore bakuli ba HD ba ka ithuta melao ea mosebetsi, empa ba sa khone ho kenya ts'ebetsong mokhoa o motle oa khetho ho arabela likotlo le moputso oa motho ka mong. Leha ho le joalo, ts'ebetso e fokotsehileng e fumanoe e amahanngoa le ho hopola le ho senyeha hoa kelello, ho lebisang bangoli ho hakanya hore bakuli ba HD ba ka ba le bothata ba ho ithuta kapa ba hopola litlamorao tsa nako e telele tsa ho khetha likarete tse tafoleng e itseng. Bakuli ba HD ba boetse ba iphumanetse holimo ho disinhibition ho feta taolo e phetseng hantle, empa tekanyetso ena e ne e sa tsamaellane le ts'ebetso ea mosebetsi. Kamor'a ho latela data e tšoanang Stout le basebetsi-mmoho, ba bapisa mehlala e meraro ea liqeto tsa kelello ho hlalosa bofokoli ba ts'ebetso ba bakuli ba HD, mme ba fumana hore sena se hlalositsoe hantle haholo ke bofokoli ba ho hopola memori le ka ho eketseha ha ho se tsotelle le ho ts'oaroa (Busemeyer le Stout, 2002). Ts'ebetso e sa senyeheng ea bakuli ba HD ho IGT e kanna ea amana le phello e fokolitsoeng ea tahlehelo ho bakuli bana, e fumanoeng ka ho lekanya likarabo tsa boitšoaro ba letlalo nakong ea IGT (Campbell et al., 2004). Ho fumana sena ho tsamaisana le ho amoheloa hantle ha maikutlo a mabe ho bakuli ba HD (Johnson et al., 2007; Ille et al., 2011), mme e fana ka maikutlo a hore ba kanna ba se amehe haholo ka likotlo tse kholo, ka hona ba ka fokotsoa ho kheloha litheko tse mpe tsa likarete. Haholo-holo karolo ea bobeli ea IGT e hloka bokhoni ba ho hatella lithuto tse mpe bakeng sa likotlo, ha e ntse e matlafatsa liketso tse nang le phaello (de Visser et al., 2011; van den Bos et al., 2013b, 2014).

Palo e lekanyelitsoeng ea liphuputso tse ling li lekile ho nka liqeto tse kotsi maemong a pele a HD, empa ha ba ka ba fumana mathata a ts'ebetso ho bakuli bana ho IGT kapa CGT (Watkins et al., 2000; Holl et al., 2013). Kahoo, ho bonahala eka mathata a ho etsa liqeto le ho ba kotsing ea mathata a papali ea chelete ha a hlahe ho fihlela methati e mahareng ea lefu lena. Leha ho le joalo, lithuto tsena li fumane ho sitisoa ke mesebetsi e hlokang ho rala le ho thibela likarabo tse bileng teng pele ho bakuli ba pele ba HD. Kahoo ho bonahala eka bakuli ba HD ba qala ho ba le mathata a potileng ka ho thibela, ho rera, ho lemoha maikutlo le ho hopola lintho tse sebetsang. Ho bakuli ba bang hona ho ka lebisa mathateng a ho ahlola lefu le ho etsa liqeto mathoasong a lefu lena, empa bakuli ba bangata ba HD ha ba na mathata a ho etsa liqeto tse kotsi ho fihlela ba fihla bohareng ba lefu lena.

Mechanisms ea Neurobiological ea ho Etsa Liqeto ho HD

Litsela tsa Neurobiological tse ka tlas'a mekhoa e tloaelehileng ea ho etsa liqeto ho IGT

Mekhoa ea methapo e ka tlase-pele ea ho etsa liqeto ho IGT e ithutile hantle le ho hlalosoa (sheba mohlala, Bechara et al., 2000; Doya, 2008; de Visser et al., 2011; van den Bos et al., 2013b, 2014). Ho etsoa ka mokhoa o tloaelehileng ha mosebetsi ona ho hloka tšebelisano lipakeng tsa lipotoloho tsa maoto le maoto a tsamaeang le kelello. Ts'ebetso ea ho potoloha hoa maoto ho nahanoa hore e atile nakong ea karolo ea pele ea IGT, eo ka nako eo e amehang boits'oarong, ho araba meputso le likotlo, le ho ithuta boleng ba liqeto tse khutšoane le tse telele tsa liqeto ho mosebetsi (Manes et al., 2002; Clark le Manes, 2004; Fellows le Farah, 2005; Gleichgerrcht et al., 2010; de Visser et al., 2011; van den Bos et al., 2014). Potoloho ea taolo ea "Associative / cuffitive control", ka lehlakoreng le leng, e bohlokoa haholo nakong ea karolo ea bobeli ea IGT, ha ho hlokahala ho hatella likarabo tse sa potlakang tsa meputso le likotlo molemong oa nako e telele, ho tiisa mekhoa e metle ea boits'oaro le ho hatella mekhoa e sa lokang (Manes et al., 2002; Clark le Manes, 2004; Fellows le Farah, 2005; Gleichgerrcht et al., 2010; de Visser et al., 2011; van den Bos et al., 2014).

Litla-morao tsa Neurobiological lits'ebetsong tsa liqeto tsa IGT ka HD

Kaha ts'ebetso ea ho etsa liqeto ho IGT e kenyelletsa ho tsamaisana ha lipotoloho tsa maoto le likamano tsa batho ba amehang ka lona, ​​ha ho makatse hore bakuli ba HD ba na le ts'oaetso ea ts'ebetso ea mosebetsi ona. E 'ngoe ea tse hlokometsoeng ke Stout le basebetsi-mmoho ke hore phello ea tahlehelo ha ho etsoa liqeto e fokotsehile ho bakuli ba HD (Campbell et al., 2004). Sena se lumellana le liphumano tsa hore bakuli bana ha ba na bothata ba letho ba ho khetholla maikutlo a mabe, 'me ba ka hlalosoa ke mathata a teng ka cortex ea orbitof Pambal (Ille et al., 2011). Cortex ea orbitofrontal e bohlokoa bakeng sa ts'ebetso ea maikutlo, mme e kenngoa lithutong tse tloaelehileng ho arabela likotlo le meputso mosebetsing o etsang liqeto (O'Doherty et al., 2001). Seo ba se fumaneng ke Stout et al. (2001) ke hore ts'ebetso ea bakuli ba HD ho IGT e hokahane le mohopolo o fokotsehileng le mehato ea memori ea nako e telele ho Scale ea Mathis Dementia. Ho sitoa ho ithuta kapa ho hopola hore na ke mekhabiso e fe e sebetsang ka nako e telele e kanna ea amahanngoa le ts'ebetso e fokotsehileng ea potoloho ea taolo ea "Associative", e hlokahalang bakeng sa moralo oa nako e telele le taolo ea tšusumetso (Manes et al., 2002; Clark le Manes, 2004; Fellows le Farah, 2005; Gleichgerrcht et al., 2010). Sena se boetse se tsamaisana le bofokoli bo itseng ba tsela e sa tobang ho HD, hobane phuputso ea morao-rao e bonts'a hore tsela e sa tsejoeng e bohlokoa bakeng sa kutloisiso ea kotlo mosebetsing o matlafatsang oa ho ithuta (Kravitz et al., 2012; Paton le Louie, 2012). Ho hloka thuso ho latela litlamorao tsa qeto le hona ho ka bakoa ke ho se sebetse hantle ha kalafo ea cortex, hobane ho se tsotelle ho tšoanang ho bonoa ho bakuli ba nang le tšenyo sebakeng sena sa pele (Bechara et al., 1994). Kahoo, ts'ebetso e fokotsehileng ea bakuli ba HD ho IGT e ka bakoa ke ho kopana ha lits'oants'o tsa cortico-striatal circuits tse amanang le orbitofrontal cortex, cortex ea ventromedial prefrontal preortal le corsex ea dorsolateral. Sena se lebisa ho karabelo e fokotseng ea kotlo karolong ea pele ea mosebetsi, le ho se khone ho ithuta hore na ke mekotla efe e tla ba teng ka nako e telele, ho rala ka tsela e nepahetseng, le ho hatella likarabo tse sa potlakang mohatong oa bobeli oa IGT.

Puisano

HD le Papali ea Papali ea Boloi: Likotsi ke Life?

Mefuta e tloaelehileng ea matšoao a motor, a maikutlo le a kelello a HD a bakoa ke matšoao a tsoelang pele a striatal a amang mekhahlelo e fapaneng ea methapo ea methapo. Leha ho qala le ho phuthulla ha matšoao a boits'oaro le a kelello a bonahala a phahame haholo, lits'ebetso tsa makoloi le tsa kelello li na le ts'oaetso e sa le pele ho lefu lena, ha mokokotlo oa litho tsa maoto o ameha hamorao. Ho khahlisang, ho tseba ho kenella papaling ea papali ea methapo le ho lemalla lintho tse ling hape ho kenyelletsa pherekano makaleng a tšoanang a cortico-striatal a amang HD. Le ha ho na le lintho tse ts'oanang tse ts'oanang, leha ho le joalo, lingoloa tsa bongaka HD ha lia ka tsa amahanngoa le papali ea papali ea kelello kapa mekhoa e meng e lemalloang. Ke phuputso e le 'ngoe feela ho tla fihlela joale e hlalositseng lelapa leo ho lona mathata a papali ea chelete a ileng a hlaha ho litho tse' maloa tsa lelapa tse anngoeng ke HD (De Marchi et al., 1998). Re hakanya hore matšoao a makoloi a bakuli, hammoho le lilemo tsa bona le tikoloho ea bona ea sechaba, e kanna ea ba thibela ho nts'etsapele mekhoa ea ho becha, leha ba na le mathata a joalo. Ka lehlakoreng le leng, khatello ea maikutlo e fumanoang khafetsa e ka lebelloa ho eketsa ho teba le kotsi ea mathata a papali ea chelete, ho ipapisitsoe le lithuto tse amanang.Clarke, 2006). Tlhaloso e 'ngoe bakeng sa ho haelloa ke ho shebella ha mathata a ho becha ho HD e kanna ea amana le phapang ea motheo oa neuropathology. Le ha likhathatso tsa kelello li bonahala li ts'oana haholo lipakeng tsa ba betšang ba pathological le bakuli ba HD, liphetoho tsa maikutlo ke tsa mofuta o fapaneng. Batho ba betang ka ho feteletseng ba bontša haholo hore ba thabela meputso, ba ba khothaletsa ho qala le ho tsoela pele ho becha. HD, ka lehlakoreng le leng, e amahantsoe le maikutlo a fokotsehileng a likotlo le maikutlo a mabe. Phapang ena e kanna ea ba lebaka la bohlokoa leo bakuli ba HD ba sa bonahale ba e-na le tloaelo e eketsehileng ea ho qala ho becha kapa ho etsa lintho tse ling tse ntle, tse lemalloang.

Leha ho le joalo, liphokotso mokhatlong oa maoto oa "cortico-striatal" oa bakuli ba HD li kanna tsa khothaletsa ho nka liqeto tse kotsi maemong a nang le sephetho se sa tsitsang, joalo ka ha ho bonts'itsoe ho IGT (Doya, 2008). Ho feta moo, ho kopana ha kutloano e fokotsehileng ea kotlo, ho sitoa ho thibela likarabo tse potlakileng tsa meputso e potlakileng, le ho se khone ho nahana ka moputso oa nako e telele le ho tiisa mekhoa e metle ea boits'oaro, ho etsa hore bakuli ba HD ba be le mathata a papali ea chelete, ha ba kopana le boemo bo kgothaletsang boitshwaro bo joalo. Mathata a bakoang ke bakuli ba HD ka ho fetoha hoa leano le matšoao a ho se sebetse hantle ha kelello le mamello li ka tlatsetsa ho hatelleng ha boitšoaro ba methapo maemong ana. Kahoo, re fana ka maikutlo a hore bakuli ba HD ha ba na tšekamelo e eketsehileng ea ho qala ho becha kapa mekhoa e meng e lemaletseng tlhaho ea bona ea neuropathology, empa ba na le monyetla oa hore ba tlohele ho lemalla hang ha ba kenella papaling ea papali ea chelete. Ho latela mohopolo ona, ho hlokometsoe hore bakuli ba pele ba lesion ha ba qobelloe ho etsa liqeto tse fosahetseng, empa ha ba bonts'e boitšoaro bo nkang likotsi tse eketsehileng (Miller, 1992; Bechara et al., 2000). Sena se fana ka maikutlo a hore liqeto tse sa senyeheng tsa ho nka liqeto le ho nka likotsi kapa ho se ts'oenyehe ha li hlile ha li kopane, le hore liphapang tse fapaneng tsa liphapang tsa taolo ea maoto le tšusumetso ea kelello li ka ba le litlamorao tse fapaneng tsa ho etsa liqeto tse kotsi le boitšoaro ba papali ea chelete. Hypothesis ea rona e ka boela ea re hlalosetsa hore na hobaneng bakuli ba HD ba sa bonoe ba sa sebetse hantle ho CGT. Kaha tlhaiso-leseling eohle e mabapi le menyetla le boleng ba katleho le tahlehelo li fumaneha ka pele mosebetsing ona, bakuli ba HD ba kanna ba se ke ba theha maano a kotsi, hobane ha ba batle likotsi ka mafolofolo. Leha ho le joalo, sena se tla hloka ho hlahlojoa ho bakuli ba nang le mafu a tsoetseng pele haholo.

Haeba bakuli ba HD ba hlile ba na le kotsi ea ho eketseha ea ts'ebetso ea papali ea ho becha ha e hlahisoa ka boemo bo loketseng, ho phahama ha menyetla ea papali ea chelete ea inthanete ho ka ba kotsi ho sehlopha sena sa bakuli. Le ha ba sa batle maemo ana ka botlalo, bakuli ba HD ba na le menyetla ea ho becha ho feta kamoo ba neng ba le ka teng nakong e fetileng. Sena ke 'nete haholo ho bakuli ba sebelisang nako ea bona e ngata malapeng ka lebaka la matšoao a bona, moo marang-rang e ka bang mokhoa oa bohlokoa oa ho ba lula ho bona. Monyetla o phahameng oa ho kopanela liketsong tsa papali ea chelete ka hona o ka baka keketseho e se nang palo ea mathata a amanang le ona ho sechaba sa HD. Re khothaletsa hore bahlokomeli ba hlokomele likotsi tsena tse ka bang teng, mme ka mokhoa o loketseng ba leke ho thibela bakuli ba HD ho etsa mesebetsi ea (ea inthaneteng) ea papali ea chelete. Ho feta moo, re pheha khang ea hore lingaka li lokela ho lekola khafetsa le ho ata ha mathata a amanang le papali ea chelete ho sechaba sa HD, ho tseba ho fana ka kalafo le tataiso e nepahetseng ho bakuli le bahlokomeli.

Litaelo tsa nakong e tlang

Ntle le lithuto tsa lefu la ho hlahloba ho ata ha papali ea chelete ea mafu a marang-rang le ho lemalla lintho tse ling ho HD, ho ka khothaletsoa ho etsa lipatlisiso tse 'maloa ho eketsa kutloisiso ea rona ea litaba tse tšohliloeng ka pampiri ena. Pele ho tsohle, e tla ba ho khahlisang ho hokahanya bofokoli ba ts'ebetso ho IGT ka kotlolloho le ho sitisoa hoa ts'ebetso ea cortico-striatal ho bakuli ba HD. Ho fihlela sena, mekhoa ea ts'ebetso ea ts'ebetso ea bakuli ba HD e ka ithutoa ka lipono tsa ts'ebetso ea matla a matla a matla ha a ntse a etsa IGT, mme a bapisoa le ts'ebetso lithutong tse tloaelehileng. Ts'ebetso ho striatum, dorsolateral prefrontal cortex le orbitofrontal cortex e lebelletsoe ho fokotseha ho bakuli ba HD nakong ea ho etsa liqeto ho IGT.

Ho ithuta likarolo le boits'oaro ba mekhoa ea ho becha ho HD ka botlalo, ho ka sebelisoa mekhoa ea lefu lena la litoeba. Boemong ba boitšoaro, liphoofolo tsena li ka lebelloa ho bonts'a ts'ebetso e fokotsehileng ho IGT, e ts'oanang le bakuli ba batho. Likopi tsa mefuta-futa tsa IGT lia fumaneha (Tlhahlobo: de Visser et al., 2011) le ho kenya letsoho ha likarolo tsa neuronal tse fapaneng mehlaleng ena ho bontšoa hantle (de Visser et al., 2011; van den Bos et al., 2013a, 2014). Ka hona, liteko tse joalo lia khoneha, 'me li ka kopanngoa le tlhaiso e tebileng ea liphetoho tsa mantlha tsa methapo ea methapo ea HD e sebelisang mekhoa e fapaneng. Ntle le moo, ha ho hlaha mekhoa le lithulusi tse sebetsang tsa tlhahlobo ea tlhaho ea tikoloho ho lekola nts'etsopele ea boits'oaro ba kelello, kotsi ea ho ntšetsa pele papali ea marang-rang e ka ithutoa tlasa maemo a tlholeho a tlhaho ho batho le liphoofolo (van den Bos et al., 2013a). Ka kopanelo, lithuto tsena tsa matšoao a amanang le ho becha le "neuropathology" ho bakuli ba batho le mefuta ea liphoofolo tsa HD li tla re fa leseli la ho utloisisa likotsi tse amanang le papali ea chelete le mekhoa e meng e lemosang ka HD, 'me e ntlafatse bokhoni ba rona ba ho fana ka eona. kalafo e loketseng le tataiso.

Tlhōlisano ea Tlhaloso

Bangoli ba bolela hore lipatlisiso li ne li etsoa ka ho se be le likamano leha e le life tsa khoebo kapa tsa lichelete tse ka nkoang e le khohlano e ka 'nang ea e-ba le thahasello.

References

E hlophisitsoeng ke:

Patrick Anselme, Univesithi ea Liège, Belgium

Hlahloba by:

Libuka tsa Damien, Université Libre de Bruxelles, Belgium
Bryan F. Sebini, Univesithi ea Michigan, USA