Ukuqhathaniswa kwe-D2 Receptor Ukuzibophelela okucacileyo Kwizinto eziqhelekileyo kunye neziqhelo eziqhelekileyo Ukusebenzisa i-PET kunye (N- [11C] methyl) benperidol (2013)

Synapse. Umbhalo-ngqangi wombhali; ifumaneka kwi-PMC 2014 Nov 1.

I-Synapse. 2013 Nov; 67(11): 748–756.

Ipapashwe kwi-intanethi ye-2013 ngoMeyi 30. doi: 10.1002/syn.21680

PMCID: PMC3778147

I-NIHMSID: I-NIHMS511440

USara A. Eisenstein,¹ U-Jo Ann V. Antenor-Dorsey,¹ UDanuta M. Gredysa,¹ UJonathan M. Koller,¹ Emily C. Bihun,¹ USamantha A. Ranck,¹ UAna Maria Arbelaez,² USamuel Klein,³ UJoel S. Perlmutter,^4,^5,^6,^7,⁸ UStephen M. Moerlein,^5,⁹ Kevin J. Mnyama,^1,^4,^5,⁶ kwaye UTamara Hershey^1,^4,⁵

Abstract

Uphononongo lwangaphambili lokucinga nge-PET lubonise iziphumo ezixubeneyo malunga nokufumaneka kwe-dopamine D2/D3 receptor kwindawo etyebe kakhulu kubantu abangatyekanga. Ii-radioligands ze-D2 / D3 ezingabonakaliyo azivumeli uqikelelo oluhlukeneyo lwe-D2 receptor (D2R) kunye ne-D3 receptor (D3R) i-subtypes yentsapho ye-D2 ye-receptor, enokuthi idlale indima eyahlukileyo ekuziphatheni kwaye isasazwe ngokuhlukileyo kwingqondo yonke. Ezi radioligands zikwashenxiswa yi-endo native dopamine, ukutolika okubhidayo kweeyantlukwano ekufumanekeni kwe-receptor ngamanqanaba ahlukeneyo okukhutshwa kwe-dopamine. Uphononongo lwangoku lusebenzise umfanekiso we-PET kunye ne-D2R-selective radioligand (N-[¹¹C] methyl) benperidol ([¹¹C]NMB), engenakushenxiswa yi-endogenous dopamine, ukuqikelela i-D2R ethile yokubopha (BP_ND) kunye nobudlelwane bayo kwi-index mass body (BMI) kunye nobudala kwi-15 ubunzima obuqhelekileyo (i-BMI ithetha = 22.6 kg / m²) kunye ne-15 obese (ithetha i-BMI = 40.3 kg / m²) amadoda nabafazi. Izifundo ezinezigulo okanye ukuthatha amayeza aphazamisana nokubonakaliswa kwe-dopamine azifakwanga. I-Striatal D2R BP_ND yabalwa kusetyenziswa indlela yegraphic ye-Logan ene-cerebellum njengendawo yereferensi. D2R BP_ND Uqikelelo lwaluphezulu kwi-putamen kunye ne-caudate malunga ne-nucleus accumbens, kodwa ayizange yahluke phakathi kwamaqela obunzima obuqhelekileyo kunye nokutyeba. Amaxabiso e-BMI awazange ahambelane ne-D2R BP_ND. Ubudala buhambelana kakubi ne-putamen D2R BP_ND kuwo omabini amaqela. Ezi ziphumo zibonisa ukuba ukubopha okuthe ngqo kwe-D2R okutshintshileyo akubandakanyekanga kwi-pathogenesis yokutyeba ngokwe-se nganye kwaye kugxininisa imfuneko yezifundo ezongezelelweyo ezivavanya ubudlelwane phakathi kwe-D3R, i-dopamine reuptake, okanye ukukhutshwa kwe-dopamine engapheliyo kunye nokutyeba kwabantu.

Internet: dopamine, ukutyeba, NMB

INTSHAYELELO

Ukutyeba ngokugqithiseleyo yingxaki enkulu yezempilo kwihlabathi jikelele kwaye inxulunyaniswa nokugula okunzulu kunye nemiphumo yezoqoqosho (Shamseddeen et al., 2011). Ukutyeba kakhulu kunokuba yi-neurobiologically kunye nokuziphatha okufana nokulutha kweziyobisi kuba zombini zinxulunyaniswa notshintsho olufanayo ekuhanjisweni kwe-dopaminergic kwiimodeli zeempuku (de Jong et al., 2012). Izifundo zabantu zibonisa ukuba ukukhotyokiswa kweziyobisi kunxulunyaniswa nokuncipha kokufumaneka kwe-D2/D3 ye-dopamine receptor, njengoko kuvavanywa kwi-vivo nge-PET imaging.Hietala et al., 1994; UVolkow et al., 1996; Volkow et al., 2001; Wang et al., 1997). Nangona kunjalo, ubudlelwane phakathi kokutyeba kakhulu kunye nenkqubo ye-dopaminergic ebantwini ihlala ingacacanga ngenxa yeziphumo eziphikisanayo phakathi kwezifundo ze-PET. Ngokucacileyo, amaqela amaninzi (de Weijer et al., 2011; UHaltia et al. 2007; Wang et al., 2001) ifumanise ukuba ukutyeba kakhulu kunxulunyaniswa nokuncipha ngexesha Dunn et al. (2012) ifumene ukwanda kokufumaneka kwe-receptor ye-striatal D2 / D3.

Ubunzima bokuvavanya ukubonakaliswa kwe-striatal dopaminergic kunokuba negalelo kwiziphumo ezingafaniyo kwizifundo zabantu abanobunzima obuqhelekileyo kunye nabatyebe kakhulu. Izifundo ze-PET kunye ne-SPECT ze-imaging ye-D2 / D3 receptor efumanekayo ekutyebeni zisetyenzisiwe [¹¹C]raclopride (IHaltia et al., 2007; Wang et al., 2001), [¹⁸F]fallypride (UDunn et al., 2012) kunye [¹²³I]IBZM (de Weijer et al., 2011). Ezi radioligands zinemida ebalulekileyo. Okokuqala, ezi radioligands azikwahluli phakathi kwe-D2 (D2R) kunye ne-D3 (D3R) ye-receptor subtypes ye-D2 dopamine receptor family (Elsinga et al., 2006; Mukherjee et al., 1999; Videbaek et al., 2000). I-D2R kunye ne-D3R yahlukile, nangona i-overlapping, ukuhanjiswa kuyo yonke ingqondo yomntu (I-Beaulieu kunye neGainetdinov, 2011) kwaye ke ngoko inokuba neendima ezisebenzayo ezahlukeneyo kwindlela yokuziphatha enxulumene nomvuzo. Okwesibini, ukukhutshwa kwe-dopamine engapheliyo kunciphisa ukubophelela okuthile [¹¹C] ubuhlanga, [¹⁸F]fallypride, okanye [¹²³I]IBZM (UDewey et al., ngo-1993; ULaruelle et al., 1995; URic Cardi et al., 2006), ukwenza ezi radioligands zibe luncedo ukulinganisa ukukhutshwa kwe-dopamine engapheliyo kodwa ukutolika okudidayo kokufumaneka kwe-D2/D3 receptor kwizifundo zangaphambili.

Ngokusekwe kubungqina bokuncipha kokubopha okuthe ngqo kwe-D2R kunye nokuncipha kokufumaneka kwe-D2/D3 ye-receptor kwiimpuku ezityebileyo (de Jong et al., 2012) kunye nokunciphisa ukufumaneka kwe-D2 / D3 receptor kubantu abatyebileyo (de Weijer et al., 2011; IHaltia et al., 2007; Wang et al., 2001), siye saqikelela ukuba ukubopha okuthe ngqo kwe-D2R kuya kuncitshiswa ngokutyeba kumadoda kunye nabasetyhini abanobunzima obuqhelekileyo. Silawule ngononophelo iminyaka kwaye singabandakanyi abo baneemeko zengqondo kunye nesifo seswekile ezinxulumene nokungasebenzi kakuhle kwe-dopaminergic (I-Blum et al., 2012; DeFronzo, 2011). Sasebenzisa iradioligand (N-[¹¹C] methyl) benperidol ([¹¹C]NMB), eneempawu ezizodwa zokubopha i-receptor. I-NMB ingaphezulu kwamaxesha angama-200 ngokukhetha i-D2R kune-D3R (Karimi et al., 2011), kwaye ikhethekileyo kwi-D2R ngaphezu kwezinye iintlobo zee-receptors zengqondo (UArnett et al., ngo-1985; Moerlein et al., 1995, 1997; Suehiro et al., 1990). Ukongeza, i-NMB ayinakususwa ngokukhululwa kwe-dopamine engapheliyo (Moerlein et al., 1997), evumela uvavanyo lwe-D2R ethile ebophelelayo engaphazanyiswa yi-synaptic dopamine concentration. Qaphela ukuba i-NMB inokuphawulwa ngayo nokuba kukuphi ¹¹C okanye ¹⁸F ngaphandle kokutshintsha i-molecular structure ye-D2 ligand (Moerlein et al., 1992; Moerlein et al., 2004). Ngoko, [¹¹C]NMB kunye [¹⁸F]I-NMB ayizo-analog kodwa zifana ngokwekhemikhali (kwaye ke ngoko ngokwamayeza) ziyafana, kwaye ziyahluka kuphela ekubhalweni ¹¹C okanye ¹⁸F, ngokulandelelanayo.

IMPAHLA NENKQUBO

nxaxheba

Ishumi elinesihlanu eliqhelekileyo-ubunzima (BMI 18.9 - 27.7 kg / m²; ubudala 22.4 - 39.9 iminyaka; Amadoda angama-4) kunye ne-15 etyebileyo (BMI 33.2 - 47 kg / m²; ubudala 25.4 - 40.9 iminyaka; Amadoda ama-3) amadoda nabasetyhini bathathe inxaxheba kolu phononongo (1 Table). Bonke abathathi-nxaxheba abanokuthi bagqibe uvavanyo olubanzi lwezonyango, kubandakanywa imbali yonyango kunye nokuhlolwa komzimba, iimvavanyo zegazi eziqhelekileyo, i-hemoglobin A1C, kunye novavanyo lokunyamezela i-glucose yomlomo (OGTT). Abo banembali yokuzimela yesifo sikashukela, i-A1C ≥ 6.5% (48 mmol / mol), okanye iziphumo ze-OGTT ezibonise ukukhubazeka kokuzila ukutya kwe-glucose, ukunyamezela kwe-glucose yomlomo, okanye isifo sikashukela (≥ 200 mg / dl,I-American Diabetic Association, ngo-2010)) bebengabandakanywa. Abathathi-nxaxheba baphinde bahlolwe kwiimeko ze-neurological and psychiatric ngokuhlolwa kwe-neurological, udliwano-ndlebe lwengqondo (i-Structured Clinical Interview ye-DSM-IV (SCID), I-Steiner et al., 1995), i-Beck Depression Inventory (i-BDI-II, i-Beck et al., i-1996), i-Wechsler efinyeziweyo yeScale of Intelligence (WASI, I-Wechsler, i-1999), kunye neCandelo A le-ADHD ye-Adult Self-Report Scale Symptom Checklist (ASRS-v1.1, UKessler et al., 2005). Abantu abafunyaniswa ukuba bane-psychosis yobomi bonke, i-mania, ukuxhomekeka kweziyobisi, ukudakumba okukhulu, ukuxhalaba kwentlalontle, ukuphazamiseka kokutya kunye nokuphazamiseka kokuphazamiseka, i-parkinsonism, i-IQ <80 okanye babenaso nasiphi na isifo sengqondo okanye isifo se-neurologic (umz. ukusetyenziswa kakubi kweziyobisi, isifo se-Parkinson, i-Tourette syndrome, i-stroke) ichaphazela ukutolikwa kwedatha yayingabandakanywanga kuphononongo. Abantu abatshayayo, abakhulelweyo okanye abancancisayo, bebengasemva kokuya exesheni, bathathe amayeza anokuthi abe nefuthe kwiziphumo zophononongo ezifana ne-dopamine agonist okanye unyango oluchasayo (umz. i-antipsychotics okanye i-metoclopramide) bebengabandakanywa. Bonke abathathi-nxaxheba basayine imvume enolwazi ngaphambi kokuthatha inxaxheba kwisifundo, esavunywa yi-Ofisi yoKhuseleko loPhando loLuntu lweYunivesithi yaseWashington.

Iimpawu ezithatha inxaxheba

Ukulungiswa kweRadiopharmaceutical

Udibaniso lwe [¹¹C]NMB lulungelelwaniso oluzenzekelayo lwendlela epapashiweyo (Moerlein et al., 2004, 2010). [¹¹C]CO₂ yaveliswa nge ¹⁴N(p,α)¹¹Ukusabela kwe-C kwiYunivesithi yaseWashington JSW BC-16/8 cyclotron, kwaye iguqulelwe kwi- [¹¹C]CH₃Ndisebenzisa i-GE PETtrace MeI MicroLab (USandell et al., 2000). [¹¹C]CH₃Mna, i-benperidol kunye nesiseko zifudunyezwe kwi-90 ° C imizuzu eyi-10, kwaye [¹¹C]I-NMB yodwa kusetyenziswa i-HPLC yolungiselelo lwesigaba esibuyiselweyo. Ukwenziwa ngokutsha kweziyobisi kusetyenziswe itekhnoloji yokukhutshwa kwesigaba esiqinileyo ukunika [¹¹C]I-NMB kwi-10% ye-ethanol kwi-Sodium Chloride ye-Injection, i-USP. Imveliso yabulawa inzala (i-0.2 μm filter), kwaye ine-radiochemical purity ≥ 95% kunye nomsebenzi othile ≥ 1066 Ci / mmol (39 TBq / mmol).

Ukufumana i-PET

[¹¹C]I-NMB (6.4 – 18.1 mCi) yafakwa emithanjeni ngaphezulu kwe-20s ngecatheter yeplastiki efakwe kumthambo wengalo. Kwisifundo ngasinye, i-< 7.3 μg ye-NMB engabhalwanga yatofwa. I-PET scans yenziwa nge-Siemens / CTI ECAT EXACT HR +, eneendandatho ze-32 ze-BGO detector elements kwaye ifumana i-63 ngaxeshanye izilayi kunye ne-2.4 mm isithuba kunye ne-axial FOV ye-15.5 cm. Ezithathu zirhoxiswa ⁶⁸Imithombo ye-Ge rod isetyenziselwa izikena zothumelo ukulinganisa imiba yokuthomalalisa umntu ngamnye. Isisombululo se-Transaxial kunye ne-axial yendawo kwiziko lesilayi yi-4.3 mm kunye ne-4.1 mm ububanzi obugcweleyo besiqingatha esiphezulu (FWHM) kwimo ye-3D (UBrix et al., ngo-1997). Idatha yokukhupha iqokelelwe kwimodi ye-3D kwiiyure ze-2 kunye nezakhelo ze-30 zizonke: 3 @ 1 min, 4 @ 2 min, 3 @ 3 min, 20 @ 5 min. I-PET scans zakhiwa ngokutsha ngeprojekti ehluziweyo ngasemva kunye ne-ramp filter enqunyulwe kwi-frequency ye-Nyquist kwaye ibandakanya ukulungiswa, ukuchithwa kunye nokulungiswa kwe-random.

Ukufunyanwa kwe-MRI

Bonke abathathi-nxaxheba baye bafumana i-MRI scans kwi-Siemens MAGNETOM Tim Trio 3T scanner isebenzisa i-3-D MPRAGE ulandelelwano (TR=2400 ms, TE=3.16 ms, flip angle=8, 176 isagittally-oriented frames, FOV=256 mm; voxels=1 ×1×1 mm).

Uhlalutyo olusekelwe kwi-ROI

Kumthathi-nxaxheba ngamnye, iifreyimu zemifanekiso ye-PET eguquguqukayo zabhaliswa kunye kunye nakumfanekiso womthathi-nxaxheba we-MPRAGE njengoko kuchaziwe.I-Eisenstein et al., 2012). I-MR-defined ROIs kunye ne-PET data yaphinda yavavanywa kwisithuba se-atlas ye-Talairach ukuya kwi-(2 mm)³ (UHershey et al., ngo-2003).

Imimandla emithathu enomdla emacala omabini (i-ROIs) (i-putamen, i-caudate kunye ne-nucleus accumbens) kunye ne-cerebellum (ummandla wesalathiso) zachongwa kwi-MPRAGE yomthathi-nxaxheba ngamnye kusetyenziswa iFreeSurfer (efumaneka e- http://surfer.nmr.mgh.harvard.edu). Ukunciphisa iimpembelelo zevolumu, imimandla ye-putamen kunye ne-caudate yachithwa yi-voxel enye yomphezulu kusetyenziswa isihluzo se-gaussian esigudileyo esidityaniswe ne-threshold, ekhokelela ekususweni kwe-2 mm ukusuka kwimigangatho yale mimandla.I-Eisenstein et al., 2012). I-Nucleus accumbens yayingenkulu ngokwaneleyo ukuba ikhukulise.

Ii-ROI zaphinda zahlaziywa kwindawo efanayo ye-atlas ye-Talairach njengemifanekiso ye-PET. Ukubola-ukulungiswa kwee-curves ze-tissue curves zaye zakhutshwa kwidatha ye-PET eguqukayo kumthathi-nxaxheba ngamnye. I-D2R ikhono elithile lokubophelela (BP_ND) ibalwe kwi-ROI nganye kusetyenziswa indlela yegraphical yeLogan enecerebellum njengendawo yesalathiso (Logan et al., 1996) njengoko bekuqinisekisiwe ngaphambili [¹⁸F]I-NMB ene-3-compartment tracer kinetic model kunye nendlela yomzobo efuna i-arterial input (Antenor-Dorsey et al., 2008; I-Eisenstein et al., 2012). Indlela ye-Logan ifanelekile kolu hlalutyo kuba i-cerebellum inokubophelela okuthe ngqo kwi-NMB kwizifundo eziphilileyo (Antenor-Dorsey et al., 2008) kwaye akunakufane kwenzeke ukuba abantu abatyebe ngokugqithiseleyo baphuhlise iziza ezithile ezibophelelayo kwi-cerebellum. Ngaphaya koko, nokuba kukho umahluko kwiqela elityebileyo ekuthatheni [¹¹C] I-NMB kwi-cerebellum efana nokutshintsha kokuhamba kwegazi lendawo, ukunyanzeliswa kokuthintela ubuchopho begazi, okanye ukubophelela okungacacanga, ukucinga okusisiseko kwe-Logan reference area approach ithatha ukuba olu tshintsho, olufana nokubophelela okungaqhelekanga, luyenzeka kwakhona I-ROI ekujoliswe kuyo kwelo qela lesifundo okanye umntu. Ngaloo ndlela i-BP ibalwa_ND ithathela ingqalelo olu tshintsho. I-Slopes ifunyenwe kwii-Logan plot points zedatha efunyenwe kwi-60-120 min emva [¹¹C]Inaliti ye-NMB. BP_ND's benziwe i-avareji kwi-caudate yasekhohlo nasekunene, iputamen kunye ne-nucleus accumbens ukunciphisa uthelekiso lwengingqi kwaye kuba akukho bungqina bucetyisayo ukuba ezi zinto zifunyanisiweyo zingalingana.

Uhlalutyo olusekelwe kwiVoxel

Uhlalutyo olusekwe kwi-voxel lwenziwa ukufumanisa umahluko onokwenzeka kwi-D2R ethile yokubopha phakathi kobunzima obuqhelekileyo kunye namaqela atyebileyo angakhange afunyanwe ngohlalutyo olusekwe kwi-ROI njengaku (IHaltia et al., 2007). Isoftware yePVEOUT efumaneka simahla (https://nru.dk/pveout/index.php) kunye nemifanekiso ebhalisiweyo ye-MR ye-structural yesifundo ngasinye yayisetyenziselwa ukulungisa iziphumo zevolumu yengxenye (PVE) ngokusebenzisa indlela epapashwe (Quarentelli et al., 2004; UHarri et al., ngo-2007). [¹¹C]Imifanekiso ye-NMB PET elungiswe kwi-PVE yenzelwe umntu ngamnye. BP_ND Iimephu ze-voxel zenziwe kwisifundo ngasinye kusetyenziswa le mifanekiso kwaye zithelekiswe kubunzima obuqhelekileyo kunye namaqela atyebileyo kwinqanaba le-voxel usebenzisa i-SPM8 (http://www.fil.ion.ucl.ac.uk/spm).

Ucatshulwa

Ukuhanjiswa okuqhelekileyo kwezinto eziguquguqukayo eziqhubekayo kwavavanywa kusetyenziswa i-D'Agostino kunye ne-Pearson omnibus iimvavanyo eziqhelekileyo kumaqela obunzima obuqhelekileyo kunye nokutyeba ngokwahlukileyo. Ukwabiwa kobuhlanga kunye nesini phakathi kwamaqela obunzima obuqhelekileyo kunye nokutyeba kwavavanywa ngovavanyo lwe-Chi-square. Ukungabandakanyi ukuba kunokwenzeka ukuba ukwabiwa kobuhlanga kumaqela anobunzima obuqhelekileyo kunye namaqela atyebileyo kuya kuchaphazela iziphumo, iimpawu zokuthatha inxaxheba kunye ne-BP yokubulala._ND Uqikelelo luthelekiswe phakathi kweCaucasian kunye nezifundo zase-Afrika zaseMelika ezityebileyo phakathi kwezifundo zoMfundi t-uvavanyo okanye univariate iimodeli zomgca jikelele (GLM) usebenzisa ubudala njenge covariate. I-BMI, ubudala, inqanaba lemfundo, i-BDI kunye ne-ASRS amanqaku eCandelo A athelekiswe phakathi kwamaqela anezifundo eziphakathi koMfundi. t-uvavanyo, okanye, kwimeko yonikezelo olungelulo oluqhelekileyo, non-parametric Mann-Whitney U-iimvavanyo. BP_ND uqikelelo lwe-putamen, i-caudate kunye ne-nucleus accumbens yafaniswa phakathi kwamaqela anemilinganiselo ephindaphindiweyo ye-GLM esebenzisa ubudala njenge-covariate. Ngomzamo wokuhambelana nee-ROI kwizifundo ezifanayo (Volkow et al., 2008; Wang et al., 2001) siphinde siqhathanise iBP edibeneyo yokubeleka_ND I-ROI (umndilili we-putamen kunye ne-caudate BP_ND values) phakathi kwamaqela ane-GLM engaguqukiyo elawula iminyaka yobudala. Ubudlelwane phakathi kwe-BMI, ubudala kunye ne-D2R BP_ND zibalwe kusetyenziswa iPearson's r okanye yeSpearman rho kwi-ROI nganye. Kuhlalutyo lwe-SPM8 olusekwe kwivoxel, amaqela athelekiswa naBafundi t-uvavanyo usebenzisa ubudala njenge-covariate. Iziphumo zithathwe njengezibalulekileyo kwi-α ≤ 0.05.

Amandla ahlalutya

Amandla okufunda kwethu ukufumanisa ukungafani kwi-D2R BP_ND Uqikelelo phakathi kwamaqela obunzima obuqhelekileyo kunye nokutyeba okuqhelekileyo kunye nokufumanisa unxulumano phakathi kwe-D2R BP_ND uqikelelo kunye ne-BMI kwiqela elityebileyo libalwe ngokusekelwe kwiziphumo ezivela kwizifundo zangaphambili ze-D2 / D3 receptor efumanekayo (de Weijer et al., 2011; UDunn et al., 2012; Wang et al., 2001) kunye neyethu sisebenzisa iG*Power 3, ekhoyo http://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3 (UFaul et al., ngo-2007). Ubungakanani beempembelelo zomahluko kwi-striatal D2/D3 receptor efumanekayo phakathi kwamaqela angatyekanga kunye namaqela atyebileyo asebenzisa [¹¹C]raclopride (Wang et al., 2001) kunye [¹²³I]IBZM (de Weijer et al., 2011) kuqikelelwa ukuba yi-1.35 kunye ne-1.13 (uCohen's d), ngokulandelelanayo. Ukuthatha iziphumo ezifanayo kuphononongo lwethu, ubungakanani bethu besampulu yabantu abali-15 kwiqela ngalinye babenamandla phakathi kwe-0.85 kunye ne-0.95 ukufumanisa umahluko wobu bukhulu besiphumo phakathi kwamaqela obunzima obuqhelekileyo kunye nokutyeba. Ulungelelwaniso phakathi kokufumaneka kwe-striatal D2/D3 receptor kunye ne-BMI kwiqela elityebileyo lalingu--0.84 usebenzisa [¹¹C]raclopride (Wang et al., 2001) kunye no-0.5–0.6 usebenzisa [¹⁸F]fallypride (UDunn et al., 2012). Ubungakanani bethu besampulu bunamandla e-0.5-0.97 ukufumanisa ezi ziphakathi ukuya kwimiphumo emikhulu.

IINKCUKACHA

Uvavanyo lwesiqhelo

Yonke imilinganiselo eqhubekayo yokuxhomekeka yayinolwabiwo oluqhelekileyo kuwo omabini amaqela (p ≥ 0.07 kuzo zonke iimvavanyo) ngaphandle kwe-BDI (p = 0.01) kunye ne-ASRS iCandelo A (p <0.05) amanqaku kwiqela eliqhelekileyo lobunzima kunye nobudala kwiqela elityebileyo (p = 0.05). Ezi ziguquko ke ngoko zaphathwa njengezingahanjiswanga ngokuqhelekileyo kuhlalutyo olulandelayo.

Iimpawu zokuthatha inxaxheba kunye ne-BP yokuzala_ND uqikelelo kuhlanga kunye nesini

Ulwabiwo lobuhlanga phakathi kwamaqela anobunzima obuqhelekileyo kunye namaqela atyebe kakhulu ahluke kakhulu (χ²(2) = 6.2, p = 0.05, 1 Table), ngelixa unikezelo lwesini lungazange (χ²(1) = 0.19, p = 0.67). I-BMI, iminyaka, kunye neminyaka yemfundo ayizange yahluke phakathi kweCaucasian etyebileyo kunye nezifundo zase-Afrika zaseMelika (p ≥ 0.2). Xa ulawula iminyaka yobudala, into eyaziwa ngokunxibelelanisa kakubi nokufumaneka kwe-striatal dopamine receptor kunye nokubopha okuthe ngqo (I-Antonini kunye neLenders, ngo-1993; UBruke et al., ngo-1993; I-Eisenstein et al., 2012; Wang et al., 2001), i-BP yokubeleka_ND awazange ahluke phakathi kwamaCaucasians kunye nama-Afrika aseMelika kwiqela elityebileyo (p ≥ 0.14 kuzo zonke izithelekiso). Ukujonga ngakumbi ukuba ngaba iiyantlukwano zesini kunye nobuhlanga bezifihla ubudlelwane phakathi kokutyeba kakhulu kunye ne-BP yokulala_ND, Univariate GLM uhlalutya ubudala covarying, lwenziwa kummandla ngamnye striatal kwi Caucasians ababhinqileyo. Ubunzima obuqhelekileyo kunye nokutyeba kwabasetyhini baseCaucasian abazange bahluke kwi-BP yokulala_ND kuyo nayiphi na indawo (p ≥ 0.19 kulo lonke uhlalutyo). Ngapha koko, i-BMI ayizange ihambelane ne-BP_ND kuwo nawuphi na ummandla kubunzima obuqhelekileyo (p ≥ 0.29, ukulawula iminyaka) okanye utyebe (p ≥ 0.11, ukulawula iminyaka) abafazi baseCaucasian. Ke ngoko, isini kunye nobuhlanga azizange zilawulwe kulo lonke uhlalutyo.

Iimpawu ezithatha inxaxheba

Abathathi-nxaxheba abatyebileyo kunye nobunzima obuqhelekileyo abazange bahluke ngeminyaka (U₂₈ = 78, p = 0.16), inqanaba lemfundo (t₂₈ = -1.58, p = 0.13), BDI (U₂₈ = 78, p = 0.16), WASI IQ (t₂₈ = -1.82, p = 0.08), okanye ASRS Icandelo A (U₂₈ = 93.5, p = 0.44) amanqaku.

[¹¹C]NMB BP_ND

Amaqela obunzima obuqhelekileyo kunye nokutyeba awazange ahluke kwi-D2R BP iyonke_ND uqikelelo (isiphumo esiphambili seqela, F_1,27 = 0.12, p = 0.73; Isazobe 1A, C, 2 Table). Njengoko bekulindelekile (I-Eisenstein et al., 2012), bekukho isiphumo esiphambili sommandla (F_2,54 = 30.88, p <0.0001), apho putamen BP_ND Uqikelelo lwaluphezulu kunolo lwecaudate (p <0.05) kunye ne-nucleus accumbens (p < 0.0001). Caudate BP_ND Uqikelelo lwaluphezulu kunolo lwenucleus accumbens (p <0.0001, Umzobo 1A). Kwakungekho ukusebenzisana phakathi kweqela kunye nommandla (iqela × intsebenziswano yengingqi, F_{2, 54} = 0.86, p = 0.43, Isazobe 1A, C). Idityanisiwe i-striatal ithetha i-BP_ND Uqikelelo lokufumaneka kwe-D2R aluzange luhluke phakathi kwamaqela aqhelekileyo kunye nobunzima (F_1,27 = 0.23, p = 0.63; Isazobe 1B, C, 2 Table). I-putamen kunye ne-BP yokuzala_NDs kumthathi-nxaxheba omnye otyebe kakhulu yayiyi-2.42 kunye ne-2.24 yophambuko olusemgangathweni ngaphezu komyinge, ngokulandelelanayo. Ke ngoko uhlalutyo oluchazwe apha ngasentla lwenziwa ngaphandle kwesi sifundo kwaye, ngokufanayo, aluzange luveze umahluko kwi-BP yokubulala._ND phakathi kwamaqela anobunzima obuqhelekileyo kunye namaqela atyebileyo (isiphumo esiphambili seqela, F_1,26 = 0.05, p = 0.82 kumanyathelo aphindaphindiweyo e-GLM; F_1,26 = 0, p = 0.98 ye-GLM engaguqukiyo).

Umzobo 1

Ukubophelela okuthe ngqo kwe-Striatal D2R akwahlukanga phakathi kwabantu abatyebe ngokugqithiseleyo nabanobunzima obuqhelekileyo

I-BP ye-Striatal_ND Uqikelelo

Uhlalutyo olusekelwe kwiVoxel

Kwakungekho nantlukwano phakathi kwamaqela kwi-D2R BP_ND emva kokulungiswa kothelekiso oluninzi ukuba ngaba i-outlier enokubakho ingabandakanyiwe kuhlalutyo (p > 0.05 kuwo onke amaqela).

[¹¹C]NMB BP_ND kwi-BMI yonke

I-BMI ayizange ihambelane ne-D2R BP_ND Uqikelelo lwayo nayiphi na i-ROI yokubetha okanye i-striatum edibeneyo phakathi kweqela lobunzima obuqhelekileyo (p ≥ 0.46) okanye iqela elityebileyo (p ≥ 0.27; Isazobe 2, A–D, 3 Table). Ngaphandle kwezinto ezinokubakho, caudate BP_ND yayinxibelelene kakuhle ne-BMI kwiqela elityebileyo (r₁₁ = 0.58, p <0.05, i-95% yexesha lokuzithemba, i-0.08 ukuya kwi-0.85) kodwa kwakungekho ubudlelwane obubalulekileyo phakathi kwe-BMI kunye neminye imimandla yokubetha (p I-0.1).

Ukubophelela okuthe ngqo kwe-Striatal D2R akunxulumananga ne-BMI kubantu abatyebe kakhulu okanye abanobunzima obuqhelekileyo

Unxulumano oluyinxenye lukaPearson (r) Phakathi kwe-BMI kunye ne-Striatal BP_ND, Ukulawula Ubudala

[¹¹C]NMB BP_ND kubo bonke ubudala

Kwizifundo eziqhelekileyo zobunzima kunye ne-obese, ubudala buhambelana kakubi ne-D2R BP_ND uqikelelo lwe putamen (p <0.05 ngolungelelwaniso ngalunye) kodwa hayi i-caudate, i-nucleus accumbens okanye i-striatum edibeneyo (p ≥ 0.09, Isazobe 3A–D, 4 Table). Ngaphandle kwesifundo esityebileyo esichazwe njengento enokubakho kwicandelo langaphambili, ubudala bebungadityaniswanga kakhulu ne-BP yokubulala._ND kwiqela labatyebe (p I-0.07).

Umzobo 3

Ukubophelela okuthe ngqo kwe-Striatal D2R kunxulunyaniswa nobudala kubunzima obuqhelekileyo kunye nabantu abatyebe kakhulu

Unxulumano lukaSpearman (rho) Phakathi kweminyaka yobudala kunye ne-Striatal BP_ND

UKUQALA

Asifumananga mahluko ekubopheni okuthe ngqo kwe-D2R, njengoko kuqikelelwe ngu [¹¹C]NMB BP_ND, phakathi kwabantu abanobunzima obuqhelekileyo kunye nabatyebe kakhulu. Sasebenzisa i-PET radioligand eyodwa [¹¹C]NMB, ke le milinganiselo ayizange ibhidaniswe kukubopha kwe-D3R okanye ngokukhutshwa kwe-dopamine engapheliyo (Karimi et al., 2011; Moerlein et al., 1997). Ngapha koko, iziphumo zethu azizange zibhideke ziimeko ezinxulumeneyo ezingabandakanyiyo ezinokuchaphazela ukubopha okuthe ngqo kwe-dopamine receptor, njengesifo seswekile, isifo se-neurologic, okanye ukuphazamiseka kwengqondo kunye nokusetyenziswa kakubi kweziyobisi.I-Blum et al., 2012, DeFronzo, 2011).

Akunakwenzeka ukuba asiphumelelanga ukufumana umahluko kwi-D2R ethile yokubopha phakathi kwamaqela obunzima obuqhelekileyo kunye nokutyeba kakhulu ngenxa yobungakanani besampulu enganelanga. Ngokusekelwe kwiziphumo zezifundo zangaphambili (de Weijer et al., 2011; UDunn et al., 2012; Wang et al., 2001), inani lezifundo ezibhalisiweyo kwisifundo sethu zinikeze amandla okwaneleyo ukufumanisa ubungakanani obuphakathi ukuya kwimpembelelo enkulu phakathi kokuthelekisa phakathi kweqela kunye nokulungelelaniswa kwe-D2R ethile ebophelelayo kunye ne-BMI. Kufuneka kuqatshelwe ukuba ubungakanani beqela lethu likhulu okanye lilingana nezo zezifundo ezininzi zangaphambili ze-D2/D3 PET zokutyeba kakhulu (de Weijer et al., 2011: n = 15/iqela; UDunn et al., 2012: n = 8–14/iqela; Wang et al., 2001: n = 10/iqela). Iziphumo zethu zibonisa ukuba xa i-comorbidities echaphazelekayo ingabandakanywayo, i-D2 i-receptors ebophelelayo ekhethekileyo ayinaxanduva lokwahluka okubonwe ngaphambili kwi-D2 / D3 ukufumaneka kokukhuluphala (de Weijer et al., 2011; UDunn et al., 2012; IHaltia et al., 2007; Wang et al., 2001). Eminye imiba yokubonakaliswa kwe-dopamine kufuneka iphononongwe, njenge-D3R receptors, ukukhutshwa kwe-dopamine engapheliyo, ukuphinda kuthathwe kwakhona nge-dopamine transporter okanye iinkqubo zesithunywa sesibini.

Ukhetho lwe [¹¹C]NMB ye-D2R yosapho lwe-D2 receptor ngaphezulu kwe-D3R (Karimi et al., 2011) inokuchaza umahluko phakathi kweziphumo zethu kunye nezifundo zangaphambili. I-PET radioligands esetyenziswe kwizifundo zangaphambili zokutyeba ezifana [¹¹C]raclopride (IHaltia et al., 2007; Wang et al., 2001) kunye [¹⁸F]fallypride (UDunn et al., 2012) kunye neSPECT radioligand [¹²³I] IBZM (de Weijer et al., 2011) abahluli kakuhle phakathi kwe-D2 kunye ne-D3 subtypes (Elsinga et al., 2006; Mukherjee et al., 1999; Videbaek et al., 2000). Ukuba ukubopha okuthe ngqo kwe-D3R kuguqulwe ekutyebeni, kunokuchaza umahluko phakathi kokufumana kwethu kunye nezinye izifundo kunye ne-D2 / D3 radioligands engacacanga. I-D2R yenzeke kumanqanaba aphezulu kwi-dorsal striatum, i-nucleus accumbens, i-extrastriatal subcortical kunye nemimandla ye-cortical ngelixa i-D3R ikhona kumanqanaba aphezulu kwi-ventral (ngokuchasene ne-lateral) i-caudate kunye ne-putamen, igobolondo le-nucleus accumbens kunye neminye imimandla ye-limbic.I-Beaulieu kunye neGainetdinov, 2011) kwaye ke inokudlala indima enkulu kumsebenzi womvuzo. Ngelixa i-D3R ngokucacileyo iyinto ekufuneni iziyobisi kunye nokulutha kwiimpuku kunye neeprimates ezingengobantu (UNewman et al., ngo-2012) ngobungqina obuthile obucebisayo ebantwini (Boileau et al., 2012), kukho ubungqina obuxubeneyo kunye nobuncinci bendima ye-D3R yokubulala kwi-rodent (Thanos et al., 2008) kunye nomntu (Dodds et al., 2012; UNathan et al., 2012) ukutyeba. Idatha evela kwisifundo sethu kunye neengxelo zangaphambili zigxininisa ukubaluleka kokubaluleka kwe-D3R ngokukhuluphala kunye nesidingo sezifundo ezizayo usebenzisa i-D3R-selective PET radioligand.

Ukushenxiswa kwe-PET radioligands yi-endo native dopamine nako kunokuba negalelo kumahluko phakathi kweziphumo zethu kunye nezo zezifundo zangaphambili. [¹¹C]I-NMB ayinakususwa yi-endogenous dopamine (Moerlein et al., 1997) kodwa [¹¹C] ubuhlanga, [¹⁸F] fallypride kunye [¹²³I]IBZM zi (UDewey et al., ngo-1993; ULaruelle et al., 1995; URic Cardi et al., 2006). Ke, ukuba ukutyeba kunxulunyaniswa nokwanda komthamo we-striatal extracellular dopamine, ngenxa yokwanda kokukhutshwa kwe-dopamine okanye ukunciphisa ukuthatha, emva koko [¹¹C] raclopride,¹⁸F] fallypride, kunye [¹²³I] Izifundo ze-IBZM zinokufumana ukunciphisa ukufumaneka kwe-D2 / D3 receptor kwi-striatum, ngenxa yokufuduka, ngelixa [¹¹C]NMB ayifuni. Utshintsho kumanqanaba e-extracellular dopamine ekutyebeni kuye kwafundwa ngokungathanga ngqo ebantwini. Idatha evela kwizifundo ze-fMRI eziqhutywe kwizifundo zabantu zibonisa ukusebenza okukhulu kokubetha ekuphenduleni okunxulumene nokutya iziboniso (okt, imifanekiso ebonakalayo yokutya okunekhalori ephezulu) kukutya okutyebileyo kunabantu abangatyekanga (I-Stoeckel et al., 2008), kodwa i-blunted striatal activation ekuphenduleni ukusebenzisa kokutya okunencasa kakhulu okuhambelana kakubi ne-BMI kubantu abatyebe kakhulu (I-Stice et al., 2010). Ke ngoko, idatha evela kuphononongo lwabantu ibonisa ukuba inkqubo yokubetha yenziwa isebenze ngokugqithisileyo kubantu abatyebe kakhulu nabatyebe kakhulu ekuphenduleni isivuseleli sokutya kodwa ingasebenzi kakuhle ngexesha lokutya okunencasa. Uncedo olukhulu lokusebenzisa [¹¹C] I-NMB kwi-PET ukulinganisa i-D2R kukuba ayinabungozi kwiinguqu ezidlulayo kwi-synaptic dopamine concentration. Nangona kunjalo, olu tshintsho lunokuba luhambelana nokutyeba. Ngenxa yokuba ukusebenza kokubethelwa kunamandla kakhulu kwaye kuxhomekeke ekuziphatheni komntu ngokuhamba kwexesha (umzekelo, ukuphendula ekutyeni. ukuvuselela ngokuchasene nokutya irisithi), izifundo zexesha elizayo kufuneka zijongane nala mathuba ngokulinganisa ukukhutshwa kwe-endogenous dopamine phantsi kweemeko ezahlukeneyo zokuhlutha kusetyenziswa.¹¹C]raclopride)]..

Isithintelo esinokwenzeka solu phononongo kukuba amadoda kunye nabasetyhini bezizwe ezininzi babandakanyiwe njengezifundo. Kungenzeka ukuba ukuguquguquka okubangelwa zezi zinto kunokuba nefuthe kwiziphumo ezichazwe apha. Uphononongo aluzange lwenziwe okanye lunikwe amandla ukugqiba ukuba ngaba kukho ukungafani okubalulekileyo kwezibalo kumanqanaba athile okubopha i-D2R phakathi kwamadoda nabasetyhini okanye phakathi kweentlanga ezahlukeneyo. Nangona kunjalo, amanqanaba athile okubopha i-D2R awazange ahluke phakathi kweCaucasian kunye nama-Afrika aseMelika kwiqela elityebileyo okanye phakathi kobunzima obuqhelekileyo kunye nabasetyhini baseCaucasian. Umahluko wesini kwisiseko awuzange uxelwe kwizifundo ze-PET zangaphambili ze-D2 / D3 receptor ukufumaneka kokukhuluphala (IHaltia et al., 2007; Wang et al., 2001) okanye enkulu [¹¹C] Isifundo se-NMB PET samadoda nabasetyhini abasempilweni (I-Eisenstein et al., 2012). Ngoko ke, akunakwenzeka ukuba ubuhlanga kunye nokwahlukana ngokwesini kube negalelo kwiziphumo zethu. .Ngaphezu koko, akunakwenzeka ukuba umahluko phakathi kwesifundo sethu kunye nabanye kwiimpawu zesifundo (umzekelo, i-BMI, isondo, okanye ubudala) uchaza umahluko kwiziphumo. Uphononongo lwethu lujolise kubantu abatyebe kakhulu kunye noluhlu lwe-BMI lwe-30 - 50 kg / m², ukuqinisekisa ukuba abantu bayayifanela imigaqo yokutyeba, kodwa bayakunqanda impilo ephambili kunye nobudala beminyaka kwaye bangene ngaphakathi kwemida yeeskena (umyinge otyebileyo we-BMI = 40.3 kg/m²; uluhlu = 33.2 - 47 kg / m²). Olunye uphononongo lujolise kubantu abafanayo (UDunn et al., 2012: umyinge otyebileyo we-BMI = 40 kg/m², uluhlu alufumaneki) okanye BMI esezantsi (IHaltia et al., 2007: i-avareji yobunzima / i-BMI enzima = 33 kg / m², uluhlu alufumaneki), kodwa uphando olunye lwalunoluhlu oluphezulu kunye nenxalenye engaphezulu ye-BMI (de Weijer et al., 2011: umyinge otyebileyo we-BMI = 46.8 kg/m^2, uluhlu = 38.7 - 61.3 kg / m²; Wang et al., 2001: umyinge otyebileyo we-BMI = 51 kg/m², uluhlu = 42-60 kg / m²). Umahluko kwizibophelelo ezithile ze-D2R zinokubonwa kuphela kubantu abatyebe kakhulu. Nangona kunjalo, iziphumo ze UHaltia et al. (2007) kwaye Dunn et al. (2012) bangaxoxa ngokuchasene nale ngcamango. Okubangela umdla, njengoko ku Dunn et al. (2012) kodwa ngokuchasene noko kufunyanisiweyo kwi U-Wang et al. (2001), i-caudate i-D2R ebophelelayo ekhethekileyo yayihambelana kakuhle ne-BMI kwiqela eligqithiseleyo xa lilawula iminyaka yobudala kwaye lingabandakanyi umntu onokuthi aphume ngaphandle. Kungenzeka ukuba ukunciphisa amanqanaba e-endo native dopamine kunye nokwanda kwe-BMI kwizifundo ezityebileyo kunegalelo ekwandeni kwe-D2R kwi-caudate njengoko kubonwe Dunn et al. (2012).

Okokugqibela, abathathi-nxaxheba bethu abanobunzima obuqhelekileyo kunye nokutyeba babebancinci (iminyaka yobudala yobunzima obuqhelekileyo: 22.4 - 39.9 iminyaka; utyebe kakhulu: 25.4 - 40.9 iminyaka) kunakwiminyaka Wang et al., (2001) (uluhlu: 25-54 iminyaka), de Weijer et al. (2011) (uluhlu = 20 - 60 iminyaka) kunye Dunn et al. (2012) (iminyaka yobudala = iminyaka engama-40, uluhlu alufumaneki). Ubudala bunxulunyaniswa kakubi ne-striatal D2/D3 receptor efumanekayo njengoko ilinganiswe ngu [¹¹C] raclopride,¹⁸F] fallypride kunye [¹²³I]IBZM (I-Antonini kunye neLenders, ngo-1993; UBruke et al., ngo-1993; Wang et al., 2001), kunye nokubophelela okuthe ngqo kwe-D2R njengoko kulinganiswe nge [¹¹C]NMB (I-Eisenstein et al., 2012), efunyenwe kuphononongo lwangoku kuwo omabini amaqela eputamen. Ngokwahlukileyo, asifumananga budlelwane bubalulekileyo phakathi kwe-D2R ethile yokubopha kunye nobudala beminye imimandla yokubetha. Oku kunokwenzeka ukuba kubangelwa kuluhlu lweminyaka emxinwa olufundiweyo, olukhethwe ngabom ukukhuphela ngaphandle ubudala njengomba obhidayo kwi-BP._ND qi kelelo.

Iziphumo zethu zisikhanyisela ngendima yokubonisa i-striatal dopaminergic ekutyebeni ngokubonisa ukuba isibophelelo esisisiseko se-striatal D2 receptor subtype yosapho lwe-D2 receptor ayahluki phakathi kwabantu abadala abanobunzima obuqhelekileyo kunye nabatyebe kakhulu. Kuba abantu abanesifo seswekile bebengabandakanywanga kolu phononongo, akukacaci ukuba i-D2R inokudlala indima kunxulumano phakathi kwesifo seswekile kunye nokukhuluphala. Izifundo ezongezelelweyo ziyafuneka ukuphendula lo mbuzo kunye nokuqonda ngcono igalelo losasazo lwe-striatal dopaminergic kunye nokubopha okuthe ngqo kwe-D3R kumqondiso we-dopaminergic kubunzima obuqhelekileyo kunye nabantu abatyebe kakhulu.

AMAKHODI

Olu pho nonongo luxhaswe nguMbutho weSizwe wezeMpilo - i-NIDDK Grant R01 DK085575-03 (SAE, ECB, SAR, TH), T32 DA007261 (SAE, JVA-D., DMG), DK 37948, DK 56341 (Iziko loPhando lweNutrition Obesity Research Centre ), NS41509, NS075321, NS058714 kunye ne-UL1 TR000448 (iMbasa yeNzululwazi yeKlinikhi kunye neNguqulelo).

Ababhali babulela uHeather M. Lugar, MA, uJerrel R. Rutlin, BA kunye noJohanna M. Hartlein, MSN ngegalelo labo kwisifundo.

Imihlathi

Ababhali babika ingxabano yomdla.

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